Potential drug-drug interactions among hospitalised TB patients.

BACKGROUND: Hospitalised TB patients are at heightened risk for developing drug-drug interactions (DDIs) due to overlapping CYP450 enzyme and/or drug transporter biotransformation of anti-TB drugs and co-medications given for treating TB-associated comorbidities. We aimed to compare the occurrence, characterisation and determinants of database identified potential DDIs (pDDIs) associated with first-line anti-TB drugs and other co-medications using a subscription and free access drug information database.METHOD: This was a single-centre retrospective study to assess pDDIs between first-line anti-TB drugs and other medications for comorbidities among hospitalised TB patients using IBM Micromedex® and Drugs.com.RESULTS: On multivariate regression analysis, hospitalised TB patients with comorbidities such as diabetes mellitus, HIV infection and hypertension, longer hospitalisation, and patients administered with more than seven drugs during their hospital stay were associated with increased risk for the occurrence of pDDIs. Significant discrepancies were observed in the detection and severity of pDDIs between IBM Micromedex and Drugs.com.CONCLUSION: We recommend using free access drug information database to a subscription drug information database in drug interaction screening protocols in clinics for enhanced identification of pDDIs and reducing monetary burden in resource-limited settings.

Reduction in unplanned hospitalizations associated with a physician focused intervention to reduce potentially inappropriate medication use among older adults: a population-based cohort study.

BACKGROUND: A multimodal general practitioner-focused intervention in the Local Health Authority (LHA) of Parma, Italy, substantially reduced the prevalence of potentially inappropriate medication (PIM) use among older adults. Our objective was to estimate changes in hospitalization rates associated with the Parma LHA quality improvement initiative that reduced PIM use. METHODS: This population-based longitudinal cohort study was conducted among older residents (> 65 years) using the Parma LHA administrative healthcare database. Crude and adjusted unplanned hospitalization rates were estimated in 3 periods (pre-intervention: 2005-2008, intervention: 2009-2010, post-intervention: 2011-2014). Multivariable negative binomial models estimated trends in quarterly hospitalization rates among individuals at risk during each period using a piecewise linear spline for time, adjusted for time-dependent and time-fixed covariates. RESULTS: The pre-intervention, intervention, and post-intervention periods included 117,061, 107,347, and 121,871 older adults and had crude hospitalization rates of 146.2 (95% CI: 142.2-150.3), 146.8 (95% CI: 143.6-150.0), and 140.8 (95% CI: 136.9-144.7) per 1000 persons per year, respectively. The adjusted pre-intervention hospitalization rate was declining by 0.7% per quarter (IRR = 0.993; 95% CI: 0.991-0.995). The hospitalization rate declined more than twice as fast during the intervention period (1.8% per quarter, IRR = 0.982; 95% CI: 0.979-0.985) and was nearly constant post-intervention (IRR: 0.999; 95% CI: 0.997-1.001). Contrasting model predictions for the intervention period (Q1 2009 to Q4 2010), the intervention was associated with 1481 avoided hospitalizations. CONCLUSION: In a large population of older adults, a multimodal general practitioner-focused intervention to decrease PIM use was associated with a decline in the unplanned hospitalization rate. Such interventions to reduce high risk medication use among older adults warrant consideration by health systems seeking to improve health outcomes and reduce high-cost acute care utilization.

Experimental and mathematical analysis of in vitro Pitavastatin hepatic uptake across species.

1. To investigate the non-linear kinetics of in vitro hepatocyte uptake across species, the OATP substrate Pitavastatin was used as a probe. 2. Experiments were conducted at AstraZeneca (Alderley Park, Macclesfield) using freshly isolated rat, dog and human hepatocytes, utilising the "oil spin" methodology described by Hassen et al. (1996). Very few mechanistic models have previously been used to characterise the uptake process. 3. Here two candidate pharmacokinetic non-linear compartmental models are proposed. Both models have been shown to be structurally identifiable and distinghishable previously, which establishes that all unknown parameters could be identified from the experimental observations available and that input/output relationships for both the candidate models were structurally different. 4. A kinetic modelling software package, FACSIMILE (MCPA Software, Faringdon, UK), was used to obtain numerical solutions for the system equations and for parameter estimation. Model fits gave good agreement with the in vitro data and suggest the current widely accepted assumption that the rate of diffusion across the hepatocyte cell membrane is the same at both 4 °C and 37 °C is not valid, at least for Pitavastatin. Although this finding has already been proposed, this is the first time it is comprehensively debunked using statistical testing.

