The ratio adipsin/MCP-1 is strongly associated with structural changes and CRP/MCP-1 with symptoms in obese knee osteoarthritis subjects: data from the Osteoarthritis Initiative.

OBJECTIVE: There is a need to identify reliable biomarkers that can predict knee osteoarthritis (OA) progression. We investigated a panel of adipokines and some related inflammatory factors alone and their ratios for their associative value at assessing cartilage volume loss over time and symptoms in obese [High body mass index (BMI)] and non-obese (Low BMI) OA subjects. DESIGN: Human OA serum was from the Osteoarthritis Initiative Progression subcohort. Baseline levels of adiponectin (high and low molecular weight forms), adipsin, chemerin, leptin, visfatin, C-reactive protein (CRP), interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) were evaluated with specific assays. Cartilage volume was assessed at baseline and 48 months by quantitative magnetic resonance imaging (MRI), and symptoms using baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. Data were analysed by linear regression with confounding factors at baseline, followed by multiple comparison adjustment. RESULTS: The levels of the nine biomarkers and their ratios (36) were studied. Among High BMI subjects, only the ratio adipsin/MCP-1 was associated with cartilage volume loss over time in the lateral compartment [ß, -2.95; 95% confidence interval (CI), -4.42, -1.49; P = 0.010], whereas MCP-1 was associated with WOMAC pain (-1.74; -2.75, -0.73; P = 0.030) and the ratio CRP/MCP-1 with WOMAC pain (0.76; 0.37, 1.14; P = 0.023), function (2.43; 1.20, 3.67; P = 0.020) and total (3.29; 1.58, 5.00; P = 0.027). No associations were found for biomarkers or ratios in Low BMI OA. CONCLUSION: In this study, the ratio adipsin/MCP-1 was found to be associated with the knee structural changes and that of CRP/MCP-1 with symptoms in obese OA subjects. Our data further underline the relevance of ratios as biomarkers to a stronger association to OA progression and symptoms.

Evaluation of occupational exposure: comparison of biological and environmental variabilities using physiologically based toxicokinetic modeling.

PURPOSE: Few studies compare the variabilities that characterize environmental (EM) and biological monitoring (BM) data. Indeed, comparing their respective variabilities can help to identify the best strategy for evaluating occupational exposure. The objective of this study is to quantify the biological variability associated with 18 bio-indicators currently used in work environments. METHOD: Intra-individual (BV(intra)), inter-individual (BV(inter)), and total biological variability (BV(total)) were quantified using validated physiologically based toxicokinetic (PBTK) models coupled with Monte Carlo simulations. Two environmental exposure profiles with different levels of variability were considered (GSD of 1.5 and 2.0). RESULTS: PBTK models coupled with Monte Carlo simulations were successfully used to predict the biological variability of biological exposure indicators. The predicted values follow a lognormal distribution, characterized by GSD ranging from 1.1 to 2.3. Our results show that there is a link between biological variability and the half-life of bio-indicators, since BV(intra) and BV(total) both decrease as the biological indicator half-lives increase. BV(intra) is always lower than the variability in the air concentrations. On an individual basis, this means that the variability associated with the measurement of biological indicators is always lower than the variability characterizing airborne levels of contaminants. For a group of workers, BM is less variable than EM for bio-indicators with half-lives longer than 10-15 h. CONCLUSION: The variability data obtained in the present study can be useful in the development of BM strategies for exposure assessment and can be used to calculate the number of samples required for guiding industrial hygienists or medical doctors in decision-making.

Impact of biological and environmental variabilities on biological monitoring--an approach using toxicokinetic models.

Biological monitoring of occupational exposure is characterized by important variability, due both to variability in the environment and to biological differences between workers. A quantitative description and understanding of this variability is important for a dependable application of biological monitoring. This work describes this variability, using a toxicokinetic model, for a large range of chemicals for which reference biological reference values exist. A toxicokinetic compartmental model describing both the parent compound and its metabolites was used. For each chemical, compartments were given physiological meaning. Models were elaborated based on physiological, physicochemical, and biochemical data when available, and on half-lives and central compartment concentrations when not available. Fourteen chemicals were studied (arsenic, cadmium, carbon monoxide, chromium, cobalt, ethylbenzene, ethyleneglycol monomethylether, fluorides, lead, mercury, methyl isobutyl ketone, penthachlorophenol, phenol, and toluene), representing 20 biological indicators. Occupational exposures were simulated using Monte Carlo techniques with realistic distributions of both individual physiological parameters and exposure conditions. Resulting biological indicator levels were then analyzed to identify the contribution of environmental and biological variability to total variability. Comparison of predicted biological indicator levels with biological exposure limits showed a high correlation with the model for 19 out of 20 indicators. Variability associated with changes in exposure levels (GSD of 1.5 and 2.0) is shown to be mainly influenced by the kinetics of the biological indicator. Thus, with regard to variability, we can conclude that, for the 14 chemicals modeled, biological monitoring would be preferable to air monitoring. For short half-lives (less than 7 hr), this is very similar to the environmental variability. However, for longer half-lives, estimated variability decreased.

