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Monoklonale Antikorper gegen den CGRP-Rezeptor (Erenumab [CGRP: „calcitonin gene-related peptide“]) oder gegen CGRP (Eptinezumab, Fremanezumab, Galcanezumab) sind neue Substanzen zur prophylaktischen Behandlung der Migrane. Sie stellen eine Erweiterung der therapeutischen Optionen in der Migraneprophylaxe dar. In Zulassungsstudien wurden die Wirksamkeit und die gute Vertraglichkeit dieser spezifischen Substanzen bei Patienten mit episodischer und chronischer Migrane nachgewiesen. Die folgende Empfehlung prasentiert eine Zusammenfassung der Daten aus den Zulassungsstudien. Weiterhin werden Empfehlungen zur gezielten Patientenauswahl sowie zur Beurteilung des Therapieerfolgs und der Dauer der Behandlung gegeben. Abschliesend werden mogliche Anwendungseinschrankungen fur diese neue Substanzgruppe diskutiert.

Background: The goal of the study was to assess the safety and tolerability of atogepant, an oral, calcitonin gene-related peptide receptor antagonist in development for migraine preventive treatment, once daily over 1 year. Methods: Multicenter, open-label trial (NCT03700320). Adults with migraine were randomized 5:2 to atogepant or oral standard-of-care (SOC) migraine prevention. Results: 744 randomized participants (n=546 atogepant), 739 safety population participants (n=543 atogepant). Adverse events (AEs) were reported by 67.0% of atogepant participants; 18.0% had AEs considered related to atogepant. AEs reported by ≥5% of atogepant-treated participants were upper respiratory tract infection (10.3%), constipation (7.2%), nausea (6.3%), and urinary tract infection (5.2%). 4.4% of atogepant participants reported serious AEs that included various, common medical conditions; no event occurred in ≥1 participant and none were atogepant-related. Two deaths were reported in atogepant-treated participants (homicide victim; toxic shock syndrome); both were considered not treatment-related. 5.7% of atogepant participants discontinued due to AEs. Alanine aminotransferase/aspartate aminotransferase levels ≥3X upper limit of normal were reported for 2.4% of atogepant participants (n=13/531) and 3.2% of SOC participants (n=6/190). No cases of potential Hy’s Law were reported. Conclusions: Once-daily use of atogepant for preventive treatment of migraine over 1 year was safe and well-tolerated with no safety concerns identified.

The mixing process of fuel with air significantly influences fuel economy and emissions of diesel combustion in CI engines. It is common understanding that the momentum of the sprays exiting the injection nozzle plays a key role in controlling mixing process. First, spray momentum directly influences the atomization of the fuel liquid core and droplet formation in close vicinity of the nozzle, as it is associated with the fluid internal turbulence and the relative velocity between fuel and air.

Zielsetzung: Im Zuge knapper Ressourcen im Gesundheitswesen gibt es diverse Aktivitaten, schlanke Prozesse zu realisieren. Daher werden vereinzelt vor geplanten einfachen operativen Eingriffen telefonische Aufklarungen gefuhrt. Ziel dieser Arbeit ist es, die Patientenakzeptanz Telefon-basierter Aufklarungsgesprache zu evaluieren. Methodik: Als Methode wurde die Fragebogentechnik eingesetzt. Der Fragebogen enthielt neben allgemeinen Angaben zur Person drei Themengebiete: Patientenzufriedenheit, Bildungsstand und Anasthesieerfahrung sowie Fragen zum Hauptkriterium (eindeutige Praferenz fur ein telefonisches Aufklarungsgesprach). Die statistische Analyse umfasste neben der deskriptiven Statistik den Chi2-Test fur Gruppenvergleiche und dem Mann-Whitney-U-Test fur metrische Vergleiche. Ergebnisse: Alle 697 Datensatze wurden ausgewertet. Bei 44 % der Patienten handelte es sich um ambulante Patienten, die ubrigen wurden stationar behandelt. Dabei gaben 6 % der Patienten eindeutig an, mit einer Telefon-basierten Aufklarung einverstanden zu sein, unabhangig vom Behandlungssetting. Schlussfolgerung: Neben den sachlichen und inhaltlichen Aspekten der Aufklarung erscheint insbesondere die Beziehungsebene von Bedeutung. Die Vertrauensbildung durch personliches Kennenlernen des Anasthesisten, auch wenn er spater die Narkose nicht selbst durchfuhrt, ist fur den Patienten wichtig, um Sorgen und Angste abzubauen. Obwohl die rechtlichen Rahmenbedingungen in einfachen Fallen eine telefonische Aufklarung zulassen, ist die Akzeptanz seitens der Patienten gering.

