Efficacy and safety of fumaric acid esters in young patients aged 10-17 years with moderate-to-severe plaque psoriasis: a randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Apart from biologics, no systemic drugs are approved in Europe for children with moderate-to-severe psoriasis. Retrospective observational studies have shown promising results for fumaric acid esters (FAE) in this setting. OBJECTIVES: To show superiority of FAE over placebo in terms of treatment response after 20 weeks in children and adolescents aged 10-17 years. METHODS: In a multicentre, randomized, double-blind, placebo-controlled phase IIIb study, patients aged 10-17 years with moderate-to-severe plaque psoriasis requiring systemic therapy were randomized 2 : 1 to receive FAE (n = 91) or placebo (n = 43) over 20 weeks, followed by an open-label FAE treatment phase. The coprimary endpoints were ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and Physician's Global Assessment (PGA) score of 0 or 1 (clear or almost clear) at week 20. The study was registered with EudraCT number 2012-000035-82. RESULTS: At week 20, 55% [95% confidence interval (CI) 0·44-0·65] of FAE-treated patients achieved a PASI 75 response vs. 19% (95% CI 0·08-0·33) in the placebo group (absolute difference 36%, 95% CI 0·20-0·53; P < 0·001). In total, 42% (95% CI 0·32-0·53) in the FAE group vs. 7% (95% CI 0·01-0·19) in the placebo group achieved a PGA score of 0 or 1 at week 20 (absolute difference 35%, 95% CI 0·21-0·49; P < 0·001). During the double-blind period, drug-related adverse events occurred more frequently in patients receiving FAE compared with placebo (76% vs. 47%). Gastrointestinal disorders were the most common adverse events. CONCLUSIONS: FAE administered over a period of 20 weeks demonstrated a better response than placebo; the difference was statistically significant and clinically meaningful. Application up to 40 weeks was generally well tolerated. However, further studies are required.

Mutagenic, cytotoxic, and genotoxic properties of tobacco smoke produced by cigarillos available on the Canadian market.

Cigarillos (aka little cigars) have been increasing in popularity unlike cigarettes; but relatively little is known about the toxicology of the mainstream smoke (MSS) from such products. Therefore, the objective of this work was to compare the toxicological properties of the MSS (Health Canada Intensive smoking conditions) from a range of cigarillo products with the toxicological properties of MSS of cigarettes. Three in vitro assays were used to evaluate the toxicities of the MSS total particulate matter (TPM): (1) mutagenicity using Ames assay with Salmonella strains TA98 and TA100 with S9 metabolic activation (+S9); (2) cytotoxicity using the Neutral Red Uptake (NRU) assay with CHO (Chinese Hamster Ovary) cells; and (3) genotoxicity using the micronucleus assay with CHO cells and short-term exposures (3-h ± S9). The Ames assay (TA100+S9) and the NRU assay were also applied to the gas/vapour phase of the MSS that passed through the Cambridge pad. On a per-milligram-nicotine basis, the preferred way of comparing toxicities of different types of tobacco products, the MSS from cigarillos was not less toxic, and in some cases more toxic (TPM fraction TA98+S9, NRU), than the MSS from cigarettes. Thus, our findings support our prior work on smoke mutagenicity that showed MSS from cigarillos was not less toxic than MSS from cigarettes.

Free-base nicotine in tobacco products. Part II. Determination of free-base nicotine in the aqueous extracts of smokeless tobacco products and the relevance of these findings to product design parameters.

