Toxic plants-Detection of colchicine in a fast systematic clinical toxicology screening using liquid chromatography-mass spectrometry

Colchicum autumnale, which can be mistaken for Allium ursinum, contains the alkaloid colchicine potentially leading to life-threatening up to fatal intoxications. We report two cases of acute intoxications with unexplained circumstances. Using the authors' systematic screening approaches, colchicine could be detected in blood plasma and urine samples using liquid chromatography coupled to linear ion trap mass spectrometry (LC-ITMSn ) and high-resolution tandem mass spectrometry (LC-HRMS/MS). Metabolites of colchicine could be identified in urine for confirmation of screening results. Gas chromatography–mass spectrometry (GC-MS) analysis was also conducted, but colchicine could not be detected. Furthermore, colchicine concentration was estimated via LC-HRMS/MS in plasma samples. Results of the systematic screening indicated the ingestion of colchicine from both subjects. In both cases, the parent compound was detected in blood plasma and urine using the LC-HRMS/MS and LC-ITMSn system. An O-demethylation metabolite was identified in urine samples of both subjects using LC-HRMS/MS; the N-deacetylation product was also found in urine samples of both cases via LC-HRMS/MS and LC-ITMSn . The use of LC-ITMSn resulted only in the detection of the O-demethylation product in case 2. Plasma concentrations were estimated at 2.5 ng/ml and 4.7 ng/ml for cases 1 and 2, respectively. We demonstrated the detection of this highly toxic alkaloid in blood plasma and urine using a time-saving and reliable clinical systematic screening. Furthermore, we identified metabolites of colchicine being rarely discussed in literature, which can be used as additional screening targets

Protected rather than protracted: strengthening displaced persons in peace processes: a state-of-the-art paper

This Paper reviews the current state of the art on the return of displaced persons as a durable solution for long-term displacement situations. It outlines the impact, challenges and actors involved in the return process. The Paper shows that present understandings of return, protracted situations and conflict are often too short-sighted and need to be revised and extended. Reintegration as part of the return process in particular has only received little attention until now. The Paper further demonstrates that the relationship between displacement, return and peace has not yet been fully understood. More field and comparative research is needed that includes the perspectives of the displaced themselves to fully comprehend the process of return and to be able to identify best practices to guarantee the sustainability of return and reintegration

Assessing Adherence to Antihypertensive Medication by Means of Dose-Dependent Reference Plasma Concentration Ranges and Ultra-High Performance Liquid Chromatography-Ion Trap Mass Spectrometry Analysis

Poor adherence to antihypertensive drug therapy is a well-recognized problem and can be assessed by mass spectrometry-based analyses of body fluids. However, contrary statements exist whether drug quantification in blood or qualitative screening in urine is more suitable. The present pilot study aimed to further elucidate the power of blood plasma drug concentrations for adherence monitoring by developing and validating a quantification procedure for nine antihypertensive drugs (amlodipine, bisoprolol, candesartan, canrenone, carvedilol, metoprolol, olmesartan, torasemide, and valsartan) in blood plasma using liquid–liquid extraction and an ultra-high-performance liquid chromatography-ion trap mass spectrometry analysis. The procedure should then be used for an adherence assessment and compared with the results of an established qualitative urine screening. Selectivity, carryover, matrix effect, accuracy, precision, dilution integrity, and stability were successfully validated, except for amlodipine. The applicability was demonstrated by analyzing 19 plasma samples containing 28 antihypertensive drugs and comparing the measured concentrations with calculated dose-dependent reference plasma concentration ranges. The interpretation of plasma concentrations was found to be more sophisticated and time-consuming than that of urine screening results, and adherence could not be assessed in two cases (10%) due to measured plasma concentrations below the lower limit of quantification. However, 14 out of 19 subjects were classified as adherent (75%) and three as nonadherent (15%), in contrast to 19 (100%) that were claimed to be adherent based on the results of the qualitative urine screening. Nevertheless, further data is needed to estimate whether plasma quantification is superior in terms of assessing adherence to antihypertensive medication

Connecting the timescales in picosecond remagnetization experiments

In femtosecond demagnetization experiments, one gains access to the elementary relaxation mechanisms of a magnetically ordered spin system on a time scale of 100 fs. Following these experiments, we report a combined micromagnetic and experimental study that connects the different regimes known from all-optical pump-probe experiments by employing a simple micromagnetic model. We identify spin-wave packets on the nanometer scale that contribute to the remagnetization process on the intermediate time scale between single-spin relaxation and collective precession.Comment: 12 pages, 3 figures, submitted to Phys. Rev. Lett, changes made with regard to review proces

