Die Verbindung von Kleinwinkelstreuung und in silico-Methodik zur Aufklärung von Konformationswechseln großer Proteinkomplexe

In dieser Dissertation wurden die Methoden Homologiemodellierung und Molekulardynamik genutzt, um die Struktur und das Verhalten von Proteinen in Lösung zu beschreiben. Mit Hilfe der Röntgenkleinwinkelstreuung wurden die mit den Computermethoden erzeugten Vorhersagen verifiziert. Für das alpha-Hämolysin, ein Toxin von Staphylococcus aureus, das eine heptamere Pore formen kann, wurde erstmalig die monomere Struktur des Protein in Lösung beschrieben. Homologiemodellierung auf Basis verwandter Proteine, deren monomere Struktur bekannt war, wurde verwendet, um die monomere Struktur des Toxins vorherzusagen. Flexibilität von Strukturelementen in einer Molekulardynamiksimulation konnte mit der Funktionalität des Proteines korreliert werden: Intrinsische Flexibilität versetzt das Protein in die Lage den Konformationswechsel zur Pore nach Assemblierung zu vollziehen. Röntgenkleinwinkelstreuung bewies die Unterschiede der monomeren Struktur zu den Strukturen der verwandten Proteine und belegt den eigenen Vorschlag zur Struktur. Überdies konnten Arbeiten an einer Mutante, die in einer sogenannten Präporenkonformation arretiert und nicht in der Lage ist eine Pore zu formen, zeigen, dass dieser Übergangszustand mit der Rotationsachse senkrecht zur Membran gelagert ist. Eine geometrische Analyse beweist, dass es sterisch möglich ist ausgehend von dieser Konformation die Konformation der Pore zu erreichen. Eine energetische und kinetische Analyse dieses Konformationswechsels steht noch aus. Ein weiterer Teil der Arbeit befasst sich mit den Konformationswechseln von Hämocyaninen. Diese wurden experimentell mittels Röntgenkleinwinkelstreuung verfolgt. Konformationswechsel im Zusammenhang mit der Oxygenierung konnten für die 24meren Hämocyanine von Eurypelma californicum und Pandinus imperator beschrieben werden. Für eine Reihe von Hämocyaninen ist nachgewiesen, dass sie unter Einfluss des Agenz SDS Tyrosinaseaktivität entfalten können. Der Konformationswechsel der Hämocyanine von E. californicum und P. imperator bei der Aktivierung zur Tyrosinase mittels SDS wurde experimentell bestätigt und die Stellung der Dodekamere der Hämocyanine als wesentlich bei der Aktivierung festgestellt. Im Zusammenhang mit anderen Arbeiten gilt damit die Relaxierung der Struktur unter SDS-Einfluss und der sterische Einfluss auf die verbindenden Untereinheiten b & c als wahrscheinliche Ursache für die Aktivierung zur Tyrosinase. Eigene Software zum sogenannten rigid body-Modellierung auf der Basis von Röntgenkleinwinkelstreudaten wurde erstellt, um die Streudaten des hexameren Hämocyanins von Palinurus elephas und Palinurus argus unter Einfluss der Effektoren Urat und Koffein strukturell zu interpretieren. Die Software ist die erste Implementierung eines Monte Carlo-Algorithmus zum rigid body-Modelling. Sie beherrscht zwei Varianten des Algorithmus: In Verbindung mit simulated annealing können wahrscheinliche Konformationen ausgefiltert werden und in einer anschließenden systematischen Analyse kann eine Konformation geometrisch beschrieben werden. Andererseits ist ein weiterer, reiner Monte Carlo-Algorithmus in der Lage die Konformation als Dichteverteilung zu beschreiben.