Structural identifiability analyses of candidate models for in vitro Pitavastatin hepatic uptake.

In this paper a review of the application of four different techniques (a version of the similarity transformation approach for autonomous uncontrolled systems, a non-differential input/output observable normal form approach, the characteristic set differential algebra and a recent algebraic input/output relationship approach) to determine the structural identifiability of certain in vitro nonlinear pharmacokinetic models is provided. The Organic Anion Transporting Polypeptide (OATP) substrate, Pitavastatin, is used as a probe on freshly isolated animal and human hepatocytes. Candidate pharmacokinetic non-linear compartmental models have been derived to characterise the uptake process of Pitavastatin. As a prerequisite to parameter estimation, structural identifiability analyses are performed to establish that all unknown parameters can be identified from the experimental observations available.

Compartmental modelling of the pharmacokinetics of a breast cancer resistance protein.

A mathematical model for the pharmacokinetics of Hoechst 33342 following administration into a culture medium containing a population of transfected cells (HEK293 hBCRP) with a potent breast cancer resistance protein inhibitor, Fumitremorgin C (FTC), present is described. FTC is reported to almost completely annul resistance mediated by BCRP in vitro. This non-linear compartmental model has seven macroscopic sub-units, with 14 rate parameters. It describes the relationship between the concentration of Hoechst 33342 and FTC, initially spiked in the medium, and the observed change in fluorescence due to Hoechst 33342 binding to DNA. Structural identifiability analysis has been performed using two methods, one based on the similarity transformation/exhaustive modelling approach and the other based on the differential algebra approach. The analyses demonstrated that all models derived are uniquely identifiable for the experiments/observations available. A kinetic modelling software package, namely FACSIMILE (MPCA Software, UK), was used for parameter fitting and to obtain numerical solutions for the system equations. Model fits gave very good agreement with in vitro data provided by AstraZeneca across a variety of experimental scenarios.

Photosynthetic responses to CO2 enrichment of four hardwood species in a forest understory.

We compared the CO2- and light-dependence of photosynthesis of four tree species (Acer rubrum, Carya glabra, Cercis canadensis, Liquidambar styraciflua) growing in the understory of a loblolly pine plantation under ambient or ambient plus 200 µl l-1 CO2. Naturally-established saplings were fumigated with a free-air CO2 enrichment system. Light-saturated photosynthetic rates were 159-190% greater for Ce. canadensis saplings grown and measured under elevated CO2. This species had the greatest CO2 stimulation of photosynthesis. Photosynthetic rates were only 59% greater for A. rubrum saplings under CO2 enrichment and Ca. glabra and L. styraciflua had intermediate responses. Elevated CO2 stimulated light-saturated photosynthesis more than the apparent quantum yield. The maximum rate of carboxylation of ribulose-1,5-bisphosphate carboxylase, estimated from gas-exchange measurements, was not consistently affected by growth in elevated CO2. However, the maximum electron transport rate estimated from gas- exchange measurements and from chlorophyll fluorescence, when averaged across species and dates, was approximately 10% higher for saplings in elevated CO2. The proportionately greater stimulation of light-saturated photosynthesis than the apparent quantum yield and elevated rates of maximum electron transport suggests that saplings growing under elevated CO2 make more efficient use of sunflecks. The stimulation of light-saturated photosynthesis by CO2 did not appear to correlate with shade-tolerance ranking of the individual species. However, the species with the greatest enhancement of photosynthesis, Ce. canadensis and L. styraciflua, also invested the greatest proportion of soluble protein in Rubisco. Environmental and endogenous factors affecting N partitioning may partially explain interspecific variation in the photosynthetic response to elevated CO2.

Is atmospheric CO2 a selective agent on model C3 annuals?