Clonality of CD4+ Blood T Cells Predicts Longer Survival With CTLA4 or PD-1 Checkpoint Inhibition in Advanced Melanoma

Recognition of cancer antigens drives the clonal expansion of cancer-reactive T cells, which is thought to contribute to restricted T-cell receptor (TCR) repertoires in tumor-infiltrating lymphocytes (TILs). To understand how tumors escape anti-tumor immunity, we investigated tumor-associated T-cell repertoires of patients with advanced melanoma and after blockade of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PD-1). TCR Vβ-gene spectratyping allowed us to quantify restrictions of T-cell repertoires and, further, diversities of T-cell clones. In this study, we show that the blood TCR repertoires were variably restricted in CD4+ and extensively restricted in CD8+ T cells of patients with advanced melanoma, and contained clones in both T-cell fractions prior to the start of immunotherapy. A greater diversification especially of CD4+ blood T-cell clones before immunotherapy showed statistically significant correlations with long-term survival upon CTLA4 or PD-1 inhibition. Analysis of TILs and corresponding blood available in one patient indicated that blood clonality may at least partially be related to the clonal expansion in the tumor microenvironment. In patients who developed severe immune-related adverse events (IrAEs), CD4+ and CD8+ TCR spectratypes became more restricted during anti-CTLA4 treatment, suggesting that newly expanded oligoclonal T-cell responses may contribute to IrAEs. This study reveals diverse T-cell clones in the blood of melanoma patients prior to immunotherapy, which may reflect the extent to which T cells are able to react against melanoma and potentially control melanoma progression. Therefore, the T-cell clonality in the circulation may have predictive value for antitumor responses from checkpoint inhibition

Definition and classification of chyle leak after pancreatic operation: A consensus statement by the International Study Group on Pancreatic Surgery

Recent literature suggests that chyle leak may complicate up to 10% of pancreatic resections. Treatment depends on its severity, which may include chylous ascites. No international consensus definition or grading system of chyle leak currently is available. The International Study Group on Pancreatic Surgery, an international panel of pancreatic surgeons working in well-known, high-volume centers, reviewed the literature and worked together to establish a consensus on the definition and classification of chyle leak after pancreatic operation. Chyle leak was defined as output of milky-colored fluid from a drain, drain site, or wound on or after postoperative day 3, with a triglyceride content ≥110 mg/dL (≥1.2 mmol/L). Three different grades of severity were defined according to the management needed: grade A, no specific intervention other than oral dietary restrictions; grade B, prolongation of hospital stay, nasoenteral nutrition with dietary restriction, total parenteral nutrition, octreotide, maintenance of surgical drains, or placement of new percutaneous drains; and grade C, need for other more invasive in-hospital treatment, intensive care unit admission, or mortality. This classification and grading system for chyle leak after pancreatic resection allows for comparison of outcomes between series. As with the other the International Study Group on Pancreatic Surgery consensus statements, this classification should facilitate communication and evaluation of different approaches to the prevention and treatment of this complicatio

The future of interpretive accounting research:A Polyphonic Debate

In 1997-99 the three of us organised a series of European Commission funded conferences aimed at building a network of young researchers in the area of accounting. At the time “young” was defined by the Commission as researchers under 35 years of age (allowing for maternity leave or national service). Over the intervening years our network had grown and we wanted to try and take stock of the field in which we had now been working for a surprising number of years. To that Page 1 of 29 Accepted Manuscript 2 end we put together the above email and a broad invitation list of people who had been at those first meetings, and others of the same generation (or even younger) whom we had met since. About half of those originally contacted managed to make the meeting where we spent a stimulating couple of hours of debate on the topics raised below—so stimulating that we developed a collective desire to leave a trace of the discussion. Writing a traditional paper with so many, so widely dispersed authors was not going to work. Instead we came up with a different form of collective writing that mirrored the original debate, and that might contribute to ongoing debates in this journal concerning the nature and status of our research (e.g. Arrington, 2004; Inanga & Schneider, 2005; Macintosh, 2004). We agreed a process in which each of us in turn would have one week to add a target of 300 words to a rolling document, going through the contributors alphabetically. After two rounds we would see what we had got