Comparison of renal effects of ibuprofen versus indomethacin during treatment of patent ductus arteriosus in contiguous historical cohorts

Background

The study aimed to investigate the pharmacokinetics of intravenous ciprofloxacin and the adequacy of 400 mg every 12 hours in critically ill Intensive Care Unit (ICU) patients on continuous veno-venous haemodiafiltration (CVVHDF) with particular reference to the effect of achieved flow rates on drug clearance.

Methods

This was an open prospective study conducted in the intensive care unit and research unit of a university teaching hospital. The study population was seven critically ill patients with sepsis requiring CVVHDF. Blood and ultrafiltrate samples were collected and assayed for ciprofloxacin by High Performance Liquid Chromatography (HPLC) to calculate the model independent pharmacokinetic parameters; total body clearance (TBC), half-life (t_1/2) and volume of distribution (Vd). CVVHDF was performed at prescribed dialysate rates of 1 or 2 L/hr and ultrafiltration rate of 2 L/hr. The blood flow rate was 200 ml/min, achieved using a Gambro blood pump and Hospal AN69HF haemofilter.

Results

Seventeen profiles were obtained. CVVHDF resulted in a median ciprofloxacin t_1/2 of 13.8 (range 5.15-39.4) hr, median TBC of 9.90 (range 3.10-13.2) L/hr, a median V_dss of 125 (range 79.5-554) L, a CVVHDF clearance of 2.47+/-0.29 L/hr and a clearance of creatinine (Cl_cr) of 2.66+/-0.25 L/hr. Thus CVVHDF, at an average flow rate of ~3.5 L/hr, was responsible for removing 26% of ciprofloxacin cleared. At the dose rate of 400 mg every 12 hr, the median estimated C_pmax/MIC and AUC_0-24/MIC ratios were 10.3 and 161 respectively (for a MIC of 0.5 mg/L) and exceed the proposed criteria of >10 for C_pmax/MIC and > 100 for AUC_0-24/MIC. There was a suggestion towards increased ciprofloxacin clearance by CVVHDF with increasing effluent flow rate.

Conclusions

Given the growing microbial resistance to ciprofloxacin our results suggest that a dose rate of 400 mg every 12 hr, may be necessary to achieve the desired pharmacokinetic - pharmacodynamic (PK-PD) goals in patients on CVVHDF, however an extended interval may be required if there is concomitant hepatic impairment. A correlation between ciprofloxacin clearance due to CVVHDF and creatinine clearance by the filter was observed (r² = 0.76), providing a useful clinical surrogate marker for ciprofloxacin clearance within the range studied.

Trial Registration

Current Controlled Trials ISRCTN52722850     

The relative plasma availabilities of ivermectin in reindeer (<Emphasis Type="Italic">Rangifer tarandus tarandus</Emphasis>) following subcutaneous and two different oral formulation applications

Background

Overwintering (breeding) reindeer (Rangifer tarandus tarandus) are commonly treated with ivermectin against parasitic infestations once yearly in autumn-winter roundups. The only preparations registered to reindeer are those for subcutaneous injection. However, also oral extra-label ivermectin administration is used. Twenty-six, 8-month-old reindeer calves were randomly allocated into three groups. Group 1 (n = 9) received oral ivermectin mixture (Ivomec® vet mixt. 0.8 mg/ml, oral ovine liquid drench formulation), Group 2 (n = 9) oral ivermectin paste (Ivomec® vet 18.7 mg/g equine paste), and Group 3 (n = 8) subcutaneous injection of ivermectin (Ivomec® 10 mg/ml vet inj.), each group at a dose of 200 μg/kg body weight. Blood samples were collected at treatment and at days 1, 2, 3, 6, 9 and 16 post treatment. Plasma concentrations of ivermectin were determined by high-pressure liquid chromatography (HPLC) with fluorescence detection.

Results

The peak plasma concentration (C_max) was reached by 2 days after each treatment. The C_max and Area Under Curve (AUC) differed significantly between the groups: C_max was 30.2 ± 3.9, 14.9 ± 5.7 and 63.1 ± 13.1 ng/ml, and AUC_∞ was 2881 ± 462, 1299 ± 342 and 6718 ± 1620 ng*h/ml for groups 1, 2 and 3, respectively (mean ± standard deviation).