Atmospheric CO2 partial pressure (pCO2) was as low as 18 Pa during the Pleistocene and is projected to increase from 36 to 70 Pa CO2 before the end of the 21st century. High pCO2 often increases the growth and reproduction of C3 annuals, whereas low pCO2 decreases growth and may reduce or prevent reproduction. Previous predictions regarding the effects of high and low pCO2 on C3 plants have rarely considered the effects of evolution. Knowledge of the potential for evolution of C3 plants in response to CO2 is important for predicting the degree to which plants may sequester atmospheric CO2 in the future, and for understanding how plants may have functioned in response to low pCO2 during the Pleistocene. Therefore, three studies using Arabidopsis thaliana as a model system for C3 annuals were conducted: (1) a selection experiment to measure responses to selection for high seed number (a major component of fitness) at Pleistocene (20 Pa) and future (70 Pa) pCO2 and to determine changes in development rate and biomass production during selection, (2) a growth experiment to determine if the effects of selection on final biomass were evident prior to reproduction, and (3) a reciprocal transplant experiment to test if pCO2 was a selective agent on Arabidopsis. Arabidopsis showed significant positive responses to selection for high seed number at both 20 and 70 Pa CO2 during the selection process. Furthermore, plants selected at 20 Pa CO2 performed better than plants selected at 70 Pa CO2 under low CO2 conditions, indicating that low CO2 acted as a selective agent on these annuals. However, plants selected at 70 Pa CO2 did not have significantly higher seed production than plants selected at 20 Pa CO2 when grown at high pCO2. Nevertheless, there was some evidence that high CO2 may also be a selective agent because changes in development rate and biomass production during selection occurred in opposite directions at low and high pCO2. Plants selected at high pCO2 showed no change or reductions in biomass relative to control plants due to a decrease in the length of the life cycle, as indicated by earlier initiation of flowering and senescence. In contrast, selection at low CO2 resulted in an average 35% increase in biomass production, due to an increase in the length of the life cycle that resulted in a longer period for biomass accumulation before senescence. From the Arabidopsis model system we conclude that some C3 annuals may have produced greater biomass in response to low pCO2 during the Pleistocene relative to what has been predicted from studies exposing a single generation of C3 plants to low pCO2. Furthermore, C3 annuals may exhibit evolutionary responses to high pCO2 in the future that may result in developmental changes, but these are unlikely to increase biomass production. This series of studies shows that CO2 may potentially act as a selective agent on C3 annuals, producing changes in development rate and carbon accumulation that could not have been predicted from single-generation studies.

Growth and carbon accumulation in root systems of Pinus taeda and Pinus ponderosa seedlings as affected by varying CO(2), temperature and nitrogen.

It has been hypothesized that increasing atmospheric CO(2) concentration enhances accumulation of carbon in fine roots, thereby altering soil carbon dynamics and nutrient cycling. To evaluate possible changes to belowground pools of carbon and nitrogen in response to elevated CO(2), an early and a late successional species of pine (Pinus taeda L. and Pinus ponderosa Dougl. ex Laws, respectively) were grown from seed for 160 days in a 35 or 70 Pa CO(2) partial pressure at low or high temperature (30-year weekly mean and 30-year weekly mean + 5 degrees C) and a soil solution nitrogen concentration of 1 or 5 mM NH(4)NO(3) at the Duke University Phytotron. Seedlings were harvested at monthly intervals and growth parameters of the primary root, secondary root and tap root fractions evaluated. Total root biomass of P. ponderosa showed a positive CO(2) response (105% increase) (P = 0.0001) as a result of significant increases in all root fractions in the elevated CO(2) treatment, but all other main effects and interactions were insignificant. In P. taeda, there were significant interactions between CO(2) and temperature (P = 0.04) and CO(2) and nitrogen (P = 0.04) for total root biomass. An allometric analysis indicated that modulation of the secondary root fraction was the main response of the trees to altered environmental conditions. In P. ponderosa, there was an increase in the secondary root fraction relative to the primary and tap root fractions under conditions of low temperature. In P. taeda, there was a shift in carbon accumulation to the secondary roots relative to the primary roots under low temperature and low nitrogen. Neither species exhibited shifts in carbon accumulation in response to elevated CO(2). We conclude that both species have the potential to increase belowground biomass substantially in response to rising atmospheric CO(2) concentration, and this response is sensitive to temperature and nitrogen in P. taeda. Both species displayed small shifts in belowground carbon accumulation in response to altered temperature and nitrogen that may have substantial ecosystem consequences over time.

Growth and photosynthesis of loblolly pine (Pinus taeda) after exposure to elevated CO(2) for 19 months in the field.