Untersuchungen zur asymmetrischen Totalsynthese von Cripowellin

Im Rahmen dieser Arbeit konnten wichtige Schritte auf dem Weg zur asymmetrischen Totalsynthese des Cripowellin-Aglycons gemacht und wichtige Erkenntnisse gewonnen werden. Es gelang dabei, einen Teil des Grundgerüsts des Kerns mit dem entscheidenden stereogenen Zentrum optisch aktiv aufzubauen. Die Aza-Claisen-Umlagerung diente hierbei als Schlüsselschritt zum stereoselektiven Aufbau eines Epoxids. Für die Aza-Claisen-Umlagerung dienten ein Allylamin und ein Säurefluorid als Ausgangsverbindungen. Das Allylamin konnte ausgehend von Piperonylalkohol über sechs Stufen (Schutzgruppen-operationen, Bromierung, metallorganische Reaktionen, Reduktion) mit einem Auxliar versehen und mit einer Gesamtausbeute von 56 % synthetisiert werden. Die Synthese des Säurefluorids konnte im Rahmen dieser Arbeit entscheidend verbessert werden, insbesondere bezüglich der Reinheit. Die Aza-Claisen-Umlagerung zu einem Pentensäurederivat selbst konnte mit einer sehr befriedigenden Ausbeute von 91 % durchgeführt werden. Dabei entstanden zwei Diastereomere im Verhältnis 92:8. Kristallisationsversuche schlugen leider fehl, sodass der Konfigurationsbeweis noch aussteht. Dieses Pentensäurederivat konnte zunächst durch einen Reduktionsschritt und saure Abspaltung der Schutzgruppe und des Auxiliars in ein Benzylchlorid überführt werden, welches dann durch Umsetzung mit Ammoniak zu einem Benzazepinon reagierte, ein weiteres wichtiges Schlüsselintermediat in dieser Synthese. Mit diesem Benzazepinon wurden viele Versuche zur Doppelbindungsfunk-tionalisierung unternommen, so z. B. Dihydroxylierungen und Epoxidierungen. Auch wurde das Amid zum Amin reduziert und mit Pentensäure erneut funktionalisiert. Mit dem so gewonnenen Dien wurden erste Versuche unternommen, über eine Grubbs-Metathese das bicyclische System des Cripowellins aufzubauen, die jedoch scheiterten.

La administración concursal como sujeto del proceso jurisdiccional español. Su posición en la determinación del patrimonio concursal

Desde tiempos inmemoriales, la presencia de sujetos encargados de la administración del patrimonio del concursado ha sido consustancial a la existencia de procesos en los que se declaraba la insolvencia del deudor. Tradicionalmente, estos sujetos ostentaban un papel de singular alcance para el correcto desarrollo del concurso. En la actualidad se erigen en el motor del concurso. El vasto cometido atribuido a la administración concursal nos obliga a restringir nuestra investigación. En particular, centraremos nuestra atención en la posición jurídico procesal de la administración concursal en aquellas actuaciones que desarrolla ésta a la hora de determinar el patrimonio concursal. Para ello, partiendo de las líneas generales que a través de la historia han definido a los órganos de administración concursal, analizaremos el régimen jurídico de la actual administración concursal en España. A continuación, estudiaremos la naturaleza jurídica de la limitación a las facultades patrimoniales que sufre el deudor con la declaración de concurso y el reconocimiento que, como parte procesal, le atribuye la Ley de Enjuiciamiento Civil al patrimonio concursal. Todo ello, nos permitirá pronunciarnos sobre la referida posición de la administración concursal, como parte o como representante. Tras lo descrito, nos ocuparemos de determinar la posición que ocupa la administración concursal en aquellos procesos que ya estuvieran pendientes en el momento de la declaración de concurso y aquellos otros procesos nuevos que inicia aquella por su propia iniciativa. Por último, analizaremos la descrita posición procesal en el ejercicio de acciones de reintegración y demás de impugnación así como en aquellos supuestos en los que se impugna el inventario o la lista de acreedores.

