Visceral Artery Aneurysms in the Presence of Upstream Stenoses.

Background: Sutton-Kadir syndrome describes a rare pathology that commonly includes an aneurysm of the inferior pancreaticoduodenal artery in combination with a celiac trunk stenosis or occlusion, often caused by median arcuate ligament compression. Several therapeutic approaches exist including open surgical, endovascular, and hybrid treatments. Other combinations of visceral artery aneurysms and upstream stenoses exist but the cumulative body of evidence on these combinations is weak due to their rarity. Methods: A retrospective analysis of patient data from a single center was carried out. Electronic patient records were filtered for keywords including "visceral aneurysm", "Sutton-Kadir", and "median arcuate ligament". Imaging studies were re-examined by two blinded vascular surgeons with a third vascular surgeon as a referee in case of diverging results. Results: Sixteen patients had a visceral artery aneurysm with an upstream stenosis. All cases had a celiac trunk obstruction while one patient also had a concomitant superior mesenteric artery stenosis. Both median arcuate ligament compression and atherosclerotic lesions were identified. The location of the aneurysms varied even though the inferior pancreaticoduodenal artery was most frequently affected. A classification system based on the different combinations of stenoses and aneurysms is presented and introduced as a new pathologic entity: visceral artery aneurysm in the presence of upstream stenosis (VAPUS). Conclusions: The concomitant presence of visceral artery aneurysms, especially in the pancreaticoduodenal arteries, and blood flow impairment of the celiac axis or superior mesenteric artery is a rare pathology. The proposed VAPUS classification system offers an accessible and transparent route to the precise localization of the affected vessels.

Enigmatic mechanism of the N-vinylpyrrolidone hepatocarcinogenicity in the rat.

N-vinyl pyrrolidone (NVP) is produced up to several thousand tons per year as starting material for the production of polymers to be used in pharmaceutics, cosmetics and food technology. Upon inhalation NVP was carcinogenic in the rat, liver tumor formation is starting already at the rather low concentration of 5 ppm. Hence, differentiation whether NVP is a genotoxic carcinogen (presumed to generally have no dose threshold for the carcinogenic activity) or a non-genotoxic carcinogen (with a potentially definable threshold) is highly important. In the present study, therefore, the existing genotoxicity investigations on NVP (all showing consistently negative results) were extended and complemented with investigations on possible alternative mechanisms, which also all proved negative. All tests were performed in the same species (rat) using the same route of exposure (inhalation) and the same doses of NVP (5, 10 and 20 ppm) as had been used in the positive carcinogenicity test. Specifically, the tests included an ex vivo Comet assay (so far not available) and an ex vivo micronucleus test (in contrast to the already available micronucleus test in mice here in the same species and by the same route of application as in the bioassay which had shown the carcinogenicity), tests on oxidative stress (non-protein-bound sulfhydryls and glutathione recycling test), mechanisms mediated by hepatic receptors, the activation of which had been shown earlier to lead to carcinogenicity in some instances (Ah receptor, CAR, PXR, PPARα). No indications were obtained for any of the investigated mechanisms to be responsible for or to contribute to the observed carcinogenicity of NVP. The most important of these exclusions is genotoxicity. Thus, NVP can rightfully be regarded and treated as a non-genotoxic carcinogen and threshold approaches to the assessment of this chemical are supported. However, the mechanism underlying the carcinogenicity of NVP in rats remains unclear.

Exploiting hot-spots; effective determination of lichen diversity in a Carpathian virgin forest.

Although lichenized fungi are among the most reliable indicators of forest quality and represent a considerable part of forest biodiversity, methods maximizing completeness of their species lists per area are lacking. Employing a novel methodological approach including a multi-expert competition and a search for local hot-spot plots, we have obtained outstanding data about epiphytic lichen biota in a part of the largest Central European virgin forest reserve Uholka-Shyrokyi Luh situated in Ukrainian Carpathians. Our field research consisted of two four-day periods: (1) an overall floristic survey and a search for spots with raised lichen diversity, and (2) survey in four one-hectare plots established in lichen diversity hot-spots along an altitudinal gradient. Recorded alpha-diversities in plots ranged from 181-228 species, but estimated species richness is in the range 207-322 species. Detected gamma-diversity was 387 species; estimates are 409-484 species. 93% of the species found in the forest were recorded in plots, but only 65% outside the plots. This underlines the high-efficiency of the multi-expert competitive survey in diversity hot-spot plots. Species richness in each one-hectare plot was equal to the numbers of species obtained by floristic surveys of much larger old-growth forest areas in Central Europe. Gamma-diversity detected in the Uholka primeval forest far exceeded all numbers achieved in Central European old-growth forests. Our method appears to be both effective (it obtains a more nearly complete inventory of species) and practical (the resources required are not unreasonably large).

