Ångstrom-Depth Resolution with Chemical Specificity at the Liquid-Vapor Interface.

The determination of depth profiles across interfaces is of primary importance in many scientific and technological areas. Photoemission spectroscopy is in principle well suited for this purpose, yet a quantitative implementation for investigations of liquid-vapor interfaces is hindered by the lack of understanding of electron-scattering processes in liquids. Previous studies have shown, however, that core-level photoelectron angular distributions (PADs) are altered by depth-dependent elastic electron scattering and can, thus, reveal information on the depth distribution of species across the interface. Here, we explore this concept further and show that the experimental anisotropy parameter characterizing the PAD scales linearly with the average distance of atoms along the surface normal obtained by molecular dynamics simulations. This behavior can be accounted for in the low-collision-number regime. We also show that results for different atomic species can be compared on the same length scale. We demonstrate that atoms separated by about 1 Å along the surface normal can be clearly distinguished with this method, achieving excellent depth resolution.

Effects of anastomotic technique on early postoperative outcome in open right-sided hemicolectomy.

Background: Despite recent improvements in colonic cancer surgery, the rate of anastomotic leakage after right hemicolectomy is still around 6-7 per cent. This study examined whether anastomotic technique (handsewn or stapled) after open right hemicolectomy for right-sided colonic cancer influences postoperative complications. Methods: Patient data from the German Society for General and Visceral Surgery (StuDoQ) registry from 2010 to 2017 were analysed. Univariable and multivariable analyses were performed. The primary endpoint was anastomotic leakage; secondary endpoints were postoperative ileus, complications and length of postoperative hospital stay (LOS). Results: A total of 4062 patients who had undergone open right hemicolectomy for colonic cancer were analysed. All patients had an ileocolic anastomosis, 2742 handsewn and 1320 stapled. Baseline characteristics were similar. No significant differences were identified in anastomotic leakage, postoperative ileus, reoperation rate, surgical-site infection, LOS or death. The stapled group had a significantly shorter duration of surgery and fewer Clavien-Dindo grade I-II complications. In multivariable logistic regression analysis, ASA grade and BMI were found to be significantly associated with postoperative complications such as anastomotic leakage, postoperative ileus and reoperation rate. Conclusion: Handsewn and stapled ileocolic anastomoses for open right-sided colonic cancer resections are equally safe. Stapler use was associated with reduced duration of surgery and significantly fewer minor complications.

Single ingestion of di-(2-propylheptyl) phthalate (DPHP) by male volunteers: DPHP in blood and its metabolites in blood and urine.

Di-(2-propylheptyl) phthalate (DPHP) is used as a plasticizer for polyvinyl chloride products. A tolerable daily intake of DPHP of 0.2 mg/kg body weight has been derived from rat data. Because toxicokinetic data of DPHP in humans were not available, it was the aim of the present work to monitor DPHP and selected metabolites in blood and urine of 6 male volunteers over time following ingestion of a single DPHP dose (0.7 mg/kg body weight). Concentration-time courses in blood were obtained up to 24 h for DPHP, mono-(2-propylheptyl) phthalate (MPHP), mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPHP), and mono-(2-propyl-6-oxoheptyl) phthalate (oxo-MPHP); amounts excreted in urine were determined up to 46 h for MPHP, OH-MPHP, oxo-MPHP, and mono-(2-propyl-6-carboxyhexyl) phthalate (cx-MPHP). All curves were characterized by an invasion and an elimination phase the kinetic parameters of which were determined together with the areas under the concentration-time curves in blood (AUCs). AUCs were: DPHP > MPHP > oxo-MPHP > OH-MPHP. The amounts excreted in urine were: oxo-MPHP > OH-MPHP> > cx-MPHP > MPHP. The AUCs of MPHP, oxo-MPHP, or OH-MPHP could be estimated well from the cumulative amounts of urinary OH-MPHP or oxo-MPHP excreted within 22 h after DPHP intake. Not considering possible differences in species-sensitivity towards unconjugated DPHP metabolites, it was concluded from a comparison of their AUCs in DPHP-exposed humans with corresponding earlier data in rats that there is no increased risk of adverse effects associated with the internal exposure of unconjugated DPHP metabolites in humans as compared to rats when receiving the same dose of DPHP per kg body weight.