Conclusions

The differences in plasma concentrations of ivermectin are concomitant with earlier observed differences in antiparasitic efficacy, which discounts the use of the equine paste in reindeer in favour of the oral ovine liquid drench formulation, or preferably, the reindeer-registered subcutaneous injection formulation.

     

Canalization effect in the coagulation cascade and the interindividual variability of oral anticoagulant response. a simulation Study

Background

The aim of the study was to find a simple intravenous glucose tolerance test (IVGTT) that can be used to estimate insulin sensitivity.

Methods

In 20 healthy volunteers aged between 18 and 51 years (mean, 28) comparisons were made between kinetic parameters derived from a 12-sample, 75-min IVGTT and the M_bw (glucose uptake) obtained during a hyperinsulinemic euglycemic glucose clamp. Plasma glucose was used to calculate the volume of distribution (V _d) and the clearance (CL) of the injected glucose bolus. The plasma insulin response was quantified by the area under the curve (AUC_ins). Uptake of glucose during the clamp was corrected for body weight (M_bw).

Results

There was a 7-fold variation in M_bw. Algorithms based on the slope of the glucose-elimination curve (CL/V _d) in combination with AUC_ins obtained during the IVGTT showed statistically significant correlations with M_bw, the linearity being r² = 0.63-0.83. The best algorithms were associated with a 25-75^th prediction error ranging from -10% to +10%. Sampling could be shortened to 30-40 min without loss of linearity or precision.

Conclusion

Simple measures of glucose and insulin kinetics during an IVGTT can predict between 2/3 and 4/5 of the insulin sensitivity.     

Pharmacokinetic profile of a 24-hour controlled-release OROS<Superscript>®</Superscript> formulation of hydromorphone in the presence and absence of food

Background

The objective of this study was to compare the pharmacokinetic profile of a novel, once-daily, controlled-release formulation of hydromorphone (OROS^® hydromorphone) under fasting conditions with that immediately after a high-fat breakfast in healthy volunteers. The effect of the opioid antagonist naltrexone on fasting hydromorphone pharmacokinetics also was evaluated.

Methods

In an open-label, three-way, crossover study, 30 healthy volunteers were randomized to receive a single dose of 16 mg OROS^® hydromorphone under fasting conditions, 16 mg OROS^® hydromorphone under fed conditions, or 16 mg OROS^® hydromorphone under fasting conditions with a naltrexone 50-mg block. Plasma samples taken pre-dose and at regular intervals up to 48 hours post-dose were assayed for hydromorphone concentrations. Analysis of variance was performed on log-transformed data; for mean ratios of 0.8 to 1.2 (20%), differences were considered minimal. Bioequivalence was reached if 90% confidence intervals (CI) of treatment mean ratios were between 80% and 125%.

Results

The mean geometric ratios of the fed and fasting treatment groups for maximum plasma concentration (C_max) and area under the concentration-time curve (AUC_0-t; AUC_0-∞) were within 20%. Confidence intervals were within 80% to 125% for AUC_0-t and AUC_0-∞ but were slightly higher for C_max (105.9% and 133.3%, respectively). With naltrexone block, the hydromorphone C_max increased by 39% and the terminal half-life decreased by 4.5 hours. There was no significant change in T_max, AUC_0-t or AUC_0-∞.

Conclusion

Standard bioavailability measures show minimal effect of food on the bioavailability of hydromorphone from OROS^® hydromorphone. Naltrexone co-administration results in a slight increase in the rate of absorption but not the extent of absorption.

Trial Registration

Clinical Trials.gov NCT00399295

     

Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors

Background

Inhibition of AKT with MK-2206 has demonstrated synergism with anticancer agents. This phase 1 study assessed the MTD, DLTs, PK, and efficacy of MK-2206 in combination with cytotoxic and targeted therapies.

Methods

Advanced solid tumor patients received oral MK-2206 45 or 60 mg (QOD) with either carboplatin (AUC 6.0) and paclitaxel 200 mg/m² (arm 1), docetaxel 75 mg/m² (arm 2), or erlotinib 100 or 150 mg daily (arm 3); alternative schedules of MK-2206 135-200 mg QW or 90-250 mg Q3W were also tested.

