Isotonitazene: Fatal intoxication in three cases involving this unreported novel psychoactive substance in Switzerland.

The paper describes the first three deaths reported in Europe involved in isotonitazene consumption, a potent benzimidazole derivate opioid consumed in the recreational drug scene. Isotonitazene powder and purity determination was performed on the sample collected in the first death scene by NMR, HRMS, GC-FTIR, ATR-FTIR and GC-MS. Isotonitazene purity was determined by GC-MS analysis and proton NMR, and was defined to be above 95 % and 98 %, respectively. Quantification of isotonitazene in biological samples was performed using a targeted analysis based on SPE extraction and ultra-high performance liquid chromatography tandem mass spectrometry. The isotonitazene median concentration in femoral whole blood was 1.20ng/mL. Isotonitazene concentration in hair was similar or even lower compared to that seen in fentanyl abusers. Isotonitazene distribution in tissues converges in the brain, lungs and heart, respectively. Surprisingly, isotonitazene concentration in liver is the lowest measured for all tissues and fluids analyzed. Based on circumstantial evidence, autopsy findings and the results of the toxicological analysis, the medical examiner concluded that the cause of all three deaths was an acute intoxication with isotonitazene. Since isotonitazene toxic concentration levels are very low, the consumption of this new psychoactive drug is a real hazard for human health.

Impact of grassland management regimes on bacterial endophyte diversity differs with grass species.

UNLABELLED: Most plant species are colonized by endophytic bacteria. Despite their importance for plant health and growth, the response of these bacteria to grassland management regimes is still not understood. Hence, we investigated the bacterial community structure in three agricultural important grass species Dactylis glomerata L., Festuca rubra L. and Lolium perenne L. with regard to fertilizer application and different mowing frequencies. For this purpose, above-ground plant material was collected from the Grassland Management Experiment (GrassMan) in Germany in September 2010 and 2011. DNA was extracted from surface-sterilized plant tissue and subjected to 16S rRNA gene PCRs. Endophytic community structures were assessed by denaturing gradient gel electrophoresis (DGGE)-based analysis of obtained PCR products. DGGE fingerprints revealed that fertilizer application significantly altered the endophytic communities in L. perenne and F. rubra but not in D. glomerata. Although no direct effect of mowing was observed, mowing frequencies in combination with fertilizer application had a significant impact on endophyte bacterial community structures. However, this effect was not observed for all three grass species in both years. Therefore, our results showed that management regimes changed the bacterial endophyte communities, but this effect was plant-specific and varied over time. SIGNIFICANCE AND IMPACT OF THE STUDY: Endophytic bacteria play an important role in plant health and growth. However, studies addressing the influence of grassland management regimes on these bacteria in above-ground plant parts are still missing. In this study, we present first evidence that fertilizer application significantly impacted bacterial community structures in three agricultural important grass species, whereas mowing had only a minor effect. Moreover, this effect was plant-specific and thus not visible for all grass species in each year. Consequently, this study sheds new light into the complex interaction of microbes and plants.

[Myocardial contrast echocardiography guided alcohol septal ablation in hypertrophic obstructive cardiomyopathy with a new echocardiographic contrast agent]. / Echokontrastmittelgesteuerte Alkoholablation bei hypertropher obstruktiver Kardiomyopathie mit neuem Echokontrastmittel.

