Serum neurofilament light chain in behavioral variant frontotemporal dementia

Objective To determine the association of serum neurofilament light chain (NfL) with functional deterioration and brain atrophy during follow-up of patients with behavioral variant frontotemporal dementia (bvFTD). Methods Blood NfL levels from 74 patients with bvFTD, 26 with Alzheimer disease (AD), 17 with mild cognitive impairment (MCI), and 15 healthy controls (Con) at baseline and follow-up were determined and analyzed for the diagnostic potential in relation to functional assessment (Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB], frontotemporal lobar degeneration-related CDR-SOB, Mini-Mental State Examination [MMSE]) and brain volumetry. Results At baseline, serum NfL level correlated with CSFNfL (bvFTD r = 0.706, p < 0.0001;AD/MCI r = 0.666, p = 0.0003). Highest serum levels were observed in bvFTD (p < 0 0.0001 vs Con and MCI, p = 0.0078 vs AD, respectively). Discrimination of bvFTD from Con/MCI/AD was possible with 91%/74%/74% sensitivity and 79%/74%/58% specificity. At follow-up, serum NfL increased in bvFTD and AD (p = 0.0039 and p = 0.0006, respectively). At baseline and follow-up, NfL correlated with functional scores of patients with bvFTD (e.g., CDR-SOB [baseline] r = 0.4157, p = 0.0006;[follow-up] r = 0.5629, p < 0.0001) and with atrophy in the gray and white matter of many brain regions including frontal and subcortical areas (e.g., frontal lobe: r = -0.5857, p < 0.0001;95% confidence interval -0.7415 to -0.3701). For patients with AD/MCI, NfL correlated with the functional performance as well (e.g., CDR-SOB [baseline] r = 0.6624, p < 0.0001;[follow-up] r = 0.5659, p = 0.0003) but not with regional brain volumes. Conclusions As serum NfL correlates with functional impairment and brain atrophy in bvFTD at different disease stages, we propose it as marker of disease severity, paving the way for its future use as outcome measure for clinical trials. Classification of evidence This study provides Class III evidence that for patients with cognitive problems, serum NfL concentration discriminates bvFTD from other forms of dementia

