Construction of lactic acid overproducing Clostridium thermocellum through enhancement of lactate dehydrogenase expression.

Rapid expansion of global market of lactic acid (LA) has prompted research towards cheaper and more eco-friendly strategies for its production. Nowadays, LA is produced mainly through fermentation of simple sugars or starchy biomass (e.g. corn) and its price is relatively high. Lignocellulose could be an advantageous alternative feedstock for LA production owing to its high abundance and low cost. However, the most effective natural producers of LA cannot directly ferment lignocellulose. So far, metabolic engineering aimed at developing microorganisms combining efficient LA production and cellulose hydrolysis has been generally based on introducing designer cellulase systems in natural LA producers. In the present study, the approach consisted in improving LA production in the natural cellulolytic bacterium Clostridium thermocellum DSM1313. The expression of the native lactate dehydrogenase was enhanced by functional replacement of its original promoter with stronger ones resulting in a 10-fold increase in specific activity, which resulted in a 2-fold increase of LA yield. It is known that eliminating allosteric regulation can also increase lactic acid production in C. thermocellum, however we were unable to insert strong promoters upstream of the de-regulated ldh gene. A strategy combining these regulations and inactivation of parasitic pathways appears essential for developing a homolactic C. thermocellum.

Statin use and lung cancer risk in chronic obstructive pulmonary disease patients: a population-based cohort study.

BACKGROUND: Patients living with chronic obstructive pulmonary disease (COPD) are at an increased risk of lung cancer. A common comorbidity of COPD is cardiovascular disease; as such, COPD patients often receive statins. This study sought to understand the association between statin exposure and lung cancer risk in a population-based cohort of COPD patients. METHODS: We identified a population-based cohort of COPD patients based on having filled at least three prescriptions for an anticholinergic or short-acting beta-agonist (SABA). We used an array of methods of defining medication exposure including three conventional methods (ever statin exposure, cumulative duration of use, and cumulative dose) and two novel methods (recency-weighted cumulative duration of use and recency-weighted cumulative dose). To assess residual confounding, a negative control exposure was used to test the validity of our results. All exposure variables were time-dependent. RESULTS: The population-based cohort of COPD had 39,879 patients with mean age of 70.6 (SD: 11.2) years and, of which, 53.5% were female. There were 12,469 patients who received at least one statin prescription. Results from the reference case multivariable analysis indicated a reduced risk from statin exposure (HR: 0.85 (95% CI: 0.73-1.00) in COPD patients, but this result not statistically significant. Using the two recency-weighted modelling approaches, statin exposure was associated with a statistically significant reduction in lung cancer risk (recency-weighted cumulative dose, HR: 0.85 (95% CI: 0.77-0.93) and recency-weighted cumulative duration of use, HR: 0.97 (95% CI: 0.96-0.99). Multivariable analysis incorporating the negative control exposure was not statistically significant (HR: 0.89 (95% CI: 0.75-1.10). CONCLUSIONS: The results of this population-based analysis indicate that statin use in COPD patients may reduce the risk of lung cancer. While the effect was not statistically significantly across all exposure definitions, the overall results support the hypothesis that COPD patients might benefit from statin therapy.

Ten-year trends in direct costs of asthma: a population-based study.

INTRODUCTION: There is little information on recent trends in the economic burden of asthma. Our objective was to estimate the excess costs of asthma and their trend in British Columbia, Canada, from 2002 to 2011. METHODS: A retrospective cohort of individuals aged 5-55 years was constructed from the provincial administrative health databases, consisting of patients with physician-diagnosed asthma and a propensity-score-matched comparison sample from the general population. Total direct medical costs were calculated as the sum of hospitalizations, outpatient visits and medication costs, adjusted to 2012 Canadian dollars ($). Excess costs were defined as the difference in costs between the asthma and comparison groups. RESULTS: A total of 341 457 individuals (mean age at entry 27.3, 54.1% female) were equally divided into the asthma and comparison groups. Excess costs in patients with asthma were $1028.0 (95% CI $982.7-$1073.4) per patient-year (PY). Medications contributed to the greatest share of excess costs ($471.7/PY), whereas hospitalization and outpatient costs were, respectively, $272.2/PY and $284.1/PY. Only $192.9/PY was attributable to asthma itself. There was a 2.9%/year increase in excess costs (P < 0.001), a combination of asthma-attributable costs declining by 0.8%/year while nonasthma excess costs increasing by 3.8%/year. The most dramatic trend was observed in asthma-related outpatient costs, which decreased by %6.6/year. CONCLUSIONS: A significant share of excess costs in asthma is not attributable to the disease itself. The pattern of costs changed significantly during the study period. The burden of comorbid conditions should be considered in developing evidence-based policies for management of patients with asthma.