HISTORY AND ADMISSION FINDINGS: Myocardial contrast echocardiography guided alcohol septal ablation (PTSMA) is an established treatment for symptomatic hypertrophic obstructive cardiomyopathy (HOCM). Most important properties of the optimal echocardiographic contrast agent are good contrast imaging and sufficient stability without fast washing out. HOCM was diagnosed in a 49-year-old female patient 4 years before first admission. Despite optimal medical treatment the patient was highly symptomatic with angina pectoris and dyspnoea NYHA II-III.Investigations, treatment and course: ECG showed signs of left ventricular hypertrophy. Echocardiography revealed asymmetric septal hypertrophy, dynamic LVOT obstruction with pronounced SAM and associated moderate mitral valve regurgitation. Coronary angiography performed in the catheterization laboratory showed coronary atherosclerosis and haemodynamic measurements verified a significant LVOT obstruction. An atypical septal branch, originating from the intermediate artery, was regarded as target branch and was occluded with a balloon catheter. For the contrast echocardiography guided septal ablation cold, agitated Gelafundin® was used. This led to a good subaortic septal contrast demarcation with confirmation of the correct choice of target branch. No arrhythmias were recorded during the administration of contrast medium. Injection of Levovist® in the same septal branch for comparison resulted in opacification of the same myocardial area without any sign of misplacement. After alcohol injection in the balloon-occluded septal branch, an effective elimination of the LVOT gradient could be haemodynamically documented. CONCLUSION: For contrast echocardiography guided PTSMA a good myocardial opacification with an appropriate contrast agent is essential, not only to recognize the obstruction dependent region but also to identify any possible misplacement. Gelafundin® seems to offer similarly sufficient contrast potential as Levovist®, so that Gelafundin® could be a possible alternative.

A randomized, double-blind study of certoparin vs. unfractionated heparin to prevent venous thromboembolic events in acutely ill, non-surgical patients: CERTIFY Study.

BACKGROUND: In medically ill patients, no contemporary double-blind head-to-head evaluation of low molecular weight heparin vs. unfractionated heparin (UFH) for the prevention of venous thromboembolic events is available. OBJECTIVES: To compare the efficacy and safety of certoparin with those of UFH. PATIENTS/METHODS: In this double-blind, randomized, controlled trial, acutely ill, non-surgical patients aged > or = 70 years were randomized to certoparin (3000 U of anti-factor Xa once daily) or to UFH (5000 IU t.i.d.). The primary endpoint was the composite of proximal deep vein thrombosis as assessed by bilateral compression ultrasonography, symptomatic non-fatal pulmonary embolism and venous thromboembolism-related death, and was assessed by a blinded central adjudication committee. Non-inferiority margins were set at 1.8 for the odds ratio (OR) and 3.45% for the absolute difference. RESULTS: Three thousand two hundred and thirty-nine patients aged 78.8 + or - 6.3 years were treated for 9.1 + or - 3.4 days. The incidence of the primary endpoint was 3.94% in the certoparin group and 4.52% in the UFH group, with a difference in proportions of - 0.59% [95% confidence interval (CI) -2.09 to 0.92; P < 0.0001 for non-inferiority], and an OR of 0.87 (95% CI 0.60-1.26; P = 0.0001 for non-inferiority). Major bleeding occurred in 0.43% of certoparin-treated patients and 0.62% of UFH-treated patients (OR 0.69; 95% CI 0.26-1.83). Any bleeding occurred at 3.20% in certoparin-treated patients vs. 4.58% in UFH-treated patients (OR 0.69; 95% CI 0.48-0.99; P < 0.05), and 5.73% of certoparin-treated patients and 6.63% of UFH-treated patients experienced serious adverse events. All-cause mortality was 1.27% in certoparin-treated patients and 1.36% in UFH-treated patients. CONCLUSIONS: In acutely ill, non-surgical elderly patients, thromboprophylaxis with certoparin (3000 U of anti-FXa once daily) was non-inferior to 5000 IU of UFH t.i.d., with a favorable safety profile.

Macrolide-based microtubule-stabilizing agents - chemistry and structure-activity relationships.

This article provides an overview on the chemistry and structure-activity relationships of macrolide-based microtubule-stabilizing agents. The primary focus will be on the total synthesis or examples thereof, but a brief summary of the current state of knowledge on the structure-activity relationships of epothilones, laulimalide, dictyostatin, and peloruside A will also be given. This macrolide class of compounds, over the last decade, has become the subject of growing interest due to their ability to inhibit human cancer cell proliferation through a taxol-like mechanism of action.

Significance of osteoporosis in craniomaxillofacial surgery: a review of the literature.