L'evoluzione della tutela cautelare nel processo amministrativo

L’effettività della tutela cautelare, intesa come tutela tempestiva, adeguata e piena, è stata la linea cardine dell’evoluzione della giustizia amministrativa, che, nel corso di un periodo durato più di un secolo, grazie all’opera della giurisprudenza e della dottrina, si è strutturata oggi su un vero processo. Approdo recente, e allo stesso tempo, simbolo di questa evoluzione, è sicuramente il Codice del processo amministrativo emanato con il d. lgs. 2 luglio 2010, n. 104. La ricerca, di cui questo contributo costituisce un resoconto, è iniziata contestualmente all’entrata in vigore del nuovo testo, e quindi è stata anche l’occasione per vederne le prime applicazioni giurisprudenziali. In particolare la lettura del Codice, prescindendo da una mera ricognizione di tutto il suo lungo articolato, è stata fatta alla luce di una ponderazione, nell’attualità, non solo del principio di effettività, ma anche del principio di strumentalità che lega tradizionalmente la fase cautelare con la fase di merito. I risultati della ricerca manifestano la volontà del legislatore di confermare questo rapporto strumentale, per fronteggiare una deriva incontrollata verso una cautela dagli effetti alle volte irreversibili, quale verificatasi nell’applicazione giurisprudenziale, ma contestualmente evidenziano la volontà di estendere la portata della tutela cautelare. Guardando a cosa sia diventata oggi la tutela cautelare, si è assistito ad un rafforzamento degli effetti conformativi, tipici delle sentenze di merito ma che si sono estesi alla fase cautelare. I giudici, pur consapevoli che la tutela cautelare non sia una risposta a cognizione piena, bensì sommaria, intendono comunque garantire una tutela tempestiva ed effettiva, anche per il tramite di tecniche processuali particolari, come quella del remand, cui, all’interno della ricerca, viene dedicato ampio spazio. Nella sua ultima parte la ricerca si è focalizzata, sempre volendo guardare in maniera globale agli effetti della tutela cautelare, sul momento dell’esecuzione e quindi sul giudizio di ottemperanza.

Nuovi metodi di diagnosi precoce dei fallimenti di protesi d'anca con accoppiamento articolare ceramica-ceramica

L’accoppiamento articolare in ceramica è sempre più utilizzato in chirurgia protesica dell’anca per le sue eccellenti proprietà tribologiche. Tuttavia la fragilità della ceramica è causa di fallimenti meccanici. Abbiamo quindi condotto una serie di studi al fine di individuare un metodo efficace di diagnosi precoce del fallimento della ceramica. Abbiamo analizzato delle componenti ceramiche espiantate e abbiamo trovato un pattern di usura pre-frattura che faceva supporre una dispersione di particelle di ceramica nello spazio articolare. Per la diagnosi precoce abbiamo validato una metodica basata sulla microanalisi del liquido sinoviale. Per validare la metodica abbiamo eseguito un agoaspirato in 12 protesi ben funzionanti (bianchi) e confrontato i risultati di 39 protesi con segni di rottura con quelli di 7 senza segni di rottura. Per individuare i pazienti a rischio rottura i dati demografici di 26 pazienti con ceramica rotta sono stati confrontati con 49 controlli comparabili in termini demografici, tipo di ceramica e tipo di protesi. Infine è stata condotta una revisione sistematica della letteratura sulla diagnosi della rottura della ceramica. Nell’aspirato la presenza di almeno 11 particelle ceramiche di dimensioni inferiori a 3 micron o di una maggiore di 3 micron per ogni campo di osservazione sono segno di rottura della ceramica. La metodica con agoaspirato ha 100% di sensibilità e 88 % di specificità nel predire rotture della ceramica. Nel gruppo delle ceramiche rotte è stato trovato un maggior numero di malposizionamenti della protesi rispetto ai controlli (p=0,001). Il rumore in protesi con ceramica dovrebbe sollevare il sospetto di fallimento ed indurre ad eseguire una TC e un agoaspirato. Dal confronto con la letteratura la nostra metodica risulta essere la più efficace.