Hsp90{beta} and p130(cas): novel regulatory factors of MMP-13 expression in human osteoarthritic chondrocytes.

BACKGROUND: Human osteoarthritic (OA) chondrocytes were previously classified into L (low)- and H (high)-OA according to matrix metalloproteinase-13 (MMP-13) basal levels and interleukin 1beta (IL1beta) inducibility. In H-OA chondrocytes, the regulatory proteins p130(cas) and nuclear matrix protein 4 (NMP4) acting on the MMP-13 promoter were identified. OBJECTIVE: To identify regulators of MMP-13 expression/production in human L-OA chondrocytes, to determine their effect on the expression of other MMPs and the effect of IL1beta on these molecules. METHODS: The identification of the L-OA chondrocyte proteins interacting specifically with the AGRE site of the MMP-13 promoter was performed by mass spectrometry. Heat shock protein 90beta (Hsp90beta), p130(cas) and NMP4 small interfering RNAs (siRNAs) were transfected into L-OA chondrocytes and incubated with or without IL1beta. Gene expression was determined by real-time PCR, MMP-1 and MMP-13 production by ELISA, and signalling pathway activation by western blotting and ELISA. RESULTS: Hsp90beta was identified as a protein of the L-OA/AGRE-specific complex. Silencing p130(cas) and Hsp90beta significantly increased MMP-13 expression (about four- and twofold, respectively) and production. sip130(cas) affected to a lesser extent MMP-1 expression (twofold) and production. siNMP4 showed no effect. Expression of MMP-2, -3, -9 and -14 was unaffected. Silencing both Hsp90beta and p130(cas) had a significant additive effect on MMP-13, but not on MMP-1 expression, the level of which was similar to that with sip130(cas) alone. IL1beta decreased p130(cas) and Hsp90beta expression/production, indicating another pathway by which this cytokine upregulates MMP expression. The IL1beta-triggered signalling pathways responsible for MMP upregulation were unaffected in the silenced cells. CONCLUSION: This study illustrates the complex regulation of MMP-13 by showing the inhibitory effect of the two cytoplasmic molecules, p130(cas) and Hsp90beta, in L-OA chondrocytes.

The BMP antagonists follistatin and gremlin in normal and early osteoarthritic cartilage: an immunohistochemical study.

OBJECTIVE: Bone morphogenic protein (BMP) activities are controlled in part by antagonists. In human osteoarthritic (OA) cartilage, the BMP antagonists follistatin and gremlin are increased but differentially regulated. Using the OA dog model, we determined if these BMP antagonists were produced at different stages during the disease process by comparing their in situ temporal and spatial distribution. METHODS: Dogs were sacrificed at 4, 8, 10 and 12 weeks after surgery; normal dogs served as control. Cartilage was removed, differentiating fibrillated and non-fibrillated areas. Immunohistochemistry and morphometric analyses were performed for follistatin, gremlin, BMP-2/4 and IL-1beta. Growth factor-induced gremlin expression was assessed in dog chondrocytes. RESULTS: Follistatin and gremlin production were very low in normal cartilage. Gremlin was significantly up-regulated in both non-fibrillated and fibrillated areas at 4 weeks, and only slightly increased with disease progression. Follistatin showed a time-dependent increased level in the non-fibrillated areas with significance reached at 8-12 weeks; in the fibrillated areas significant high levels were seen as early as 4 weeks. In the whole cartilage, follistatin and IL-1beta temporal production showed similar patterns; this was also true for gremlin and BMP-2/4, though BMP-2/4 production was already high in the normal dogs. Interestingly, data revealed that basic fibroblast growth factor (bFGF) could be another factor increasing gremlin expression early in the disease process. Comparison between superficial and deep zones revealed similar patterns for follistatin and IL-1beta in the superficial zone only; gremlin and BMP-2/4 had similar patterns in both zones. CONCLUSION: Data show, for the first time, different spatial and temporal production of gremlin and follistatin in cartilage during OA progression. These findings may reflect different roles for each antagonist in this disease.