Pain and fertility outcomes of nerve-sparing, full-thickness disk or segmental bowel resection for deep infiltrating endometriosis-A prospective cohort study.

INTODUCTION: Choosing the optimal treatment for bowel endometriosis, ie, conservative vs radical surgery, is under debate. We aimed to evaluate the surgical outcomes of segmental resection and disk resection regarding fertility, pain symptoms, and quality of life score of women with colorectal deep infiltrating endometriosis. MATERIAL AND METHODS: From March 2011 to December 2016, 134 consecutive patients with symptomatic deep infiltrating endometriosis of the rectosigmoid up to 25 cm from the anal verge undergoing segmental resection or disk resection were prospectively evaluated regarding reduction in pain symptoms, fertility outcomes, and complication rates according to Clavien-Dindo classification. RESULTS: Of the 134 women included, segmental resection was performed in 102 (76.1%) women and disk resection was performed in 32 (23.9%) women. There was no difference in duration of surgery, complication rates, mean hospital stay, or discrepancy in hemoglobin level comparing the two groups. There was no significant difference regarding reduction of pain symptoms, fertility, and functional outcomes. One hundred and twelve (83.6%) women were followed up long-term. In both cohorts, there was a significant reported decrease in pain symptoms and increase in quality of life scores. Of all the 61 infertile women, 26 (42.6%) became pregnant spontaneously, and 13 (21.3%) by in vitro fertilization with an overall pregnancy rate of 63.4%. The overall complication rate (Clavien-Dindo III-IV) was 8 of 134 (5.9%) without statistically significant difference between the cohorts. CONCLUSIONS: Both conservative surgery with disk resection, and nerve- and vessel-sparing segmental resection reduce pain symptoms with equal morbidity. Fertility is improved with surgery with both techniques.

Considerations and consequences of allowing DNA sequence data as types of fungal taxa.

Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.

Assessment of skin sensitization under REACH: A case report on vehicle choice in the LLNA and its crucial role preventing false positive results.

In the EU, chemicals with a production or import volume in quantities of one metric ton per year or more have to be tested for skin sensitizing properties under the REACH regulation. The murine Local Lymph Node Assay (LLNA) and its modifications are widely used to fulfil the data requirement, as it is currently considered the first-choice method for in vivo testing to cover this endpoint. This manuscript describes a case study highlighting the importance of understanding the chemistry of the test material during testing for 'skin sensitization' of MCDA (mixture of 2,4- and 2,6-diamino-methylcyclohexane) with particular focus on the vehicle used. While the BrdU-ELISA modification of the LLNA using acetone/olive oil (AOO) as vehicle revealed expectable positive results. However, the concentration control analysis unexpectedly revealed an instability of MCDA in the vehicle AOO. Further studies on the reactivity showed MCDA to rapidly react with AOO under formation of various imine structures, which might have caused the positive LLNA result. The repetition of the LLNA using propylene glycol (PG) as vehicle did not confirm the positive results of the LLNA using AOO. Finally, a classification of MCDA as skin sensitizer according to the Globally Harmonized System (GHS) was not justified.

Profiling of mercapturic acids of acrolein and acrylamide in human urine after consumption of potato crisps.

SCOPE: Acrolein (AC) and acrylamide (AA) are food contaminants generated by heat treatment. We studied human exposure after consumption of potato crisps by monitoring excretion of mercapturic acids (MAs) in urine. METHODS AND RESULTS: MA excretion was monitored in human urine collected up to 72 h after ingestion of a test meal of experimental (study 1: 1 mg AA/150 g) or commercially available (study 2: 44 µg AA plus 4.6 µg AC/175 g) potato crisps. MA contents were analysed after purification via SPE using HPLC-ESI-MS/MS. On the basis of the area under the curve values of MAs excreted in urine, the total excretion of AC-related MAs exceeded that of AA-related MAs up to 12 times in study 1 and up to four times in study 2. Remarkably, AC content of potato crisps of study 2 was found to be only about 1/10 the AA content, as determined by isotope dilution headspace GC/MS. CONCLUSION: Our results indicate substantially higher exposure to AC from potato crisps than to AA. Total AC in such foods may encompass bioavailable AC forms not detected by headspace GC/MS. Both findings may also apply to other heat processed foods.

N7-glycidamide-guanine DNA adduct formation by orally ingested acrylamide in rats: a dose-response study encompassing human diet-related exposure levels.