Results

MTD of MK-2206 (N?=?72) was 45 mg QOD or 200 mg Q3W (arm 1); MAD was 200 mg Q3W (arm 2) and 135 mg QW (arm 3). DLTs included skin rash (arms 1, 3), febrile neutropenia (QOD, arms 1, 2), tinnitus (Q3W, arm 2), and stomatitis (QOD, arm 3). Common drug-related toxicities included fatigue (68%), nausea (49%), and rash (47%). Two patients with squamous cell carcinoma of the head and neck (arm 1; Q3W) demonstrated a complete and partial response (PR); additional PRs were observed in patients (1 each) with melanoma, endometrial, neuroendocrine prostate, NSCLC, and cervical cancers. Six patients had stable disease ≥6 months.

Conclusion

MK-2206 plus carboplatin and paclitaxel, docetaxel, or erlotinib was well-tolerated, with early evidence of antitumor activity.

Trial registration

ClinicalTrials.gov: NCT00848718.     

Pharmacokinetic investigation of dose proportionality with a 24-hour controlled-release formulation of hydromorphone

Background

The purpose of this study was investigate the dose proportionality of a novel, once-daily, controlled-release formulation of hydromorphone that utilizes the OROS^® Push-Pull? osmotic pump technology.

Methods

In an open-label, four-way, crossover study, 32 healthy volunteers were randomized to receive a single dose of OROS^® hydromorphone 8, 16, 32, and 64 mg, with a 7-day washout period between treatments. Opioid antagonism was provided by three or four doses of naltrexone 50 mg, given at 12-hour intervals pre- and post-OROS^® hydromorphone dosing. Plasma samples for pharmacokinetic analysis were collected pre-dose and at regular intervals up to 48 hours post-dose (72 hours for the 64-mg dose), and were assayed for hydromorphone concentration to determine peak plasma concentration (C_max), time at which peak plasma concentration was observed (T_max), terminal half-life (t_1/2), and area under the concentration-time curve for zero to time t (AUC_0-t) and zero to infinity (AUC_0–∞). An analysis of variance (ANOVA) model on untransformed and dose-normalized data for AUC_0-t, AUC_0–∞, and C_max was used to establish dose linearity and proportionality.

Results

The study was completed by 31 of 32 subjects. Median T_max (12.0–16.0 hours) and mean t_1/2 (10.6–11.0 hours) were found to be independent of dose. Regression analyses of C_max, AUC_0–48, and AUC_0–∞ by dose indicated that the relationship was linear (slope, P ≤ 0.05) and that the intercept did not differ significantly from zero (P > 0.05). Similar analyses with dose-normalized parameters also indicated that the slope did not differ significantly from zero (P > 0.05).

Conclusion

The pharmacokinetics of OROS^® hydromorphone are linear and dose proportional for the 8, 16, 32, and 64 mg doses.

Trial Registration

Clinical Trials.gov NCT00398957

     

Investigation of the diurnal variation in bone resorption for optimal drug delivery and efficacy in osteoporosis with oral calcitonin

Background  

Bone resorption displays marked diurnal variation. Reversible inhibition of bone resorption may result in best possible efficacy when bone resorption peaks. The aim of the study was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of 0.8 mg of oral salmon calcitonin (sCT) and the effect of timing of drug intake.     

Steady State Bioequivalence of Generic and Innovator Formulations of Stavudine,Lamivudine, and Nevirapine in HIV-Infected Ugandan Adults

Background

Generic antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and brand name formulations. We compared the steady-state pharmacokinetics of lamivudine, stavudine and nevirapine in HIV-infected subjects who were receiving a generic formulation (Triomune®) or the corresponding brand formulations (Epivir®, Zerit®, and Viramune®).