Osteoporosis is a common problem in orthopedic surgery. The purpose of this review of the literature was to examine whether osteoporosis is also an important factor in patient treatment in the field of craniomaxillofacial surgery. Emphasis was given to the consequences of osteoporosis for the maxilla and mandible, the influence of osteoporosis on fracture treatment, the use of dental implants, the importance of soft tissues and the effect of osteoporosis therapies. It was found that osteoporosis does affect the bones of the skull. The effect of osteoporosis on treatment, however, is controversial and necessitates better ways of quantifying bone loss. Large inter-individual and site-specific differences in bone density, as well as other effects such as removal of teeth, periodontitis, implant insertion, augmentation procedures and altered loading with dystrophic consequences need to be considered in future studies. Special attention should be given to osteoporosis during fracture treatment.

Synthesis and biological evaluation of N-(7-indazolyl)benzenesulfonamide derivatives as potent cell cycle inhibitors.

We herein describe a new synthesis of N-(7-indazolyl)benzenesulfonamide derivatives. These compounds were evaluated for their antiproliferative activities toward L1210 murine leukemia cells. One of them, 4-methoxy-N-(3-chloro-7-indazolyl)benzenesulfonamide, was identified as the most potent with an IC(50) of 0.44 microM.

Incomplete conventional colonoscopy: magnetic resonance colonography in the evaluation of the proximal colon.

BACKGROUND AND STUDY AIMS: The purpose of this study was to evaluate dark-lumen magnetic resonance (MR) colonography prospectively in patients with incomplete conventional colonoscopy. PATIENTS AND METHODS: Thirty-two patients with incomplete conventional colonoscopy underwent same-day dark-lumen MR colonography on the basis of a standard protocol. The depiction of colorectal diseases was assessed in the following colon segments: cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum. The reasons for incomplete colonoscopy included high-grade stenosis in 26 patients (four with occlusive cancer, 12 with fibrotic stenosis based on recurrent sigmoid diverticulitis, eight with Crohn's-induced stenosis, and two with nonsteroidal anti-inflammatory drug colonopathy), extreme patient intolerance in one patient, and technical challenges associated with an elongated colon in five patients. The results of MR colonography were compared with the findings of the initial conventional colonoscopy, the histopathological outcome, and follow-up colonoscopy when possible. RESULTS: All high-grade stenoses were confirmed on MR colonographic data sets. Of the 26 patients with high-grade stenosis, 19 underwent surgery with histopathological confirmation of the initial diagnosis. Follow-up colonoscopy was carried out in 14 patients with surgically treated high-grade stenosis. In six of these 14 patients, nine polyps identified at the initial MR colonography were confirmed and removed during a postoperative conventional colonoscopy. Two polyps (5 mm and 8 mm in diameter) identified on postoperative conventional colonoscopy had not been seen preoperatively at MR colonography. One polyp seen on MR colonography was not identified in the follow-up colonoscopy. CONCLUSION: Dark-lumen MR colonography is a feasible and useful method of evaluating the entire colon in patients with incomplete conventional colonoscopy.

Half-life of the doubly magic r-process nucleus 78Ni.

Nuclei with magic numbers serve as important benchmarks in nuclear theory. In addition, neutron-rich nuclei play an important role in the astrophysical rapid neutron-capture process (r process). 78Ni is the only doubly magic nucleus that is also an important waiting point in the r process, and serves as a major bottleneck in the synthesis of heavier elements. The half-life of 78Ni has been experimentally deduced for the first time at the Coupled Cyclotron Facility of the National Superconducting Cyclotron Laboratory at Michigan State University, and was found to be 110(+100)(-60) ms. In the same experiment, a first half-life was deduced for 77Ni of 128(+27)(-33) ms, and more precise half-lives were deduced for 75Ni and 76Ni of 344(+20)(-24) ms and 238(+15)(-18) ms, respectively.

Synthesis and anticancer activity of new pyrrolocarbazoles and pyrrolo-beta-carbolines.

'Bended' 1, 3 or 'linear' 2 pyrrolidino-fused (aza)carbazoles were prepared and screened towards a few cancer-related targets. Whereas 'bended' derivatives 1 and 3 proved to be weakly toxic, several members of the 'linear' family strongly interact with DNA, especially derivative 28a.

N=82 shell quenching of the classical r-process "waiting-point" nucleus 130Cd.

