Search

Background: The probability to receive intravenous thrombolysis (IVT) for treatment of acute ischemic stroke declines with increasing age and is consequently the lowest in very elderly patients. Safety concerns likely influence individual IVT treatment decisions. Using data from a large IVT registry, we aimed to provide more evidence on safety of IVT in the very elderly. Methods: In this prospective multicenter study from the TRISP (Thrombolysis in Ischemic Stroke Patients) registry, we compared patients ≥90 years with those Results: Of 16 974 eligible patients, 976 (5.7%) were ≥90 years. Patients ≥90 years had higher median National Institutes of Health Stroke Scale on admission (12 versus 8) and were more often dependent prior to the index stroke (prestroke modified Rankin Scale score of ≥3; 45.2% versus 7.4%). Occurrence of symptomatic intracranial hemorrhage (5.7% versus 4.4%, odds ratio adjusted 1.14 [0.83–1.57]) did not differ significantly between both groups. However, the probability of death (odds ratio adjusted 3.77 [3.14–4.53]) and poor functional outcome (odds ratio adjusted 2.63 [2.13–3.25]) was higher in patients aged ≥90 years. Results for the sample of centenarians (n=21) were similar. Conclusions: The probability of symptomatic intracranial hemorrhage after IVT in very elderly patients with stroke did not exceed that of their younger counterparts. The higher probability of death and poor functional outcome during follow-up in the very elderly seems not to be related to IVT treatment. Very high age itself should not be a reason to withhold IVT.

Supplemental Digital Content is available in the text., Background and Purpose: Timely reperfusion is an important goal in treatment of eligible patients with acute ischemic stroke. However, during the coronavirus disease 2019 (COVID-19) pandemic, prehospital and in-hospital emergency procedures faced unprecedented challenges, which might have caused a decline in the number of acute reperfusion therapy applied and led to a worsening of key quality measures for this treatment during lockdown. Methods: This prospective multicenter cohort study used data from the TRISP (Thrombolysis in Ischemic Stroke Patients) registry of patients with acute ischemic stroke treated with reperfusion therapies, that is, intravenous thrombolysis or endovascular therapy. We compared prehospital and in-hospital time-based performance measures (stroke-onset-to-admission, admission-to-treatment, admission-to-image, and image-to-treatment time) during the first 6 weeks after announcement of lockdown (lockdown period) with the same period in 2019 (reference period). Secondary outcomes included stroke severity (National Institutes of Health Stroke Scale) after 24 hours and occurrence of symptomatic intracranial hemorrhage (following the ECASS [European-Australasian Acute Stroke Study]-II criteria). Results: Across 20 stroke centers, 540 patients were treated with intravenous thrombolysis/endovascular therapy during lockdown period compared with 578 patients during reference period (−7% [95% CI, 5%–9%]). Performance measures did not change significantly during the lockdown period (2020/2019 minutes median: onset-to-admission 133/145; admission-to-treatment 51/48). Same was true for admission-to-image (20/19) and image-to-treatment (31/30) time in patients with available time of first image (n=871, 77.9%). Median National Institutes of Health Stroke Scale on admission (2020/2019: 11/11) and after 24 hours (2020/2019: 6/5) and percentage of symptomatic intracranial hemorrhage (2020/2019: 6.2/5.7) did not differ significantly between both periods. Conclusions: The COVID-19 pandemic lockdown resulted in a mild decline in the number of patients with stroke treated with acute reperfusion therapies. More importantly, the solid stability of key quality performance measures between the 2020 and 2019 period may indicate resilience of acute stroke care service during the lockdown, at least in well-established European stroke centers.