To detect seasonal and long-term differences in growth and photosynthesis of loblolly pine (Pinus taeda L.) exposed to elevated CO(2) under ambient conditions of precipitation, light, temperature and nutrient availability, seedlings were planted in soil representative of an early, abandoned agricultural field and maintained for 19 months in the field either in open-top chambers providing one of three atmospheric CO(2) partial pressures (ambient, ambient +15 Pa, and ambient +30 Pa) or in unchambered control plots. An early and positive response to elevated CO(2) substantially increased total plant biomass. Peak differences in relative biomass enhancement occurred after 11 months of CO(2) treatment when biomass of plants grown at +15 and +30 Pa CO(2) was 111 and 233% greater, respectively, than that of plants grown at ambient CO(2). After 19 months, there was no significant difference in biomass between +15 Pa CO(2)-treated plants and ambient CO(2)-treated plants, whereas biomass of +30 Pa CO(2)-treated plants was 111% greater than that of ambient CO(2)-treated plants. Enhanced rates of leaf-level photosynthesis were maintained in plants in the elevated CO(2) treatments throughout the 19-month exposure period despite reductions in both leaf N concentration and ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) activity during the first 11 months of CO(2) exposure. Reductions in Rubisco activity indicated photosynthetic adjustment to elevated CO(2), but Rubisco-mediated control of photosynthesis was small. Seasonal shifts in sink strength affected photosynthetic rates, greatly magnifying the positive effects of elevated CO(2) on photosynthesis during periods of rapid plant growth. Greater carbon assimilation by the whole plant accelerated plant development and thereby stimulated new sinks for carbon through increased plant biomass, secondary branching and new leaf production. We conclude that elevated CO(2) will enhance photosynthesis and biomass accumulation in loblolly pine seedlings under high nutrient conditions; however, reductions over time in the relative biomass response of plants to elevated CO(2) complicate predictions of the eventual magnitude of carbon storage in this species under future CO(2) conditions.

Socioeconomic change and patterns of growth in the Andes.

Changes in the pattern of growth over a 20-year period are described for a combined rural and semi-urban population in the District of Nuñoa (Puno) in southern Peruvian Andes. Over the past two decades, Andean regions have experienced many socioeconomic changes, including the implementation of agrarian reform policies and increased integration into a market economy. Local changes in Nuñoa have included improved transportation networks, new markets, an expanded public school system, and improved health care facilities. Secular trends in stature and weight have been found to be associated with social and economic development throughout the developing world, including Peru. The purpose of this paper is to present the findings from a re-study of growth in the Nuñoan population, and to assess whether changing conditions in Nuñoa have resulted in secular increases in growth. A cross-sectional sample of 1,466 children and adults and mixed-longitudinal sample of 404 children (age 3-22), measured between 1983 and 1984, are compared to similar samples collected from the same location between 1964 and 1966. Adolescents are taller, heavier, and somewhat fatter in the present population, although these differences diminish or disappear in adulthood. Age of maturation, peak growth velocities, and cessation of growth may come 1 to 2 years earlier than in the 1960s. As was found in earlier studies, growth velocities are low, the adolescent growth spurt is small, and sexual dimorphism is delayed. No secular trends in adult stature were found. Thus, the effects of social and economic change on nutrition, health, and growth in the population are uneven and generally unclear. This points to inequalities in access to the benefits of change throughout the region.

Effects of low and elevated CO2 on C3 and C4 annuals : I. Growth and biomass allocation.

In order study C3 and C4 plant growth in atmospheric CO2 levels ranging from past through predicted future levels, Abutilon theophrasti (C3) and Amaranthus retroflexus (C4) were grown from seed in growth chambers controlled at CO2 partial pressures of 15 Pa (below Pleistocene minimum), 27 Pa (pre-industrial), 35 Pa (current) and 70 Pa (predicted future). After 35 days of growth, CO2 had no effect on the relative growth rate, total biomass or partitioning of biomass in the C4 species. However, the C3 species had greater biomass accumulation with increasing CO2 partial pressure. C3 plants grown in 15 Pa CO2 for 35 days had only 8% of the total biomass of plants grown in 35 Pa CO2, C3 plants had lower relative growth rates and lower specific leaf mass than plants grown in higher CO2 partial pressures, and aborted reproduction. C3 plants grown in 70 Pa CO2 had greater root mass and root-to-shoot ratios than plants grown in lower CO2 partial pressures. These findings, support other studies that show C3 plant growth is more responsive to CO2 partial pressure than C4 plant growth. Differences in growth responses to CO2 levels of the Pleistocene through the future suggest that competitive interactions of C3 and C4 annuals have changed through geologic time. This study also provided evidence that C3 annuals may be operating near a minimum CO2 partial pressure for growth and reproduction at 15 Pa CO2.