Toxicokinetics of p-tert-octylphenol in male and female Sprague-Dawley rats after intravenous, oral, or subcutaneous exposures.

This study was undertaken to characterize the toxicokinetics of p-tert-octylphenol (OP), a weak estrogenic compound, in male and female rats. Male and female Sprague-Dawley rats were given a single dose of OP either by oral gavage (50, 125 or 250 mg/kg), by intravenous (iv) injection (2, 4, or 8 mg/kg), or by subcutaneous (sc) injection (125 mg/kg). In a repeated dosing experiment, rats were given OP (oral) daily (25, 50, or 125 mg/kg) for 35 d (female) or 60 d (male). Blood and tissue samples were collected and analyzed for OP content using gas chromatography with detection by mass spectrometry. Blood OP concentrations were generally higher in female than male rats following a single oral or sc administration but were similar following a single iv injection. Tissue OP concentrations were also higher in female than male rats following oral exposure, consistent with the faster metabolism of OP observed in male rat liver microsomes. After subchronic administration, blood OP concentrations were higher at the end of exposure for female (33 d) (2.26-fold, not significant) and male (57 d) (3.47-fold) rats than single dosing but there was no change in the tissue OP concentrations. Gender differences in tissue OP concentrations may contribute, in part, to gender differences in the toxicity of OP in rats. The fact that OP was found in all reproductive tissues confirms its potential for direct endocrine-like effects.

Determination of p-tert-octylphenol in blood and tissues by gas chromatography coupled with mass spectrometry.

A sensitive and reproducible procedure using gas chromatography coupled with mass spectrometry is described for the determination of p-tert-octylphenol (OP), a persistent degradation product of alkylphenol ethoxylates that binds to the estrogen receptor in blood and tissues. The first step involved the extraction of blood (200 microL) or tissue homogenate (400 microL) with methyl tert-butyl ether, including p-tert-butylphenol (BP) as internal standard. After extraction, the sample was evaporated to dryness with a gentle stream of nitrogen at 45 degrees C, and OP and BP were derivatized with an acetylation reaction involving acetic anhydride and catalyzed by pyridine. Samples were then analyzed by a gas chromatograph equipped with a mass spectrometer (single ion monitoring) with a Varian VF-5ms capillary column. The limit of detection and the limit of quantification of the method in blood were 4.6 and 15.5 ng/mL, respectively. The linearity and reproducibility of the method were acceptable, with coefficients of variation of approximately 10% for blood and ranging between 9% and 27% for tissues. This method was applied to the determination of unchanged OP in blood and tissues obtained from Sprague-Dawley rats after oral and IV OP administration.

The new collagenase, collagenase-3, is expressed and synthesized by human chondrocytes but not by synoviocytes. A role in osteoarthritis.

Recently, a new human collagenase, collagenase-3 has been identified. Since collagen changes are of particular importance in cartilage degeneration, we investigated if collagenase-3 plays a role in osteoarthritis (OA). Reverse transcriptase-PCR analysis revealed that in articular tissues collagenase-3 was expressed by the chondrocytes but not by the synoviocytes. Northern blot analysis of the chondrocyte mRNA revealed the presence of two major gene transcripts of 3.0 and 2.5 kb, and a third one of 2.2 kb was occasionally present. Compared to normal, OA showed a significantly higher (3.0 kb, P < or = 0.05; 2.5 kb, P < or = 0.03) level of collagenase-3 mRNA expression. Collagenase-3 had a higher catalytic velocity tate (about fivefold) than collagenase-1 on type II collagen. With the use of two specific antibodies, we showed that human chondrocytes had the ability to produce collagenase-3 as a proenzyme and as a glycosylated doublet. The chondrocyte collagenase-3 protein is produced in a significantly higher (P < or = 0.04) level in OA (approximately 9.5-fold) than in normal. The synthesis and expression of this new collagenase could also be modulated by two proinflammatory cytokines, IL-1 beta and TNF-alpha, in a time- and dose-dependent manner. This study provides novel and interesting data on collagenase-3 expression and synthesis in human cartilage cells and suggest its involvement in human OA cartilage patho-physiology.