ObjectiveTo evaluate whether pretreatment with metformin (MET) is associated with less stroke severity and better outcome after IV thrombolysis (IVT), we analyzed a cohort of 1,919 patients with stroke with type 2 diabetes mellitus in a multicenter exploratory analysis.MethodsData from patients with diabetes and ischemic stroke treated with IVT were collected within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration. We applied propensity score matching (PSM) to obtain balanced baseline characteristics of patients treated with and without MET.ResultsOf 1,919 patients with stroke with type 2 diabetes who underwent IVT, 757 (39%) had received MET before stroke (MET+), whereas 1,162 (61%) had not (MET−). MET+ patients were younger with a male preponderance. Hypercholesterolemia and pretreatment with statins, antiplatelets, or antihypertensives were more common in the MET+ group. After PSM, the 2 groups were well balanced with respect to demographic and clinical aspects. Stroke severity on admission (NIH Stroke Scale 10.0 ± 6.7 vs 11.3 ± 6.5), 3-month degree of independence on modified Rankin Scale (2 [interquartile range (IQR) 1.0–4.0] vs 3 [IQR 1.0–4.0]), as well as mortality (12.5% vs 18%) were significantly lower in the MET+ group. The frequency of symptomatic intracerebral hemorrhages did not differ between groups. HbA1c levels were well-balanced between the groups.ConclusionsPatients with stroke and diabetes on treatment with MET receiving IVT had less severe strokes on admission and a better functional outcome at 3 months. This suggests a protective effect of MET resulting in less severe strokes as well as beneficial thrombolysis outcome.

Introduction Alterations in haemoglobin levels are frequent in stroke patients. The prognostic meaning of anaemia and polyglobulia on outcomes in patients treated with intravenous thrombolysis is ambiguous. Patients and methods In this prospective multicentre, intravenous thrombolysis register-based study, we compared haemoglobin levels on hospital admission with three-month poor outcome (modified Rankin Scale 3–6), mortality and symptomatic intracranial haemorrhage (European Cooperative Acute Stroke Study II-criteria (ECASS-II-criteria)). Haemoglobin level was used as continuous and categorical variable distinguishing anaemia (female: 15.5 g/dl; male: >17 g/dl). Anaemia was subdivided into mild and moderate/severe (female/male: Results Among 6866 intravenous thrombolysis-treated stroke patients, 5448 (79.3%) had normal haemoglobin level, 1232 (17.9%) anaemia – of those 903 (13.2%) had mild and 329 (4.8%) moderate/severe anaemia – and 186 (2.7%) polyglobulia. Anaemia was associated with poor outcome (ORadjusted 1.25 (1.05–1.48)) and mortality (ORadjusted 1.58 (1.27–1.95)). In anaemia subgroups, both mild and moderate/severe anaemia independently predicted poor outcome (ORadjusted 1.29 (1.07–1.55) and 1.48 (1.09–2.02)) and mortality (ORadjusted 1.45 (1.15–1.84) and ORadjusted 2.00 (1.46–2.75)). Each haemoglobin level decrease by 1 g/dl independently increased the risk of poor outcome (ORadjusted 1.07 (1.02–1.11)) and mortality (ORadjusted 1.08 (1.02–1.15)). Anaemia was not associated with occurrence of symptomatic intracranial haemorrhage. Polyglobulia did not change any outcome. Discussion The more severe the anaemia, the higher the probability of poor outcome and death. Severe anaemia might be a target for interventions in hyperacute stroke. Conclusion Anaemia on admission, but not polyglobulia, is a strong and independent predictor of poor outcome and mortality in intravenous thrombolysis-treated stroke patients.