Effects of low and elevated CO2 on C3 and C4 annuals : II. Photosynthesis and leaf biochemistry.

Abutilon theophrasti (C3) and Amaranthus retroflexus (C4), were grown from seed at four partial pressures of CO2: 15 Pa (below Pleistocene minimum), 27 Pa (pre-industrial), 35 Pa (current), and 70 Pa (future) in the Duke Phytotron under high light, high nutrient, and wellwatered conditions to evaluate their photosynthetic response to historic and future levels of CO2. Net photosynthesis at growth CO2 partial pressures increased with increasing CO2 for C3 plants, but not C4 plants. Net photosynthesis of Abutilon at 15 Pa CO2 was 70% less than that of plants grown at 35 Pa CO2, due to greater stomatal and biochemical limitations at 15 Pa CO2. Relative stomatal limitation (RSL) of Abutilon at 15 Pa CO2 was nearly 3 times greater than at 35 Pa CO2. A photosynthesis model was used to estimate ribulose-1,5-bisphosphate carboxylase (rubisco) activity (Vcmax), electron transport mediated RuBP regeneration capacity (J max), and phosphate regeneration capacity (PiRC) in Abutilon from net photosynthesis versus intercellular CO2 (A-C i) curves. All three component processes decreased by approximately 25% in Abutilon grown at 15 Pa compared with 35 Pa CO2. Abutilon grown at 15 Pa CO2 had significant reductions in total rubisco activity (25%), rubisco content (30%), activation state (29%), chlorophyll content (39%), N content (32%), and starch content (68%) compared with plants grown at 35 Pa CO2. Greater allocation to rubisco relative to light reaction components and concomitant decreases in J max and PiRC suggest co-regulation of biochemical processes occurred in Abutilon grown at 15 Pa CO2. There were no significant differences in photosynthesis or leaf properties in Abutilon grown at 27 Pa CO2 compared with 35 Pa CO2, suggesting that the rise in CO2 since the beginning of the industrial age has had little effect on the photosynthetic performance of Abutilon. For Amaranthus, limitations of photosynthesis were balanced between stomatal and biochemical factors such that net photosynthesis was similar in all CO2 treatments. Differences in photosynthetic response to growth over a wide range of CO2 partial pressures suggest changes in the relative performance of C3 and C4 annuals as atmospheric CO2 has fluctuated over geologic time.

Phosphorus supply affects the photosynthetic capacity of loblolly pine grown in elevated carbon dioxide.

Effects of phosphorus supply and mycorrhizal status on the response of photosynthetic capacity to elevated CO(2) were investigated in loblolly pine (Pinus taeda L.) seedlings. Seedlings were grown in greenhouses maintained at either 35.5 or 71.0 Pa CO(2) in a full factorial experiment with or without mycorrhizal inoculum (Pisolithus tinctorius (Pers.) Coker & Couch) and with an adequate or a limiting supply of phosphorus. Assimilation versus internal CO(2) partial pressure (C(i)) curves were used to estimate maximum Rubisco activity (V(c,max)), electron transport mediated ribulose 1,5-bisphosphate regeneration capacity (J(max)), phosphate regeneration capacity (PiRC) and daytime respiration rates (R(d)). Nonmycorrhizal seedlings grown with limiting phosphorus had significantly reduced V(c,max) and PiRC compared to seedlings in other treatments. Elevated CO(2) increased photosynthetic capacity in nonmycorrhizal seedlings in the low phosphorus treatment by increasing PiRC, whereas it induced phosphorus limitation in mycorrhizal seedlings in the low phosphorus treatment and did not affect the photosynthetic capacity of seedlings in the high phosphorus treatment. Despite the variety of effects on photosynthetic capacity, seedlings in the elevated CO(2) treatments had higher net assimilation rates than seedlings in the ambient CO(2) treatments. We conclude that phosphorus supply affects photosynthetic capacity during long-term exposure to elevated CO(2) through effects on Rubisco activity and ribulose 1,5-bisphosphate regeneration rates.