Local corticosteroid injection for carpal tunnel syndrome.

BACKGROUND: Carpal tunnel syndrome is a clinical syndrome manifested by signs and symptoms of irritation of the median nerve at the carpal tunnel in the wrist. Local corticosteroid injection for carpal tunnel syndrome has been studied but its effectiveness is unknown. OBJECTIVES: To evaluate the effectiveness of local corticosteroid injection for carpal tunnel syndrome versus placebo injection or other non-surgical interventions. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials register (searched May 2006), MEDLINE (searched January 1966 to May 2006), EMBASE (searched January 1980 to May 2006) and CINAHL (searched January 1982 to May 2006). SELECTION CRITERIA: Randomized or quasi-randomized studies. DATA COLLECTION AND ANALYSIS: Three authors independently selected the trials and rated their overall quality. Relative risks and 95% confidence intervals were calculated for each trial and summary relative risks and 95% confidence intervals were also calculated. MAIN RESULTS: We included 12 studies with altogether 671 participants. Two high quality randomized controlled trials with altogether 141 participants demonstrated clinical improvement of carpal tunnel syndrome at one month or less following local corticosteroid compared to placebo injection (relative risk 2.58 (95% confidence intervals 1.72 to 3.87)). One trial compared local corticosteroid injection to oral corticosteroid and at 12 weeks after treatment there was significantly more improvement in the injection group (mean difference -7.10 (95% confidence intervals -11.68 to -2.52)). In one trial, the rate of improvement after one month was greater after local than systemic corticosteroid injection (relative risk 3.17 (95% confidence intervals 1.02 to 9.87)). In one trial, symptoms did not improve significantly more in the injection group at eight weeks after injection compared to treatment with anti-inflammatory medication and splinting (mean difference 0.10 (95% confidence intervals -0.33 to 0.53)). Two injections versus one injection of local corticosteroid did not provide further clinical improvement, mean difference -3.80 (95% CI -9.27 to 1.67). AUTHORS' CONCLUSIONS: Local corticosteroid injection for carpal tunnel syndrome provides greater clinical improvement in symptoms one month after injection compared to placebo. Significant symptom relief beyond one month has not been demonstrated. Local corticosteroid injection provides significantly greater clinical improvement than oral corticosteroid for up to three months. Local corticosteroid injection does not significantly improve clinical outcome compared to either anti-inflammatory treatment and splinting after eight weeks or Helium-Neon laser treatment after six months. Two local corticosteroid injections do not provide significant added clinical benefit compared to one injection.

Physiologically based modeling of the inhalation pharmacokinetics of ethylbenzene in B6C3F1 mice.

A physiologically based pharmacokinetic (PBPK) model was developed for inhaled ethylbenzene (EB) in B6C3F1 mice. The mouse physiological parameters were obtained from the literature, but the blood:air and tissue:air partition coefficients were determined by vial equilibration technique. The maximal velocity for hepatic metabolism (Vmax) obtained from a previously published rat study was increased by a factor of approximately 3 to account for enzyme induction during repeated exposures. The Michaelis affinity constant (Km) for hepatic metabolism of EB, obtained from a previously published rat PBPK modeling study, was kept unchanged during single and repeated exposure scenarios. Hepatic metabolism alone could not adequately describe the clearance of EB from mouse blood. Additional metabolism was assumed to be localized in the lung. The parameters for pulmonary metabolism were obtained by optimization of PBPK model fits to kinetic data collected following exposures to 75-1000 ppm. The PBPK model successfully predicted all available blood and tissue concentration data in mice exposed to 75 or 750 ppm EB. Overall, the results indicate that the rate of EB clearance is markedly higher in B6C3F1 mice than rats or humans and exceeds the hepatic metabolism capacity. Available biochemical evidence is consistent with a significant role for pulmonary metabolism; however, the extent to which the extrahepatic metabolism is localized in the lung is unclear. Overall, the PBPK model developed for the mouse adequately simulated the blood and tissue kinetics of EB by accounting for its high rate of clearance.