Objective To quantify radiation exposure (RE) of endovascular stroke treatment (EST) in the anterior circulation per thrombectomy attempt and determine causes for interventions associated with high RE. Methods A retrospective single-center study of an institutional review board−approved stroke database of patients receiving EST for large vessel occlusions in the anterior circulation between January 2013 and April 2018 to evaluate reference levels (RL) per thrombectomy attempt. ESTs with RE above the RL were analyzed to determine causes for high RE. Results Overall, n = 544 patients (occlusion location, M1 and M2 segments of the middle cerebral artery 53.5% and 27.2%, carotid artery 17.6%; successful recanalization rate 85.7%) were analyzed. In the overall population, DAP (in Gy cm2, median (IQR)) was 113.7 (68.9–181.7) with a median fluoroscopy time of 31 min (IQR, 17–53) and a median of 2 (IQR, 1–4) thrombectomy attempts. RE increased significantly with every thrombectomy attempt (DAP1, 68.7 (51.2–106.8); DAP2, 106.4 (84.8–115.6); p value1vs2, 3, 130.2 (89.1–183.6); p value2vs3, 0.044; DAP4, 169.9 (128.4–224.1); p value3vs4, 0.001; and DAP5, 227.6 (146.3–294.6); p value4vs5, 0.019). Procedures exceeding the 90th percentile of the attempt-dependent radiation exposure level were associated with procedural complications (n = 17/52, 29.8%) or a difficult vascular access (n = 8/52, 14%). Conclusions Radiation exposure in endovascular stroke treatment is depending on the number of thrombectomy attempts. Radiation exposure doubles when three attempts and triples when five attempts are necessary compared with single-maneuver interventions. Procedural complications and difficult vascular access were associated with a high radiation exposure in this collective. Key Points • Radiation exposure of endovascular stroke treatment (EST) is dependent on the number of thrombectomy attempts. • Reference levels as means for quality control in hospitals performing endovascular stroke treatment should be defined by the number of thrombectomy attempts—we suggest 107 Gy cm2, 156 Gy cm2, 184 Gy cm2, 244 Gy cm2, and 295 Gy cm2for 1 to 5 maneuvers, respectively, for EST of the anterior circulation • Cases with high rates of radiation exposure are associated with periprocedural complications and difficult anatomical access as a probable cause for a high radiation exposure.

The strain‐promoted azide alkyne cycloaddition (SPAAC) is a powerful tool for forming covalent bonds between molecules even under physiological conditions, and therefore found broad application in fields ranging from biological chemistry and biomedical research to materials sciences. For many applications, knowledge about reaction kinetics of these ligations is of utmost importance. Kinetics are commonly assessed and studied by NMR measurements. However, these experiments are limited in terms of temperature and restricted to deuterated solvents. By using an inline ATR‐IR probe we show that the cycloaddition of azides and alkynes can be monitored in aqueous and even complex biological fluids enabling the investigation of reaction kinetics in various solvents and even human blood plasma under controlled conditions in low reaction volumes., Taking a closer look: We show that azide cycloadditions can be monitored in complex reaction environments by using an inline ATR‐IR probe in a small‐volume reaction flask also facilitating full temperature control. This method enables following bioorthogonal azide cyclooctyne ligations even in biological fluids such as human plasma.

A series of nine soluble, symmetric chalcogenophenes bearing hexyl-substituted triphenylamines, indolocarbazoles, or phenylcarbazoles was designed and synthesized as potential two-photon absorption (2PA) initiators. A detailed photophysical analysis of these molecules revealed good 2PA properties of the series and, in particular, a strong influence of selenium on the 2PA cross sections, rendering these materials especially promising new 2PA photoinitiators. Structuring and threshold tests proved the efficiency and broad spectral versatility of two selenium-containing lead compounds as well as their applicability in an acrylate resin formulation. A comparison with commercial photoinitiators Irg369 and BAPO as well as sensitizer ITX showed that the newly designed selenium-based materials TPA-S and TPA-BBS outperform these traditional initiators by far both in terms of reactivity and dose. Moreover, by increasing the ultralow concentration of TPA-BBS, a further reduction of the polymerization threshold can be achieved, revealing the great potential of this series for application in two-photon polymerization (2PP) systems where only low laser power is available.200020-184607

International audience; BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I(2)=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [\textless1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

Deoxynivalenol (DON) is considered to be one of the most important contaminants in cereals and food commodities produced thereof. So far it is not clear i) to which extent DON is degraded during baking and ii) if a degradation results in reduced toxicity. We have elucidated the fate of DON during baking of crackers, biscuits and bread, which were produced from fortified dough and processed under pilot plant conditions. Untargeted stable isotope assisted liquid chromatography (LC) high resolution mass spectrometry was used to determine all extractable degradation products. Targeted LC - tandem mass spectrometry based quantification revealed that DON was partially degraded to isoDON (1.3-3.9%), norDON B (0.2-0.9%) and norDON C (0.3-1.2%). A DON degradation of 6% (crackers), 5% (biscuits) and 2% (bread), respectively, was observed. In vitro translation experiments indicate that isoDON is less toxic than DON.