Synthesis, properties and application of polyphenylene phosphonium salts

The central objective of this work was to generate weakly coordinating cations of unprecedented molecular size providing an inherently stable hydrophobic shell around a central charge. It was hypothesized that divergent dendritic growth by means of thermal [4+2] Diels-Alder cycloaddition might represent a feasible synthetic method to circumvent steric constraints and enable a drastic increase in cation size.rnThis initial proposition could be verified: applying the divergent dendrimer synthesis to an ethynyl-functionalized tetraphenylphosphonium derivative afforded monodisperse cations with precisely nanoscopic dimensions for the first time. Furthermore, the versatile nature of the applied cascade reactions enabled a throughout flexible design and structural tuning of the desired target cations. The specific surface functionalization as well as the implementation of triazolyl-moieties within the dendrimer scaffold could be addressed by sophisticated variation of the employed building block units (see chapter 3). rnDue to the steric screening provided by their large, hydrophobic and shape-persistent polyphenylene shells, rigidly dendronized cations proved more weakly coordinating compared to their non-dendronized analogues. This hypothesis has been experimentally confirmed by means of dielectric spectroscopy (see chapter 4). It was demonstrated for a series of dendronized borate salts that the degree of ion dissociation increased with the size of the cations. The utilization of the very large phosphonium cations developed within this work almost achieved to separate the charge carriers about the Bjerrum length in solvents of low polarity, which was reflected by approaching near quantitative ion dissociation even at room temperature. In addition to effect the electrolyte behavior in solution, the steric enlargement of ions could be visualized by means of several crystal structure analyses. Thus an insight into lattice packing under the effect of extraordinary large cations could be gathered. rnAn essential theme of this work focused on the application of benzylphosphonium salts in the classical Wittig reaction, where the concept of dendronization served as synthetic means to introduce an exceptionally large polyphenylene substituent at the -position. The straightforward influence of this unprecedented bulky group on the Wittig stereochemistry was investigated by NMR-analysis of the resulting alkenes. Based on the obtained data a valuable explanation for the origin of the observed selectivity was brought in line with the up-to-date operating [2+2] cycloaddition mechanism. Furthermore, a reliable synthesis protocol for unsymmetrically substituted polyphenylene alkenes and stilbenes was established by the design of custom-built polyphenylene precursors (see chapter 5).rnFinally, fundamental experiments to functionalize a polymer chain with sterically shielded ionic groups either in the pending or internal position were outlined within this work. Thus, inherently hydrophobic polysalts shall be formed so that future research can invesigate their physical properties with regard to counter ion condensation and charge carrier mobility.rnIn summary, this work demonstrates how the principles of dendrimer chemistry can be applied to modify and specifically tailor the properties of salts. The numerously synthesized dendrimer-ions shown herein represent a versatile interface between classic organic and inorganic electrolytes, and defined macromolecular structures in the nanometer-scale. Furthermore the particular value of polyphenylene dendrimers in terms of a broad applicability was illustrated. This work accomplished in an interdisciplinary manner to give answer to various questions such as structural modification of ions, the resulting influence on the electrolyte behavior, as well as the stereochemical control of organic syntheses via polyphenylene phosphonium salts. rn

[Microbiological point of care tests]

It is well known that the early initiation of a specific antiinfective therapy is crucial to reduce the mortality in severe infection. Procedures culturing pathogens are the diagnostic gold standard in such diseases. However, these methods yield results earliest between 24 to 48 hours. Therefore, severe infections such as sepsis need to be treated with an empirical antimicrobial therapy, which is ineffective in an unknown fraction of these patients. Today's microbiological point of care tests are pathogen specific and therefore not appropriate for an infection with a variety of possible pathogens. Molecular nucleic acid diagnostics such as polymerase chain reaction (PCR) allow the identification of pathogens and resistances. These methods are used routinely to speed up the analysis of positive blood cultures. The newest PCR based system allows the identification of the 25 most frequent sepsis pathogens by PCR in parallel without previous culture in less than 6 hours. Thereby, these systems might shorten the time of possibly insufficient antiinfective therapy. However, these extensive tools are not suitable as point of care diagnostics. Miniaturization and automating of the nucleic acid based method is pending, as well as an increase of detectable pathogens and resistance genes by these methods. It is assumed that molecular PCR techniques will have an increasing impact on microbiological diagnostics in the future.