Reports in the peer-reviewed literature and popular press have alleged that smokeless tobacco product (STP) manufacturers increase the addictiveness of their products by adjusting formulae to increase the relative percentage of nicotine in STP that is not protonated. Such nicotine is more popularly, but incorrectly, known as free-base nicotine ("FBN") as it is a calculated amount as opposed to a real chemical species in the STP. Some regulators have mandated reporting of FBN as estimated by Henderson-Hasselbalch equation ("HHE") using the pH-value of an aqueous suspension (or extract) of STP. This is technically incorrect because the HHE is only valid in pure dilute aqueous solution of a single base and its conjugate acid. The aqueous suspensions (or extracts) of STP often contain high concentrations of salts and polymeric anions such as pectate and many other compounds, and there is a molar excess of ammonia over nicotine in some products. These are heretofore-unrecognized sources of error in use of the HHE to estimate relative amount of nicotine that is not protonated results in inaccurate FBN-values. Thus, it is not surprising that attempts to show the relevance of estimated value of FBN in STP to human physiology have failed.

Free-base nicotine in tobacco products. Part I. Determination of free-base nicotine in the particulate phase of mainstream cigarette smoke and the relevance of these findings to product design parameters.

The free-base nicotine (FBN) content of mainstream cigarette smoke (MSS) has been discussed in the peer-reviewed literature and popular press. It has been alleged that manufacturers adjust product design features to increase the percentage of total nicotine (TN) in the MSS gas-vapor phase that is unprotonated [P(g)(,nic)(%)] and/or the fraction of nicotine in the MSS total particulate matter (TPM) that is unprotonated (FBN/TN). Our research showed the Health Canada Intensive smoking conditions negated the effects of blend and cigarette design features reported to raise the pH of TPM collected under ISO or US FTC conditions. Our research also showed that when additive-free Canadian cigarettes were smoked under ISO conditions, the FBN/TN ratio increased as the tar/nicotine ratio decreased. Our findings are in line with other studies that have questioned allegations of a relationship between use of ammonia and its compounds as tobacco additives and amounts of unprotonated nicotine in MSS. In addition, the experimental work demonstrated how use of solid-phase microextraction to estimate FBN can yield erroneously high results due to improper conditioning and/or smoking of the cigarettes. Our research showed that there is no longer any scientific support for regulators to require smoke pH and FBN determinations on cigarette products.

Chemical and toxicological characterization of commercial smokeless tobacco products available on the Canadian market.

Some health experts are recommending that smokers who refuse to quit or refuse to use nicotine replacement therapy (NRT) such as nicotine-containing chewing gum switch to certain types of smokeless tobacco products (STP) such as Swedish snus. Other health experts disagree citing the uncertainty in the composition of commercially available STP, the lack of governmental regulations to ensure that STP advertised to meet certain standards (i.e., GothiaTek) do actually meet such standards, and the uncertainty that any STP can provide as safe as alternative to smoking as NRT. One reason for uncertainty is the dearth of detailed chemical and toxicological information on contemporary STP. Unlike the situation with cigarettes, there are few standardized methods for analytical and toxicological studies of STP. Consequently, the objective for this work was to characterize several types of STP available on the Canadian market using the modifications of the Official Health Canada chemical and toxicological methods developed for cigarettes. Moist snuff samples tested had TSNA and B[a]P levels somewhat above the GothiaTek standard while samples of Swedish snus, low-moisture snuff, and US-style chewing tobacco did not. Use of in vitro assays to assess STP toxicity was of limited utility in distinguishing product types.

Reductions in the tobacco specific nitrosamine (TSNA) content of tobaccos taken from commercial Canadian cigarettes and corresponding reductions in TSNA deliveries in mainstream smoke from such cigarettes.