Low back pain (LBP) is a common symptom in the populations of western countries, and adolescent athletes seem to be prone to LBP. The main objective of this study was to analyze the point (LBP within the last 48 h), 1-year (LBP within the last 12 months) and lifetime (LBP within the entire life) prevalence rates of LBP in adolescent athletes participating in various sports. We also assessed the characteristics of LBP and its association with potential risk factors. To this end, 272 competitive adolescent athletes involved in 31 different sports (158 males, 113 females, 15.4 ± 2.0 years, body mass index [BMI] 20.3 ± 2.4 kg/m(2)) were enrolled in a 10-month prospective clinical trial that included a questionnaire and physical examination. We found a point prevalence of 14%, a 1-year prevalence of 57%, and a lifetime prevalence of 66% for LBP. The mean age of first appearance of LBP was 13.1 ± 2.0 years. The lifetime prevalence was significantly higher in volleyball than in biathletes (74.3 vs. 45.7%, p = 0.015). Our findings confirm that LBP is a common symptom in adolescent athletes; LBP prevalence correlates with sports participation and individual competitive level. Adolescent athletes with LBP should receive a thorough diagnostic work-up and adapt training and technique correspondingly when indicated.

Zielsetzung: Im Rahmen der anasthesiologischen Patientenaufklarung ubt der Arzt-Patientenkontakt einen nachhaltigen Einfluss auf die Ergebnisqualitat aus. Dabei kann diese Leistung nennenswerte Storungen durch fehlende medizinische Informationen erfahren. Das Ziel dieser Studie lag in der zeitlichen Erfassung aller Storfaktoren, die wahrend der anasthesiologischen Patientenaufklarung auftraten. Methodik: Im Bereich einer Pramedikationsambulanz wurden alle Storungen zeitlich erfasst, dem arztlichen Ausbildungsstand (Arzte in der Weiterbildung [AiW] versus Facharzte [FA]) zugeordnet und verglichen. Ergebnisse: Von insgesamt 139 Patientengesprachen erfuhren 77 Gesprache (55,4 %) eine Storung. Hierbei waren AiW doppelt so haufig betroffen wie FA (66,3 vs. 31,8 %, p = 0,015). Die Storungszeit betrug dabei unabhangig vom Ausbildungsgrad ca. 10 % der Pramedikationszeit. Wahrend sich AiW wahrend des Gesprachs uber medizinische Aspekte informierten, waren FA zumeist von fehlenden Untersuchungsbefunden und einer eingeschrankten Patientencompliance betroffen. Unabhangig vom Ausbildungsstand erforderte die IT-Systemnutzung zwischen 15 % und 19 % der jeweiligen Storungszeit. Schlussfolgerung: Storungen sind haufig und generieren summiert einen nennenswerten Zeitaufwand. Konsentierte Verfahrensanordnungen und die strukturierte Einbindung der Patienten im Informationstransfer konnten eine bedeutende Zeitersparnis ermoglichen.

The new European chemicals policy for the Registration, Evaluation, Authorisation and Restriction of Chemicals (the REACH system), requires the routine toxicological testing of chemicals produced in volumes of more than one tonne per year, in order to enhance environmental and consumer safety (1). Under the REACH system policy, it will be most probably necessary to test several thousand chemicals for their toxicological properties.

The role of rodents as a possible source of allergens should not be underestimated, especially because this group of mammals comprises a great number of subspecies, people may come into contact with both at work and in the home environment. The causative allergens can be found in the fur, saliva, urine and epithelia. Few, and in part, contradictory data on the sensitization with rodent allergens prompted us to perform our own clinical and laboratory tests for guinea-pig allergy. 9% of our patients with suspected inhalation allergy proved to be sensitive to guinea-pig allergens, with 6% showing an established allergy; the proportion of patients who developed an asthma bronchiale being distinctly higher than that with other allergies. It was possible to isolate and characterize 2 main allergens (Cav p 1 and Cav p 2) which both belong to the group oflipocalines. In this way, the basis was created for an allergen standardization and further investigations of dusts regarding the presence of guinea-pig allergens.