In this work we present the design, synthesis and systematic investigation of the optical properties of symmetric triphenylamine (TPA)-substituted thiophenes. The use of electron-donating (–OMe, –tBu, –Me, –TMS), -neutral (–H) or -withdrawing (–F, –CN, –SO2Me) substituents gives rise to D–A–D based two-photon absorption (2PA) chromophores. The photophysical properties of these compounds, including one-photon absorption and 2PA using two-photon-excited fluorescence, were investigated in different organic solvents with varying polarity. The maximum 2PA cross sections prove to be strongly dependent on the nature of the TPA substituent and range between ∼173 GM (Goeppert-Mayer units) and 379 GM. Although most of the investigated substances also exhibit high fluorescence quantum yields, two-photon absorption screening tests of an acrylate monomer formulation revealed the efficiency of these materials as 2PA photoinitiators. These results are supported by quantum chemical calculations of the spin density distribution indicating that the mechanism of polymerization initiation using acrylate monomer is favored by strong localization of the unpaired electrons in the triplet state on the C2 carbon of the thiophene moiety.

Background: Transient ischemic attack (TIA) needs further diagnostic evaluation to prevent future ischemic stroke. However, prophylaxis can be harmful in elderly if the diagnosis is wrong. We aimed at characterizing differences in TIA mimics in younger and older patients to enhance diagnostic accuracy in elderly patients.Methods: In a dedicated neurological emergency room (nER) of a tertiary care University hospital, patients with transient neurological symptoms suspicious of TIA (70 years using descriptive, univariable, and multivariable statistics.Results: From November 2018 until August 2019, 386 consecutive patients were included. 271 (70%) had cardiovascular risk factors and all patients received cerebral imaging, mostly CT [376 (97%)]. There was no difference in the rate of diagnosed TIA between the age groups [85 (46%) vs. 58 (39%); p = 0.213].TIA mimics in the elderly were more often internal medicine diseases [35 (19%) vs. 7 (5%); p < 0.001] and epileptic seizures [48 (26%) vs. 24 (16%); p = 0.032] but less often migraine [2 (1%) vs. 20 (13%); p < 0.001]. The most frequent symptoms in all patients were aphasia and dysarthria [107 (28%) and 92 (24%)]. Sensory impairments were less frequent in elderly patients [23 (11%) vs. 54 (30%); p < 0.001]. Impaired consciousness and orientation were independent predictors for TIA mimics (p < 0.001) whereas facial palsy (p < 0.001) motor weakness (p < 0.001), dysarthria (p = 0.022) and sensory impairment (p < 0.001) were independent predictors of TIA.Conclusion: TIA mimics in elderly patients are more likely to be internal medicine diseases and epilepsy compared to younger patients. Excluding internal medicine diseases seems to be important in elderly patients. Facial palsy, motor weakness, dysarthria and sensory impairment are associated with TIA.

PurposeThe Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration was a concerted effort initiated in 2010 with the purpose to address relevant research questions about the effectiveness and safety of intravenous thrombolysis (IVT). The collaboration also aims to prospectively collect data on patients undergoing endovascular treatment (EVT) and hence the name of the collaboration was changed from TRISP to EVA-TRISP. The methodology of the former TRISP registry for patients treated with IVT has already been published. This paper focuses on describing the EVT part of the registry.ParticipantsAll centres committed to collecting predefined variables on consecutive patients prospectively. We aim for accuracy and completeness of the data and to adapt local databases to investigate novel research questions. Herein, we introduce the methodology of a recently constructed academic investigator-initiated open collaboration EVT registry built as an extension of an existing IVT registry in patients with acute ischaemic stroke (AIS).Findings to dateCurrently, the EVA-TRISP network includes 20 stroke centres with considerable expertise in EVT and maintenance of high-quality hospital-based registries. Following several successful randomised controlled trials (RCTs), many important clinical questions remain unanswered in the (EVT) field and some of them will unlikely be investigated in future RCTs. Prospective registries with high-quality data on EVT-treated patients may help answering some of these unanswered issues, especially on safety and efficacy of EVT in specific patient subgroups.Future plansThis collaborative effort aims at addressing clinically important questions on safety and efficacy of EVT in conditions not covered by RCTs. The TRISP registry generated substantial novel data supporting stroke physicians in their daily decision making considering IVT candidate patients. While providing observational data on EVT in daily clinical practice, our future findings may likewise be hypothesis generating for future research as well as for quality improvement (on EVT). The collaboration welcomes participation of further centres willing to fulfill the commitment and the outlined requirements.

