Access Matting Reduces Mixedgrass Prairie Soil and Vegetation Responses to Industrial Disturbance.

Substantial interest exists in understanding the role of low-disturbance construction methods in mitigating industrial impacts to native grassland soils and vegetation. We assessed soil and vegetation responses to conventional high-disturbance sod-stripping and revegetation on sandy soils, and the alternative practice of low-disturbance access matting to provide a temporary work surface on sandy and loamy soils. Treatments were associated with high-voltage transmission tower construction during 2014 within the Mixedgrass Prairie. High-disturbance sites were hydroseeded in May of 2015, while low-disturbance sites recovered naturally. We assessed soil physical (bulk density, water infiltration) and chemical properties (organic matter, pH, and electrical conductivity) after construction and herbage biomass for three growing seasons. Sod-stripping led to 53% greater soil bulk density and 51% less organic matter than nondisturbed controls, while water infiltration increased by 32% in these high-sand (>80%) soils. In contrast, access matting led to minimal soil property changes regardless of the texture. While total herbage biomass was unaffected by all construction treatments, sod-stripping reduced grass biomass by 80% during the first growing season, which coincided with a 119% increase in forb mass. Root biomass (0-15 cm) also declined 77% with sod-stripping. Vegetation biomass on sites with access matting remained largely unaffected by the disturbance. Overall, low-disturbance construction methods using access matting were more effective than sod-stripping in mitigating the negative impacts of industrial development on Mixedgrass soil properties, as well as vegetation biomass, and are recommended as a best management practice during industrial disturbance.

Sampling and inactivation of wet disseminated spores from flooring materials, using commercially available robotic vacuum cleaners.

AIMS: Four commercially available robotic vacuum cleaners were assessed for sampling efficiency of wet disseminated Bacillus atrophaeus spores on carpet, polyvinyl chloride (PVC) and laminate flooring. Furthermore, their operability was evaluated and decontamination efficiency of one robot was assessed, using a sodium hypochlorite solution. METHODS AND RESULTS: In an environmental chamber, robots self-navigated around 4 m2 of flooring containing a single contaminated 0·25 m2 tile (c. 104 spores per cm2 ). Contamination levels at predetermined locations were assessed by macrofoam swabs (PVC and laminate) or water soluble tape (carpet), before and after sampling. Robots were dismantled postsampling and spore recoveries assessed. Aerosol contamination was also measured during sampling. Robot sampling efficiencies were variable, however, robots recovered most spores from laminate (up to 17·1%), then PVC and lastly the carpet. All robots spread contamination from the 'hotspot' (all robots spread <0·6% of the contamination to other areas) and became surface contaminated. Spores were detected at low levels during air sampling (<5·6 spores per litre). Liquid decontamination inactivated 99·1% of spores from PVC. CONCLUSIONS: Robotic vacuum cleaners show promise for both sampling and initial decontamination of indoor flooring. SIGNIFICANCE AND IMPACT OF THE STUDY: In the event of a bioterror incident, e.g. deliberate release of Bacillus anthracis spores, areas require sampling to determine the magnitude and extent of contamination, and to establish decontamination efficacy. In this study, we investigate robotic sampling methods against high concentrations of bacterial spores applied by wet deposition to different floorings, contamination spread to other areas, potential transfer of spores to the operators and assessment of a wet vacuum robot for spore inactivation. The robots' usability was evaluated and how they can be employed in real life scenarios. This will help to reduce the economic cost of sampling and the risk to sampling/decontamination teams.

Ketoprofen pharmacokinetics of R- and S-isomers in juvenile loggerhead sea turtles (Caretta caretta) after single intravenous and single- and multidose intramuscular administration.