Compacted graphite iron (CGI) is the material for the upcoming new generation of high-power diesel engines. Due to its increased strength compared to grey cast iron (CI) it allows an increase in the cylinder-pressures and therefore a better fuel economy and a higher power output are possible. First examples of such engines are the 3.3 L Audi V8 TDI and the 4.0 L BMW V8. The reason why CGI is not used to a larger extent in large scale production up to now is its much more difficult machinability as compared to conventional CI, especially at high cutting speeds. In modern transfer lines high cutting speeds are used in the cylinder-boring operation. And especially in these continuous cutting operations the tool life decreased due to the change from CI to CGI by about a factor of 20. As was found out previously by us, the difference in tool lifetime can be explained by the formation of a MnS-layer on the tool surface in the case of CI. This layer cannot form when machining CGI because the formation of MnS-inclusions is not possible in this material due to the higher magnesium content which in turn is responsible for the formation of the graphite vermicles. The MnS-layer acts as a lubricant and prevents the adhesion of workpiece particles. This is the reason for the greatly reduced wear of CI in high speed machining operations. This MnS-layer is inspected closer by X-ray diffraction, X-ray induced photoelectron spectrometry, atomic force microscopy and secondary ion mass spectrometry in this work. Furthermore, available information on the performance of MnS as lubricant in PM-steels is comparatively discussed. This knowledge led to an economic solution of high productivity machining of CGI. The key was to reduce the cutting speed, replacing single insert tools with multiple insert tools. This allowed to increase the feed rate. By increasing the feed rate in the same amount as decreasing the cutting speed, the same productivity can be realized. This concept is leading to a number of multiple insert tools thus realizing a high productivity machining of CGI cylinder-bores with multi-layer-coated carbide tools.

Fun to drive, styling and quality belong to the top customer preferences for premium automobiles, particularly in the sport and luxury segment. Therefore, vehicle dynamics and performance have always have major attributes in vehicle development. Especially in urban areas, however, traffic has been increasing significantly over the last decade. More and more, drivers find themselves in stop-and-go situations, where the active part of driving and enjoying the dynamics of the vehicle is strongly reduced. Therefore, driving comfort and driver assistance are gaining more and more importance. Furthermore, severe CO2 and emission regulations lead to a strong shift towards E-mobility technologies in the entire automotive industry. The weight of traction batteries causes a significant increase of overall vehicle weight, which has a negative impact on driving dynamics. In view of these trends and other megatrends, fig. 1, one can ask the question, if fun to drive and performance will keep their meaning as major attributes in product strategy. This paper intends to discuss some aspects of this in more detail.

BACKGROUND: Use of preventive therapy for migraine is often recommended for only 6-9 months, but no randomised, placebo-controlled trials have investigated migraine frequency after the end of prophylaxis. We assessed the effects of discontinuation of topiramate after a treatment period of 6 months. METHODS: 818 patients who have migraines were enrolled from 88 clinics in 21 countries. After a 4-8-week lead-in period, patients received topiramate in a 26-week open-label phase. Daily dose was increased from 25 mg to 100 mg in steps of 25 mg every week; the dose could be adjusted further in the range 50-200 mg/day, but was stable for the final 4 weeks. Patients were randomly assigned to continue this dose or switch to placebo for a 26-week double-blind phase. The primary endpoint was the difference in number of days with migraine during the last 4 weeks of the double-blind phase compared with the last 4 weeks of the open-label phase. Analysis was by intention to treat. This trial is registered with EudraCT, number 2005-000321-29. FINDINGS: 559 patients (68.3%) completed the open-label phase; 514 entered the double-blind phase and were assigned to topiramate (n=255) or placebo (n=259). The mean increase in number of migraine days was greater in the placebo group (1.19 days in 4 weeks, 95% CI 0.71 to 1.66; p

Deployment of light construction on the Moon surface after landing is a real way to create a Moon base. The construction has to be soft at deployment and hard at exploitation. A number of methods for solidification of deployed constructions in space was proposed, but the best way is a chemical reaction which leads to formation of the hard frame of space construction. The technology of large-size Moon module for industrial and scientific applications is developed by the way of the polymerisation process in composite material with liquid polymer matrix. Experiments with chemical reactions of polymerisation in composite materials under high vacuum, ion beam and plasma discharge have shown a possibility to use the liquid polymer matrix of composite materials under space conditions without hermetic coating. Epoxy resins with thermal initiation system of polymerisation were studied. The effects of initiation of the polymerisation reaction under simulated space factors were observed. Structure and mechanical properties of cured composite under simulated space conditions were analysed and compared with composite cured by usual ground technology. The proposed frame technology can be used for energetic, electronic and other industry building on the Moon.