BACKGROUND: We analyzed the effects of the SARS-CoV-2 pandemic on neurologic emergencies, depending on the patients' triage score in a setting with relatively few COVID-19 cases and without lack of resources. METHODS: Consecutive patients of a tertiary care center with a dedicated neurologic emergency room (nER) were analyzed. The time period of the first lockdown in Germany (calendar weeks 12-17, 2020) was retrospectively compared to the corresponding period in 2019 regarding the number of patients presenting to the nER, the number of patients with specific triage scores (Heidelberg Neurological Triage Score), the number of patients with stroke, and the quality of stroke care. RESULTS: A total of 4330 patients were included. Fewer patients presented themselves in 2020 compared to 2019 (median [interquartile range] per week: 134 [118-143] vs. 187 [182-192]; p = 0.015). The median numbers of patients per week with triage 1 (emergent) and 4 (non-urgent) were comparable (51 [43-58] vs. 59 [54-62]; p = 0.132, and 10 [4-16] vs. 16 [7-18]; p = 0.310, respectively).The median number of patients per week declined in categories 2 and 3 in 2020 (41 [37-45] vs. 57 [52-61]; p = 0.004, and 28 [23-35] vs. 61 [52-63]; p = 0.002, respectively. No change was observed in the absolute number of strokes (138 in 2019 and 141 in 2020). Quality metrics of stroke revascularization therapies (symptom-to-door time, door-to-needle time or relative number of therapies) and stroke severity remained constant. CONCLUSION: During the lockdown period in 2020, the number of patients with emergent symptoms remained constant, while fewer patients with urgent symptoms presented to the nER. This may imply behavioral changes in care-seeking behavior.

The (2-benzyloxyphenyl)acetyl group has been identified as a new protecting group for hydroxyl functions. Various alcohols could be easily protected with high yields, and deprotection was achieved by a relay approach using Pd/H2 in combination with 1,8-bis(dimethylamino)naphthalene, conditions that are orthogonal to ester groups. The new protecting group is stable in glycosylation reactions demonstrating an effective neighboring group participation leading to the exclusive formation of 1,2-trans glycosides and glycosyl esters.

Objective Seizure at onset (SaO) has been considered a relative contraindication for intravenous thrombolysis (IVT) in patients with acute ischemic stroke, although this appraisal is not evidence based. Here, we investigated the prognostic significance of SaO in patients treated with IVT for suspected ischemic stroke. Methods In this multicenter, IVT-registry-based study we assessed the association between SaO and symptomatic intracranial hemorrhage (sICH, European Cooperative Acute Stroke Study II definition), 3-month mortality, and 3-month functional outcome on the modified Rankin Scale (mRS) using unadjusted and adjusted logistic regression, coarsened exact matching, and inverse probability weighted analyses. Results Among 10,074 IVT-treated patients, 146 (1.5%) had SaO. SaO patients had significantly higher National Institutes of Health Stroke Scale score and glucose on admission, and more often female sex, prior stroke, and prior functional dependence than non-SaO patients. In unadjusted analysis, they had generally less favorable outcomes. After controlling for confounders in adjusted, matched, and weighted analyses, all associations between SaO and any of the outcomes disappeared, including sICH (odds ratio [OR]unadjusted = 1.53 [95% confidence interval (CI) = 0.74-3.14], ORadjusted = 0.52 [95% CI = 0.13-2.16], ORmatched = 0.68 [95% CI = 0.15-3.03], ORweighted = 0.95 [95% CI = 0.39-2.32]), mortality (ORunadjusted = 1.49 [95% CI = 1.00-2.24], ORadjusted = 0.98 [95% CI = 0.5-1.92], ORmatched = 1.13 [95% CI = 0.55-2.33], ORweighted = 1.17 [95% CI = 0.73-1.88]), and functional outcome (mRS ≥ 3/ordinal mRS: ORunadjusted = 1.33 [95% CI = 0.96-1.84]/1.35 [95% CI = 1.01-1.81], ORadjusted = 0.78 [95% CI = 0.45-1.32]/0.78 [95% CI = 0.52-1.16], ORmatched = 0.75 [95% CI = 0.43-1.32]/0.45 [95% CI = 0.10-2.06], ORweighted = 0.87 [95% CI = 0.57-1.34]/1.00 [95% CI = 0.66-1.52]). These results were consistent regardless of whether patients had an eventual diagnosis of ischemic stroke (89/146) or stroke mimic (57/146 SaO patients). Interpretation SaO was not an independent predictor of poor prognosis. Withholding IVT from patients with assumed ischemic stroke presenting with SaO seems unjustified. ANN NEUROL 2019;86:770-779.