Household food insecurity and dietary diversity as correlates of maternal and child undernutrition in rural Cambodia.

OBJECTIVES: To assess household food insecurity and dietary diversity as correlates of maternal and child anthropometric status and anemia in rural Cambodia. METHODS: Trained interviewers administered a survey to 900 households in four rural districts of Prey Veng, Cambodia. The Household Food Insecurity Access Scale (HFIAS) and Household Dietary Diversity Score (HDDS) were used to assess household food insecurity and dietary diversity. The height, weight and hemoglobin concentration of the mother and youngest child under 5 years in each household were measured. Multivariate logistic regression models were constructed to assess the association between household food insecurity and dietary diversity, and child stunting and wasting, maternal thinness, maternal and child anemia. RESULTS: The mean (s.d.) HFIAS and HDDS scores were 5.3 (3.9) and 4.7 (1.6), respectively. The respective prevalences of mild, moderate and severe food insecurity were 33, 37 and 12%. Maternal thinness, child stunting and child wasting were present in 14.6, 25.4 and 8.1% of respondents, respectively. The risk of maternal thinness, but not child stunting or wasting, increased as the severity of household food insecurity increased. Household food insecurity was also positively associated with maternal, but not child, anemia. Household dietary diversity status was not significantly associated with any of the outcomes we assessed. CONCLUSIONS: Efforts to improve household food security are important as a means of promoting maternal nutritional status; however, additional research is needed to better understand the role of other factors that are driving the burden of child undernutrition in Cambodia.

Profile of secreted hydrolases, associated proteins, and SlpA in Thermoanaerobacterium saccharolyticum during the degradation of hemicellulose.

Thermoanaerobacterium saccharolyticum, a Gram-positive thermophilic anaerobic bacterium, grows robustly on insoluble hemicellulose, which requires a specialized suite of secreted and transmembrane proteins. We report here the characterization of proteins secreted by this organism. Cultures were grown on hemicellulose, glucose, xylose, starch, and xylan in pH-controlled bioreactors, and samples were analyzed via spotted microarrays and liquid chromatography-mass spectrometry. Key hydrolases and transporters employed by T. saccharolyticum for growth on hemicellulose were, for the most part, hitherto uncharacterized and existed in two clusters (Tsac_1445 through Tsac_1464 for xylan/xylose and Tsac_1344 through Tsac_1349 for starch). A phosphotransferase system subunit, Tsac_0032, also appeared to be exclusive to growth on glucose. Previously identified hydrolases that showed strong conditional expression changes included XynA (Tsac_1459), XynC (Tsac_0897), and a pullulanase, Apu (Tsac_1342). An omnipresent transcript and protein making up a large percentage of the overall secretome, Tsac_0361, was tentatively identified as the primary S-layer component in T. saccharolyticum, and deletion of the Tsac_0361 gene resulted in gross morphological changes to the cells. The view of hemicellulose degradation revealed here will be enabling for metabolic engineering efforts in biofuel-producing organisms that degrade cellulose well but lack the ability to catabolize C5 sugars.

Population-based surveillance of asthma among workers in British Columbia, Canada.