Ketoprofen is a nonsteroidal anti-inflammatory and analgesic agent that nonselectively inhibits cyclooxygenase, with both COX-1 and COX-2 inhibition. Recent studies on COX receptor expression in reptiles suggest that nonselective COX inhibitors may be more appropriate than more selective inhibitors in some reptiles, but few pharmacokinetic studies are available. The goal of this study was to determine single- and multidose (three consecutive days) pharmacokinetics of racemic ketoprofen administered intravenously and intramuscularly at 2 mg/kg in healthy juvenile loggerhead turtles (Caretta caretta). The S-isomer is the predominant isomer in loggerhead sea turtles, similar to most mammals, despite administration of a 50:50 racemic mixture. Multidose ketoprofen administration demonstrated no bioaccumulation; therefore, once-daily dosing will not require dose adjustment over time. S-isomer pharmacokinetic parameters determined in this study were Cmax of 10.1 µg/ml by IM injection, C0 of 13.4 µg/ml by IV injection, AUC of 44.7 or 69.4 µg*hr/ml by IM or IV injection, respectively, and T½ of 2.8 or 3.6 hr by IM or IV injection, respectively. Total ketoprofen plasma concentrations were maintained for at least 12 hr above concentrations determined to be effective for rats and humans. A dose of 2 mg/kg either IM or IV every 24 hr is likely appropriate for loggerhead turtles.

Induced defences alter the strength and direction of natural selection on reproductive traits in common milkweed.

Evolutionary biologists have long sought to understand the ecological processes that generate plant reproductive diversity. Recent evidence indicates that constitutive antiherbivore defences can alter natural selection on reproductive traits, but it is unclear whether induced defences will have the same effect and whether reduced foliar damage in defended plants is the cause of this pattern. In a factorial field experiment using common milkweed, Asclepias syriaca L., we induced plant defences using jasmonic acid (JA) and imposed foliar damage using scissors. We found that JA-induced plants experienced selection for more inflorescences that were smaller in size (fewer flowers), whereas control plants only experienced a trend towards selection for larger inflorescences (more flowers); all effects were independent of foliar damage. Our results demonstrate that induced defences can alter both the strength and direction of selection on reproductive traits, and suggest that antiherbivore defences may promote the evolution of plant reproductive diversity.

Impact of empiric weight-based vancomycin dosing on nephrotoxicity and mortality in geriatric patients with methicillin-resistant Staphylococcus aureus bacteraemia.

WHAT IS KNOWN AND OBJECTIVE: Few studies have evaluated the effect of vancomycin dosing on the health outcomes in geriatric patients. Data are needed to determine whether higher vancomycin dosing strategies are more effective in geriatric patients and/or lead to excessive rates of adverse events. METHODS: This study used a subset of patients aged ≥65 years from a multicentre, retrospective, cohort study of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia. Patients received ≥ 48 h of empiric vancomycin between 1 July 2002 and 30 June 2008. We compared the incidence of nephrotoxicity and in-hospital mortality in patients who received guideline-recommended dosing (at least 15 mg/kg/dose) to patients who received lower dosing. Multivariable generalized mixed-effect models were constructed to determine independent risk factors for nephrotoxicity and in-hospital mortality. RESULTS AND DISCUSSION: Half of the cohort (46% of 92 patients) received guideline-recommended dosing. Empiric use of weight-based dosing did increase the percentage of patients achieving a vancomycin trough ≥ 15 mg/L (57% vs. 42%). Nephrotoxicity occurred in 32% of patients and 26% died during their hospitalization. Guideline-recommended dosing was not associated with significant changes in nephrotoxicity (OR 1·13; 95% CI 0·40-3·19) or in-hospital mortality (OR 1·14; 95% CI 0·41-3·18) in the multivariable analysis. WHAT IS NEW AND CONCLUSION: In this study of geriatric patients, guideline-recommended dosing was not associated with significant changes in nephrotoxicity or mortality. As 40% of the patients who received guideline-recommended dosing failed to achieve a target vancomycin trough of ≥ 15 mg/L, future studies should focus on dosing strategies to increase target attainment rate.

Microbial processes in the Athabasca Oil Sands and their potential applications in microbial enhanced oil recovery.