Association between conventional risk factors and different ultrasound-based markers of atherosclerosis at carotid and femoral levels in a middle-aged population

Ultrasound detection of sub-clinical atherosclerosis (ATS) may help identify individuals at high cardiovascular risk. Most studies evaluated intima-media thickness (IMT) at carotid level. We compared the relationships between main cardiovascular risk factors (CVRF) and five indicators of ATS (IMT, mean and maximal plaque thickness, mean and maximal plaque area) at both carotid and femoral levels. Ultrasound was performed on 496 participants aged 45-64 years randomly selected from the general population of the Republic of Seychelles. 73.4 % participants had ≥ 1 plaque (IMT thickening ≥ 1.2 mm) at carotid level and 67.5 % at femoral level. Variance (adjusted R2) contributed by age, sex and CVRF (smoking, LDL-cholesterol, HDL-cholesterol, blood pressure, diabetes) in predicting any of the ATS markers was larger at femoral than carotid level. At both carotid and femoral levels, the association between CVRF and ATS was stronger based on plaque-based markers than IMT. Our findings show that the associations between CVRF and ATS markers were stronger at femoral than carotid level, and with plaque-based markers rather than IMT. Pending comparison of these markers using harder cardiovascular endpoints, our findings suggest that markers based on plaque morphology assessed at femoral artery level might be useful cardiovascular risk predictors.

Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: A systematic review

BACKGROUND: Transient left ventricular apical ballooning syndrome (TLVABS) is an acute cardiac syndrome mimicking ST-segment elevation myocardial infarction characterized by transient wall-motion abnormalities involving apical and mid-portions of the left ventricle in the absence of significant obstructive coronary disease. METHODS: Searching the MEDLINE database 28 case series met the eligibility criteria and were summarized in a narrative synthesis of the demographic characteristics, clinical features and pathophysiological mechanisms. RESULTS: TLVABS is observed in 0.7-2.5% of patients with suspected ACS, affects women in 90.7% (95% CI: 88.2-93.2%) with a mean age ranging from 62 to 76 years and most commonly presents with chest pain (83.4%, 95% CI: 80.0-86.7%) and dyspnea (20.4%, 95% CI: 16.3-24.5%) following an emotionally or physically stressful event. ECG on admission shows ST-segment elevations in 71.1% (95% CI: 67.2-75.1%) and is accompanied by usually mild elevations of Troponins in 85.0% (95% CI: 80.8-89.1%). Despite dramatic clinical presentation and substantial risk of heart failure, cardiogenic shock and arrhythmias, LVEF improved from 20-49.9% to 59-76% within a mean time of 7-37 days with an in-hospital mortality rate of 1.7% (95% CI: 0.5-2.8%), complete recovery in 95.9% (95% CI: 93.8-98.1%) and rare recurrence. The underlying etiology is thought to be based on an exaggerated sympathetic stimulation. CONCLUSION: TLVABS is a considerable differential diagnosis in ACS, especially in postmenopausal women with a preceding stressful event. Data on longterm follow-up is pending and further studies will be necessary to clarify the etiology and reach consensus in acute and longterm management of TLVABS.