Results obtained in long-term carcinogenicity studies with animals should be evaluated, first and foremost, by statistical comparisons of the data obtained from the treated group with that from the concurrent control group. Often the results are compared with data from so-called historical control groups in order to take variations in the incidences of spontaneous tumours into account. Because historical control data change in the course of time and for a variety of reasons, certain requirements must be met before they may be used in the evaluation of the results of long-term studies. The present paper discusses potential sources of variability of tumour incidences in untreated animals, presents databanks for historical control data, mentions the factors that affect tumour incidences in untreated animals and describes biostatistical data evaluation. Finally, details are given of the criteria used by the DFG Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area to decide whether historical control data may be applied. These include the requirement that the historical control data were obtained with animals of the same species and strain and from the same breeder. The data were obtained in the same laboratory, the study design, experimental methods and assessment criteria were the same, and the studies used for the comparison were carried out within a limited time window. Historical control data that have not been published may be used provided they fulfil the above criteria and have been made available in sufficient detail to be comprehensible.

Various experiments were performed to investigate the wear mechanism of cubic boron nitride (cBN) tools used for the machining of compacted graphite iron (CGI). Comparative studies for tools used to machine grey cast iron (CI) were also performed in order to find out why in this case the tool lifetime is significantly higher. Two main effects were found that are responsible for tool wear, namely: (1) oxidation of the tool, and (2) interdiffusion of constituting elements between tool and CGI. These wear mechanisms are more or less the same for the machining of CGI and grey CI. The difference in tool lifetime can be explained by the formation of a MnS layer on the tool surface in the case of grey CI. This layer is missing in the case of CGI. The MnS layer acts as a lubricant and as a diffusion barrier and is the reason for the reduced wear in the case of grey CI.

Cubic boron nitride (cBN) is a common material for tools for the machining of cast irons at high cutting speed. During the machining of compacted graphite iron (CGI) in continuous cutting the wear of the cBN tools was found to be significantly higher compared to the machining of grey cast iron. This is possibly a result of a heating of the tool surface during the cutting of CGI. One possible reason for the wear is diffusion of some elements from the cutting tool into the CGI or from the CGI into the cutting tool. SIMS measurements were carried out which prove the existence of such diffusion processes. A static model experiment has been performed by heating cBN tools to 700 °C while in contact with CGI or cast iron (CI). SIMS depth profiles of the cBN tools and of CGI/CI show that there is a diffusion of several elements in both directions (B, W and Ti from the cBN tools into the CGI or CI, Fe and Si from the CGI or CI samples into the cBN) up to a depth of 20 μm.

Carcinogenic chemicals in the work area were previously classified into three categories in section III of the German List of MAK and BAT values (the list of values on maximum workplace concentrations and bio‐logical tolerance for occupational exposures). This classification was based on qualitative criteria and reflected essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. In the new classification scheme the former sections IIIA1, IIIA2, and IIIB are retained as categories 1, 2, and 3, to correspond with European Union regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, these three categories are supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not contribute significantly to the risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. Chemicals known to act typically by non-genotoxic mechanisms, and for which information is available that allows evaluation of the effects of low-dose exposures, are classified in category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose/response relationships and toxicokinetics and for which risk at low doses can be assessed are classified in category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for category 4 (1,4-dioxane) and category 5 (styrene) are presented.

Relative to the wellknowng-factor of56Fe(2 1 + ) at 0.847 MeV, theg-factor of the54Fe(2 1 + ) state at 1.408 MeV has been remeasured employing the technique of transient magnetic fields (TF) with the ions slowed down in ferromagnetic Gd host at initial velocities of 2.5 ν0. Coulomb excitation on beams of54,56Fe was accomplished with a Si target. The value obtained,g=1.05(17), is in excellent agreement with two previous results but disagrees with the value from a TF measurement where the ions passed through ferromagnetic Fe.

A matrix separation is essential for most samples in the analysis of polyhalogenated dibenzofurans (HalXDF) and dibenzodioxins (HalXDD). The widely used clean-up procedures, like the sulfur removal with benzene on superactive alumina, discriminate against Cl1-Cl4DF with substitution in the 4,6-position rather selectively as does the treatment of the sample with silica/sulfuric acid for the Hal1DD.