Methodology/Principal Findings

An open-label, randomized, crossover study was carried out in 18 HIV-infected Ugandan subjects stabilized on Triomune-40. Subjects received lamivudine (150 mg), stavudine (40 mg), and nevirapine (200 mg) in either the generic or brand formulation twice a day for 30 days, before switching to the other formulation. At the end of each treatment period, blood samples were collected over 12 h for pharmacokinetic analysis. The main outcome measures were the mean AUC_0–12h and C_max. Bioequivalence was defined as a geometric mean ratio between the generic and brand name within the 90% confidence interval of 0.8–1.25. The geometric mean ratios and the 90% confidence intervals were: stavudine C_max, 1.3 (0.99–1.71) and AUC_0–12h, 1.1 (0.87–1.38); lamivudine C_max, 0.8 (0.63–0.98) and AUC_0–12h, 0.8 (0.65–0.99); and nevirapine C_max, 1.1 (0.95–1.23) and AUC_0–12h, 1.1 (0.95–1.31). The generic formulation was not statistically bioequivalent to the brand formulations during steady state, although exposures were comparable. A mixed random effects model identified about 50% intersubject variability in the pharmacokinetic parameters.

Conclusions/Significant Findings

These findings provide support for the use of Triomune in resource-limited settings, although identification of the sources of intersubject variability in these populations is critical.     

Nitrogen application enhanced the expression of developmental plasticity of root systems triggered by mild drought stress in rice

Background

The promoted root growth under developmental plasticity triggered specifically by mild drought stress (MDS) is known to contribute to maintained water uptake and dry matter production (DMP).

Aims

To examine whether the expression of developmental plasticity of root systems and its contribution to DMP would be affected by the levels of nitrogen (N) application.

Methods

Two genotypes (CSSL50 derived from Nipponbare/Kasalath cross and Nipponbare) were grown under soil moisture gradients with a line source sprinkler system. Three N fertilizer treatments were used; 25 (low), 75 (standard) and 150 kg N ha^?1 (high) in 2009 and 60 (low), 120 (standard) and 180 kg N ha^?1 (high) in 2011.

Results

Across varying N level treatments, there were no significant differences in any of the traits examined between the two genotypes under well-watered and severe drought stress conditions. In contrast, under MDS conditions (15–25 % w/w of soil moisture content (SMC) in 2009 and 17–25 % w/w of SMC in 2011), CSSL50 showed greater DMP than Nipponbare. The difference, however, varied with N level treatments since CSSL50’s greater root system development under MDS, was more pronounced at standard and high N levels than at low N level than it was for Nipponbare.

Conclusions

N application enhanced the expression of plasticity in root system development at standard and high N levels as compared with low N level under MDS conditions, which contributed to the maintenance of DMP.     

Dissociation by steroids of eosinophilic inflammation from airway hyperresponsiveness in murine airways

Background

The link between eosinophils and the development of airway hyperresponsiveness (AHR) in asthma is still controversial. This question was assessed in a murine model of asthma in which we performed a dose ranging study to establish whether the dose of steroid needed to inhibit the eosinophil infiltration correlated with that needed to block AHR.

Methods

The sensitised BALB/c mice were dosed with vehicle or dexamethasone (0.01–3 mg/kg) 2 hours before and 6 hours after each challenge (once daily for 6 days) and 2 hours before AHR determination by whole-body plethysmography. At 30 minutes after the AHR to aerosolised methacholine the mice were lavaged and differential white cell counts were determined. Challenging with antigen caused a significant increase in eosinophils in the bronchoalveolar lavage (BAL) fluid and lung tissue, and increased AHR.

Results

Dexamethasone reduced BAL and lung tissue eosinophilia (ED₅₀ values of 0.06 and 0.08 mg/kg, respectively), whereas a higher dose was needed to block AHR (ED₅₀ of 0.32 mg/kg at 3 mg/ml methacholine. Dissociation was observed between the dose of steroid needed to affect AHR in comparison with eosinophilia and suggests that AHR is not a direct consequence of eosinophilia.

Conclusion

This novel pharmacological approach has revealed a clear dissociation between eosinophilia and AHR by using steroids that are the mainstay of asthma therapy. These data suggest that eosinophilia is not associated with AHR and questions the rationale that many pharmaceutical companies are adopting in developing low-molecular-mass compounds that target eosinophil activation/recruitment for the treatment of asthma.     

Acute ST-segment elevation myocardial infarction after amoxycillin-induced anaphylactic shock in a young adult with normal coronary arteries: a case report

Background

Sirolimus-eluting stents (CYPHER stents) demonstrated remarkable efficacy in reducing restenosis rates in patients with coronary artery disease. There is a concern of sub-acute and late stent thrombosis. Tissue factor (TF) is critical in thrombosis. This study investigated the effect of sirolimus on TF expression and activity in cultured human vascular smooth muscle cells (SMCs).

