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A sexual enhancer dietary supplement in pre-commercialization phase was analyzed. It contained the two phosphodiesterase-5 inhibitors (PDE-5i) sildenafil and methisosildenafil as major adulterants. Fourteen more sildenafil derivatives were detected and after isolation, their structures were elucidated thanks to NMR, high resolution and tandem mass spectrometry, and UV spectroscopy. Ten of them were never described. All these compounds are probably by-products of different reaction steps during the synthesis of the two PDE-5i that were not properly eliminated during the purification procedure. The total amount of sildenafil-related compounds was estimated at 68 mg per capsule, sildenafil and methisosildenafil accounting for 20 mg and 38 mg respectively., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The use of nanocarriers for hydrophobic photosensitizers, in the context of photodynamic therapy (PDT) to improve pharmacokinetics and bio-distribution, is well-established. However, the mechanisms at play in the internalization of nanocarriers are not well-elucidated, despite its importance in nanocarrier design. In this study, we focus on the mechanisms involved in copolymer poly(ethylene oxide)- block -poly(-caprolactone) PEO-PCL and poly(ethylene oxide)- block -poly styrene PEO-PS micelles - membrane interactions through complementary physico-chemical studies on biomimetic membranes, and biological experiments on two-dimensional (2D) and three-dimensional (3D) cell cultures. Förster Resonance Energy Transfer measurements on fluorescently-labelled lipid vesicles, and flow cytometry on two cancerous cell lines enabled the evaluation in the uptake of a photosensitizer, Pheophorbide a (Pheo), and copolymer chains towards model membranes, and cells, respectively. The effects of calibrated light illumination for PDT treatment on lipid vesicle membranes, i.e., leakage and formation of oxidized lipids, and cell viability, were assessed. No significant differences were observed between the ability of PEO-PCL and PEO-PS micelles in delivering Pheo to model membranes, but Pheo was found in higher concentrations in cells in the case of PEO-PCL. These higher Pheo concentrations did not correspond to better performances in PDT treatment. We demonstrated that there are subtle differences in PEO-PCL and PEO-PS micelles for the delivery of Pheo., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Red yeast rice dietary supplements (RYR DS) are largely sold in Western countries for their cholesterol-lowering/regulating effect due to monacolins, mainly monacolin K (MK), which is, in fact, lovastatin, the first statin drug on the market. 1 H-NMR was used as an easy, rapid and accurate method to establish the chemical profiles of 31 RYR DS and to quantify their monacolin contents. Among all the 1 H resonances of the monacolins found in RYR, only those of the ethylenic protons of the hexahydronaphthalenic ring at 5.84 and 5.56 ppm are suitable for quantification because they show no overlap with the matrix signals. The total content in monacolins per capsule or tablet determined in 28 DS (the content in 3 DS being below the limit of quantification of the method, ≈ 0.25 mg per unit dose) was close to that measured by UHPLC, as shown by the good linear correlation between the two sets of values (slope 1.00, y-intercept 0.113, r 2 0.986). Thirteen of the 31 RYR DS analyzed (i.e., 42%) did not provide label information on the concentration of monacolins and only nine of the 18 formulations with an indication (i.e., 50%) actually contained the declared amount of monacolins.

The tyrosine dimer (Tyr2), a covalent bond between two tyrosines (Tyr), is one of the most important modifications of the oxidative damage of proteins. This compound is increasingly used as a marker of aging, stress and pathogenesis. At physiological pH, Tyr2 is able to absorb radiation at wavelengths significantly present in the solar radiation and artificial sources of light. As a result, when Tyr2 is formed in vivo, a new chromophore appears in the proteins. Despite the biomedical importance of Tyr2, the information of its photochemical properties is limited due to the drawbacks of its synthesis. Therefore, in this work we demonstrate that at physiological pH, Tyr2 undergoes oxidation upon UV excitation yielding different products which conserve the dimeric structure. During its photodegradation different reactive oxygen species, like hydrogen peroxide, superoxide anion and singlet oxygen, are produced. Otherwise, we demonstrated that Tyr2 is able to sensitize the photodegradation of tyrosine. The results presented in this work confirm that Tyr2 can act as a potential photosensitizer, contributing to the harmful effects of UV-A radiation on biological systems.