Protective role of olesoxime against wild-type α-synuclein-induced toxicity in human neuronally differentiated SHSY-5Y cells.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is usually diagnosed clinically from classical motor symptoms, while definitive diagnosis is made postmortem, based on the presence of Lewy bodies and nigral neuron cell loss. α-Synuclein (ASYN), the main protein component of Lewy bodies, clearly plays a role in the neurodegeneration that characterizes PD. Additionally, mutation in the SNCA gene or copy number variations are associated with some forms of familial PD. Here, the objective of the study was to evaluate whether olesoxime, a promising neuroprotective drug can prevent ASYN-mediated neurotoxicity. EXPERIMENTAL APPROACH: We used here a novel, mechanistically approachable and attractive cellular model based on the inducible overexpression of human wild-type ASYN in neuronally differentiated human neuroblastoma (SHSY-5Y) cells. This model demonstrates gradual cellular degeneration, coinciding temporally with the appearance of soluble and membrane-bound ASYN oligomers and cell death combining both apoptotic and non-apoptotic pathways. KEY RESULTS: Olesoxime fully protected differentiated SHSY-5Y cells from cell death, neurite retraction and cytoplasmic shrinkage induced by moderate ASYN overexpression. This protection was associated with a reduction in cytochrome c release from mitochondria and caspase-9 activation suggesting that olesoxime prevented ASYN toxicity by preserving mitochondrial integrity and function. In addition, olesoxime displayed neurotrophic effects on neuronally differentiated SHSY-5Y cells, independent of ASYN expression, by promoting their differentiation. CONCLUSIONS AND IMPLICATIONS: Because ASYN is a common underlying factor in many cases of PD, olesoxime could be a promising therapy to slow neurodegeneration in PD.

Reduced expression of glucocorticoid receptor levels in human osteoarthritic chondrocytes. Role in the suppression of metalloprotease synthesis.

Glucocorticoid occupancy of a large percentage of glucocorticoid receptor (GR) is necessary for the suppression of matrix metalloprotease synthesis by human articular chondrocytes. In this study, we evaluated the levels of GR binding, cellular GR protein, and messenger RNA expression in both normal and osteoarthritic (OA) human articular chondrocytes and compared the degree of suppression of collagenase synthesis by glucocorticoids in cultures of the two cell types in order to investigate whether or not the GR system played an important role in the pathophysiology of OA. By radioreceptor binding assay, we recorded 56,320 +/- 8,230 sites per cell (mean +/- SE, n = 9) in primary cultures of normal chondrocytes and 27,480 +/- 14,240 sites in OA cells (n = 10, P < 0.0001). Equilibrium dissociation constant (Kd) values did not vary between normal (12.4 +/- 1.4 nmol/L) and OA (13.0 +/- 1.8 nmol/L). Subculturing of primary OA chondrocytes resulted in the up-regulation of the number of GR binding sites per cell to values comparable to those obtained in normal chondrocytes. Analysis of protein-immuno dot-blots of cytosolic extracts from normal (n = 4) and OA chondrocytes (n = 4) revealed that the former cytosols contained a 1.9 +/- 0.2 (P < 0.05) higher relative density of GR protein than the latter. By comparing the optical densities of GR-polymerase chain reaction products generated from normal (n = 6) and OA (n = 9) chondrocyte total RNA (normalized using an internal standard, glyceraldehyde phosphate dehydrogenase), we established a relative ratio, normal/OA, of 1.4. Experiments comparing the biological responsiveness of normal and OA chondrocytes to glucocorticoid suppression of interleukin-1-stimulated metalloprotease synthesis showed that dexamethasone inhibited collagenase synthesis in a dose-dependent manner with an IC50 of 6.3 +/- 1.2 x 10(-10) mol/L (n = 5) in normal cells while an IC50 of 5.0 +/- 0.4 x 10(-9) mol/L (P < 0.05) was recorded using OA (n = 5) chondrocytes. The results suggest that OA chondrocytes express fewer GR than normal cells as a result of a decrease in specific gene expression. The decreased responsiveness of OA cells to circulating glucocorticoids may be among the factors responsible for an increased level of metalloprotease synthesis by chondrocytes in OA cartilage.

Use of SEOPF regional crossmatch trays to share kidneys for sensitized patients. Local experience of three centers.