Methods

SMCs were cultured from human saphenous veins and aortas. Quiescent cells were stimulated with sirolimus (0.1 – 20 ng/ml) over 24 hours. Cellular TF expression and activity released into culture medium were measured. The effect of sirolimus on activation of mammalian target of rapamycin (mTOR) was measured by phosphorylation of the substrate p70s6k at T389, and activation of RhoA was measured by pull-down assay.

Results

Sirolimus increased TF protein level in cultured human SMCs in a concentration and time-dependent manner (about 2-fold, p < 0.01) reaching maximal effect at 5 ng/ml. The stimulation of TF expression by sirolimus was associated with inhibition of basal activity of mTOR. No effects of sirolimus on RhoA or p38mapk activation that are positive regulators of TF in vascular wall cells were observed. The stimulation of TF expression by sirolimus (20 ng/ml) was prevented by the HMG-CoA reductase inhibitor fluvastatin (1 μmol/L). However, no increase in TF activity released from SMC into culture medium was observed after sirolimus treatment.

Conclusion

Although sirolimus stimulates TF protein expression in human SMC associated with inhibition of mTOR, it does not enhance TF activity released from the cells, suggesting a relatively safe profile of CYPHER stents. The inhibition of TF expression by fluvastatin favors clinical use of statins in patients undergoing coronary stenting.     

No relevant cardiac, pharmacokinetic or safety interactions between roflumilast and inhaled formoterol in healthy subjects: an open-label, randomised, actively controlled study

Background

Roflumilast is an oral, selective phosphodiesterase 4 inhibitor with anti-inflammatory effects in chronic obstructive pulmonary disease (COPD). The addition of roflumilast to long-acting bronchodilators improves lung function in patients with moderate-to-severe COPD. The present study investigated drug-drug interaction effects between inhaled formoterol and oral roflumilast.

Methods

This was a single-centre (investigational clinic), open, randomised, multiple-dose, parallel-group study. In Regimen A, healthy men were treated with roflumilast (500 μg tablet once daily; Day 2-18) and concomitant formoterol (24 μg twice daily; Day 12-18). In Regimen B, healthy men were treated with formoterol (24 μg twice daily; Day 2-18) and concomitant roflumilast (500 μg once daily; Day 9-18). Steady-state plasma pharmacokinetics of roflumilast, roflumilast N-oxide and/or formoterol (C_max and AUC_0-τ) as well as pharmacodynamics - blood pressure, transthoracic impedance cardiography (ZCG), 12-lead digital electrocardiography, peripheral blood eosinophils, and serum glucose and potassium concentrations - were evaluated through Day 1 (baseline), Day 8 (Regimen B: formoterol alone) or Day 11 (Regimen A: roflumilast alone), and Day 18 (Regimen A and B: roflumilast plus formoterol). Blood and urine samples were taken for safety assessment at screening, pharmacokinetic profiling days and Day 19. Adverse events were monitored throughout the study.

Results

Of the 27 subjects enrolled, 24 were evaluable (12 in each regimen). No relevant pharmacokinetic interactions occurred. Neither roflumilast nor formoterol were associated with significant changes in cardiovascular parameters as measured by ZCG, and these parameters were not affected during concomitant administration. Formoterol was associated with a slight increase in heart rate and a corresponding shortening of the QT interval, without changes in the heart rate-corrected QTc interval. There were small effects on the other pharmacodynamic assessments when roflumilast and formoterol were administered individually, but no interactions or safety concerns were seen after concomitant administration. No severe or serious adverse events were reported, and no adverse events led to premature study discontinuation.

Conclusions

No clinically relevant pharmacokinetic or pharmacodynamic interactions were found when oral roflumilast was administered concomitantly with inhaled formoterol, including no effect on cardiac repolarisation. Roflumilast was well tolerated.

Trial Registration

Clinicaltrials.gov NCT00940329     

Catesbeianin-1, a novel antimicrobial peptide isolated from the skin of <Emphasis Type="Italic">Lithobates catesbeianus</Emphasis> (American bullfrog)

Objectives

To identify and characterize a novel antimicrobial peptide, catesbeianin-1.