INTRODUCTION: Population-based health databases were used for the surveillance of asthma among workers in British Columbia for the period 1999 to 2003. The purpose was to identify high-risk groups of workers with asthma for further investigation, education and prevention. METHODS: Workers were identified using an employer-paid health premium field in the provincial health registry, and were linked to their physician visit, hospitalization, workers' compensation and pharmaceutical records; asthma cases were defined by the presence of an asthma diagnosis (International Classification of Diseases [ICD]-9-493) in these health records. Workers were assigned to an ''at-risk'' exposure group based on their industry of employment. RESULTS: For males, significantly higher asthma rates were observed for workers in the Utilities, Transport/Warehousing, Wood and Paper Manufacturing (Sawmills), Health Care/Social Assistance and Education industries. For females, significantly higher rates were found for those working in the Waste Management/Remediation and Health Care/Social Assistance industries. CONCLUSION: The data confirm a high prevalence of active asthma in the working population of British Columbia, and in particular, higher rates among females compared to males and in industries with known respiratory sensitizers such as dust and chemical exposures.

Cellulose- and xylan-degrading thermophilic anaerobic bacteria from biocompost.

Nine thermophilic cellulolytic clostridial isolates and four other noncellulolytic bacterial isolates were isolated from self-heated biocompost via preliminary enrichment culture on microcrystalline cellulose. All cellulolytic isolates grew vigorously on cellulose, with the formation of either ethanol and acetate or acetate and formate as principal fermentation products as well as lactate and glycerol as minor products. In addition, two out of nine cellulolytic strains were able to utilize xylan and pretreated wood with roughly the same efficiency as for cellulose. The major products of xylan fermentation were acetate and formate, with minor contributions of lactate and ethanol. Phylogenetic analyses of 16S rRNA and glycosyl hydrolase family 48 (GH48) gene sequences revealed that two xylan-utilizing isolates were related to a Clostridium clariflavum strain and represent a distinct novel branch within the GH48 family. Both isolates possessed high cellulase and xylanase activity induced independently by either cellulose or xylan. Enzymatic activity decayed after growth cessation, with more-rapid disappearance of cellulase activity than of xylanase activity. A mixture of xylan and cellulose was utilized simultaneously, with a significant synergistic effect observed as a reduction of lag phase in cellulose degradation.

Low-molecular-weight heparin versus unfractionated heparin for prophylaxis of venous thromboembolism in medicine patients--a pharmacoeconomic analysis.

BACKGROUND: Prevention of in-hospital venous thromboembolism (VTE) is identified internationally as a priority to improve patient safety. Advocated alternatives include low-dose unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Although LMWHs are as effective as UFH, less frequent administration and potentially safer adverse effect profile associated with LMWHs might off-set greater drug acquisition costs. The objective of this study was to determine the most cost-effective thromboprophylaxis strategy for hospitalized medicine patients and specific subgroups in Canada. METHODS: A decision-analytic model assessed costs and outcomes of LMWH compared to UFH for thromboprophylaxis in at-risk hospitalized medicine patients from an institutional perspective. The outcome of interest was the incremental cost-effectiveness ratio (ICER) for preventing deep vein thrombosis (DVT) and combined untoward events (pulmonary embolism [PE], major bleed, and death). The time horizon of the model was the hospital stay. RESULTS: In the base-case analysis, LMWH thromboprophylaxis resulted in higher costs ($7.40), but 3.6 and 1.1 fewer DVT and untoward events per 1000 patients, respectively, with associated ICERs of $2042 and $6832. Results remained predominantly stable when alternative assumptions were evaluated in the sensitivity analysis. Low-molecular-weight heparin had the most favorable economic profile in patients with a history of DVT. In the probabilistic sensitivity analysis, in 33% of simulations LMWH was less costly and more effective, whereas the reverse was true for UFH only in 13% of simulations. CONCLUSIONS: Low-molecular-weight heparin administration is a cost-effective alternative for thromboprophylaxis strategy in Canadian hospitalized medicine patients.

Biosynthesis of radiolabeled cellodextrins by the Clostridium thermocellum cellobiose and cellodextrin phosphorylases for measurement of intracellular sugars.

