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Isotretinoin is effective in the treatment of severe acne and rosacea. Both parent drug and its main metabolite 4-oxo-isotretinoin are potentially teratogenic compounds and contain a carboxylic acid moiety. In the presence of ethanol, naturally occurring as well as synthetic retinoids also containing a carboxylic acid moiety are capable of undergoing an ethyl esterification with the metabolic formation of more lipophilic compounds with a much longer terminal half-life.To determine if isotretinoin (13-cis-RA), its main metabolite 4-oxo-isotretinoin (4-oxo-13-cis-RA), and other possible metabolites in the presence or absence of ethanol are converted to their corresponding ethyl derivatives in patients with severe acne or rosacea after multiple isotretinoin dosing. In addition, pharmacokinetic parameters of the parent drug and its 4-oxo metabolite were determined.Eleven patients with severe acne or rosacea were treated with isotretinoin daily for 3 months and investigated pharmacokinetically during 24 h after 1 month of treatment and for up to 28 days after discontinuation of therapy. A possible influence of ethanol was evaluated using a simple self-administered questionnaire and by measuring serum ethanol levels during treatment. The concentrations of isotretinoin, 4-oxo-isotretinoin and possible ethylated and nonethylated metabolites were measured by reverse-phase high-performance liquid chromatography.Although seven of 11 patients had a considerable weekly alcohol intake, no endogenous synthesis of ethyl derivatives of isotretinoin, the main 4-oxo metabolite or the all-trans compounds was chromatographically detectable in any of the patients' plasma samples during the treatment period. Multiple dose pharmacokinetic data for the parent drug and its main metabolite were comparable to previous studies.The metabolism and pharmacokinetics of isotretinoin and its main metabolites are not influenced by ethanol during long-term isotretinoin treatment. After ceasing long-term isotretinoin therapy the recommended period of 1 month for using anticonceptive measures in fertile women seems adequate.

AbstractAlthough canopy height has long been a focus of interest in ecology, it has remained difficult to study at large spatial scales. Recently, satellite‐borne LiDAR equipment produced the first systematic high resolution maps of vegetation height worldwide. Here we show that this new resource reveals three marked modes in tropical canopy height ~40, ~12, and ~2 m corresponding to forest, savanna, and treeless landscapes. The distribution of these modes is consistent with the often hypothesized forest‐savanna bistability and suggests that both states can be stable in areas with a mean annual precipitation between ~1,500 and ~2,000 mm. Although the canopy height states correspond largely to the much discussed tree cover states, there are differences, too. For instance, there are places with savanna‐like sparse tree cover that have a forest‐like high canopy, suggesting that rather than true savanna, those are thinned relicts of forest. This illustrates how complementary sets of remotely sensed indicators may provide increasingly sophisticated ways to study ecological phenomena at a global scale.

Antiprotons have been suggested as a possibly superior modality for radiotherapy, due to the energy released when antiprotons annihilate, which enhances the Bragg peak and introduces a high-LET component to the dose. However, concerns are expressed about the inferior lateral dose distribution caused by the annihilation products.We use the Monte Carlo code FLUKA to generate depth-dose kernels for protons, antiprotons, and carbon ions. Using these we then build virtual treatment plans optimized according to ICRU recommendations for the different beam modalities, which then are recalculated with FLUKA. Dose-volume histograms generated from these plans can be used to compare the different irradiations.The enhancement in physical and possibly biological dose from annihilating antiprotons can significantly lower the dose in the entrance channel; but only at the expense of a diffuse low dose background from long-range secondary particles. Lateral dose distributions are improved using active beam delivery methods, instead of flat fields.Dose-volume histograms for different treatment scenarios show that antiprotons have the potential to reduce the volume of normal tissue receiving medium to high dose, however, in the low dose region antiprotons are inferior to both protons and carbon ions. This limits the potential usage to situations where dose to normal tissue must be reduced as much as possible.

In medial tibial stress syndrome (MTSS) bone marrow and periosteal edema of the tibia on the magnetic resonance imaging (MRI) is frequently reported. The relationship between these MRI findings and recovery has not been previously studied. This prospective study describes MRI findings of 52 athletes with MTSS. Baseline characteristics were recorded and recovery was related to these parameters and MRI findings to examine for prognostic factors. Results showed that 43.5% of the symptomatic legs showed bone marrow or periosteal edema. Absence of periosteal and bone marrow edema on MRI was associated with longer recovery (P = 0.033 and P = 0.013). A clinical scoring system for sports activity (SARS score) was significantly higher in the presence of bone marrow edema (P = 0.027). When clinical scoring systems (SARS score and the Lower Extremity Functional Scale) were combined in a model, time to recovery could be predicted substantially (explaining 54% of variance, P = 0.006). In conclusion, in athletes with MTSS, bone marrow or periosteal edema is seen on MRI in 43,5% of the symptomatic legs. Furthermore, periosteal and bone marrow edema on MRI and clinical scoring systems are prognostic factors. Future studies should focus on MRI findings in symptomatic MTSS and compare these with a matched control group.