[Surgical treatment of achalasia - endoscopic or laparoscopic? : Proposal for a tailored approach]. / Operative Therapie bei Achalasie ­ endoskopisch oder laparoskopisch? : Vorschlag für die maßgeschneiderte Verfahrenswahl.

Primary idiopathic achalasia is the most common form of the rare esophageal motility disorders. A curative therapy which restores the normal motility does not exist; however, the therapeutic principle of cardiomyotomy according to Ernst Heller leads to excellent symptom control in the majority of cases. The established standard approach is Heller myotomy through the laparoscopic route (LHM), combined with Dor anterior fundoplication for reflux prophylaxis/therapy. At least four meta-analyses of randomized controlled trials (RCTs) have demonstrated superiority of LHM over pneumatic dilation (PD); therefore, LHM should be used as first line therapy (without prior PD) in all operable patients. Peroral endoscopic myotomy (POEM) is a new alternative approach, which enables Heller myotomy to be performed though the endoscopic submucosal route. The POEM procedure has a low complication rate and also leads to good control of dysphagia but reflux rates can possibly be slightly higher (20-30%). Long-term results of POEM are still scarce and the results of the prospective randomized multicenter trial POEM vs. LHM are not yet available; however, POEM seems to be the preferred treatment option for certain indications. Within the framework of the tailored approach for achalasia management of POEM vs. LHM established in Würzburg, we recommend long-segment POEM for patients with type III achalasia (spasmodic) and other hypercontractile motility disorders and potentially type II achalasia (panesophageal compression) with chest pain as the lead symptom, whereas LHM can also be selected for type I. For sigmoid achalasia, especially with siphon-like transformation of the esophagogastric junction, simultaneous hiatal hernia and epiphrenic diverticula, LHM is still the preferred approach. The choice of the procedure for revisional surgery in case of recurrent dysphagia depends on the suspected mechanism (morphological vs. functional/neuromotor).

Di-(2-propylheptyl) phthalate (DPHP) and its metabolites in blood of rats upon single oral administration of DPHP.

Di-(2-propylheptyl) phthalate (DPHP) does not act as a reproductive toxicant or endocrine disruptor in contrast to other phthalates. Considering adverse effects of phthalates to be linked to their metabolism, it was the aim of the present study to investigate in the rat the blood burden of DPHP and its metabolites as a basis for understanding the toxicological behavior of DPHP. Rats were administered single oral doses of DPHP of 0.7 and 100mg/kg body weight. Concentration-time courses of DPHP and metabolites were monitored in blood. The areas under the concentration-time curves in blood (AUCs), normalized for the dose of DPHP, showed the following order: DPHP

[Diagnostics and therapy of achalasia]. / Diagnostik und Therapie der Achalasie.

The low incidence (1:100,000) makes primary idiopathic achalasia a problem of special importance. Patients often have a long medical history of suffering before the diagnosis is established and adequate therapy provided. Surgeons who perform antireflux surgery must be certain of detecting achalasia patients within their collective of gastroesophageal reflux disease (GERD) patients to avoid contraindicated fundoplication. The current gold standard for establishing the diagnosis of achalasia is manometry. Especially in early stages, symptom evaluation, endoscopy and barium swallow lack adequate sensitivity. High-resolution manometry (HRM) is increasingly used and allows characterization of different achalasia types (i.e. type I classical achalasia, type II panesophageal pressurization and type III spasmodic achalasia) and differentiation from other motility disorders (e.g. distal esophageal spasm, jackhammer esophagus and nutcracker esophagus). For patients over 45 years of age additional endoscopic ultrasound and computed tomography are recommended to exclude pseudoachalasia. A curative treatment restoring normal esophageal function does not exist; however, there are good options for symptom control. Therapy aims are abolishment of dysphagia, improvement of esophageal clearance, prevention of reflux and abolishment of chest pain. The current standard treatment is cardiomyotomy, which was first described 100 years ago by the German surgeon Ernst Heller and has been shown to be clearly superior when compared to endoscopic treatment (e.g. botox injection and balloon dilatation). Heller's myotomy procedure is preferentially performed via the laparoscopic route and combined with partial fundoplication. Currently, an alternative to performing Heller's myotomy via the endoscopic route is under intensive investigation in several centers worldwide. The peroral endoscopic myotomy (POEM) procedure has shown very promising initial results and warrants further clinical evaluation.