Regional organ procurement (ROP) crossmatch trays are used by members of the South-Eastern Organ Procurement Foundation (SEOPF) to facilitate sharing of cadaver kidneys for highly sensitized patients. ROP trays carry a single representative serum sample from over 900 patients with panel reactive antibody (PRA) levels of greater than or equal to 60%. Trays are centrally prepared periodically and distributed to member laboratories where they are used for preliminary crossmatching against locally obtained donors. Crossmatching results are used in conjunction with the SEOPF computer match program for sharing of kidneys. Proficiency testing studies by the 40-member laboratories show a greater than 90% concordance rate on results with these highly and broadly reactive sera. Data were available from 3 centers on 74 kidneys shared between SEOPF-member institutions on the basis of a remote, preliminary, negative ROP tray crossmatch. Of these, 44 (59%) crossmatched negative locally with the same and other sera, and were thus considered acceptable to be transplanted to the intended highly sensitized patients. Sixteen (22%) donors had a positive crossmatch locally, but with sera other than that present on the ROP tray used for screening. In 14 cases (19%) the same serum as on the ROP tray gave a positive crossmatch. The majority of ROP tray inconsistencies appeared to be due to use of more sensitive crossmatching techniques at the recipient center. Of the 27 patients transplanted at these 3 centers with kidneys received on the basis of ROP tray results, none experienced hyperacute or early irreversible rejection and actual graft survival at 6-48 months is 74%. These studies indicate that regional sharing of patient sera by the existing network of histocompatibility testing laboratories is an effective and reliable mechanism to identify crossmatch-negative donors for highly sensitized patients.

The importance of measured end-points in demonstrating the occurrence of interactions: a case study with methylchloroform and m-xylene.

Mixed exposures may result in significant changes in one biomarker of exposure without altering another biomarker, and this may have unknown significance in terms of exposure assessment and overall toxicity of the mixture. Results from a previous investigation showed that human exposure to methylchloroform (MC, 400 ppm) and m-xylene (XYL, 200 ppm) during 4 h did not result in any significant effect on blood concentrations of these solvents, suggesting the absence of interaction between MC and XYL. Those results were adequately described by conducting a physiologically-based toxicokinetic (PBTK) modeling of the MC-XYL interaction in humans; however, the model suggested that urinary excretion of MC metabolites would be reduced as a result of combined exposure, whereas that of XYL metabolites would not be modified. An experimental verification of this model prediction was then undertaken with rats. In this study, Sprague-Dawley rats (n, 5) were exposed during 4 h to MC (400 ppm) or XYL (200 ppm), alone or as a mixture. Results showed that combined exposure did not affect the blood concentration of MC whereas that of XYL was increased throughout the 2-h blood collection period following exposure. The excretion of MC metabolites during a period of 48 h following the onset of exposure, i.e., trichloroethanol (TCE: -71%) and trichloroacetic acid (TCA: -73%), were significantly reduced. Methylhippuric acid (MHA) was not affected by co-exposure to MC as expected from the PBTK model forecasts. These results exemplify the use of a priori PBPK modeling for designing interaction studies and choosing appropriate/sensitive end-points for demonstrating the occurrence of potential interactions.

Influence of oral administration of a quaternary mixture of trihalomethanes on their blood kinetics in the rat.

Trihalomethanes (THMs; chloroform, bromoform, bromodichloromethane, dibromochloromethane), formed as by-products of chlorine disinfection, are found to occur in combination in drinking water supplies. THMs are metabolized by cytochromes P-450 and are likely substrates of CYP2E1. Therefore, it is possible that mixed exposure results in toxicokinetic interactions among THMs. The toxicokinetics of THMs during mixed exposures has not been investigated previously. The purpose of this study was to characterize the blood kinetics of the four THMs administered singly or in combination in the rat. A single dose of 0.25 mmol/kg or 0.5 mmol/kg b.w., of each THM alone, or of a quaternary mixture containing 0.25 mmol/kg of each THM (total dose of 1.0 mmol/kg) was administered by gavage. The venous blood concentrations of the THMs were measured by headspace gas chromatography (GC) at 20, 40, 60, 120, 180, 270 and 360 min post-administration. Results showed a nonlinear relationship between the area under the blood concentration versus time curves (AUCs) and administered doses of THMs, suggesting that metabolism is saturated in this dose range. The venous blood concentrations of THMs following administration of the quaternary mixture were significantly higher compared to single exposures. The altered kinetics of THMs during combined exposures is consistent with the occurrence of mutual inhibition of their hepatic metabolism. Simulation exercises conducted with physiologically based toxicokinetic models support metabolic inhibition as the possible mechanism of the interaction among THMs. The data reported in this study provide the starting point for evaluating the significance of interactions among THMs in the risk assessment process.

Minimum standards for electromyography in Canada: a statement of the Canadian Society of Clinical Neurophysiologists.