Objectives: Cutaneous manifestations (CM) in ANCA-associated vasculitides (AAV) are frequent, but data on clinical significance and clinical-pathological correlations are lacking., Methods: We conducted a multicenter, retrospective study including 1553 AAV patients. Clinical, biological and pathological features have been analyzed, and tissue samples from 46 biopsies were reviewed in a blind manner., Results: CM were more frequent in EGPA (53.0%) and MPA (51.9%) than in GPA (36.7%). Lesions more frequently associated with GPA were oral ulcers (4.6% vs. 2.5% in EGPA and 0.3% in MPA), while pyoderma gangrenosum and palpebral xanthoma were specific to GPA. Lesions associated with MPA were segmentary edema (19.5% vs. 12.7% in EGPA and 4.3% in GPA) and livedo (12.4% vs. 0.5% and 2.6%, respectively), whereas those associated with EGPA were urticarial lesions (11.5% vs. 1.9% in GPA and 3.5% in MPA) and nodules (12,2% vs. 8.9% in GPA and 4.7% in MPA). In GPA, CM patients had more frequent vasculitis than granulomatous phenotype, and poorer relapse-free and overall survival. Pathological analysis showed vasculitis and/or granulomatous infiltrates in 87.5% of GPA, in 61.1% of EGPA and in all MPA. Vasculitis was more frequently observed in purpura and nodules, while granulomas were differently located and organized within vessels or interstitium according to the type of lesions., Conclusion: Each AAV seemed to be associated with a peculiar pattern of cutaneous lesions. CM are associated with poorer prognosis in GPA. Clinical-pathological correlations showed no specific feature of each AAV, whereas granulomatous infiltrates differ according to the type of lesions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Tris-Acetate buffer is currently used in the selection and the characterization of ssDNA by capillary electrophoresis (CE). By applying high voltage, the migration of ionic species into the capillary generates a current that induces water electrolysis. This phenomenon is followed by the modification of the pH and the production of Tris derivatives. By injecting ten times by capillary electrophoresis ssDNA (50 nM), the whole oligonucleotide was degraded. In this paper, we will show that the Tris buffer in the running vials is modified along the electrophoretic process by electrochemical reactions. We also observed that the composition of the metal ions changes in the running buffer vials. This phenomenon, never described in CE, is important for fluorescent ssDNA analysis using Tris buffer. The oligonucleotides are degraded by electrochemically synthesized species (present in the running Tris vials) until it disappears, even if the separation buffer in the capillary is clean. To address these issues, we propose to use a sodium phosphate buffer that we demonstrate to be electrochemically inactive., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The sildenafil analogue adulterant previously identified as a nitroso derivative (nitrosoprodenafil) in a dietary supplement (DS) marketed to increase sexual performance and sold in Europe in the early 2010s is the same as that found in the same type of DS available in Japan whose structure was established as a nitro derivative (mutaprodenafil or nitroprodenafil). Indeed, the compound isolated from the Man Power DS has identical UV, IR, NMR and MS spectroscopic characteristics and hydrolysis behavior than nitrosoprode-nafil. By revisiting its NMR assignments and MS and MS/MS data interpretation, it is demonstrated that the compound is actually a nitrothioimidazole-methisosildenafil hybrid, i.e. nitroprodenafil, whose structure is unequivocally confirmed by X-ray crystallography and synthesis experiments. Because the product is converted to methisosildenafil by hydrolysis, it is named nitropromethisosildenafil., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background and Study Aims: Esophageal squamous papilloma (ESP) is a rare lesion. The aims of this study were to assess the prevalence of ESP in northeastern France and the risk of associated squamous cell carcinoma (SCC)., Patients and Methods: The charts of 78 patients who were diagnosed with ESP between January 2005 and February 2013 at three hospitals in northeastern France were reviewed., Results: A total of 55 305 endoscopies were performed and 78 ESP were diagnosed (0.01 %). Patients with ESP included 44 males (56.4 %), 34 females (43.6 %); median age 50, interquartile range (IQR) 19 - 86. Median follow-up was 21 months (IQR 0 - 91 mo) and median time between first and second endoscopy was 7 months (IQR 0.5 - 74 mo). Of the total number of patients, 35 (44.9 %) had a second endoscopy. Main endoscopy indication was dyspepsia (24.4 %). Most ESP were isolated (93.6 %) and located at distal esophagus (27 cm, IQR 16 - 40 cm). Median size was 3 mm (IQR 1 - 20 mm). ESP-associated endoscopic lesions were hiatal hernia in 12 patients and esophagitis in 11 patients. Endoscopic treatment was mainly excisional biopsies (60.3 %). Human papillomavirus (HPV) was not detected in the 6 patients with available data. Low dysplasia was found in 2 ESP. During follow-up endoscopies, 2 SCC were detected in 2 different patients; the first SCC was located at the previous resection site of the ESP and the second had a different location. Prevalence of associated cancer was 1.3 %., Conclusion: Prevalence of ESP in northeastern France is similar to that previously reported. Endoscopic findings were also broadly the same as in previous reports. The occurrence of dysplasia and SCC should strongly encourage the endoscopist to totally remove the ESP and to start an endoscopic surveillance, given the potential risk of malignant transformation.