Analysis and design model for order patterns in multi variant serial production

Ein immer turbulenter werdendes Umfeld und die damit verbundenen höheren Anforderungen an die Stabilität und Flexibilität von ganzen Netzwerken stellt Industrieunternehmen vor eine neue Ausgangssituation. Die veränderten Umfeldbedingungen sind mit Risiken verbundenen, bieten aber allen Beteiligten auch die große Chance, sich zukünftige Wettbewerbsvorteile zu sichern. Das Thema gewinnt insofern an Bedeutung, als eigentlich jedes Industrieunternehmen ungeachtet seiner Größe tagtäglich in Netzwerken über seine zahlreichen Schnittstellen agiert. Genau hier unterstützt die vorliegende Arbeit die Schaffung einer neuen Qualität der Prozess-Synchronisation an der Schnittstelle zu anderen Unternehmen. Die hier formulierten Anforderungen und die Darstellung des Standes der Technik zeigen, dass verbesserte und neue Prinzipien, Verfahren und Modelle zur Harmonisierung von Kunden-Lieferanten-Beziehungen notwendig sind. Das in dieser Arbeit entwickelte Modell basiert auf den zwei Kernbausteinen Analyse und Gestaltung von Bestellverhalten. Im ersten Teil wird eine Methode zur Quantifizierung von Bestellverhalten beschrieben, mit deren Hilfe das Bestellverhaltens einer Güteklasse zugeordnet wird. Ein Unternehmen kann damit sowohl sein eigenes Bestellverhalten oder das seines Kunden bewerten. Auf Basis dieser Ergebnisse wird dann das Bestellverhalten interpretiert. Diese Interpretation belegt, inwieweit das gemessene Bestellverhalten ein Problem im Netzwerk darstellt, und inwieweit dieses Bestellverhalten „logisch nachvollziehbar“ ist. Das Analysemodell berücksichtigt dabei die wesentlichen vier Handlungsbedarfe, die bei der Bewertung des Standes der Technik identifiziert wurden. Diese vier Handlungsbedarfe beziehen sich auf die ganzheitliche Berücksichtigung der drei Dimensionen Bestellmenge, Bestelltermin und Zeitpunkt der Bestellung, die Identifikation des tatsächlichen Kundenwunsches, die mit einer Schwankung verbundenen Risiken sowie den Zusammenhang zwischen Schwankungscharakteristik und möglichen Schwankungsursachen. Diese Interpretation liefert damit die Basis für den Gestaltungsteil des hier entwickelten Modells. Darin werden konkrete Handlungsempfehlungen für eigen- und fremdinduzierte Turbulenzkeime vorgeschlagen. Bei der Reduzierung eigeninduzierter Bestellschwankungen helfen konkrete Ursachen-Wirkungs-Zusammenhänge zwischen beispielhaften Schwankungsmustern und dazugehörenden typischen „Stolpersteinen“ aus der Praxis. Da sich eine Vielzahl an Turbulenzen aufgrund ihres fremdinduzierten Charakters nicht vermeiden lassen, wird dargestellt, wie Kunde und Lieferant die zu erwartenden Turbulenzen mittels Schwankungskorridoren vereinbaren können. Bei der Analyse des „Standes der Technik“ wurden zwei besonders wichtige Kriterien identifiziert: die Berücksichtigung spezifischer Abhängigkeiten zwischen Produkten oder Varianten bezüglich der Lieferflexibilität sowie eine praxisnahe Vorgehensweise für Kunde und Lieferant zur Erlangung einer derartigen Vereinbarung. Das hier vorgestellte Modell leistet einen wichtigen Beitrag zur besseren Zusammenarbeit an der Schnittstelle Kunde-Lieferant und damit zur Stabilität ganzer Netzwerke. Die Verifizierung des Modells mit einem abstrahierten Datenmodell belegt, dass die Anforderungen an ein derartiges Modell erfüllt werden können. Darüber hinaus können auch Teilelemente des entwickelten Modells in der Praxis eingesetzt werden, etwa bei der Vereinbarung einer Kunden-Lieferanten-Vereinbarung, die auch ohne vorangehende retrograde Analyse des Bestellverhaltens möglich ist.Recent developments have called into question the established principles of successful business management. These developments find expression in the increasing saturation of “first world“ markets, where demand tends towards individualization. Reasons are a demographic shift resulting in an aging population and a fragmentation of target groups. In addition, an ongoing and deepening process of internationalization and deregulation has taken place over the past years. It has opened up new sales and supply markets, but also initiated a new type of competition at international level. From a technological point of view, the innovation cycles have steadily shortened due to new technological solutions at product and process level and in information and communication technology. Numerous expert papers on manufacturing engineering describe the trend towards a more dynamic environment, along with more customized products, using the terms „turbulence“ or „environmental turbulence“. A highly complex and dynamic environment makes it difficult to generate forecasts and confronts manufacturing companies with new challenges in global competition. Customers call for highly customized products with state-of-the art technology to be delivered as soon as possible, while being less and less willing to pay for it. To remain successful, companies must counteract the increasing requirements at product, price and service level. The future will only see those companies survive in the market that continue to meet the exact needs of their customers. These companies must be able, at any time, to identify new trends or spark new ones. With a lower degree of vertical integration, they need to focus on their core competencies and produce products in value chains or networks of competent, creative and innovative companies. That is why learning how to manage a network, and to think and to act in terms of a network, are essential capabilities. Many of the activities carried out by companies - often to cut down on costs - increase the significance of high-quality network management. Examples are known as „global sourcing“, „outsourcing“ (focus on core competencies by contracting out value-adding activities, e.g. modularization in vehicle construction), but also the ongoing reduction of stocks and the amount of capital tied-up. A greater inclusion of partners distributed across the world, as well as the reduction of safety stocks to a minimum, require a well-functioning network. To this must be added the growing market demand for short delivery times, for a more flexible handling of customer change requests and for high schedule reliability. As a result, the call for greater stability and flexibility does not only affect the network as a whole, but each individual customer-supplier interface in the network. Moreover, the number of interfaces grows with ongoing intertwining of the network. Above all, these changes require raising the quality of process synchronization in order to optimize the customer-supplier-interfaces. Several solutions have been pursued as part of supply chain management, but they do not go far enough. The following three key problems arise in industrial practice: - There are no universal indicators - resulting in a lack of visibility - which allow to measure the quality of a customer’s order and call-off patterns. That’s why this advance information is not considered appropriately, even though it has a considerable impact on the delivery performance of the supplier. - There are numerous turbulence germs in the companies that trigger fluctuations in the order and call-off patterns. There is a lack of methods to identify and eliminate self-induced turbulence. - Growing environmental turbulence results more often in externally driven turbulence, i.e. market- or consumer-driven turbulence. There are no appropriate approaches in science and business that enable arrangements which minimize turbulence between customer and supplier. The aim of this thesis is therefore to find concrete solutions to the three problems described above in order to contribute to the process synchronization of customer-supplier interfaces. The quality of the customer-supplier interface is a key determinant of competitiveness in a manufacturing environment where series products are manufactured at regular intervals over an extended period. Both the continuous order flow and the deliveries at short intervals provide the necessary basis for a model that allows analyzing and designing the order pattern. The model developed in this thesis is based on two key components for the analysis and design of order patterns. The first part describes a method to quantify order patterns so that they can be sorted into quality categories. A company can thus assess both its own order pattern as well as that of its customers. The outcome allows interpreting the order pattern. The interpretation determines if and how problematic the measured order pattern is for the network and if this order pattern is „logically comprehensible“. The analysis model considers the four key trouble spots identified when assessing the state of the art. These four areas of action require taking into full consideration the three dimensions of order quantity, order date and delivery date, the identification of actual customer needs, the risks associated with fluctuation, and the relationship between fluctuation characteristics and possible causes of fluctuations. This interpretation provides the basis for the design part of the developed model. It recommends specific actions to eliminate self- and externally induced turbulence germs. Specific cause-and-effect relationships referring to exemplary fluctuation patterns and associated typical ‘obstacles’ in real life help to reduce the self-induced order fluctuations. Due to the fact that many turbulence germs are externally induced and therefore cannot be avoided, this thesis suggests how customer and supplier can handle the expected fluctuations by agreeing on fluctuation margins. The analysis of the „state of the art“ revealed two major criteria: specific dependencies between products or variants in terms of flexible delivery need to be considered, and a practical approach developed for customers and suppliers to come to such an agreement. The model presented here makes an important contribution to improving collaboration at the customer-supplier interface and thus to making networks more stable. The model has been verified by an abstract data model proving that the requirements set for such a model can be satisfied. Moreover, it is also possible to apply subcomponents of the developed model in practice, for example, when working out customer-supplier agreements, which is also possible without an advance retrograde analysis of the order pattern