First beta- and gamma-spectroscopic decay studies of the N=82 r-process "waiting-point" nuclide 130Cd have been performed at CERN/ISOLDE using the highest achievable isotopic selectivity. Several nuclear-physics surprises have been discovered. The first one is the unanticipatedly high energy of 2.12 MeV for the [pi g(9/2) multiply sign in circle nu g(7/2)] 1(+) level in 130In, which is fed by the main Gamow-Teller transition. The second surprise is the rather high Q(beta) value of 8.34 MeV, which is in agreement only with recent mass models that include the phenomenon of N=82 shell quenching. Possible implications of these new results on the formation of the A approximately 130 r-process abundance peak are presented.

[Measuring opening pressure in lumbar puncture--a new method]. / Bestimmung des Eröffnungsdruckes während der Lumbalpunktion--ein neues Verfahren.

Determination of the opening pressure (OP) during diagnostic lumbar puncture (LP) yields additional information that may impact on treatment and prognosis in disorders affecting the central nervous system (e.g. meningitis). Established methods contain systematic errors as well as risks to the patient. We therefore present a new procedure that allows measurement of the OP by timing the flow of cerebrospinal fluid through a capillary attached to an LP needle. A resistance located between needle and capillary slows down the flow of cerebrospinal fluid so that it becomes independent of the capillary forces acting on it. The time required for the fluid to travel between two marks on the capillary (defining a given volume) can be used to calculate the flow. Since the combined resistance of needle and resistance can be calibrated, the pressure driving the flow--in this case the opening pressure--can be calculated. A simple model was used to evaluate the impact of different resistances and different needles on OP determination. The effects of cellular elements and proteins in the CSF are discussed.

Modelling of the production of gaseous by-products in anaerobic digestion.

Goal of the EU-Project AMONCO (Advanced Prediction, Monitoring and Controlling of Anaerobic Digestion Processes Behaviour towards Biogas Usage in Fuel Cells) is demonstration of the practical use of biogas in fuel cells. The right precondition is a biogas quality which fits into the fuel cells tolerances. Therefore the mission of the workgroup Environmental biotechnology is to control anaerobic digestion in a way that production of potential harmful by-products for fuel cells is reduced. A good understanding of the production of these by products is essential for an applicable decision support tool. This poster presents the modelling of hydrogen sulfide by means of hierarchical neural networks and a classical mathematical method.

A fuzzy logic approach to control anaerobic digestion.

One of the goals of the EU-Project AMONCO (Advanced Prediction, Monitoring and Controlling of Anaerobic Digestion Process Behaviour towards Biogas Usage in Fuel Cells) is to create a control tool for the anaerobic digestion process, which predicts the volumetric organic loading rate (Bv) for the next day, to obtain a high biogas quality and production. The biogas should contain a high methane concentration (over 50%) and a low concentration of components toxic for fuel cells, e.g. hydrogen sulphide, siloxanes, ammonia and mercaptanes. For producing data to test the control tool, four 20 l anaerobic Continuously Stirred Tank Reactors (CSTR) are operated. For controlling two systems were investigated: a pure fuzzy logic system and a hybrid-system which contains a fuzzy based reactor condition calculation and a hierachial neural net in a cascade of optimisation algorithms.

Induction of cyclin E and inhibition of DNA synthesis by the novel acronycine derivative S23906-1 precede the irreversible arrest of tumor cells in S phase leading to apoptosis.

S23906-1 is a diester derivative of 1,2-dihydrobenzo[b]acronycine with an unknown mechanism of action. This cytotoxic compound was 20-fold more potent than acronycine in inhibiting the proliferation of six tumor cell lines. Using a clonogenic assay of cell survival, the HT29 human colon carcinoma cell line was 100-fold more sensitive to S23906-1 than acronycine. Cell cycle analysis, by flow cytometry, showed that S23906-1 induced a partially reversible arrest of HT29 cells in G2+M at 1 microM and below and an irreversible arrest in S phase at 2.5 microM and above. These cell cycle effects were followed by cell death through apoptosis, quantified by annexin-V labeling. Inhibition of DNA synthesis was observed by complete prevention of bromodeoxyuridine (BrdU) incorporation after only 4 h of incubation with 5 microM S23906-1. Interestingly, under the same experimental conditions, a significant increase of cyclin E protein level was observed without any modification of cyclins D1, D2, D3, or A. This overexpressed cyclin E protein was not complexed with Cdk2, as shown by western blotting for Cdk2 in immunoprecipitates of cyclin E. Similar inhibition of BrdU incorporation and elevation of cyclin E protein were observed after treatment with cytosine arabinoside, which reversibly inhibited progression into S phase, but not after DNA damage induced by cisplatin. S23906-1 thus has a novel mechanism of action. A cell line resistant to S23906-1 showed that overexpression of cyclin E was implicated in the novel cytotoxic activity of this compound.