Tobacco specific nitrosamines (TSNAs) are suspected to cause smoking-related neoplastic diseases. The change from direct-fired to indirect-fired barns (aka kilns) for curing bright (aka Virginia, flue-cured) tobaccos was made to reduce the TSNA concentrations. The effectiveness of such processes in reducing the deliveries of TSNAs to the users of the products should be monitored. However, it is difficult to assess the effects of this reduction on the TSNA levels in mainstream smoke when cigarette blends contain burley tobaccos and other blend components that can increase smoke TSNA concentrations. Canadian cigarettes made prior to and in the few years just after the conversion to indirect-fired curing should not be subject to such interferences. Thus, the TSNA content of tobaccos and mainstream smoke from six brands of Canadian cigarettes produced in 2003, 2004, and 2005 were determined. Reductions in NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone], the most important TSNA in flue-cured tobaccos, levels in the tobacco blends ranged from 60% to 85%. The corresponding reductions in mainstream smoke TSNA levels ranged from 59% to 72% (ISO smoking conditions) and 58-76% (Health Canada Intensive smoking conditions). These results show that other factors (microorganisms, nitrite levels) may be negating the TSNA reductions achieved by indirect-fired curing.

A comparative study of the mutagenicity of various types of tobacco products.

Toxicological data are an important aspect of tobacco product characterization. In this study, TPM (Total Particulate Matter) (three replicates) was collected from cigarettes [five brands, ISO conditions: puff volume, 35 mL; duration, 2s; interval, 60s (35/2/60)], cigars (two brands, 45/2/30), cigarillos (two brands, 35/2/60), bidis (two brands, 45/2/30), and pipe tobacco (two brands, 50/2/12). TPM was extracted from the Cambridge filter pad using dimethyl sulfoxide (DMSO). Smokeless tobacco (ST) (six brands) was extracted with DMSO using an ultrasonic homogenizer. Both types of extracts were filtered and stored at -80 degrees C. All extracts were analyzed for humectants, water and nicotine. Mutagenic activity was assessed per OECD guideline 471 using Salmonella typhimurium TA98+S9 and TA100+S9. TA98+S9 response (specific activity expressed as revertants/mg nicotine) was greatest for the cigarette fabricated with dark, air-cured tobaccos. Average product responses with TA98+S9 based on nicotine and relative to cigarettes (excluding dark tobacco) were cigars, 242%; cigarillos, 238%; bidis, 91%; and pipe tobacco, 44%. ST response was not significant for TA98+S9. Corresponding values for TA100+S9 were cigars, 189%; cigarillos, 155%; pipe tobacco, 130%; bidis, 114% and ST, 34%. ST TA100+S9 response ranged from a low of 501 to a high of 8547 revertants/mg nicotine, depending on ST composition.

Spatio-temporal pattern formation during CO oxidation on Pt(100) at low and intermediate pressures: A comparative study.

Experimental studies of CO oxidation on Pt(100) over two different ranges of reactant pressures will be reviewed. Using photoemission electron microscopy (PEEM), spatio-temporal pattern formation was observed at temperatures between 420 and 540 K in the 10(-5) mbar pressure range. In an attempt to bridge the "pressure-gap," ellipsomicroscopy for surface imaging was used to follow pattern formation at temperatures around 600 K in the 10(-2) mbar pressure range. The features of the nonlinear phenomena, observed in these two different pressure regimes, are markedly different. This is shown by comparison of various qualitative and quantitative features of spatio-temporal pattern formation as well as the dynamics of the macroscopic reaction rate. Subsurface oxygen is proposed as a tentative alternative to the surface phase transition for oscillations in the reaction rate at higher temperatures and intermediate pressures. (c) 2002 American Institute of Physics.

[Clinical and biochemical aspects of accidental poisoning with tetraethyl lead in a 2.5 year old patient--long term observation]. / Kliniczne i biochemiczne aspekty przypadkowego zatrucia tetraetylkiem olowiu u 2,5 letniego dziecka--dlugofalowa obserwacja przypadku.