Antarctic biota evolved under the influence of a suite of geological and climatic factors, including geographic isolation of the landmass and continental shelves, extremely low temperatures and seasonality. Current warming trends in the continent and surrounding oceans may trigger substantial shifts in community composition and biodiversity, impacting the dominance of cold-adapted over more generalist species. Until recently, the diversity of microorganisms in cold environments was investigated only in terms of distribution, with little attention to their functional roles in important environmental processes. The 'omic' methodologies now offer effective tools to investigate the relationships between biodiversity and ecosystem functioning and to understand the evolutionary principles of adaptation and tolerance/resistance to extreme conditions. In this review we summarise how cold temperatures affect the physiology of microorganisms and focus on the molecular mechanisms of cold adaptation revealed by recent biochemical and genetic studies.

In rats, high ethanol doses during early postnatal life exert deleterious effects upon brain development that impact diverse social and cognitive abilities. This stage in development partially overlaps with the third human gestational trimester, commonly referred to as the brain growth spurt period. At this stage in development, human fetuses and rat neonates (postnatal days [PD] 3-9) exhibit relatively high respiratory rates that are affected by subteratogenic ethanol doses. Recent studies suggest conditioned breathing responses in the developing organism, given that there are explicit associations between exteroceptive stimuli and the state of ethanol intoxication. Furthermore, studies performed with near-term rat fetuses suggest heightened sensitivity to ethanol's motivational effects. The present study was meant to analyze the unconditioned effects of ethanol intoxication and the possible co-occurrence of learning mechanisms that can impact respiratory plasticity, and to analyze the preference for cues that signal the state of intoxication as well as the effects of the drug, related with motor stimulation. Neonatal rats were subjected to differential experiences with salient tactile cues explicitly paired or not paired with the effects of vehicle or ethanol (2.0 g/kg). A tactile discrimination procedure applied during PDs 3, 5, 7, and 9 allowed the identification of the emergence of ethanol-derived non-associative and associative learning processes that affect breathing plasticity, particularly when considering apneic disruptions. Ethanol was found to partially inhibit the disruptions that appeared to be intimately related with stressful circumstances defined by the experimental procedure. Tactile cues paired with the drug's effects were also observed to exert an inhibitory effect upon these breathing disruptions. The level of contingency between a given tactile cue and ethanol intoxication also resulted in significant changes in the probability of seeking this cue in a tactile preference test. In addition, the state of intoxication exerted motor-stimulating effects. When contrasting the data obtained via the analysis of the different dependent variables, it appears that most ethanol-derived changes are modulated by positive and/or negative (anti-anxiety) reinforcing effects of the drug. As a whole, the study indicates co-existence of ethanol-related functional changes in the developing organism that simultaneously affect respiratory plasticity and preference patterns elicited by stimuli that signal ethanol's motivational effects. These results emphasize the need to consider significant alterations due to minimal ethanol experiences that argue against "safe" levels of exposure in a critical stage in brain development.

AbstractAim: To compare effects of three cetylpyridinium chloride (CPC) formulations with and without alcohol and Tween80 on physico‐chemical properties of salivary pellicles, bacterial detachment in vitro and bacterial killing in vivo.Material and Methods: Adsorption of CPC to salivary pellicles in vitro was studied using X‐ray photoelectron spectroscopy and water contact angle measurements. Adhesion and detachment of a co‐adhering bacterial pair was determined in vitro using a flow chamber. Killing was evaluated after live/dead staining after acute single use in vivo on 24‐ and 72‐h‐old plaques after 2‐week continuous use.Results: The most pronounced effects on pellicle surface chemistry and hydrophobicity were observed after treatment with the alcohol‐free formulation, while the pellicle thickness was not affected by any of the formulations. All CPC formulations detached up to 33% of the co‐adhering pair from pellicle surfaces. Bacterial aggregate sizes during de novo deposition were enhanced after treatment with the alcohol‐free formulation. Immediate and sustained killing in 24 and 72 h plaques after in vivo, acute single use as well as after 2‐week continuous use were highest for the alcohol‐free formulation.Conclusions: CPC bioavailability in a formulation without alcohol and Tween80 could be demonstrated through measures of pellicle surface properties and bacterial interactions in vitro as well as bacteriocidal actions on oral biofilms in vivo.

Ectothermic animals like fishes are extremely dependent on temperature, as they are not able to change body temperature physiologically. When populations are found in isolated water bodies such as small lakes they will have to respond to stressful high temperatures by behavioral avoidance, phenotypic plasticity or microevolutionary change. We analyzed threespine sticklebacks from two large and two small lakes, representing different isolated populations. We determined maximum critical thermal limits (CTmax) and the associated gene expression responses in three heat shock (hsp60, hsp70, hsp90) and two key metabolic (idh2, fbp2) genes at ecologically relevant moderate heat stress (26 °C) as well as at the critical thermal limit (CTmax). CTmax showed slight variation across populations with no strong indication of local adaptation. Likewise, there was no strong evidence for local adaptation at the level of gene expression. The expression of the metabolic genes indicated a shift from aerobic towards anaerobic energy production with extreme heat stress. We conclude that threespine sticklebacks do not show severe stress during the warmest temperatures they are likely to encounter during current temperature regimes in Denmark, and following this show no sign of local adaptation even in small, isolated water bodies.