Results

Catesbeianin-1 is 25 amino acids long and is α-helical, cationic and amphipathic. It had antimicrobial activity against Gram-positive and Gram-negative bacteria. It was resistant against trypsin and pepsin. Catesbeianin-1 exhibited moderate hemolytic activity (approx 8%) at 100 μg/ml, and its HC₅₀ (50% hemolytic concentration) was 300 μg/ml. Its cytotoxicity was approx 10–20% at 100 μg/ml, and its CC₅₀ (50% cytotoxic concentration) was >100 μg/ml. The LD₅₀ of catesbeianin-1 in mice was 80 mg/kg. At 3.1 µg/ml, catesbeianin-1 significantly inhibited the growth of methicillin-resistant Staphylococcus aureus.

Conclusions

A new antimicrobial peptide from the skin of Lithobates catesbeianus (American bullfrog) may represent a template for the development of novel antimicrobial agents.

     

The role of aldosterone blockade in murine lupus nephritis

Background

The purpose of this study was to examine the effect of aldosterone receptor blockade on the immunopathogenesis and progression of nephritis in the (NZB × NZW) F₁ murine lupus model.

Methods

Female NZB/W F₁ mice (11 weeks old) were treated daily with 25 or 50 mg/kg oral spironolactone or vehicle. Proteinuria, renal function, and serum autoantibody levels were monitored. Renal histopathology, immune complex deposition, and immunohistochemistry were analyzed at various time points. Targeted microarray analysis was performed on renal tissue, with subsequent real-time PCR analysis of several differentially expressed genes.

Results

Treatment with spironolactone was well tolerated by the mice throughout the course of their disease progression, with no significant differences in azotemia or serum potassium levels between vehicle-treated and spironolactone-treated animals. By 36 weeks of age, fewer spironolactone-treated mice developed nephrotic range proteinuria as compared with the control mice (control 70.8%, 25 mg/kg spironolactone 51.3%, and 50 mg/kg spironolactone 48.6%). Compared with control mice, mice treated with 25 mg/kg spironolactone had significantly lower serum anti-single-stranded DNA levels (2,042 μg/ml versus 1,036 μg/ml; P = 0.03) and anti-double-stranded DNA levels (3,433 μg/ml versus 614 μg/ml; P = 0.05). Spironolactone-treated mice exhibited decreased histopathologic evidence of inflammation and tissue damage, as compared with control mice. Additionally, spironolactone treatment resulted in decreased expression in the kidney of several inflammatory and proapoptotic genes, including those encoding interferon-γ, B lymphocyte stimulator (BlyS), tumor necrosis factor related apoptosis inducing ligand (TRAIL), tumor necrosis factor related weak inducer of apoptosis (TWEAK), and Fas ligand.

Conclusion

Aldosterone receptor blockade is safe and well tolerated in progressive murine lupus nephritis, and it results in decreased levels of clinical proteinuria, lower serum levels of autoantibodies, and decreased kidney damage. It appears to modulate inflammatory changes during the progression of glomerulonephritis and may also have a previously undescribed role in attenuating apoptosis     

Comparing the feasibility, acceptability, clinical-, and cost-effectiveness of mental health e-screening to paper-based screening on the detection of depression, anxiety, and psychosocial risk in pregnant women: a study protocol of a randomized, parallel-group, superiority trial

Background

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20% to 25% of paediatric uveitis is associated with JIA. Major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity. In the initial stages of mild to moderate inflammation the uveitis is asymptomatic. This has led to current practice of screening all children with JIA for uveitis. Approximately 12% to 38% of patients with JIA develop uveitis in seven years following onset of arthritis. In 30% to 50% of children with JIA-associated uveitis structural complications are present at diagnosis. Furthermore about 50% to 75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract and glaucoma. Defining the severity of inflammation and structural complications in uveitis patients is now possible following Standardised Uveitis Nomenclature (SUN) guidelines, and modified to incorporate the consensus of end point and outcome criteria into the design of randomised trials. Despite current screening and therapeutic options (pre-biologics) 10% to 15% of children with JIA-associated uveitis may develop bilateral visual impairment and certified legally blind. To date, there remains no controlled trial evidence of benefits of biologic therapy.