The Athabasca Oil Sands are located within the Western Canadian Sedimentary Basin, which covers over 140,200 km(2) of land in Alberta, Canada. The oil sands provide a unique environment for bacteria as a result of the stressors of low water availability and high hydrocarbon concentrations. Understanding the mechanisms bacteria use to tolerate these stresses may aid in our understanding of how hydrocarbon degradation has occurred over geological time, and how these processes and related tolerance mechanisms may be used in biotechnology applications such as microbial enhanced oil recovery (MEOR). The majority of research has focused on microbiology processes in oil reservoirs and oilfields; as such there is a paucity of information specific to oil sands. By studying microbial processes in oil sands there is the potential to use microbes in MEOR applications. This article reviews the microbiology of the Athabasca Oil Sands and the mechanisms bacteria use to tolerate low water and high hydrocarbon availability in oil reservoirs and oilfields, and potential applications in MEOR.

Detection of SARS-CoV-2 within the healthcare environment: a multi-centre study conducted during the first wave of the COVID-19 outbreak in England.

BACKGROUND: Understanding how severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is spread within the hospital setting is essential in order to protect staff, implement effective infection control measures, and prevent nosocomial transmission. METHODS: The presence of SARS-CoV-2 in the air and on environmental surfaces around hospitalized patients, with and without respiratory symptoms, was investigated. Environmental sampling was undertaken within eight hospitals in England during the first wave of the coronavirus disease 2019 outbreak. Samples were analysed using reverse transcription polymerase chain reaction (PCR) and virus isolation assays. FINDINGS: SARS-CoV-2 RNA was detected on 30 (8.9%) of 336 environmental surfaces. Cycle threshold values ranged from 28.8 to 39.1, equating to 2.2 x 105 to 59 genomic copies/swab. Concomitant bacterial counts were low, suggesting that the cleaning performed by nursing and domestic staff across all eight hospitals was effective. SARS-CoV-2 RNA was detected in four of 55 air samples taken <1 m from four different patients. In all cases, the concentration of viral RNA was low and ranged from <10 to 460 genomic copies/m3 air. Infectious virus was not recovered from any of the PCR-positive samples analysed. CONCLUSIONS: Effective cleaning can reduce the risk of fomite (contact) transmission, but some surface types may facilitate the survival, persistence and/or dispersal of SARS-CoV-2. The presence of low or undetectable concentrations of viral RNA in the air supports current guidance on the use of specific personal protective equipment for aerosol-generating and non-aerosol-generating procedures.

Isoforms of Wilms' tumor suppressor gene (WT1) have distinct effects on mammary epithelial cells.

The role of WT1 (Wilm's tumor suppressor gene) in breast cancer is controversial, with evidence for both tumor-promoting and tumor-suppressing activities. In order to address this question, we expressed different WT1 isoforms in the mammary epithelial cell line H16N-2, which does not express endogenous WT1. Cells were stably transfected with either WT1 (-Ex5/-KTS) or WT1 (+Ex5/+KTS) under the control of the inducible metallothionein promoter. Induction of WT1 (-Ex5/-KTS) upregulated p21, causing a slowing of proliferation and a G2-phase cell cycle arrest. In artificial basement membrane, the WT1 (-Ex5/-KTS) isoform promoted the appearance of highly organized acinar cellular aggregates. In contrast, WT1 (+Ex5/+KTS) had no effect on p21 or proliferation, but rather caused an epithelial-mesenchymal transition and a redistribution of E-cadherin from the cell membrane to the cytoplasm. This isoform also causes the cellular aggregates growing in artificial basement membrane to appear significantly less organized than control cells. Thus, different WT1 isoforms have distinct effects in this cell line, suggesting that depending on the ratio of WT1 isoform expression in mammary epithelial cells, WT1 could function to either promote or suppress a transformed phenotype.

Relationship of pressure to be thin with gains in body weight and fat mass in adolescents.