The Clostridium thermocellum cellobiose and cellodextrin phosphorylases (glucosyl transferases) in the cell extract were used to synthesize radiolabeled cellodextrins with a degree of polymerization (DP=2-6) from nonradioactive glucose-1-phosphate and radioactive glucose. Chain lengths of synthesized cellodextrin were controlled by the absence or presence of dithiothreitol and by reaction conditions. All cellodextrins have the sole radioactive glucose unit located at the reducing ends. Mixed cellodextrins (G2-G6) were separated efficiently by size-exclusion chromatography or less efficiently by thin-layer chromatography. A new rapid sampling device was developed using disposable syringes containing an ultracold methanol-quenching buffer. It was simple, less costly, and especially convenient for anaerobic fermentation. After an impulse feed of radiolabeled cellobiose, the intracellular sugar levels were measured after a series of operations-sampling, extracting, concentrating, separating, and reading. Results showed that the largest amount of radioactivity was cellobiose with lesser amounts of glucose, cellotriose, and cellotetraose, and an average DP of intracellular cellodextrins was ca. 2.

The impact of low family income on self-reported health outcomes in patients with rheumatoid arthritis within a publicly funded health-care environment.

OBJECTIVE: Self-rated health (SRH) is an independent, strong predictor of morbidity and mortality. Socio-economic status (SES) is strongly associated with SRH. This study investigated the relationship between SES and SRH outcomes in a sample of patients with rheumatoid arthritis (RA) in Canada. METHODS: Both generic preference-based [Health Utilities Index Mark 3 (HUI3) and Short Form 6D (SF-6D)] and non-preference-based [disease-specific (Rheumatoid Arthritis Quality of Life, RAQoL) and a functional status (Health Assessment Questionnaire, HAQ)] SRH questionnaires were administered to 313 RA patients. Both proximate (education and annual household income) and contextual (neighbourhood income, education and unemployment) measures of SES were captured. Ordinary least squares (OLS) regression was used to adjust for RA severity while assessing the relationship between SRH and SES measures. Two-stage least-squares (TSLS) regression was used to determine if there was an inter-relationship between SES and SRH measures. RESULTS: The sample was well distributed across RA severity and SES measures. Contextual and proximate measures of SES were poorly correlated. Lower levels of proximate SES measures (but not contextual) were associated with poorer SRH outcomes. The OLS regressions showed significant associations between the HUI3 and the SF-6D overall scores and the HAQ for self-reported income. The RAQoL did not differ significantly across SES. TSLS regression confirmed the finding that self-reported income was similarly associated with the SRH measures. CONCLUSIONS: Even in a country with universal access to health-care, the impact of a chronic disease such as RA on SRH is associated with self-reported income. The finding that preference-based measures vary with income independently of RA severity could bias economic evaluation.

Cloning of L-lactate dehydrogenase and elimination of lactic acid production via gene knockout in Thermoanaerobacterium saccharolyticum JW/SL-YS485.

The gene encoding L-lactate dehydrogenase from Thermoanaerobacterium saccharolyticum JW/SL-YS485 was cloned, sequenced, and used to obtain an L-ldh deletion mutant strain (TD1) following a site-specific double-crossover event as confirmed by PCR and Southern blot. Growth rates and final cell densities were similar for strain TD1 and the wild-type grown on glucose and xylose. Lactic acid was below the limit of detection (0.3 mM) for strain TD1 on both glucose and xylose at all times tested, but was readily detected for the wild-type strain, with average final concentrations of 8.1 and 1.8 mM on glucose and xylose, respectively. Elimination of lactic acid as a fermentation product was accompanied by a proportional increase in the yields of acetic acid and ethanol. The results reported here represent a step toward using metabolic engineering to develop strains of thermophilic anaerobic bacteria that do not produce organic acids, and support the methodological feasibility of this goal.

High-value renewable energy from prairie grasses.

Projected economic benefits of renewable energy derived from a native prairie grass, switchgrass, include nonmarket values that can reduce net fuel costs to near zero. At a farm gate price of $44.00/dry Mg, an agricultural sector model predicts higher profits for switchgrass than conventional crops on 16.9 million hectares (ha). Benefits would include an annual increase of $6 billion in net farm returns, a $1.86 billion reduction in government subsidies, and displacement of 44-159 Tg/year (1 Tg = 1012 g) of greenhouse gas emissions. Incorporating these values into the pricing structure for switchgrass bioenergy could accelerate commercialization and provide net benefits to the U.S. economy.

A comparison of liquid hot water and steam pretreatments of sugar cane bagasse for bioconversion to ethanol.

