Introduction: Forensic Fail

Background: About 60% of Pheochromocytoma (PCC) and Paraganglioma (PGL) patients have either germline or somatic mutations in one of the 12 proposed disease causing genes; SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127, MAX and H-RAS. Selective screening for germline mutations is routinely performed in clinical management of these diseases. Testing for somatic alterations is not performed on a regular basis because of limitations in interpreting the results. Aim: The purpose of the study was to investigate genetic events and phenotype correlations in a large cohort of PCC and PGL tumours. Methods: A total of 101 tumours from 89 patients with PCC and PGL were re-sequenced for a panel of 10 disease causing genes using automated Sanger sequencing. Selected samples were analysed with Multiplex Ligation-dependent Probe Amplification and/or SNParray. Results: Pathogenic genetic variants were found in tumours from 33 individual patients (37%), 14 (16%) were discovered in constitutional DNA and 16 (18%) were confirmed as somatic. Loss of heterozygosity (LOH) was observed in 1/1 SDHB, 11/11 VHL and 3/3 NF1-associated tumours. In patients with somatic mutations there were no recurrences in contrast to carriers of germline mutations (P = 0.022). SDHx/VHL/ EPAS1 associated cases had higher norepinephrine output (P = 0.03) and lower epinephrine output (P<0.001) compared to RET/NF1/H-RAS cases. Conclusion: Somatic mutations are frequent events in PCC and PGL tumours. Tumour genotype may be further investigated as prognostic factors in these diseases. Growing evidence suggest that analysis of tumour DNA could have an impact on the management of these patients

LC/MS/MS Analysis of N-Terminal Protein Adducts with Improved Sensitivity: A Comparison of Selected Edman Isothiocyanate Reagents

This study provides a basis for a new and straightforward method for LC/MS/MS-based screening of N-terminal protein adducts. This procedure is denoted the “FIRE procedure” as fluorescein isothiocyanate (FITC) gave superior sensitivity by LC/MS/MS when measuring adducts (R) of electrophilic compounds with a modified Edman procedure. The principles of the FIRE-procedure are that adducts to N-terminal amino acids selectively are detached and measured from of proteins after derivatisation by isothiocyanate Edman reagents. In this study, FITC, 4-N,N-dimethylaminoazobenzene 4′-isothiocyanate (DABITC) and 4-dimethylamino-1-naphthyl isothiocyanate (DNITC) were used to synthesize thiohydantoin analytes from valine and N-methylvaline. The sensitivity by LC/MS/MS was enhanced by up to three orders of magnitude as compared to phenyl isothiocyanate and higher as compared to pentafluorophenyl isothiocyanate. The FITC reagent will enable measurements of low background adduct levels. Synthesized analytes were characterised with, for example, 1H NMR, 13C NMR, LC/MS/MS, and UV

Water and Risk: Developing sustainable and resilient communities

Key Messages • Sweden has an ideal opportunity to become a more important effect, reflecting the views of several Swedish organisations active international partner in DRR and resilience activities, originating in this area. from its strong history of donor support and long engagement • Acting on this opportunity would enable timely Swedish in DRR. contributions to the increasing global debate on the need to build • The Swedish Ministry for Foreign Affairs plays an important role resilience to a multi-risk environment. This includes small scale and in contributing to relevant global processes; mainly the successor slow-onset disasters, violent conflict, uncontrolled urbanisation, framework to the Hyogo Framework for Action (HFA2) the rising consumption, environmental degradation Post-2015 Agenda and associated Sustainable Development and climate change. Goals. This document outlines some recommendations to thi

Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson's disease:A dose-finding study

In advanced stages of Parkinson's disease, serotonergic terminals take up l-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of l-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks l-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against l-DOPA-induced dyskinesias in patients with Parkinson's disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of l-DOPA (Sinemet®) in 22 patients with Parkinson's disease (16 male/six female; 66.6 ± 8.8 years old) with l-DOPA-induced dyskinesias. A Wilcoxon Signed Ranked Test was used to compare each eltoprazine dose level to paired randomized placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and maximum change of Unified Parkinson's Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of l-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [-1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [-0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [-1.14(1.59); P = 0.005]. The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson's Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to l-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson's disease. The data support further clinical studies with chronic oral eltoprazine to treat l-DOPA-induced-dyskinesias

Quantitative trait evolution and environmental change

Peer reviewe

Is the Roux Limb a Determinant for Meal Size After Gastric Bypass Surgery?