The Wunderlich syndrome found after the rupture of primitive renal Ewing's sarcoma is not a situation that we find often in everyday practice. The clinical findings are not specific, which is why the differential diagnosis must be made with a multitude of benign and malignant renal masses until the correct diagnosis can be made by the pathologist. The CT and MRI images are not characteristic. One treatment option is the multidisciplinary approach; however, the prognosis remains poor for patients with metastatic disease.

Oxidized pterins, efficient photosensitizers under UV-A irradiation, accumulate in the skin of patients suffering from vitiligo, a chronic depigmentation disorder. In this work, we have investigated the ability of pterin (Ptr), the parent compound of oxidized pterins, to photosensitize the oxidation of the peptide α-melanocyte-stimulating hormone (α-MSH), which stimulates the production and release of melanin by melanocytes in skin and hair. Our results showed that Ptr is able to photoinduce the degradation of α-MSH upon UV-A irradiation and that the reaction is initiated by an electron transfer from the peptide to the triplet excited state of Ptr. The photosensitized process produces chemical changes in at least two different amino acid residues: tryptophan and tyrosine (Tyr). It was shown that α-MSH undergoes dimerization and oxidation, the former process taking place after the formation of Tyr radicals. The present findings are analyzed in the context of the general behavior of pterins as photosensitizers and the biological implications are discussed.

Introduction: Toxocariasis is a common helminth infection that causes visceral larva migrans in humans. It has a wide and varied clinical spectrum., Case: A 60-year-old woman consulted after 6 months of recurrent biliary pain with fever. Laboratory tests showed moderate disturbance of liver enzymes and hypereosinophilia (10 400/mm3). Imaging studies revealed a pseudotumor in hepatic segment IV, hyperechoic in abdominal ultrasound and low density in computed tomography. The diagnostic conclusion after ultrasound-guided liver biopsy was unspecific granulomatous hepatitis and eosinophilic infiltrate. The course of the antibody titer to Toxocara canis finally resulted in a diagnosis of Toxocara infection. Outcome was good following treatment with diethylcarbamazine., Discussion: Some clinical features of liver toxocariasis can mimic tumors and may be interpreted histologically as granulomatous hepatitis, eosinophilic infiltrate of the hepatic portal vein, and/or necrotizing eosinophilic abscesses. Treatment is not yet well codified, but the symptomatic forms call for albendazole or diethylcarbamazine.

Purpose: The glutathione detoxification pathway includes glutathione S-transferase (GST) and peroxidase (GPX) isoenzymes as well as glutathione reductase (GSSR). Though well established from cultured cancer cell lines, its involvement in resistance is still unclear in the tumours. This study aimed to describe the parameters that influence the glutathione contents and associated activities in breast cancer., Methods: The components of the glutathione pathway were measured in the tumours from 41 women with primary breast cancer in comparison with those in the matched tumour-free samples. Appropriate statistical studies (regression analysis, Wilcoxon signed rank test) explored the influence of clinical and prognostic factors., Results: Reduced and total glutathione contents were largely increased (P < 0.0001) and all related activities were significantly enhanced in the tumours. Interindividual variations were described, probably due to various parameters (age, menopause, axillary lymph node status, S and G2 + M cell fractions, ER, cathepsin-D and c-ErbB-2 expressions) that influence particular components of the glutathione pathway, especially the glutathione levels., Conclusions: The breast tumours improved their redox status and detoxification capacities depending on various parameters of significance for cell proliferation and aggressiveness, which supports the involvement of the glutathione pathway in malignant cell resistance to oxidative stress and apoptosis.

The history of a 28-year-old woman with anaplastic large cell lymphoma (ALCL) in the first trimester of her pregnancy is reported. Investigations allowed to diagnose a T-cell CD30 positive ALCL, which appearance is rare during pregnancy. Moreover, the atypical lymphoid cells were found in the peripheral blood and were predominantly small to medium sized with nuclear irregularities and cytoplasmic azurophilic granules, which allowed the hypothesis of leukaemic presentation of a small cell variant ALCL. A variant of the t(2:5)(p23:q35) was found [del(2)(p22)]. The patient died shortly after diagnosis.

2 cases of rectal metastatic breast carcinoma were treated by an abdomino-perineal resection. The rectal involvement is quite uncommon, and only 6 others cases treated with surgery have been described in the international literature. We think that only radical surgery can give a good palliation.

A round mass was found by an abdominal ultrasonography in the head of the pancreas of a 63 year-old woman. Ultrasonography was performed because of abdominal pain. Percutaneous aspiration cytology suggested pancreatic adenocarcinoma. A pancreatoduodenectomy was performed heading to the discovery of an intrapancreatic lipoma. This lesion should be added to the list of benign connective tissue tumors of the pancreas.

The authors study the Pancreas divisum's rate in 242 cadavers. With two successive studies, they establish a rate of about 6.6%. They conform the sexual disparity and the presence of muscular fibre cells on a level with papilla duodeni minor.