Methods/design

This study will randomise 154 patients aged 2 to 18 years with active JIA-associated uveitis (despite methotrexate (MTX) treatment for at least 12 weeks). All participants will be treated for 18 months, with follow up of 3 years from randomisation (continuing on MTX throughout). All participants will receive a stable dose of MTX and in addition either adalimumab (20 mg/0.8 ml for patients <30 kg or 40 mg/0.8 ml for patients weighing 30 kg or more, subcutaneous (s/c) injection every 2 weeks based on body weight), or placebo (0.8 ml as appropriate according to body weight) s/c injection every 2 weeks.

Discussion

This is the first randomised controlled trial that will assess the clinical effectiveness, safety and cost effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis.

Trial registration

ISRCTN10065623     

Molecular epidemiology of hepatitis E virus infections in Shanghai, China

Background

Avian origin canine influenza virus was reported in Korea. The dog to dog contact transmission of the avian origin canine influenza virus (CIV) H3N2 and CIV H3N8 was shown by experimental contact transmission. This study was focused on viral excretion and fever in order to elucidate the epidemiological associations which might be helpful to control the disease transmissions in CIV outbreak in dogs.

Methods

An influenza seronegative 10-week-old Beagle dog was experimentally inoculated with the canine influenza virus A/canine/01/2007, subtype H3N2. Eight hours after inoculation, the infected dog was cohoused with seven uninfected Beagle dogs. Clinical signs including fever were recorded for 14 days post inoculation.

Results

The infected dog and four of seven contact dogs in the study showed clinical signs (sneezing, nasal discharge and coughing) during the study. Viral shedding occurred in all of the animals tested and began on 1 to 6 DPI in dogs with clinical signs. Elevated body temperatures above 39.5°C (geometric mean temperature of 39.86°C±0.49) were observed in all symptomatic dogs. The mean viral titer during fever was 2.99 log EID₅₀/ml, which was significantly higher than the viral titer detected in the non fever.

Conclusions

The data show that contact dogs with a canine influenza infected dog shed different levels of virus in their nasal excretions and demonstrate that clinical signs, including fever, significantly correlate with the viral shedding.     

Phenotypic seedling responses of a metal-tolerant mutant line of sunflower growing on a Cu-contaminated soil series: potential uses for biomonitoring of Cu exposure and phytoremediation

Background and aims

The potential use of a metal-tolerant sunflower mutant line for both biomonitoring and phytoremediating a Cu-contaminated soil series was investigated.

Methods

The soil series (21–1,170 mg Cu kg^?1) was sampled in field plots at control and wood preservation sites. Sunflowers were cultivated 1 month in potted soils under controlled conditions.

Results

pH and dissolved organic matter influenced Cu concentration in the soil pore water. Leaf chlorophyll content and root growth decreased as Cu exposure rose. Their EC₁₀ values corresponded to 104 and 118 μg Cu L^?1 in the soil pore water, 138 and 155 mg Cu kg^?1 for total soil Cu, and 16–18 mg Cu kg^?1 DW shoot. Biomass of plant organs as well as leaf area, length and asymmetry were well correlated with Cu exposure, contrary to the maximum stem height and leaf water content.

Conclusions

Physiological parameters were more sensitive to soil Cu exposure than the morphological ones. Bioconcentration and translocation factors and distribution of mineral masses for Cu highlighted this mutant as a secondary Cu accumulator. Free Cu²⁺ concentration in soil pore water best predicted Cu phytoavailability. The usefulness of this sunflower mutant line for biomonitoring and Cu phytoextraction was discussed.     

Oxidation and reduction of sulfite contribute to susceptibility and detoxification of SO2 in Populus × canescens leaves

Key Message

The critical level for SO ₂ susceptibility of Populus × canescens is approximately 1.2 μL L ^?1 SO ₂ . Both sulfite oxidation and sulfite reduction and assimilation contribute to SO ₂ detoxification.