Entwicklung von Lieferantenparks in Europa

Im Rahmen des Vortrages werden zunächst die in Europa vorhandenen ca. 40 Lösungen vorgestellt und mit Bezug zu ihrem Entstehungszeitpunkt sowie 8 weiterer typologischer Merkmale eingeordnet. Im Anschluss erfolgt die Darstellung der vom Autor entwickelten 10 Erfolgsfaktoren von Lieferantenparks, basierend auf der Marktstudie "Lieferantenparks in der europäischen Automobilindustrie". Abschließend spricht der Autor Handlungsempfehlungen im Themengebiet für Automobilhersteller, die Öffentliche Hand, Zulieferer und Dienstleister aus

Anforderungen und Lösungen für eine schlanke Produktionslogistik

Das Ziel einer schlanken Produktionslogistik ist es, mit geringstem Aufwand die Güter bereitzustellen, die der Kunde / Markt wünscht. Hierzu muss Verschwendung im Produktions- und Logistikprozess eliminiert werden. Anhand von Praxisbeispielen zeigt der Autor auf, wie diese Eliminierung von Verschwendung innerhalb und im Zusammenspiel der folgenden vier Handlungsfelder erfolgen kann: Struktur- und Layoutplanung, Planungs- und Steuerungslogik, Informationstechnik und Mitarbeiterqualifikation