The Quechua manta pouch: a caretaking practice for buffering the Peruvian infant against the multiple stressors of high altitude.

The manta pouch--a caretaking practice of tightly swaddling and enclosing the infant in a set of cloths and blankets--and other caretaking practices are described for high-altitude resident (> 4,000 m) Quechua mother-infant pairs (N = 14). The manta pouch modifies the microenvironment inside the pouch so that, compared to the ambient environment, the temperature is higher and more stable, the humidity is higher, the partial pressure of O2 is lower, and stimulation levels are reduced. As the infant gets older, the characteristics of the pouch are modified such that the infant is increasingly exposed to ambient conditions. These caretaking practices may benefit the infant by buffering the infant from the multiple ecological stressors of high altitude, but they may also incur costs by exposing the infant to additional microenvironmental stressors (e.g., higher CO2 levels) and by reducing stimulation and limiting infant movement.

Effects of leaf nutrient status on photosynthetic capacity in loblolly pine (Pinus taeda L.) seedlings grown in elevated atmospheric CO(2).

We measured needle photosynthesis of loblolly pine seedlings grown in a factorial experiment with two CO(2) partial pressures (35 and 65 Pa) and three nutrient treatments (7 mM NH(4)NO(3) + 1 mM PO(4); 7 mM NH(4)NO(3) + 0.2 mM PO(4); 1 mM NH(4)NO(3) + 1 mM PO(4)). The data were used to parameterize a physiologically based photosynthetic model that included limitations imposed by ribulose-1,5-bisphosphate carboxylase/oxygenase activity, electron transport capacity and inorganic phosphate availability. With nonlimiting nutrients, seedlings grown at 65 Pa CO(2) had significantly higher net photosynthesis and lower stomatal conductance than seedlings grown at 35 Pa CO(2). Nutrient limitations by either N or P significantly reduced photosynthetic capacity. When either N or P was limiting, there was no effect of growth CO(2) partial pressure on photosynthesis, but stomatal conductance was significantly lower for seedlings grown at 65 Pa CO(2). Modeled biochemical parameters suggest that, in all cases, photosynthesis was co-limited by carboxylation, electron transport and phosphate regeneration. Acclimation to growth in elevated CO(2) involved a reduction in leaf N content. In the low-N and low-P treatments, modeled parameters indicated that the biochemical processes of photosynthesis were down regulated to the point that there was no effect of increasing CO(2) partial pressure. The capacity to regenerate phosphate was reduced in both low nutrient treatments, but was only reduced by elevated CO(2) when seedlings were grown under low soil P conditions. Increased photosynthetic water use efficiency and nutrient use efficiency in response to CO(2) enrichment occurred in all three nutrient treatments and have important implications for whole-plant water and nutrient balance. These data support the contention that soil nutrient status in forest ecosystems will be a critical influence on tree seedling response to increasing atmospheric CO(2) partial pressures.

Direct and Indirect Effects of Atmospheric Carbon Dioxide Enrichment on Leaf Respiration of Glycine max (L.) Merr.

Long-term and short-term effects of CO2 enrichment on dark respiration were investigated using soybean (Glycine max [L.] Merr.) plants grown at either 35.5 or 71.0 Pa CO2. Indirect effects, or effects of growth in elevated CO2, were examined using a functional model that partitioned respiration into growth and maintenance components. Direct effects, or immediate effects of a short-term change in CO2, were examined by measuring dark respiration, first, at the CO2 partial pressure at which plants were grown, and second, after equilibration in the reciprocal CO2 partial pressure. The functional component model indicated that the maintenance coefficient of respiration increased 34% with elevated CO2, whereas the growth coefficient was not significantly affected. Changes in maintenance respiration were correlated with a 33% increase in leaf total nonstructural carbohydrate concentration, but leaf nitrogen content of soybean leaves was not affected by CO2 enrichment. Thus, increased maintenance respiration may be a consequence of increased nonstructural carbohydrate accumulation. When whole soybean plants were switched from low CO2 to high CO2 for a brief period, leaf respiration was always reduced. However, this direct effect of CO2 partial pressure was approximately 50% less in plants grown in elevated CO2. We conclude from this study that there are potentially important effects of CO2 enrichment on plant respiration but that the effects are different for plants given a short-term increase in CO2 partial pressure versus plants grown in elevated CO2.