Sugar cane bagasse was pretreated with either liquid hot water (LHW) or steam using the same 25 l reactor. Solids concentration ranged from 1% to 8% for LHW pretreatment and was > or = 50% for steam pretreatment. Reaction temperature and time ranged from 170 to 230 degrees C and 1 to 46 min, respectively. Key performance metrics included fiber reactivity, xylan recovery, and the extent to which pretreatment hydrolyzate inhibited glucose fermentation. In four cases, LHW pretreatment achieved > or = 80% conversion by simultaneous saccharification and fermentation (SSF). > or = 80% xylan recovery, and no hydrolyzate inhibition of glucose fermentation yield. Combined effectiveness was not as good for steam pretreatment due to low xylan recovery. SSF conversion increased and xylan recovery decreased as xylan dissolution increased for both modes. SSF conversion, xylan dissolution. hydrolyzate furfural concentration, and hydrolyzate inhibition increased, while xylan recovery and hydrolyzate pH decreased, as a function of increasing LHW pretreatment solids concentration (1-8%). These results are consistent with the notion that autohydrolysis plays an important. if not exclusive, role in batch hydrothermal pretreatment. Achieving concurrently high (greater than 90%) SSF conversion and xylan recovery will likely require a modified reactor configuration (e.g. continuous percolation or base addition) that better preserves dissolved xylan.

Double trouble: impact of inappropriate use of asthma medication on the use of health care resources.

BACKGROUND: There is considerable controversy about the regular use of short-acting beta-agonists for the treatment of asthma. Although case-control studies have suggested that excessive use of these drugs may worsen asthma control and increase the risk of fatal or near-fatal asthma, the controversy remains unresolved because of the confounding that exists among disease control, disease severity and the use of short-acting beta-agonists. Whatever the cause-and-effect relation between the use of short-acting beta-agonists and disease severity, we hypothesized that their excessive use, in conjunction with underuse of inhaled corticosteroids, would be a marker for poorly controlled asthma and excessive use of health care resources. METHODS: To characterize the pattern of health services utilization among asthmatic patients taking various doses of inhaled beta-agonists and corticosteroids in British Columbia, we linked the relevant health administrative databases. All patients between 5 and 50 years of age for whom a prescription for a short-acting beta-agonist was filled in 1995 and whose prescription data were captured through the provincial drug plan were included in a retrospective analysis of prescriptions for asthma drugs, physician prescribing patterns and health services utilization. Patients' use of asthma medication was classified as appropriate (low doses of short-acting beta-agonist and high doses of inhaled corticosteroid) or inappropriate (high doses of short-acting beta-agonist and low doses of inhaled corticosteroid), and the 2 resulting groups were compared, by means of logistic, Poisson and gamma regression, for differences in prescribing patterns, physician visits and use of hospital resources. RESULTS: A total of 23,986 patients were identified as having filled a prescription for a short-acting beta-agonist (for inhalation) in 1995. Of these, 3069 (12.8%) filled prescriptions for 9 or more canisters of beta-agonist, and of this group of high-dose beta-agonist users, 763 (24.9%) used no more than 100 micrograms/day of inhaled beclomethasone. On average, those with inappropriate use of beta-agonists visited significantly more physicians for their prescriptions (1.8 v. 1.4), and each of these physicians on average wrote significantly more prescriptions for asthma medications per patient than the physicians who prescribed to appropriate users (5.2 v. 2.5 prescriptions). Patients with inappropriate use were more likely to be admitted to hospital (adjusted relative risk [RR] 1.68, 95% confidence interval [CI] 1.25-2.26), were admitted to hospital more frequently (adjusted RR 1.81, 95% CI 1.41-2.32) and were more likely to require emergency admission (adjusted RR 1.93, 95% CI 1.35-2.77). INTERPRETATION: Despite the widespread distribution of guidelines for asthma pharmacotherapy, inappropriate use of asthma medications persists (specifically excessive use of inhaled short-acting beta-agonists combined with underuse of inhaled corticosteroids). Not only are patients who use medication inappropriately at higher risk for fatal or near-fatal asthma attacks, but, as shown in this study, they use significantly more health care resources than patients with appropriate medication use.