BACKGROUND: Electromyography (EMG) is a widely used diagnostic technique for disorders of the nervous system. The Canadian Society of Clinical Neurophysiologists (CSCN) promotes the education, evaluation and standards of EMG in Canada. A statement of practice standards was needed to clarify the position of the CSCN on several issues relevant to the practice of EMG. METHODS AND RESULTS: A subcommittee of the CSCN reviewed current patterns of practice and established guidelines for review by the CSCN. The guidelines developed by the subcommittee were reviewed by the CSCN and adopted as recommendations for EMG practice. The subcommittee was charged with formulation of a document for publication. CONCLUSIONS: This document deals with minimum standards for electromyographer education, laboratory operation, equipment and a variety of special circumstances relevant to the practice of EMG. The standards can be adopted by EMG laboratories to guide quality assurance.

Local corticosteroid injection for carpal tunnel syndrome.

BACKGROUND: Carpal tunnel syndrome (CTS) is a clinical syndrome manifested by signs and symptoms of irritation of the median nerve at the level of the carpal tunnel in the wrist. Treatment of CTS can be surgical or non-surgical. Local corticosteroid injection for CTS has been previously studied but most studies have been either retrospective or uncontrolled. The effectiveness and duration of benefit of local corticosteroid injection for CTS remain unknown. OBJECTIVES: To evaluate the effectiveness of local steroid injection for carpal tunnel syndrome versus placebo injection or other non-surgical interventions in improving clinical outcome and to determine the length of symptom relief post injection. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group register, MEDLINE, EMBASE and CINAHL. SELECTION CRITERIA: Studies using either a randomized or quasi-randomized methodology were eligible for inclusion. The studies included participants with the diagnosis of carpal tunnel syndrome and the treatment intervention was local corticosteroid injection. The primary outcome measure was clinical improvement after injection. DATA COLLECTION AND ANALYSIS: Three reviewers independently selected the trials to be included in the study. Studies were rated for their overall quality independently by the reviewers. Studies were compared for heterogeneity using the chi square statistic. Relative risks and 95% confidence intervals were calculated for each trial and summary relative risks and 95% confidence intervals (CI) were also calculated. MAIN RESULTS: We identified four randomized controlled trials studying local corticosteroid injection for the treatment of CTS. Two trials were excluded. One did not include clinical assessment as an outcome and the other did not provide patient outcomes, but only statistical values. Each of the remaining two trials had demonstrated clinical improvement of CTS at one month following local corticosteroid injection compared to placebo injection. The pooled relative risk (RR) favouring treatment was 3.62 (95% CI 1.94 to 6.73). REVIEWER'S CONCLUSIONS: Local corticosteroid injection for CTS provides greater clinical improvement in symptoms one month after injection compared to placebo. Symptom relief beyond one month compared to placebo has not been demonstrated. The effectiveness of local corticosteroid injection has not been compared to other non-surgical or surgical interventions for CTS in randomized controlled trials.

Local corticosteroid injection for carpal tunnel syndrome.

BACKGROUND: Carpal tunnel syndrome is a clinical syndrome manifested by signs and symptoms of irritation of the median nerve at the level of the carpal tunnel in the wrist. Local corticosteroid injection for carpal tunnel syndrome has been studied but its effectiveness and duration of benefit of local corticosteroid injection for Carpal tunnel syndrome remain unknown. OBJECTIVES: To evaluate the effectiveness of local steroid injection for carpal tunnel syndrome versus placebo injection or other non-surgical interventions in improving clinical outcome and to determine the length of symptom relief. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group register (searched June 2002), MEDLINE (searched January 1966 to May 2002), EMBASE (searched January 1980 to May 2002)and CINAHL(searched January 1982 to May 2002). SELECTION CRITERIA: We included randomized or quasi-randomized studies of participants with carpal tunnel syndrome treated with local corticosteroid injection. The primary outcome measure was clinical improvement. DATA COLLECTION AND ANALYSIS: Three reviewers independently selected the trials to be included rated for their overall quality. Relative risks and 95% confidence intervals were calculated for each trial and summary relative risks and 95% confidence intervals were also calculated. MAIN RESULTS: We identified nine randomized controlled trials. Four were excluded. One trial demonstrated clinical improvement of carpal tunnel syndrome at one month following local corticosteroid compared to placebo injection (Relative risk 3.83 (95% confidence intervals 1.82 to 8.05)). One trial compared local corticosteroid injection to oral steroid and at three months after treatment there was a significant improvement in the injection group (mean difference -7.00 (95% confidence intervals -11.58 to -2.42)). In one trial the rate of improvement after one month was greater after local than systemic corticosteroid injection (Relative risk 3.17(95% confidence intervals 1.02 to 9.87)). In one trial symptoms did not improve significantly for the injection group at eight weeks after injection compared to treatment with anti-inflammatory medication and splinting (mean difference 0.10 (95% confidence intervals -0.33 to 0.53)). Although local steroid injection did provide benefit compared to Helium-Neon Laser treatment at two weeks after onset of treatment (Relative risk 0.27 (95% CI 0.09 to 0.83), this effect did not hold at six months follow-up (Relative risk 0.76 (95% confidence intervals 0.48 to 1.21). REVIEWER'S CONCLUSIONS: Local corticosteroid injection for carpal tunnel syndrome provides greater clinical improvement in symptoms one month after injection compared to placebo. Symptom relief beyond one month compared to placebo has not been demonstrated. Local corticosteroid injection provides significantly greater clinical improvement compared to oral steroid up to three months after treatment. Local corticosteroid injection does not provide improved clinical outcome compared to either anti-inflammatory treatment and splinting after eight weeks or Helium -Neon laser treatment after six months.