Loblolly pine grown under elevated CO2 affects early instar pine sawfly performance.

Seedlings of loblolly pine Pinus taeda (L.), were grown in open-topped field chambers under three CO2 regimes: ambient, 150 µl l-1 CO2 above ambient, and 300 µl l-1 CO2 above ambient. A fourth, non-chambered ambient treatment was included to assess chamber effects. Needles were used in 96 h feeding trials to determine the performance of young, second instar larvae of loblolly pine's principal leaf herbivore, red-headed pine sawfly, Neodiprion lecontei (Fitch). The relative consumption rate of larvae significantly increased on plants grown under elevated CO2, and needles grown in the highest CO2 regime were consumed 21% more rapidly than needles grown in ambient CO2. Both the significant decline in leaf nitrogen content and the substantial increase in leaf starch content contributed to a significant increase in the starch:nitrogen ratio in plants grown in elevated CO2. Insect consumption rate was negatively related to leaf nitrogen content and positively related to the starch:nitrogen ratio. Of the four volatile leaf monoterpenes measured, only ß-pinene exhibited a significant CO2 effect and declined in plants grown in elevated CO2. Although consumption changed, the relative growth rates of larvae were not different among CO2 treatments. Despite lower nitrogen consumption rates by larvae feeding on the plants grown in elevated CO2, nitrogen accumulation rates were the same for all treatments due to a significant increase in nitrogen utilization efficiency. The ability of this insect to respond at an early, potentially susceptible larval stage to poorer food quality and declining levels of a leaf monoterpene suggest that changes in needle quality within pines in future elevated-CO2 atmospheres may not especially affect young insects and that tree-feeding sawflies may respond in a manner similar to herb-feeding lepidopterans.

Urine leukotriene E4 levels are elevated in patients with active systemic lupus erythematosus.

The peptidoleukotrienes, leukotriene (LT) C4 and its metabolites LTD4 and LTE4, cause diverse physiologic effects and have been implicated in several disease processes. A potential role for enhanced peptidoleukotriene synthesis in the pathogenesis of autoimmune disease in general and systemic lupus erythematosus (SLE) in particular has been suggested by animal studies. Therefore, we measured the urinary levels of LTE4 in patients with active and inactive SLE as well as in patients with rheumatoid arthritis (RA), scleroderma (Scl), and in healthy controls. Comparisons were made to other standard clinical tests in assessing individual patient disease activity. A marked increase in urinary LTE4 levels in patients with active SLE was noted (319 +/- 49 pg/mg creatinine, n = 20) relative to patients with inactive SLE (80 +/- 8 pg/mg creatinine, n = 7 [p less than 0.02]), patients with RA (86 +/- 8 pg/mg creatinine [p less than 0.01]), and healthy controls (68 +/- 4.3 pg/mg creatinine, n = 6 [p less than 0.01]). Patients with Scl also had elevated urinary LTE4 levels (188 +/- 33 pg/mg creatinine, n = 7) relative to controls (p less than 0.02), while values from patients with RA were not significantly different from controls. Using the Systemic Lupus Activity Measurement as a gauge of clinical activity, a rise in urinary LTE4 levels was noted during stages of active disease with a subsequent decline following the resolution of these symptoms. Our data indicate that increased synthesis of leukotrienes is associated with active SLE and Scl and suggest that these leukotrienes may mediate certain symptoms associated with these diseases.

Cutaneous fistulas to the vas deferens.

Cutaneous fistulas to the vas deferens are a rare occurrence. A careful review of the literature revealed only 16 cases reported within the last 70 years. We present a case of such a fistula occurring after inguinal orchiectomy for suppurative epididymo-orchitis and review the etiologies of all reported cases to provide recommendations for management.

Adenocarcinoma in a female urethral diverticulum.

Carcinoma occurring within a diverticulum of the female urethra is an exceedingly rare disease for which the treatment is ill-defined. We present here the first reported case of this condition from Australasia and review some of the recommendations for treatment.