The paper describes an accidental, acute toxic exposure of a 2.5-year-old girl to tetraethyl lead. The authors discuss the clinical picture and treatment within the acute phase of intoxication as well as during the ambulatory follow-up of chronic sequelae of the exposure. Systemic, periodic monitoring of lead (Pb) levels in the blood (B-Pb) and urine (U-Pb) over a 2-year period gave the authors a unique opportunity to observe the dynamics of urinary excretion of this element. In the acute phase of intoxication the Pb blood value reached the plateau at the 46 micrograms/dl after 3 days from the exposure. Mild encephalopathy and gastrointestinal tract irritation was observed at that time. After 3 weeks of hospitalisation Pb levels decreased to the values 32 micrograms/dl whereas urinary Pb diminished from the initial 600 micrograms/L to 56 micrograms/L. During the 2-years outpatient follow-up Pb in the blood decreased to 7 micrograms/dl. Urinary Pb is still maintained above the population value's range. No detectable, permanent detrimental health effects were observed in the child. The girl is followed-up in annual intervals. Several other tissues are and will be assessed by non-invasive methods (e.g. hair, primary teeth) and analysed for accumulated Pb. The collected data will allow the authors for describing Pb distribution in the body as well as long term excretion in the growing and developing organism of the child.

Chemically sensitive high throughput parallel analysis of solid phase supported library members

This paper introduces Fourier transform infrared imaging as a powerful spectroscopic tool for the parallel identification of members of resin-supported combinatorial libraries. This technique combines the chemical specificity and high sensitivity of FTIR with the ability to rapidly analyze multiple supported resin beads simultaneously. It is shown here that the chemical identity of ligands on a variety of supported resin beads can be identified in a single experiment without destroying or otherwise perturbing the system.

Ellipsomicroscopy for surface imaging: contrast mechanism, enhancement, and application to CO oxidation on Pt(110).

Ellipsomicroscopy for surface imaging (EMSI) is a powerful new tool for studying spatiotemporal adsorbate pattern formation on catalyst surfaces. It is a surface-sensitive technique that is able to measure submonolayer coverage of adsorbates. The imaging of the sample's surface achieves a spatial sensitivity, making it possible to measure nonuniformity of adsorbate coverage. The image contrast, however, depends strongly on the setup of the instrument. The optimum setup can be calculated from the ellipsometric properties of the catalyst/adsorbate system and the intrinsic parameters of the EMSI instrument. Optimizing the setup of the EMSI instrument permitted enhancement of the image contrast over the previous setup. As a result, new features in CO oxidation on Pt(110) were discovered.

Fourier-transform infrared imaging using a rapid-scan spectrometer.

We present a major improvement to the Fourier-transform infrared (FTIR) imaging technique brought about by replacement of the commonly used step-scan spectrometer with a rapid-scanning spectrometer. This advancement dramatically decreases the time required for data collection without decreasing the data quality. With this new instrumental setup, an imaging data set consisting of 64x64 spectra with a 4-cm (-1) spectral resolution over a 1360-cm (-1) spectral range can be collected in 34 s. As a practical example, we demonstrate what we believe to be the first application of FTIR imaging to the screening of adsorbates on the elements of a combinatorial library containing different supported catalyst materials in the same reactant feed.

Severe polyneuropathy in a 3-year-old child after dichlorophenoxyacetic herbicide--chwastox intoxication, treated successfully with plasmapheresis (PF).

The clinical picture of intoxication with dichlorophenoxy acetic herbicides is well recognised in adults and some treatment recommendations are established. To the best of our knowledge there is scarcity of well documented cases of intoxication with this substance in children. Our report describes the clinical picture of Chwastox intoxication in a 3-year-old child. Some similarities and differences between adults and children are discussed, as well as the indications for plasmapheresis, which could be a valuable mode of treatment in such cases.

Effects of Boundaries on Pattern Formation: Catalytic Oxidation of CO on Platinum.

The effect of boundaries on pattern formation was studied for the catalytic oxidation of carbon monoxide on platinum surfaces. Photolithography was used to create microscopic reacting domains on polycrystalline foils and single-crystal platinum (110) surfaces with inert titanium overlayers. Certain domain geometries give rise to patterns that have not been observed on the untreated catalyst and bring to light surface mechanisms that have no analog in homogeneous reaction-diffusion systems.