Physiologically based modeling of the maximal effect of metabolic interactions on the kinetics of components of complex chemical mixtures.

The objective of this study was to predict and validate the theoretically possible, maximal impact of metabolic interactions on the blood concentration profile of each component in mixtures of volatile organic chemicals (VOCs) [dichloromethane (DCM), benzene (BEN), trichloroethylene (TCE), toluene (TOL), tetrachloroethylene (PER), ethylbenzene (EBZ), styrene (STY), as well as para, ortho-, and meta-xylene (p-XYL, o-XYL, m-XYL)] in the rat. The methodology consisted of: (1) obtaining the validated, physiologically based toxicokinetic (PBTK) model for each of the mixture components from the literature, (2) substituting the Michaelis-Menten description of metabolism with an equation based on the hepatic extraction ratio (E) for simulating the maximal impact of metabolic interactions (i.e., by setting E to 0 or 1 for simulating maximal inhibition or induction, respectively), and (3) validating the PBTK model simulations by comparing the predicted boundaries of venous blood concentrations with the experimental data obtained following exposure to various mixtures of VOCs. All experimental venous blood concentration data for 9 of the 10 chemicals investigated in the present study (PER excepted) fell within the boundaries of the maximal impact of metabolic inhibition and induction predicted by the PBTK model. The modeling approach validated in this study represents a potentially useful tool for screening/identifying the chemicals for which metabolic interactions are likely to be important in the context of mixed exposures and mixture risk assessment.

Evaluation of the pharmacokinetic interactions between orally administered trihalomethanes in the rat.

The blood kinetics of trihalomethanes has recently been reported to differ between an oral administration of any single trihalomethane (0.25 mmol/kg) [THMs: chloroform, bromoform, bromodichloromethane (BDCM), dibromochloromethane (DBCM)] and a combined administration of 0.25 mmol/kg of each of the 4 THMs. The significant increase in blood concentrations of THMs could be a consequence of pharmacokinetic interactions between two or more of the THMs present simultaneously. The objective of the present study was to characterize the blood kinetics of THMs following oral administration singly or as binary mixtures in order to assess the relative contribution of each THM to the kinetic interferences observed with the quaternary mixture. A single dose of each THM (0.5 mmol/kg) alone or of a binary mixture containing 0.5 mmol/kg of each THM was administered by gavage to male Sprague-Dawley rats. The venous blood concentrations of unchanged THMs were measured for up to 720 min postadministration by headspace gas chromatography. Results showed that, compared to single administration, each binary mixture caused a significant increase in the blood concentrations of both THMs present and this effect increased with time. The impact, however, was not similar for each mixture, especially during the first hour following administration of the compounds (bromoform and DBCM). Among the four THMs, bromoform and DBCM kinetics appeared to be more sensitive to the mixture effect and to exert the greatest impact on the kinetics of the second THM present in the mixture. Simulation exercises conducted with physiologically based toxicokinetic models suggest metabolic inhibition as the possible mechanism of the interaction between THMs. In conclusion, the results of this study show that, at the dose level investigated, every binary combination of THMs, when orally administered, resulted in a significant modulation of their pharmacokinetics and suggest that this is probably the consequence of a mutual metabolic inhibition between the THMs.