Influence of the interleukin-converting enzyme inhibitor HMR-3480 on myocardial stunning in pigs in vivo

BACKGROUND: The proinflammatory cytokine interleukin-1 beta is converted into its active form by interleukin-1 beta-converting enzyme (ICE). Circulating cytokines may promote myocardial dysfunction (stunning) after ischemia. OBJECTIVE: To investigate whether ICE inhibition by HMR-3840 improves myocardial stunning in vivo. METHODS: Anesthetized (isoflurane and fentanyl) pigs were used for measurement of left ventricular (LV) pressure, cardiac output and blood flow in the left anterior descending coronary artery (LAD) and left circumflex coronary artery. Regional myocardial function was assessed by sonomicrometry as systolic wall thickening and mean systolic thickening velocity in the anteroapical and posterobasal walls. The animals were subjected to 10 min of LAD occlusion followed by 4 h of reperfusion. The ICE inhibitor (flow-adjusted to achieve coronary plasma concentrations of 10 mug/mL) (ISCH, n=7) or the vehicle (CON, n=7) was infused via a side branch into the LAD during ischemia, or during ischemia and the first 60 min of reperfusion (REP, n=6). RESULTS: Occlusion of the LAD resulted in systolic outward movement (bulging) of the anteroapical wall during ischemia in all groups. Infusion of the ICE inhibitor had no effect on functional recovery when given during ischemia or when given during reperfusion (at the end of reperfusion in the anteroapical wall, values for systolic wall thickening were: CON 17.3+/-7.3%, ISCH 23.2+/-9.8% and REP 19.3+/-6.1%; and values for mean systolic thickening velocity were: CON 4.3+/-1.1 mm/s, ISCH 6.1+/-3.9 mm/s and REP 5.2+/-1.7 mm/s; all P values not significant for CON versus ISCH or REP). LAD blood flow was not affected by HMR-3840 (23.4+/-5.2 mL/min versus 24.3+/-8.1 mL/min; P not significant). Global myocardial function (LV pressure, maximum rate of LV pressure increase and cardiac output) was not different between controls and treatment groups during reperfusion. CONCLUSION: ICE inhibition by HMR-3480 had no effect on myocardial stunning in pigs in viv

Cardioprotection against reperfusion injury is maximal with only two minutes of sevoflurane administration in rats

PURPOSE: Volatile anesthetics can protect the heart against reperfusion injury. When sevoflurane is given for the first 15 min of reperfusion, a concentration corresponding to one minimum alveolar concentration (MAC) provides a maximum protective effect. The present study addresses the question of how long sevoflurane has to be administered to achieve the best cardioprotection. METHODS: Chloralose anesthetized rats were subjected to a 25-min occlusion of a major coronary artery, followed by 90 min of reperfusion. During the initial phase of reperfusion, an end-tidal concentration of 2.4 vol.% of sevoflurane (1 MAC) was given for two (n = 8), five (n = 8) or ten minutes (n = 7). Seven rats served as untreated controls. We measured left ventricular (LV) pressure, mean aortic pressure and infarct size (triphenyltetrazolium staining). RESULTS: Administration of sevoflurane for two minutes resulted in the greatest reduction of infarct size to 15% (8-22 [mean (95% confidence interval)] of the area at risk compared with controls [51 (47-55) %, P < 0.001]. Five or ten minutes of sevoflurane administration reduced infarct size to 26 (18-34) and 26 (18-35) % [P < 0.05], respectively. The cardiodepressant effect of sevoflurane varied with the duration of its administration: LV dP/dt was reduced from 6332 mmHg x sec(-1) (5771-6894) during baseline to 4211 mmHg x sec(-1) (3031-5391), 3811 mmHg x sec(-1) (2081-5540) and 3612 mmHg x sec(-1) (2864-4359) after two, five and ten minutes of reperfusion, respectively. CONCLUSION: Administration of 1 MAC sevoflurane for the first two minutes of reperfusion effectively protects the heart against reperfusion injury in rats in vivo. A longer administration time had lesser cardioprotective effects in this experimental mode