Software als Schutzgegenstand des Europäischen Urheberrechts

After 20 years of silence, two recent references from the Czech Republic (Bezpečnostní softwarová asociace, Case C-393/09) and from the English High Court (SAS Institute, Case C-406/10) touch upon several questions that are fundamental for the extent of copyright protection for software under the Computer Program Directive 91/25 (now 2009/24) and the Information Society Directive 2001/29. In Case C-393/09, the European Court of Justice held that “the object of the protection conferred by that directive is the expression in any form of a computer program which permits reproduction in different computer languages, such as the source code and the object code.” As “any form of expression of a computer program must be protected from the moment when its reproduction would engender the reproduction of the computer program itself, thus enabling the computer to perform its task,” a graphical user interface (GUI) is not protected under the Computer Program Directive, as it does “not enable the reproduction of that computer program, but merely constitutes one element of that program by means of which users make use of the features of that program.” While the definition of computer program and the exclusion of GUIs mirror earlier jurisprudence in the Member States and therefore do not come as a surprise, the main significance of Case C-393/09 lies in its interpretation of the Information Society Directive. In confirming that a GUI “can, as a work, be protected by copyright if it is its author’s own intellectual creation,” the ECJ continues the Europeanization of the definition of “work” which began in Infopaq (Case C-5/08). Moreover, the Court elaborated this concept further by excluding expressions from copyright protection which are dictated by their technical function. Even more importantly, the ECJ held that a television broadcasting of a GUI does not constitute a communication to the public, as the individuals cannot have access to the “essential element characterising the interface,” i.e., the interaction with the user. The exclusion of elements dictated by technical functions from copyright protection and the interpretation of the right of communication to the public with reference to the “essential element characterising” the work may be seen as welcome limitations of copyright protection in the interest of a free public domain which were not yet apparent in Infopaq. While Case C-393/09 has given a first definition of the computer program, the pending reference in Case C-406/10 is likely to clarify the scope of protection against nonliteral copying, namely in how far the protection extends beyond the text of the source code to the design of a computer program and where the limits of protection lie as regards the functionality of a program and mere “principles and ideas.” In light of the travaux préparatoires, it is submitted that the ECJ is also likely to grant protection for the design of a computer program, while excluding both the functionality and underlying principles and ideas from protection under the European copyright directives.

The Levy Runs Dry: A Legal and Economic Analysis of EU Private Copying Levies

This article provides a legal and economic analysis of private copying levies in the EU, against the background of the Copyright Directive (2001/29), a number of recent rulings by the European Court of Justice and the recommendations presented by mediator Vitorino earlier this year. It concludes that notwithstanding these rulings and recommendations, there remains a lack of concordance on the relevance of contractual stipulations and digital rights management technologies (DRM) for setting levies, and the concept of harm. While Mr Vitorino and AG Sharpston (in the Opinion preceding VG Wort v. Kyocera) use different lines of reasoning to argue that levies raised on authorised copies would lead to double payment, the Court of Justice’s decision in VG Wort v. Kyocera seems to conclude that such copies should nonetheless be levied. If levies are to provide fair compensation for harm resulting from acts of private copying, economic analysis suggests one should distinguish between various kinds of private copies and take account of the extent to which the value said copies have for consumers can be priced into the purchase. Given the availability of DRM (including technical protection measures), the possibility of such indirect appropriation leads to the conclusion that the harm from most kinds of private copies is de minimis and gives no cause for levies. The user value of copies from unauthorised sources (e.g. from torrent networks or cyber lockers), on the other hand, cannot be appropriated indirectly by rightholders. It is, however, an open question in references for preliminary rulings pending at the Court of Justice whether these copies are included in the scope of the private copying exception or limitation and can thus be levied for. If they are not, as currently happens in several EU Member States, legal and economic analysis leads to the conclusion that the scope of private copying acts giving rise to harm susceptible of justifying levies is gradually diminishing.

Digital First Sale Doctrine Ante Portas – Exhaustion in the Online Environment

The purpose of the article is to provide first a doctrinal summary of the concept, rules and policy of exhaustion, first, on the international and EU level, and, later, under the law of the United States. Based upon this introduction, the paper turns to the analysis of the doctrine by the pioneer court decisions handed over in the UsedSoft, ReDigi, the German e-book/audio book cases, and the pending Tom Kabinet case from the Netherlands. Questions related to the licence versus sale dichotomy; the so-called umbrella solution; the “new copy theory”, migration of digital copies via the internet; the forward-and-delete technology; the issue of lex specialis and the theory of functional equivalence are covered later on. The author of the present article stresses that the answers given by the respective judges of the referred cases are not the final stop in the discussion. The UsedSoft preliminary ruling and the subsequent German domestic decisions highlight a special treatment for computer programs. On the other hand, the refusal of digital exhaustion in the ReDigi and the audio book/e-book cases might be in accordance with the present wording of copyright law; however, they do not necessarily reflect the proper trends of our ages. The paper takes the position that the need for digital exhaustion is constantly growing in society and amongst businesses. Indeed, there are reasonable arguments in favour of equalizing the resale of works sold in tangible and intangible format. Consequently, the paper urges the reconsideration of the norms on exhaustion on the international and EU level.