[Peroral endoscopic myotomy for treatment of achalasia. Literature review and own initial experience]. / Perorale endoskopische Myotomie zur Therapie der Achalasie. Literaturüberblick und eigene initiale Erfahrung.

Peroral endoscopic myotomy (POEM) is a new, purely endoscopic procedure for treatment of achalasia. Due to the lack of incisions POEM can be regarded as a true NOTES procedure. With POEM a myotomy is created in a similar fashion to the previous standard treatment, laparoscopic Heller myotomy (LHM). The relatively free choice of length and localization of the myotomy may be regarded as advantages of POEM. The procedure starts with a mucosal incision (mucosal entry) followed by preparation of a submucosal tunnel crossing the esophagogastric junction and creation of a myotomy in an antegrade direction before the mucosal access is closed with endoscopic clip placement. Since the first description of the application of POEM in humans in 2010 by the pioneer Haruhiro Inoue, Yokohama, Japan, it has been used increasingly and investigated in some centers in Asia, the U.S.A. and also Europe. The results are very promising. Although the procedure is technically demanding it can be performed safely with low complication rates. The POEM procedure achieves very good control of dysphagia and gastroesophageal reflux witch is only a rare side-effect witch is well-controllable with proton pump inhibitors (PPI). We review the currently available data from the literature and present our own initial series of 14 patients treated with POEM.

[Newly recognized side-effects of proton pump inhibitors. Arguments in favour of fundoplication for GERD?]. / Neu erkannte Nebenwirkungen von Protonenpumpeninhibitoren. Argumente Pro Fundoplicatio bei GERD?

Among other indications proton pump inhibitors (PPIs) are used as medical treatment of gastroesophageal reflux disease (GERD) and are the most frequently prescribed and most frequently used drugs in gastroenterology. Until recently PPIs were regarded as very safe and associated with very few side-effects. However, during recent years study results have revealed many severe adverse events associated especially with long-term PPI use. We review the currently available evidence, regarding the side-effects of PPIs and discuss the potential impact on treatment strategies for GERD (conservative treatment vs. antireflux surgery). Currently available data suggest that PPIs are associated with osteoporosis-related fractures, Clostridium difficile associated diarrhea (CDAD), community and hospital-acquired pneumonia, pharmacologic interaction with clopidogrel and acetylsalicylic acid with subsequent increased rate of cardiovascular events, refractory hypomagnesemia and rebound reflux symptoms etc. The risk-benefit ratio of PPIs is increasingly recognized as being less favourable. This leads to a more critical viewpoint and raises the question whether the side-effects of PPIs may outweigh the benefits, especially with long-term use. The side-effects of PPIs seem to make a strong argument in favour of laparoscopic fundoplication in the treatment of GERD.

Biological effects of imidazolium ionic liquids with varying chain lengths in acute Vibrio fischeri and WST-1 cell viability assays.

Detailed biological studies of methyl- and some ethylimidazolium ionic liquids in luminescent bacteria as well as in the IPC-81 (leukemia cells) and C6 (glioma cells) rat cell lines are presented. Effective concentrations in these test systems are generally some orders of magnitude lower than effective concentrations [corrected] of the conventional solvents acetone, acetonitrile, methanol, and methyl t-butyl ether. No general influence of the anionic compound in the ionic liquids on toxicity could be found, although they seem to modulate toxicity in some cases. The clear influence of the alkyl chain length on toxicity was quantified by linear regression analysis. Alkyl chain length of the longer alkyl chain was varied from 3 to 10 carbon atoms. Consequences for a design of sustainable alternative solvents are briefly sketched.

A toxicokinetic model for styrene and its metabolite styrene-7,8-oxide in mouse, rat and human with special emphasis on the lung.