Salt accumulation resulting from base added for pH control, and not ethanol, limits growth of Thermoanaerobacteriumthermosaccharolyticum HG-8 at elevated feed xylose concentrations in continuous culture.

Thermoanaerobacter thermosaccharolyticum HG-8 was grown in continuous culture to characterize growth limitation at high feed substrate and product concentrations. Continuous fermentation of 50 and 73 g/L xylose at a dilution rate based on the feed flow, D(f), of 0.053 h(-)(1) and with the pH controlled at 7.0 by addition of KOH resulted in steady state utilization of >99% of the xylose fed and production of ethanol and acetic acid at a mass ratio of about 2:1. Continuous cultures of T. thermosaccharolyticum growing at D(f) = 0.053 h(-)(1) achieved complete utilization of 75 g/L xylose in the presence of 19.1 g/L K(+) (0.49 M) and an ethanol concentration of 22.4 g/L ethanol. When the feed to a culture initially at steady state with a 75 g/L xylose feed and D(f) = 0.053 h(-)(1) was increased to 87.5 g/L xylose, limitation of growth and xylose utilization was observed. This limitation was not relieved by repeating this feed upshift experiment in the presence of increased nutrient levels and was not reproduced by addition of ethanol to a steady-state culture fed with 75 g/L xylose. By contrast, addition of KCl to a steady-state culture fed with 75 g/L xylose reproduced the K(+) concentration, limitation of growth and xylose utilization, and product concentration profiles observed in the feed upshift experiment. The maximum concentration at which growth of batch cultures was observed was 0.43 M for KCl, NaCl, and equimolar mixtures of these salts, suggesting that the observed limitation is not ion-specific. These data support the interpretation that inhibition salt accumulation resulting from addition of KOH for pH control is the limiting factor manifested in the feed upshift experiment and that both nutrient limitation and ethanol inhibition played little or no role as limiting factors. More generally, salt inhibition would appear to be a possible explanation for the discrepancy between the tolerance to added ethanol and the maximum concentration of produced ethanol reported in the literature for fermentation studies involving thermophilic bacteria.

Characterization of 13 newly isolated strains of anaerobic, cellulolytic, thermophilic bacteria.

Characteristics of 13 newly isolated thermophilic, anaerobic, and cellulolytic strains were compared with previously described strains of Clostridium thermocellum: ATCC 27405 and JW20 (ATCC 31549). Colony morphology, antibiotic sensitivity, fermentation end-products, and cellulose degradation were documented. All 13 strains were sensitive to erythromycin (5 microg/ml) and chloramphenicol (25 microg/ml), and all strains but one were sensitive to kanamycin (20 microg/ml). Polymerase chain reaction (PCR) amplification using primers based on gene sequences from C. thermocellum ATCC 27405 was successful for all 13 strains in the case of the hydrogenase gene and 11 strains in the case of phosphotransacetylase/acetate kinase genes. Ten strains amplified a product of the expected size with primers developed to be specific for C. thermocellum 16SrRNA primers. Two of the 13 strains did not amplify any product with the PCR primers designed for the phosphotransacetylase/acetate kinase and 16SrRNA primers. A MboI-like GATC- recognizing restriction activity was present in all of the five strains examined. The results of this study have several positive implications with respect to future development of a transformation system for cellulolytic thermophiles.

Selective serotonin-reuptake inhibitor-induced movement disorders.