BACKGROUND: Sociocultural pressure to be thin is commonly reported by adolescents; yet, to what extent such pressure is associated with weight gain has not been evaluated longitudinally. OBJECTIVE: Examine whether pressure to be thin was positively associated with weight and fat gain in adolescents. METHODS: Participants were 196 healthy adolescent (age 15 ± 1 years old) girls (65%) and boys of varying weights (BMI 25 ± 7 kg/m2 ) studied at baseline and 1-year follow-up. At baseline, adolescents and their mothers reported pressure to be thin by questionnaire. At baseline and follow-up, BMI was calculated, and fat mass was assessed with air displacement plethysmography. Multiple regression was used to examine associations between baseline pressure to be thin and 1-year changes in BMI and fat mass. RESULTS: Accounting for multiple covariates, including baseline BMI or fat, adolescent-reported pressure from parents and peers and mother-reported pressure toward their teen were associated with greater gains in either adolescent BMI or fat (ps < .05). Adolescent weight status was a moderator of multiple effects (ps < .05). CONCLUSIONS: Parental and peer pressure to be thin were associated with increases in BMI and fat mass during adolescence, particularly in heavier adolescents. Further research is necessary to clarify how this association operates reciprocally and to identify underlying explanatory mechanisms.

Persistence of influenza on surfaces.

BACKGROUND: Close contact transmission (either direct or large droplet/droplet nuclei) is considered the main driver of influenza outbreaks but there is limited information regarding the role of fomites in transmission. AIM: To investigate the surface stability of influenza strains and thereby the role of fomites in transmission. METHODS: The viability and quantitative reverse transcription-polymerase chain reaction (qt-RT-PCR) signal of five influenza strains (A/PR/8/34/H1N1, A/Cal/7/09/H1N1, A/Cal/4/09/H1N1, A/Sol/54/06/H1N1, and A/Bris/59/07/H1N1) seeded on to three surfaces (cotton, microfibre, and stainless steel) were assessed over time. Coupons of material were seeded with 10µL of a 106-108pfu/mL suspension of cell culture-derived virus stock supplemented with 0.3% bovine serum albumin. Coupons were assayed by plaque assay and qt-RT-PCR at 1, 24h, and weekly for seven weeks using a vortex-mixing elution method. FINDINGS: Viable virus was detected from coupons for up to two weeks (stainless steel) and one week (cotton and microfibre), whereas detection of viruses by PCR was made for the entire seven-week study period. No strain differences were found. Ninety-nine percent reduction values (as a function of the seeding stock) were determined to be 17.7h for cotton (R2=0.86), 34.3h for microfibre (R2=0.80), and 174.9h for stainless steel (R2=0.98). CONCLUSION: Viable influenza was recovered from surfaces for up to two weeks. By contrast, influenza could be detected by PCR for more than seven weeks. These results have important implications for determining infection control protocols, cleaning regimes and sampling methods in healthcare settings.

Contamination of hospital tap water: the survival and persistence of Pseudomonas aeruginosa on conventional and 'antimicrobial' outlet fittings.