Styrene (ST) occurs ubiquitously in the environment and it is an important industrial chemical. After its uptake by the exposed mammalian organism, ST is oxidized to styrene-7,8-oxide (SO) by cytochrome P450 dependent monooxygenases. This reactive intermediate is further metabolized by epoxide hydrolase (EH) and glutathione S-transferase (GST). In long-term animal studies, ST induced lung tumors in mice but not in rats. Considering the lung to be the relevant target organ for ST induced carcinogenicity in mice, we extended a previously developed physiological toxicokinetic model in order to simulate the lung burden with ST and SO in the ST exposed mouse, rat and human. The new model describes oral and pulmonary uptake of ST, its distribution into various tissues, its exhalation and its metabolism to SO in lung and liver. It also simulates the distribution of the produced SO into the tissues and its EH and GST mediated metabolism in liver and in lung. In both organs the ST induced GSH consumption is described together with the formation of adducts to hemoglobin and to DNA of lymphocytes in ST exposed mice, rats and humans. The model includes compartments for arterial, venous and pulmonary blood, liver, muscle, fat, richly perfused tissues and lung. The latter organ is represented by two compartments, namely by the conducting and the alveolar zone. The physiological description of the pulmonary compartments relies on measured alveolar retentions, literature values of surface area of capillary endothelium, of the thickness of the tissue 'air-to-plasma', of the partition coefficient lung:blood and of metabolic parameters of ST and SO measured in pulmonary cell fractions of rodents and humans. Simulations of average pulmonary GSH levels in ST exposed rodents agree with measured data. The model predicts a significant GSH depletion (40%) in the conducting zone of mice exposed for 6 h to a ST concentration of only 20 ppm. In the conducting zone of rats, exposure to 200 ppm ST results in a loss of GSH of about 15% only. In humans, a pulmonary GSH reduction does not occur. The highest average pulmonary SO concentrations are predicted for mice, somewhat lower values for rats and by far the lowest ones for humans. Following steady state exposure to 20 ppm ST, the average SO concentration in mouse lungs is expected to be only three times higher than in rats. This difference diminishes to a factor of less than two at 70 ppm. In humans exposed to 20 ppm ST for 8 h, the average pulmonary SO burden of 0.016 micromol/kg is predicted to be about 17 and 50 times smaller than the corresponding values for rat and mouse. In agreement with reported values, pulmonary DNA adduct levels in rodents exposed to 160 ppm ST were simulated to be similar in rats and mice. In summary, there was no dramatic difference in the calculated average pulmonary SO burden between both animal species. However, pulmonary GSH loss was by far more expressed in ST exposed mice than rats. Since the model was validated on all available ST/SO data in mice, rats and humans, we consider it to be useful for estimating the risk resulting from exposure to ST.

Distribution and unspecific protein binding of the xenoestrogens bisphenol A and daidzein.

Physiological toxicokinetic (PT) models are used to simulate tissue burdens by chemicals in animals and humans. A prerequisite for a PT model is the knowledge of the chemical's distribution among tissues. This depends on the blood flow and also on the free fraction of the substance and its tissue:blood partition coefficients. In the present study we determined partition coefficients in human tissues at 37 degrees C for the two selected xenoestrogens bisphenol A (BA) and daidzein (DA), and their unspecific binding to human serum proteins. Partition coefficients were obtained by incubating blood containing BA or DA with each of the following tissues: brain, liver, kidney, muscle, fat, placenta, mammary gland, and adrenal gland. Blood samples were analysed by HPLC. For BA and DA, all partition coefficients in non-adipose tissues were similar (average values: BA 1.4, DA 1.2). However, the lipophilic properties of both compounds diverge distinctly. Fat:blood partition coefficients were 3.3 (BA) and 0.3 (DA). These values indicate that with the exception of fat both compounds are distributed almost equally among tissues. In dialysis experiments, the unspecific binding of BA and DA with human serum proteins was measured by HPLC. For BA, the total concentration of binding sites and the apparent dissociation constant were calculated as 2000 and 100 nmol/ml, respectively. Because of the limited solubility of DA, only the ratio of the bound to the free DA concentration could be determined and was found to be 7.2. These values indicate that at low concentrations only small percentages of about 5% (BA) and 12% (DA) are as unbound free fractions in plasma. Since only the unbound fraction can bind to the estrogen receptor, binding to serum proteins represents a mechanism that limits the biological response in target tissues.