Acrylamide (AA) is formed during the heating of food and is classified as a genotoxic carcinogen. The margin of exposure (MOE), representing the distance between the bench mark dose associated with 10% tumor incidence in rats and the estimated average human exposure, is considered to be of concern. After ingestion, AA is converted by P450 into the genotoxic epoxide glycidamide (GA). GA forms DNA adducts, primarily at N7 of guanine (N7-GA-Gua). We performed a dose-response study with AA in female Sprague-Dawley (SD) rats. AA was given orally in a single dosage of 0.1-10 000 µg/kg bw. The formation of urinary mercapturic acids and of N7-GA-Gua DNA adducts in liver, kidney, and lung was measured 16 h after application. A mean of 37.0 ± 11.5% of a given AA dose was found as mercapturic acids (MAs) in urine. MA excretion in urine of untreated controls indicated some background exposure from endogenous AA. N7-GA-Gua adduct formation was not detectable in any organ tested at 0.1 µg AA/kg bw. At a dose of 1 µg/kg bw, adducts were found in kidney (around 1 adduct/10(8) nucleotides) and lung (below 1 adduct/10(8) nucleotides) but not in liver. At 10, respectively, 100 µg/kg bw, adducts were found in all three organs, at levels close to those found at 1 µg AA/kg, covering a range of about 1-2 adducts/10(8) nucleotides. As compared to DNA adduct levels from electrophilic genotoxic agents of various origin found in human tissues, N7-GA-Gua adduct levels within the dose range of 0.1-100 µg AA/kg bw were at the low end of this human background. We propose to take the background level of DNA lesions in humans more into consideration when doing risk assessment of food-borne genotoxic carcinogens.

Biological effects of acrylamide after daily ingestion of various foods in comparison to water: a study in rats.

SCOPE: Acrylamide (AA), classified as a genotoxic carcinogen, is generated by heating foods. We studied whether the food matrix modulates bioavailability and/or biotransformation and investigated kinetics and biological effectiveness of AA in rats. METHODS AND RESULTS: AA was given to the animals at a daily intake level of AA containing foods for up to 9 days, resulting in an exposure of 50 or 100 µg AA/kg body weight (b.w.)/day. Positive controls received the same dosages of AA in water, negative controls just water. As biomarkers urinary mercapturic acids, hemoglobin adducts, plasma levels of AA and glycidamide (GA) and DNA integrity in white blood cells and hepatocytes were measured. Altogether, no significant differences in bioavailability of AA from water and the different food matrices were observed. Only with bread crust, biomarkers indicated a slightly reduced bioavailability. Monitoring glycidamide valine adduct adducts did not provide evidence for treatment-related significantly enhanced GA-haemoglobin adduct formation in blood although glycidamide mercapturic acid excretion in urine indicated significant GA formation. CONCLUSIONS: The results suggest AA at dietary intake levels, exceeding estimated human mean intake by a factor of at least 100 to become detoxified in Sprague-Dawley rats to a major extent through glutathione coupling.

In vivo role of cytochrome P450 2E1 and glutathione-S-transferase activity for acrylamide toxicokinetics in humans.

Acrylamide, a potential food carcinogen in humans, is biotransformed to the epoxide glycidamide in vivo. Both acrylamide and glycidamide are conjugated with glutathione, possibly via glutathione-S-transferases (GST), and bind covalently to proteins and nucleic acids. We investigated acrylamide toxicokinetics in 16 healthy volunteers in a four-period change-over trial and evaluated the respective role of cytochrome P450 2E1 (CYP2E1) and GSTs. Participants ingested self-prepared potato chips containing acrylamide (1 mg) without comedication, after CYP2E1 inhibition (500 mg disulfiram, single dose) or induction (48 g/d ethanol for 1 week), and were phenotyped for CYP2E1 with chlorzoxazone (250 mg, single dose). Unchanged acrylamide and the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) and N-acetyl-S-(2-hydroxy-2-carbamoylethyl)-cysteine (GAMA) accounted for urinary excretion [geometric mean (percent coefficient of variation)] of 2.9% (42), 65% (23), and 1.7% (65) of the acrylamide dose in the reference period. Hemoglobin adducts increased clearly following the acrylamide test-meal. The cumulative amounts of acrylamide, AAMA, and GAMA excreted and increases in AA adducts changed significantly during CYP2E1 blockade [point estimate (90% confidence interval)] to the 1.34-fold (1.14-1.58), 1.18-fold (1.02-1.36), 0.44-fold (0.31-0.61), and 1.08-fold (1.02-1.15) of the reference period, respectively, but were not changed significantly during moderate CYP2E1 induction. Individual baseline CYP2E1 activity, CYP2E1*6, GSTP1 313A>G and 341T>C single nucleotide polymorphisms, and GSTM1-and GSTT1-null genotypes had no major effect on acrylamide disposition. The changes in acrylamide toxicokinetics upon CYP2E1 blockade provide evidence that CYP2E1 is a major but not the only enzyme mediating acrylamide epoxidation in vivo to glycidamide in humans. No obvious genetic risks or protective factors in xenobiotic-metabolizing enzymes could be determined for exposed subjects.