BACKGROUND: Pseudomonas aeruginosa infections have been linked to contaminated hospital taps, highlighting the potential for tap outlet fittings (OF) to harbour biofilm. P. aeruginosa may be transferred to OFs via contaminated cleaning cloths. Suggested interventions include flushing regimens and alternative OF designs. AIM: To investigate the transfer of P. aeruginosa from a contaminated cleaning cloth to conventional and 'antimicrobial/antibiofilm' OFs and to determine whether this contamination persists and/or leads to contamination of tap water. METHODS: Microfibre cloths contaminated with P. aeruginosa (108 cfu/mL) were used to wipe four different types of OF [one of conventional design (OF-A) and three marketed as 'antimicrobial' and/or 'antibiofilm' (OF- B, -C and -D)]. OFs were inserted into an experimental water distribution system for up to 24 h. Survival was assessed by culture. Single and multiple water samples were collected and cultured for P. aeruginosa. FINDINGS: The median number of P. aeruginosa transferred from cloth to OF was 5.7 × 105 cfu (OF-A), 1.9 × 106 cfu (OF-B), 1.4 × 105 cfu (OF-C) and 2.9 × 106 cfu (OF-D). Numbers declined on all OFs during the 24 h period with log reductions ranging from 3.5 (OF-C) to 5.2 (OF-B; P > 0.05). All water samples delivered immediately after OF contamination contained P. aeruginosa at ≥10 cfu per 100 mL. Contamination of water delivered from OF-A persisted despite continued flushing. Water delivered from OF-B did not contain P. aeruginosa beyond the first flush. CONCLUSION: Contaminated cleaning cloths may transfer P. aeruginosa to OFs, leading to contamination of tap water. Although not removing the potential for contamination, 'antimicrobial/antibiofilm' OFs may prevent P. aeruginosa from continually contaminating water delivered from the outlet.

2-Deoxy-D-glucose accumulation in adipocytes: apparent transport discrimination between 2-deoxy-D-glucose and 3-O-methyl-D-glucose.

The uphill accumulation of free 2-deoxy-D-glucose and 2-deoxy-D-glucose 6-phosphate in rat adipocytes was found not to affect the steady-state distribution of 3-O-methyl-D-glucose although both hexoses share a common transport pathway. This observation argues against a possible effect of 2-deoxy-D-glucose phosphate on the equilibrating nature of the carrier. The results are discussed in light of hypotheses advanced to explain free 2-deoxy-D-glucose accumulation in a variety of cells.

The accumulation of free and phosphorylated sugars in adipocytes based on a dynamic diffusion barrier.

The simple theory of a dynamic diffusion barrier is described and it is shown how this could account for the accumulation, in adipocytes, of those free sugars which are also phosphorylated. The standing concentration gradient established by this mechanism depends on the recycling of free sugar and sugar phosphate in submembrane structures which start in juxtaposition to conventional membrane hexose transporters. Although a continual expenditure of metabolic energy is involved, there can be a net gain from the potential-energy store of accumulated substrates. The hypothesis leads to a series of simple equations which can be used as the basis for computer simulations of experimental procedures.

Clinical features and basic mechanisms of quinidine-induced arrhythmias.

Quinidine therapy is one of the most common causes of the acquired long QT syndrome and the morphologically distinctive tachyarrhythmia torsade de pointes. Clinical data from our institution and others have revealed a number of characteristic features: quinidine plasma concentrations are generally low, marked QRS prolongation is absent, hypokalemia is frequent and abrupt heart rate slowing just before the initiation of a paroxysm is almost invariable. The lack of correlation between plasma quinidine concentrations and this adverse drug effect raises the possibility either that external factors (for example, hypokalemia) modulate the response to quinidine in vivo or that one or more unmeasured active metabolites play a role. Therefore, the effect of alterations in extracellular potassium and stimulation rate on the electrophysiologic effects of quinidine were examined in canine Purkinje fibers. It was found that a form of triggered automaticity, early afterdepolarizations, is reliably produced in the presence of quinidine when extracellular potassium is lowered and the stimulation rate is slowed. More recently, the effects of a number of quinidine metabolites, as well as the commonly found impurity dihydroquinidine, were characterized in canine Purkinje fibers in a similar fashion. Although quinidine was the most potent of the substances tested, both dihydroquinidine and 3-hydroxyquinidine prolonged action potential and produced early afterdepolarizations as did quinidine at long cycle lengths. Quinidine-induced torsade de pointes is a potentially lethal adverse drug effect, occurring in 1 to 3% of patients. Hypokalemia and slow heart rates are commonly observed in a clinical setting and, in the tissue bath, quinidine and several of its metabolites induce abnormal automatic behavior when extracellular potassium is lowered and stimulation rate is slowed.(ABSTRACT TRUNCATED AT 250 WORDS)

Intranuclear localization of insulin in rat hepatoma cells: insulin/matrix association.