The synthesis of (2-nitrophenyl)acetyl (NPAc)-protected glucosyl donors is described that were designed for the neighboring-group assisted glucosylation of base-labile natural products also being sensitive to hydrogenolysis. Glycosylation conditions were optimized using a trichloroacetimidate glucosyl donor, and cyclohexylmethanol and (+)-menthol as model acceptors. The approach was then extended to a one-pot procedure for the synthesis of 1,2-trans-glycosides. This method was finally applied for improved synthesis of the masked mycotoxin T2-O-β,d-glucoside.

A versatile and efficient protocol for Schmidt glycosylation of 3-acetyldeoxynivalenol (3-ADON) and subsequent deprotection has been developed to gain access to deoxynivalenol-15-O-glycosides in reasonable amounts for bioanalysis and further investigations. Applying this protocol in combination with [13C6]glycosyl donors we were able to prepare isotope labeled deoxynivalenol-15-O-glycosides, which are pivotal to enable accurate quantification of masked mycotoxins by LC-MS.

The Fusarium mycotoxin deoxynivalenol (DON) is a frequent contaminant of cereal-based food and feed. Mammals metabolize DON by conjugation to glucuronic acid (GlcAc), the extent and regioselectivity of which is species-dependent. So far, only DON-3-glucuronide (DON-3-GlcAc) and DON-15-GlcAc have been unequivocally identified as mammalian DON glucuronides, and DON-7-GlcAc has been proposed as further DON metabolite. In the present work, qualitative HPLC-MS/MS analysis of urine samples of animals treated with DON (rats: 2 mg/kg bw, single bolus, gavage; mice: 1 mg/kg bw, single i.p. injection; pigs: 74 µg/kg bw, single bolus, gavage; cows: 5.2 mg DON/kg dry mass, oral for 13 weeks) revealed additional DON and deepoxy-DON (DOM) glucuronides. To elucidate their structures, DON and DOM were incubated with human (HLM) and rat liver microsomes (RLM). Besides the expected DON/DOM-3- and 15-GlcAc, minor amounts of four DON- and four DOM glucuronides were formed. Isolation and enzymatic hydrolysis of four of these compounds yielded iso-DON and iso-DOM, the identities of which were eventually confirmed by NMR. Incubation of iso-DON and iso-DOM with RLM and HLM yielded two main glucuronides for each parent compound, which were isolated and identified as iso-DON/DOM-3-GlcAc and iso-DON/DOM-8-GlcAc by NMR. Iso-DON-3-GlcAc, most likely misidentified as DON-7-GlcAc in the literature, proved to be a major DON metabolite in rats and a minor metabolite in pigs. In addition, iso-DON-8-GlcAc turned out to be one of the major DON metabolites in mice. DOM-3-GlcAc was the dominant DON metabolite in urine of cows and an important DON metabolite in rat urine. Iso-DOM-3-GlcAc was detected in urine of DON-treated rats and cows. Finally, DON-8,15-hemiketal-8-glucuronide, a previously described by-product of DON-3-GlcAc production by RLM, was identified in urine of DON-exposed mice and rats. The discovery of several novel DON-derived glucuronides in animal urine requires adaptation of the currently used methods for DON-biomarker analysis.