A novel series of 2,6,7-substituted 2,3-dihydro-1,4-benzodioxin and 2,6,7-substituted 1,4-benzodioxin derivatives as lipid peroxidation inhibitors. Structure-activity relationships for high inhibition of human low-density lipoprotein peroxidation.

A series of 6- or 7-substituted 2-carboxamido- or 2-(aminomethyl)-1,4-benzodioxin and -2,3-dihydro-1,4-benzodioxin derivatives were synthesized and evaluated to determine the necessary structural requirements for a high inhibition of human low-density lipoprotein copper-induced peroxidation. The most active compounds (21, 25, 28, 36, and 37) were found between 5 and >45 times more active than probucol itself. Due to both their potency and their structural features, compounds 25 and 36 were selected with others for complementary in vitro and in vivo investigations. Both of them exhibit calcium antagonist properties in the same range of potency as flunarizine itself. Compound 36 was also found to have significant hypolipaemic activity in mice at 100 and 300 mg/kg po, while compound 25 proved to be clearly active in a normobar hypoxia test.

(22)Ne(alpha,n)(25)Mg: the key neutron source in massive stars.

The excitation function of the reaction (22)Ne(alpha,n)(25)Mg, the key neutron source in the astrophysical s process in massive stars, has been determined from threshold at E(alpha) = 570 up to 1450 keV with an experimental sensitivity of 10(-11) b. For all resonances in this energy range new resonance parameters have been measured. For a possible resonance at about 635 keV a new upper limit omega gamma < 60 neV for the strength was obtained. Based on the new data, improved reaction rates were calculated as a function of temperature. The new uncertainty limits are considerably smaller than in previous determinations, ruling out the large enhancement factors, up to 500, assumed in some stellar model calculations.

Synthesis and cytotoxic activity of benzophenanthrolinone analogues of acronycine.

Condensation of either 2-bromobenzoic acid (4) or 2-chloro-3-nitrobenzoic acid (5) with suitable aminoquinolines 6-8 afforded phenylquinolylamines 9-13. Acid mediated cyclization gave the corresponding 12H-benzo[b][1,7]phenanthrolin-7-ones 14 and 15, and 12H-benzo[b][1,10]phenanthrolin-7-ones 16-18. Compounds 14, 16, and 17 were subsequently N-methylated to 6-demethoxyacronycine and acronycine analogues 19-21, whereas reduction of the aromatic nitro group of 18 gave the amino derivative 22. Unsubstituted 12H-benzo[b][1,10]phenanthrolin-7-ones 16, 17, 20, and 21 were devoid of significant cytotoxic activity, whereas 18 and 22, bearing a nitrogen substituent at position 11, were significantly active. Unsubstituted 12H-benzo[b][1,7]phenanthrolin-7-ones 14 and 19, which include a pyridine nitrogen in the same 4-position as the pyran oxygen of acronycine exhibited cytotoxic activities within the same range of magnitude as acronycine itself.

5-substituted 3,4-dihydro-3-amino-2H-1-benzopyran derivatives: synthesis and interaction with serotoninergic receptors.

A new series of 3,4-dihydro-3-amino-2H-1-benzopyran derivatives (1 and 2) bearing various substituents on the 5-position was successfully prepared via palladium-mediated cross-coupling reactions. Some of the new compounds showed high affinity for 5-HT1A and 5-HT7 receptors. The best affinity for the 5-HT1A and 5-HT7 receptors was obtained for 2b (Ki = 0.3 nM for 5-HT1A and 3.1 nM for 5-HT7). The anxiolytic activity of compound 2b was evaluated.