The well established phenomenon of heavy ion beam induced attenuations of transient magnetic fields (TF) was studied by measuring the in-beam magnetization of bombarded Fe foils employing the magneto-optical Kerr-effect. Whereas the macroscopic magnetization did not show any deterioration, the simultaneously measured TF of recoiling108Pd(2+) ions was found to be substantially attenuated.

It is shown that transient magnetic fields in Gd-host for20Ne ions at a mean velocity of 12.5v0(v0=c/137), considerably beyond the Bohr velocity of 1s electrons of Ne ions (v1s=10v0), are dominated by the Fermi contact field of these electrons. The first excited 2+-state of2Ne was used as probe. The derived value for the mean degree of polarization p1s=0.32(13), is surprisingly large, though still consistent with values obtained at lower velocities. Present calculations of spin exchange cross sections severely underestimate the observed polarization at this high velocity.

From measurements of transient magnetic fields (TF) on56Fe(21+) ions in Gd host there is evidence that beam induced attenuations of TF not only depend on the energy loss of the beam ions in the ferromagnet but also on the electron ns-orbitals of the probe ion contributing to the field. This has been demonstrated for 2s- and 3s-electron states of56Fe ions which are preferentially populated by setting the ion velocity to their respective orbital Bohr velocities.

In time-differential measurements it is shown that 1s electrons of single-electron 16O(3−) ions have their spin polarized on emergence from magnetized thin Fe foils into vacuum. The mean degree of polarization deduced, p 1 s =0.060(6) , is approximately half of what is observed inside the Fe foil.

For the design of separation processes in systems showing azeotropic behaviour and two liquid phases, VLLE data must be represented with high accuracy. The ternary system ethanol/water/cyclohexane has been investigated for model development. The static method of p ( x , T ) measurement was applied to evaluate VLE of this highly non-ideal system which exhibits a wide miscibility gap. The tie-lines and the LL coexistence curve were determined by analysing samples of two liquid phases in equilibrium. The vapour composition of the heterogeneous azeotrope was determined by analysis of the head product of a rectification at infinite reflux ratio. To obtain full thermodynamic information on multicomponent VLE from p ( x , T ) measurement, a consistent description of the excess Gibbs energy of the liquid phase is required. The experimental data were described consistently, facilitating a modification of the NRTL equation with considerably increased flexibility in the ternary region.

Measurements of transient magnetic fields in Fe for Coulomb-excited24Mg(2↓)-ions at high velocity confirm strong attenuations as observed earller for single-electron28Si ions. In a measurement in which the beam was stopped in a non-magnetic buffer layer sandwiched between the target and the Fe layer the perturbation was shown to result from the interaction of the heavy Ni beam with the ferromagnet. The attenuations seem to be correlated with the dE/dx of the beam-ions in the ferromagnet.

Migraine attacks are characterized as unilateral and pulsating headache with autonomic features. In about 15 % of Migraine patients the attacks are accompanied by, mostly visual, transient focal neurologic disturbances, the migraine aura. Migraine attacks of mild or moderate intensity should initially be treated with non-steroidal anti-inflammatory drugs (NSAID). A combination with prokinetic and antiemetic drugs like metoclopramide or domperidone has proved to relieve nausea and increase efficacy of the analgesic drugs. In case of severe attacks or lack of treatment efficacy the migraine attacks should be treated with 5-HT (1B/1D) receptor agonists (triptans). Patients that suffer under very frequent and/or very severe migraine attacks should receive a prophylactic treatment. Prophylactic drugs of first choice are Betablockers (Propranolol and Metoprolol), Topiramate and Flunarizine. Prophylactic treatment should be administered over a period of at least 6 - 12 months.

The shared anatomical and physiological substrate for headache syndromes is the neural innervation of the cranial circulation. Evidence suggests, that the observed dilatation of vessels in trigeminal pain is not inherent to a specific headache syndrome but rather a feature of the physiology of the trigeminal neural innervation of the cranial circulation. Moreover, the impact of vascular changes for the generation of headaches remains elusive. The trigeminal nerve innervates blood vessels within ipsilateral meninges. Upon activation neuropeptides such as CGRP are released. Blockade of both the trigeminal nerve system and neuropeptides are crucial targets for headache alleviating drugs. While these mechanisms are well known the events within and outside the CNS which initiate headaches are poorly understood. This article will review the anatomy and physiology of the trigeminovascular system which demand renewed consideration of the neural influences in many primary headaches.