The synthesis, characterization, and field-effect transistor (FET) properties of new alkylated indolo[3,2-b]carbazole (ICz) based materials are reported. Dialkyl substitution at the 2,8-positions of the ICz core structure do not affect strong N H⋯ π interactions, thus favoring a herringbone packing motif. OFET devices fabricated by compounds of this substitution pattern displayed a charge carrier mobility of ∼10 −2 cm 2 V s −1 . These interactions are suppressed when introducing substituents at the 5,11-positions, resulting in greatly enhanced solubility. A solution processable ICz derivative was finally used in a newly developed pneumatic printing setup to yield a crystalline film with aligned crystals along the printing direction.

Highlight Barley HvUGT13248 catalyzes conversion of nivalenol (NIV) to its non-toxic form 3-O-glucoside, and in transgenic wheat confers resistance to NIV-producing Fusarium graminearum, Fusarium Head Blight is a disease of cereal crops that causes severe yield losses and mycotoxin contamination of grain. The main causal pathogen, Fusarium graminearum, produces the trichothecene toxins deoxynivalenol or nivalenol as virulence factors. Nivalenol-producing isolates are most prevalent in Asia but co-exist with deoxynivalenol producers in lower frequency in North America and Europe. Previous studies identified a barley UDP-glucosyltransferase, HvUGT13248, that efficiently detoxifies deoxynivalenol, and when expressed in transgenic wheat results in high levels of type II resistance against deoxynivalenol-producing F. graminearum. Here we show that HvUGT13248 is also capable of converting nivalenol into the non-toxic nivalenol-3-O-β-d-glucoside. We describe the enzymatic preparation of a nivalenol-glucoside standard and its use in development of an analytical method to detect the nivalenol-glucoside conjugate. Recombinant Escherichia coli expressing HvUGT13248 glycosylates nivalenol more efficiently than deoxynivalenol. Overexpression in yeast, Arabidopsis thaliana, and wheat leads to increased nivalenol resistance. Increased ability to convert nivalenol to nivalenol-glucoside was observed in transgenic wheat, which also exhibits type II resistance to a nivalenol-producing F. graminearum strain. Our results demonstrate the HvUGT13248 can act to detoxify deoxynivalenol and nivalenol and provide resistance to deoxynivalenol- and nivalenol-producing Fusarium.

Background and Purpose— Women have a worse outcome after stroke compared with men, although in intravenous thrombolysis (IVT)–treated patients, women seem to benefit more. Besides sex differences, age has also a possible effect on functional outcome. The interaction of sex on the functional outcome in IVT-treated patients in relation to age remains complex. The purpose of this study was to compare outcome after IVT between women and men with regard to age in a large multicenter European cohort reflecting daily clinical practice of acute stroke care. Methods— Data were obtained from IVT registries of 12 European tertiary hospitals. The primary outcome was poor functional outcome, defined as a modified Rankin scale score of 3 to 6 at 3 months. We stratified outcome by age in decades. Safety measures were symptomatic intracranial hemorrhage and mortality at 3 months. Results— In this cohort, 9495 patients were treated with IVT, and 4170 (43.9%) were women with a mean age of 71.9 years. After adjustments for baseline differences, female sex remained associated with poor functional outcome (odds ratio, 1.15; 95% confidence interval, 1.02–1.31). There was no association between sex and functional outcome when data were stratified by age. Symptomatic intracranial hemorrhage rate was similar in both sexes (adjusted odds ratio, 0.93; 95% confidence interval, 0.73–1.19), whereas mortality was lower among women (adjusted odds ratio, 0.83; 95% confidence interval, 0.70–0.99). Conclusions— In this large cohort of IVT-treated patients, women more often had poor functional outcome compared with men. This difference was not dependent on age.

High-purity, symmetrically substituted perylene and naphthalene bisimides were obtained by hydrothermal condensation of monoamines with the corresponding bisanhydride. The hydrothermal imidization proceeds quantitatively, without the need for organic solvents, catalysts or excess of the amines. published

The recombinant whole-cell mediated biooxygenation of various quinolines and isoquinolines was investigated employing three different dioxygenases of bacterial origin. Substrate screening focused on the biotransformation of cyano-substituted azaarenes, in particular. Efficiently accepted substrates were submitted to scale-up of the enzyme mediated reaction to preparative scale. The regio- and stereoselectivity of the obtained metabolites was established by NMR and X-ray diffraction after appropriate derivatization.