OBJECTIVE: To compile and evaluate all available data suggesting an association between selective serotonin-reuptake inhibitor (SSRI) administration and the occurrence of movement disorders, and to characterize these reactions in terms of onset, duration, treatment and outcome, and potential predisposing factors. METHODOLOGY: Reports of movement disorders were identified by conducting a comprehensive literature search that included tertiary adverse drug reaction resources, MEDLINE, EmBASE, Biological Abstracts, Current Contents, Reactions, ClinAlert, and International Pharmaceutical Abstracts. In addition, reports were solicited from the Canadian proprietary manufacturers of SSRIs, and from the Therapeutic Products Program of Health Canada. Each case was then classified according to the description of the movement disorder, based on predefined diagnostic criteria. RESULTS: A total of 127 published reports of SSRI-induced movement disorders were identified involving akathisia (n = 30), dystonia (19), dyskinesia (12), tardive dyskinesia (6), parkinsonism (25), and 15 cases of mixed disorders. Ten isolated cases of bruxism were identified. Ten additional reports could not be classified. Manufacturers of SSRIs provided 49 reports of akathisia, 44 of dystonia, 208 of dyskinesia, 76 of tardive dyskinesia, 516 of parkinsonism, and 60 of bruxism. Treatment strategies included discontinuation of the SSRI; dosage reduction; or the addition of a benzodiazepine, beta-blocker, or anticholinergic agent. CONCLUSIONS: SSRI use appears to be associated with the development of movement disorders, as either a direct result of the drug or exacerbation of an underlying condition. Predisposing factors may include the use of neuroleptics, existing neurologic diagnoses, or preexisting movement disorders. Clinicians should be cognizant of the potential for these reactions, as prompt recognition and management is essential in preventing potentially significant patient morbidity.

Sumatriptan contraindications and the serotonin syndrome.

OBJECTIVE: To determine the risk for serotonin syndrome associated with the concomitant use of sumatriptan and the currently contraindicated therapies, that is, the monoamine oxidase inhibitors (MAOIs), serotonin selective-reuptake inhibitors (SSRIs), and lithium. METHODOLOGY: A comprehensive search for reports of serotonin syndrome associated with sumatriptan use was conducted by using tertiary drug interaction literature, MEDLINE, EmBASE, Biological Abstracts, Current Contents, Reactions, ClinAlert, and the International Pharmaceutical Abstracts. In addition, related reports from the proprietary manufacturers, the Health Protection Branch of Health Canada, and the World Health Organization Collaborative Centre for International Drug Monitoring were also solicited. RESULTS: The concurrent use of sumatriptan with an SSRI or lithium has been reported to cause symptoms suggestive of serotonin syndrome in 16 and 2 cases, respectively. There were no reports involving MAOIs. In general, the reports indicated a mild-to-moderate, self-limited course with some features consistent with the serotonin syndrome. We found published reports of sumatriptan use without adverse events involving 148 patients receiving SSRIs, 31 patients taking MAOIs, and a small number using lithium. CONCLUSIONS: Clinical evidence supporting the strict contraindication of MAOIs, SSRIs and lithium was not identified. The balance of documented clinical experience pertaining to the use of sumatriptan concurrently with SSRIs or lithium suggests that most patients tolerate this combination without incident. Because there is little reliable experience with sumatriptan in combination with MAOIs, we suggest that sumatriptan should continue to be avoided in patients taking these agents until further data demonstrating safety become available.

Applicability of competitive and noncompetitive kinetics to the reductive dechlorination of chlorinated ethenes.

Reductive dechlorination of chlorinated ethenes has typically been modeled using standard Michaelis-Menten kinetic equations, implying that each dechlorination step is catalyzed by a unique biological factor. An alternative kinetic model is based on the assumption that all steps are mediated by a single factor. These two options are considered in the context of chlorinated ethene degradation by a previously characterized anaerobic culture. Competitive kinetics afford better chi-squared and visual fits of the data set tested.

Allocation of ATP to synthesis of cells and hydrolytic enzymes in cellulolytic fermentative microorganisms: bioenergetics, kinetics, and bioprocessing.

Under anaerobic, carbon limited conditions, celluloytic fermentative microorganisms face a metabolic choice with respect to the allocation of relatively scarce ATP: to invest it in cells or in hydrolytic enzymes. A model is proposed that defines an allocation parameter reflecting the fractional expenditure of ATP on cell synthesis relative to the total ATP available (gross ATP synthesized less maintenance). This parameter is then incorporated into an ATP-centered model of anaerobic cellulose fermentation based on the ethanol fermentation of yeast and the cellulase system of Trichoderma reesei. Results indicate that high processing rates are possible via a consolidated bioprocessing strategy, especially at high cellulase specific activities, and that cell/cellulase allocation represents an interesting system in which to study, and perhaps exploit, microbial evolution and metabolic control.