First-pass metabolism of 1,3-butadiene in once-through perfused livers of rats and mice.

First-pass metabolism of 1,3-butadiene (BD) leading to 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), 3-butene-1,2-diol (B-diol), 3,4-epoxy-1,2-butanediol (EBD) and crotonaldehyde (CA) was studied quantitatively in the once-through BD perfused liver of mouse and rat by means of an all-glass gas-tight perfusion system. Metabolites were analyzed using gas chromatography equipped with mass selective detection. The perfusate consisted of Krebs-Henseleit buffer (pH 7.4) containing bovine erythrocytes (40%v/v) and BD. The perfusion flow rates through the livers were 3-4 ml/min (mouse) and 17-20 ml/min (rat). The BD concentrations in the liver perfusates were 330 nmol/ml (mouse) and 240 nmol/ml (rat) being high enough to reach almost saturation of BD metabolism. The mean rates of BD transformation were about 0.014 and 0.055 mmol/h per liver of a mouse and a rat, respectively, being similar to the values expected from in-vivo measurements. There were marked species differences in the formation of BD metabolites. In the effluent of mouse livers, all three epoxides (EB: 9.4 nmol/ml; DEB: 0.06 nmol/ml; EBD: 0.07 nmol/ml) and B-diol (8.2 nmol/ml) were detected. In the perfusate leaving naïve rat livers, only EB and B-diol were found. In that of rat liver, EB concentration was 8.5 times smaller than in that of mouse liver, whereas B-diol concentrations were similar in the effluent liver perfusate of both species. CA was below the limit of its detection (60 nmol/l) in the liver perfusate of mice and of naïve rats. Of BD metabolized, the sum of the metabolites investigated in the effluent amounted to only 30% (mouse) and 20% (rat). In first experiments with rat liver, glutathione (GSH) was depleted by pretreating the animals with diethylmaleate. With the exception of EBD (not quantifiable due to an interfering peak), all other metabolites including CA were found in the effluent perfusate summing up to about 70 and 100% of BD metabolized, which indicates the quantitative importance of the GSH dependent metabolism. In summary, the results demonstrate the relevance of an intrahepatic first-pass metabolism for metabolic intermediates of BD, which undergo further transformation immediately after their production in the liver before leaving this organ. Hitherto, the occurrence of this first-pass metabolism was only hypothesized. The findings will help to explain the drastic species difference between mice and rats in the carcinogenic potency of BD.

Toxicokinetics of inhaled and endogenous isoprene in mice, rats, and humans.

Isoprene (IP) is ubiquitous in the environment and is used for the production of polymers. It is metabolized in vivo to reactive epoxides, which might cause the tumors observed in IP exposed rodents. Detailed knowledge of the body and tissue burden of inhaled IP and its intermediate epoxides can be gained using a physiological toxicokinetic (PT) model. For this purpose, a PT-model was developed for IP in mouse, rat, and human. Experimentally determined partition coefficients were taken from the literature. Metabolic parameters were obtained from gas-uptake experiments. The measured data could be described by introducing hepatic and extrahepatic metabolism into the model. At exposure concentrations up to 50 ppm, the rate of metabolism at steady-state is 14 times faster in mice and about 8 times faster in rats than in humans (2.5 micromol/h/kg at 50 ppm IP in air). IP does accumulate only barely due to its fast metabolism and its low thermodynamic partition coefficient whole body:air. IP is produced endogenously. This production is negligible in rodents compared to that in humans (0.34 micromol/h/kg). About 90% of IP produced endogenously in humans is metabolized and 10% is exhaled unchanged. The blood concentration of IP in non-exposed humans is predicted to be 9.5 nmol/l. The area under the blood concentration-time curve (AUC) following exposure over 8 h to 10 ppm IP is about 4 times higher than the AUC resulting from the unavoidable endogenous IP over 24 h. A comparison of such AUCs can be used for establishing workplace exposure limits. For estimation of the absolute risk, knowledge of the body burden of the epoxide intermediates of IP is required. Unfortunately, such data are not yet available.