Previous studies have documented nuclear insulin accumulation in a variety of cell types. The present investigation extends these observations by demonstrating that insulin associates with the matrix fraction of H35 rat hepatoma cell nuclei. Nuclei were isolated from [125I]insulin-loaded cells and extracted with DNase I, RNase A and high salt. The resulting matrix fraction was found to contain greater than 75% of the radiolabel initially present. Ultrastructural studies to confirm these findings were carried out using an agarose-encapsulated nuclear matrix preparation. Electron microscopic immunocytochemistry specifically detected insulin in matrices prepared from insulin-treated cells. No reaction was observed in matrices obtained from non-insulin-treated (control) cells. Further biochemical analysis revealed that matrix-associated insulin could be solubilized with 1% sodium dodecyl sulfate (SDS) or in the presence of high urea concentrations. Gel filtration analysis of urea-solubilized matrix material revealed the presence of apparently intact [125I]insulin and a higher molecular weight peak. It is hypothesized that the latter may represent a tightly associated complex of insulin with some matrix protein(s).

Plasma concentrations of quinidine, its major metabolites, and dihydroquinidine in patients with torsades de pointes.

We examined the hypothesis that excess accumulation of major quinidine metabolites or the commercial impurity dihydroquinidine contributes to the development of polymorphic ventricular tachycardia (torsades de pointes, [TdP]) in patients taking quinidine. Total and free plasma concentrations of these compounds were measured by reverse-phase HPLC with fluorescence detection and equilibrium dialysis in 19 patients with TdP and 38 control patients tolerating quinidine therapy without toxicity. No significant differences were found between the two groups of patients. Ratios of metabolite or dihydroquinidine to quinidine varied up to tenfold among patients but were similarly distributed in the TdP and control groups. Only the metabolite 3-hydroxyquinidine was present at free plasma concentrations that exceeded free concentrations of quinidine. We conclude that although quinidine metabolism is highly variable, there does not appear to be any correlation between the plasma concentrations of quinidine, its metabolites or dihydroquinidine, and the subsequent development of TdP.

The development and testing of intravenous dosing regimens: application to flecainide for the suppression of ventricular arrhythmias.

A two-part pharmacokinetic approach was used to prospectively develop and test intravenous flecainide infusion regimens for the acute therapy for ventricular arrhythmias. Initially, each of nine known responders to oral flecainide was given a rapid flecainide infusion to characterize pharmacokinetic parameters and determine the minimum effective concentration for each patient. These data were used to calculate individually appropriate three-stage flecainide infusions of predetermined durations in eight patients. The three-stage infusions (0.15 +/- 0.02 mg flecainide acetate/kg/min for 5 minutes, 0.046 +/- 0.004 mg/kg/min for 60 minutes, and 0.31 +/- 0.05 mg/kg/hr for 5 to 47 hours; mean +/- SE) resulted in 95% +/- 0.1% suppression of ventricular ectopic depolarizations. Based on these results, six additional patients received a uniform infusion regimen (0.1 mg/kg/min for 5 minutes, 0.025 mg/kg/min for 2 hours, and 0.25 mg/kg/hr for 46 hours). Supplemental doses of 0.25 mg/kg were given (four doses per patient). With this protocol, ventricular ectopic depolarizations were 82.6% +/- 8.5% suppressed. Measured plasma flecainide concentrations were not significantly different from those predicted by pharmacokinetic models. A prompt and sustained antiarrhythmic effect was obtained with an intravenous regimen of flecainide determined by a prospective pharmacokinetic approach. However, the dosages developed in this study may have to be modified for patients with impaired cardiac or renal function.

Pharmacokinetics and pharmacodynamics of SB 209670, an endothelin receptor antagonist: effects on the regulation of renal vascular tone.

OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of an infusion of SB 209670, a non-peptide endothelin-A/endothelin-B receptor antagonist. METHODS: The study was conducted in 2 parts. Part 1 was a placebo-controlled, single-blind, rising-dose crossover evaluation of the pharmacokinetics and safety of SB 209670 infused at doses that ranged from 0.2 to 1.5 mirog kg(-1) for approximately 8 hours in 17 healthy male volunteers. In part 2, renal hemodynamic effects of a 4-hour infusion of SB 209670 were assessed in 10 healthy male volunteers in a 2-period, period-balanced, single-blind, randomized, placebo-controlled crossover study. RESULTS: SB 209670 appeared to display linear kinetics over the dose range from 0.2 to 1.5 microg kg(-1) min(-1). The half-life was approximately 4 to 5 hours. Plasma immunoreactive endothelin-1 increased in an apparent dose-dependent manner. Mean renal hemodynamic responses (para-aminohippurate clearance) increased by approximately 15% relative to placebo (P = .007). Renal sodium excretion was similar during SB 209670 and placebo infusion. CONCLUSION: The pharmacokinetics of intravenous SB 209670 appeared to be linear, and infusion resulted in dose-related increases in immunoreactive endothelin-1. The lack of anti-natriuretic effect and the renal vasodilator response observed in this study indicate that SB 209670 does not possess any partial agonist activity. Further, the renal hemodynamic response supported a potential physiologic role for endogenous endothelin in the maintenance of renal vascular tone in humans.

One-hour paclitaxel plus carboplatin in the treatment of advanced non-small cell lung cancer: results of a multicentre, phase II trial.

The aim of this phase II study was to determine the activity and toxicity of paclitaxel (administered by 1-h infusion) and carboplatin in advanced non-small cell lung cancer when used in a multicentre, community-based treatment setting. 100 chemotherapy-naive patients with stage IIIB or IV non-small cell lung cancer were treated between March 1995 and February 1996. All patients had Karnofsky performance status 70-100, measurable disease and adequate bone marrow, kidney and liver function. All patients received intravenous (i.v.) paclitaxel 225 mg/m2 by 1-h infusion followed immediately by carboplatin at a targeted area under the concentration time curve (AUC) of 6.0 using the Calvert formula. Courses were repeated every 21 days. Colony stimulating factors were not used routinely. 38 of 94 evaluable patients (40%) had objective responses to treatment (3 complete responses, 35 partial responses). An additional 32 patients had stable disease at initial re-evaluation. Weight gain during treatment was experienced by 47% of patients with objective response or stable disease. The median survival in this group of 100 patients was 8 months, with an actuarial 1-year survival of 42%. Leucopenia was common, but hospitalisation for treatment of neutropenia and fever occurred in only 3% of courses. Cumulative peripheral neuropathy was common, but usually appeared after the third or fourth course and was severe (grade 3) in only 15% of patients. Other grade 3 and 4 toxicity was uncommon. There was one treatment-related death due to sepsis. This large multicentre community-based phase II trial demonstrated the efficacy of paclitaxel and carboplatin combination chemotherapy in advanced non-small cell lung cancer. When paclitaxel is given by 1-h infusion, this regimen is easily administered in the outpatient setting.

Tocainide plus quinidine for treatment of ventricular arrhythmias.

Tocainide and quinidine were administered both as single agents and in combination to 14 patients with chronic ventricular arrhythmias. Therapy with tocainide was limited by the occurrence of dose-related adverse reactions in 8 patients, but could be titrated to a dose that was well-tolerated in 13 of 14 and effective in 2 of 13. The addition of quinidine gluconate to the tolerated dose of tocainide increased the number of patients with arrhythmia suppression from 2 to 6. After tocainide washout, quinidine alone suppressed arrhythmias in only 3 patients. Analysis of electrocardiogram intervals showed that the drugs had additive effects on the coupling interval of the sinus beat to the predominant ectopic beat, but exerted antagonistic effects on the corrected QT interval. These findings suggest that the combination may be clinically useful, exerting pharmacologic effects unlike either agent alone.