The Roux-Y gastric bypass (RYGBP) is an effective weight-reducing procedure but the involved mechanisms of action are obscure. The Roux limb is the intestinal segment that following surgery is the primary recipient for food intake. The aims of the study were to explore the mechanosensory and biomechanical properties of the Roux limb and to make correlations with preferred meal size. Ten patients participated and were examined preoperatively, 6 weeks and 1 year after RYGBP. Each subject ingested unrestricted amounts of a standardized meal and the weight of the meal was recorded. On another study day, the Roux limb was subjected to gradual distension by the use of an intraluminal balloon. Luminal volume–pressure relationships and thresholds for induction of sensations were monitored. At 6 weeks and 1 year post surgery, the subjects had reduced their meal sizes by 62% and 41% (medians), respectively, compared to preoperative values. The thresholds for eliciting distension-induced sensations were strongly and negatively correlated to the preferred meal size. Intraluminal pressure during Roux limb distension, both at low and high balloon volumes, correlated negatively to the size of the meal that the patients had chosen to eat. The results suggest that the Roux limb is an important determinant for regulating food intake after Roux-Y bypass bariatric surgery

Late gadolinium uptake demonstrated with magnetic resonance in patients where automated PERFIT analysis of myocardial SPECT suggests irreversible perfusion defect

<p>Abstract</p> <p>Background</p> <p>Myocardial perfusion single photon emission computed tomography (MPS) is frequently used as the reference method for the determination of myocardial infarct size. PERFIT^®is a software utilizing a three-dimensional gender specific, averaged heart model for the automatic evaluation of myocardial perfusion. The purpose of this study was to compare the perfusion defect size on MPS, assessed with PERFIT, with the hyperenhanced volume assessed by late gadolinium enhancement magnetic resonance imaging (LGE) and to relate their effect on the wall motion score index (WMSI) assessed with cine magnetic resonance imaging (cine-MRI) and echocardiography (echo).</p> <p>Methods</p> <p>LGE was performed in 40 patients where clinical MPS showed an irreversible uptake reduction suggesting a myocardial scar. Infarct volume, extent and major coronary supply were compared between MPS and LGE as well as the relationship between infarct size from both methods and WMSI.</p> <p>Results</p> <p>MPS showed a slightly larger infarct volume than LGE (MPS 29.6 ± 23.2 ml, LGE 22.1 ± 16.9 ml, p = 0.01), while no significant difference was found in infarct extent (MPS 11.7 ± 9.4%, LGE 13.0 ± 9.6%). The correlation coefficients between methods in respect to infarct size and infarct extent were 0.71 and 0.63 respectively. WMSI determined with cine-MRI correlated moderately with infarct volume and infarct extent (cine-MRI vs MPS volume r = 0.71, extent r = 0.71, cine-MRI vs LGE volume r = 0.62, extent r = 0.60). Similar results were achieved when wall motion was determined with echo. Both MPS and LGE showed the same major coronary supply to the infarct area in a majority of patients, Kappa = 0.84.</p> <p>Conclusion</p> <p>MPS and LGE agree moderately in the determination of infarct size in both absolute and relative terms, although infarct volume is slightly larger with MPS. The correlation between WMSI and infarct size is moderate.</p

Потребительский экстремизм как правовое явление

Материалы XIII Междунар. науч. конф. студентов, магистрантов, аспирантов и молодых ученых, Гомель, 21–22 мая 2020 г