Subclinical thyroid dysfunction and cardiovascular outcomes among prospective cohort studies

The association between subclinical thyroid dysfunction and cardiovascular outcomes has been recently clarified with the publication of three individual participant data (IPD) analyses from the Thyroid Studies Collaboration. We identified original cohort studies with a systematic review and pooled individual data from over 70'000 participants to obtain a more precise estimate of the risks of cardiovascular outcomes associated with subclinical thyroid dysfunction. Subclinical hypothyroidism and subclinical hyperthyroidism, defined as normal thyroxine (FT4) levels with increased or decreased Thyroid-Stimulating Hormones (TSH or thyrotropin) respectively, are associated with increased risk of cardiovascular outcomes compared to euthyroid state, particularly in those with a more pronounced thyroid dysfunction. Specifically, subclinical hypothyroidism is associated with an increased risk of coronary heart disease (CHD) events, CHD mortality and heart failure (HF) events in individuals with higher TSH levels, particularly in those with TSH levels ≥10.0 mIU/L. Conversely, subclinical hyperthyroidism is associated with an increased risk of total mortality, CHD mortality, HF and atrial fibrillation, particularly in those with suppressed TSH levels <0.10 mIU/L. Pending ongoing randomized controlled trials, these observational findings allow identifying potential TSH thresholds for thyroid medication initiation based on risk of clinical outcomes, although clinical decision based solely on observational data need caution. The impact of thyroid replacement among the elderly with subclinical hypothyroidism is currently studied in a multicenter international randomized controlled trial (Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial, TRUST trial).

A reliable, traffic-adaptive and energy-efficient link layer for wireless sensor networks

The paper presents a link layer stack for wireless sensor networks, which consists of the Burst-aware Energy-efficient Adaptive Medium access control (BEAM) and the Hop-to-Hop Reliability (H2HR) protocol. BEAM can operate with short beacons to announce data transmissions or include data within the beacons. Duty cycles can be adapted by a traffic prediction mechanism indicating pending packets destined for a node and by estimating its wake-up times. H2HR takes advantage of information provided by BEAM such as neighbour information and transmission information to perform per-hop congestion control. We justify the design decisions by measurements in a real-world wireless sensor network testbed and compare the performance with other link layer protocols.

Molecular detection of hepatitis E virus in German domestic pigs

In industrial countries, Hepatitis E virus (HEV) transmission to humans is predominantly assumed to be a zoonotic infection. Recently, it has been demonstrated that about 50% of domestic pigs in Germany carry HEV-specific antibodies. However, further investigations concerning the distribution of HEV in different age groups of German domestic pigs, phylogenetic analyses and the viral load in the porcine liver are still pending. Liver samples of all age groups from herds in a pig-dense region in north-western Germany were investigated for the presence and quantity of HEV RNA and subsequently genotyped. Out of 251 liver samples, 34 contained ORF2-specific RNA, whereas 19 samples were positive using ORF1-specific primers, resulting in an overall detection rate of 13.5% and 7.6%, respectively. Especially nursery pigs and growers were tested positive for viral RNA. Furthermore, determination of the HEV copy numbers revealed high replication levels. Up to 10(9) genome copies per g of liver tissue could be detected suggesting a likely high degree of viral spread to the environment. In the HEV-positive liver samples we found no hints for pathohistological changes reflecting the HEV status.The HEV sequences showed marked diversity but could be assigned to HEV genotype 3 without exception. However, by comparing two different genomic fragments, we found indications for infections with two different HEV variants in domestic pigs. Apart from this, the current study confirms the outcome of our recent serological HEV survey and for the first time gives direct proof of HEV infections in the German domestic pig population.