Abstract

In the present study, uptake, susceptibility and metabolism of SO₂ were analyzed in the deciduous tree species poplar (Populus × canescens). A particular focus was on the significance of sulfite oxidase (SO) for sulfite detoxification, as SO has been characterized as a safety valve for SO₂ detoxification in herbaceous plants. For this purpose, poplar plants were exposed to different levels of SO₂ (0.65, 0.8, 1.0, 1.2 μL L^?1) and were characterized by visible injuries and at the physiological level. Gas exchange parameters (stomatal conductance for water vapor, CO₂ assimilation, SO₂ uptake) of the shoots were compared with metabolite levels (sulfate, thiols) and enzyme activities [SO, adenosine 5′-phosphosulfate reductase (APR)] in expanding leaves (80–90 % expanded). The critical dosage of SO₂ that confers injury to the leaves was 1.2 μL L^?1 SO₂. The observed increase in sulfur containing compounds (sulfate and thiols) in the expanding leaves strongly correlated with total SO₂ uptake of the plant shoot, whereas SO₂ uptake rate was strongly correlated with stomatal conductance for water vapor. Furthermore, exposure to high concentration of SO₂ revealed channeling of sulfite through assimilatory sulfate reduction that contributes in addition to SO-mediated sulfite oxidation to sulfite detoxification in expanding leaves of this woody plant species.     

Airway cellularity, lipid laden macrophages and microbiology of gastric juice and airways in children with reflux oesophagitis

Background and methods

Human metapneumovirus (hMPV) is a recently discovered respiratory virus associated with bronchiolitis, pneumonia, croup and exacerbations of asthma. Since respiratory viruses are frequently detected in patients with acute exacerbations of COPD (AE-COPD) it was our aim to investigate the frequency of hMPV detection in a prospective cohort of hospitalized patients with AE-COPD compared to patients with stable COPD and to smokers without by means of quantitative real-time RT-PCR.

Results

We analysed nasal lavage and induced sputum of 130 patients with AE-COPD, 65 patients with stable COPD and 34 smokers without COPD. HMPV was detected in 3/130 (2.3%) AE-COPD patients with a mean of 6.5 × 10⁵ viral copies/ml in nasal lavage and 1.88 × 10⁵ viral copies/ml in induced sputum. It was not found in patients with stable COPD or smokers without COPD.

Conclusion

HMPV is only found in a very small number of patients with AE-COPD. However it should be considered as a further possible viral trigger of AE-COPD because asymptomatic carriage is unlikely.     

Mode of competition for light and water amongst juvenile beech and spruce trees under ambient and elevated levels of O3 and CO2

Key message

Our study provides evidence that neither elevated CO ₂ nor elevated O ₃ alters the positive asymmetric competition for light and the symmetric competition for water among beech and spruce individuals grown in monoculture. We conclude that the mechanism of competition (i.e. symmetric/asymmetric) above (e.g shading or overtopping effect) and belowground (e.g. non-preemption or foraging) rather than abiotic treatments such as elevated CO ₂ , O ₃ and CO ₂ /O ₃ regimes, plays a dominant role for ensuring competitive success among tree saplings.

Abstract

Despite numerous studies conducted on plant responses to increasing CO₂ and O₃ concentrations, there is still a gap in understanding on how these gasses would affect the mode of competition (e.g., the ability by which larger and smaller plants capture resources) at the individual level of intra-specific beech and spruce saplings. Using empirical data and simulations from the plant-growth model PLATHO, we analyzed underlying mechanisms of competition and extrapolated effects beyond the time span of the experiment. We hypothesized that among juvenile beech and spruce trees planted in monoculture, +CO₂ would diminish the positive asymmetric competition for light. Conversely, +O₃ would enhance this outcome. In addition, we hypothesized that the symmetric mode of competition belowground for water would remain unchanged, irrespective of +CO₂ and/or +O₃ treatments. Our results showed that +CO₂ and/or +O₃ treatments did not alter the mode of competition aboveground for light. Conversely, we accepted our hypothesis that the mode of competition for water would remain unchanged under both treatments. Overall, we conclude that neither +CO₂ nor +O₃ alters the positive asymmetric competition for light and the symmetric competition for water among beech and spruce individuals grown in monoculture. We further conclude that competitive mechanism above (e.g., shading or overtopping effect) and belowground (e.g., non-preemption or foraging) rather than abiotic treatments, such as elevated CO₂, O₃ and CO₂/O₃ regimes, plays a dominant role for ensuring competitive success among tree saplings.