By reviving an old idea, we demonstrate that alkoxycarbonyl groups can be used in glycosylation reactions to achieve full stereocontrol through participation of a carbonate moiety at O-2. Various benzyloxycarbonyl-protected glycosyl donors were prepared and used for efficient 1,2-trans glycosylation of base-labile compounds and the synthesis of glycosyl esters.

A reliable synthetic protocol toward a series of fused chalcogenopheno[1]benzochalcogenophene (CBC) building blocks was developed based on a Fiesselmann reaction. The obtained CBC units were applied in McMurry and Stille coupling reactions toward symmetric regioisomeric ene-linked dimers. These π-conjugated compounds were characterized regarding their photophysical and electrochemical properties and proved to be materials with reduced HOMO-LUMO gaps compared to their sulfur-based analogues. Single-crystal X-ray diffraction experiments revealed strong intermolecular selenium-selenium and selenium-carbon interactions depending on the position and number of incorporated selenium atoms. Good field-effect transistor performance with charge carrier mobilities up to 4×10-3 cm2 V-1 s-1 and high on/off ratios could be observed.

Plant-derived mycotoxin conjugates like deoxynivalenol-3-glucoside can be partly hydrolyzed to their aglycones in vivo, albeit to different extent depending on the mycotoxin conjugate and on the animal species. The aim of this work was to investigate the metabolization of the trichothecene mycotoxin nivalenol (NIV) and the fate of its modified form NIV-3-glucoside (NIV3G) in rats. To that end, 350 μg/kg body weight of NIV and the equimolar dose of NIV3G were administered to six rats by gavage in a 5 × 6 design and excreta were collected for 2 days after each treatment. For further analysis of NIV and NIV3G metabolites in rat urine and feces, seven novel NIV- and NIV3G metabolites including NIV sulfonates (NIVS) 1, 2 and 3, deepoxy-NIV (DNIV), DNIV sulfonate 2, NIV3G sulfonate (NIV3GS) 2 and NIV-3-glucuronide were produced, isolated and characterized. Subsequently, LC–MS/MS based methods for determination of NIV, NIV3G and their metabolites in excreta samples were developed, validated and applied. The biological recoveries of administered toxins in the form of their fecal and urinary metabolites were 57 ± 21% for NIV and 94 ± 36% for NIV3G. The majority of NIV and NIV3G metabolites was excreted into feces, with DNIV and NIVS 2 as major NIV metabolites and NIV3GS 2 and DNIV as major metabolites of NIV3G. Only 1.5% of the administered NIV3G was recovered in urine, with NIV3G itself as major urinary metabolite. The biological recovery of free NIV in urine was approximately 30 times lower after treatment with NIV3G than after administration of NIV, indicating that exposure of rats to NIV3G results in lower toxicity than exposure to NIV.

In this work, a set of ion-selective electrodes for the detection of antipyrine and some of its structurally closely related derivatives is developed. These novel potentiometric sensors rely on metallocarborane, cobalt bis(dicarbollide) anion ([3,3′-Co(1,2-C2B9H11)2]−) complexes with the protonated antipyrine derivative as active recognition element. All complexes were characterized, embedded in a PVC membrane, and coated on top of commercial and self-fabricated electrodes. All systems were in-depth evaluated and optimized with focus on their analytical performance, leading to a set of electrodes for antipyrine, 4-aminoantipyrine and 4-(acetamido)antipyrine, which showed a near Nernstian slope (55–57 mV/dec) in the range of 10−5 to 10−2 mol/L and a limit of detection in the μM range. To lower the detection limit and to enable environmental stream water pollution monitoring, we implemented a solid-phase extraction step which could be used to achieve a pre-concentration of a factor >300 (recovery rates: 81–84%) and to lower the detection limit from the μM to the nM range. The combination of our new and highly selective electrodes with this SPE step enables the possibility to monitor antipyrine derivatives simultaneously in either an environmental surrounding or in pharmaceutical formulations. The combination of metallocarborane based ISEs with an SPE pre-concentration step and the in-depth evaluation of the closely related derivatives finally provides a set of valuable tools as well as new insights into their selectivity and real-life applicability.