No background concentrations of di(2-ethylhexyl) phthalate and mono(2-ethylhexyl) phthalate in blood of rats.

We measured the background levels of di(2-ethylhexyl) phthalate (DEHP) and its hydrolytic metabolite mono(2-ethylhexyl) phthalate (MEHP) in blood from naive female Sprague-Dawley rats and in de-ionized charcoal-purified water using an analytical procedure that is based on sample treatment with acetonitrile, n-hexane extraction and analysis by gas chromatography. In blood, blank values of 91.3 +/- 34.7 micrograms DEHP/l (n = 31) and 30.1 +/- 13.1 micrograms MEHP/l (n = 20) were obtained, and in water, values of 91.6 +/- 44.2 micrograms DEHP/l (n = 26) and 26.7 +/- 10.4 micrograms MEHP/l (n = 15) were found. Since there is no difference between the background valves obtained from blood of naive rats and water, we conclude that DEHP and MEHP result from contamination during the analytical procedure.

Kinetics of propylene oxide metabolism in microsomes and cytosol of different organs from mouse, rat, and humans.

Kinetics of the metabolic inactivation of 1,2-epoxypropane (propylene oxide; PO) catalyzed by glutathione S-transferase (GST) and by epoxide hydrolase (EH) were investigated at 37 degrees C in cytosol and microsomes of liver and lung of B6C3F1 mice, F344 rats, and humans and of respiratory and olfactory nasal mucosa of F344 rats. In all of these tissues, GST and EH activities were detected. GST activity for PO was found in cytosolic fractions exclusively. EH activity for PO could be determined only in microsomes, with the exception of human livers where some cytosolic activity also occurred, representing 1-3% of the corresponding GST activity. For GST, the ratio of the maximum metabolic rate (V(max)) to the apparent Michaelis constant (K(m)) could be quantified for all tissues. In liver and lung, these ratios ranged from 12 (human liver) to 106 microl/min/mg protein (mouse lung). Corresponding values for EH ranged from 4.4 (mouse liver) to 46 (human lung). The lowest V(max) value for EH was found in mouse lung (7.1 nmol/min/mg protein); the highest was found in human liver (80 nmol/min/mg protein). K(m) values for EH-mediated PO hydrolysis in liver and lung ranged from 0.83 (human lung) to 3.7 mmol/L (mouse liver). With respect to liver and lung, the highest V(max)/K(m) ratios were obtained for GST in mouse and for EH in human tissues. GST activities were higher in lung than in liver of mouse and human and were alike in both rat tissues. Species-specific EH activities in lung were similar to those in liver. In rat nasal mucosa, GST and EH activities were much higher than in rat liver.

The relevance of physical activity for the kinetics of inhaled gaseous substances.

Inhalation is the most important route of absorption for many volatile substances. The inhaled chemical is distributed via the bloodstream into the organs and tissues. It is eliminated mainly unchanged by exhalation and also via metabolism. The blood concentration can be considered as a surrogate for the body burden of the chemical. It depends on the rate of uptake and on the rate of elimination. The rate of uptake by inhalation is determined by the blood:air partition coefficient of the gaseous compound, the actual concentration of the chemical already in the blood entering the lungs, the blood flow through the lungs, and the alveolar ventilation. The latter is greatly influenced by physical activity, which thus has a crucial impact on the rate of uptake. Consequently, the blood concentration of an inhaled chemical and the resulting alveolar retention, representing the rate of metabolism at steady-state, are dependent on the intensity of physical work. Both parameters can be calculated for steady-state conditions using simple algebraic equations, if one assumes that the rate of metabolic elimination is limited by the blood flow through the metabolizing organs. This assumption is valid for many rapidly metabolized inhaled gases and vapours at low concentrations present under workplace conditions. The derived equations give the theoretical background for the observations presented from a series of experimental studies which demonstrate that physical activity can be a major determinant of the toxicokinetics of inhaled compounds. Practical examples illustrate the procedure. We conclude that workplace-related physical activity should be taken into account for compounds with blood:air partition coefficients above 6 in the determination of occupational limit concentrations in air.