Single-chamber Versus Dual-chamber Implantable Cardioverter Defibrillators: Do We Need Physiologic Pacing in The Course?

Background: Many patients with ICD receive different antiarrhythmic drugs (e.g. sotalol, amiodarone, β-blockers) because of ventricular or atrial tachycardias. These drugs can cause AV-block or chronotropic incompetence resulting in a higher percentage of ventricular pacing. Methods: We analyzed in a retrospective study the impact of DDD(R) versus VVI(R) mode on subjective (NYHA classification) and objective parameters [brain natriuretic peptide (BNP), 6 minute walk test, echocardiography] in 12 of 120 patients (age 60.2 ± 11.2 years; 10 males, 2 females) who needed an upgrading of a single to a dual chamber ICD. The ICD had to be upgraded because of chronotropic incompetence in all patients with signs of progressing heart failure. Data were collected in VVI(R)-pacing and after 6 and 12 months in DDD(R)-pacing with a long AV-interval and AV hysteresis to reduce ventricular pacing. Results: The 6 minute walk test (392.4 ± 91.4 vs. 324.6 ± 93.3 m, P < 0.001), NYHA-classification (1.4 ± 0.3 vs. 2.6 ± 0.8, P < 0.0001), BNP (234.1 ± 73.5 vs. 410.4 ± 297.0 pg/ml, P < 0.001), left ventricular ejection fraction (49.8 ± 9.6 vs. 36.5 ± 10.9 %, P < 0.0001) and A-wave (73.6 ± 13.7 vs. 41.0 ± 14.0 cm/sec, P < 0.0001) improved with DDD(R)-pacing after 12 months. The ventricular pacing decreased (84.2 ± 18.1 vs. 1.1 ± 1.7 %, P < 0.0001) after 12 months by DDD(R)-pacing with long AV-interval (220.0 ± 10.4 ms) and AV hysteresis. Conclusion: Our data show a superiority of DDD(R) mode versus VVI(R) mode regarding subjective and objective parameters as NYHA-classification, BNP, 6 minute walk test, left ventricular ejection fraction and left ventricular endsystolic volume after 12 months. The improvements seem to depend on the reduction of ventricular pacing with advanced atrial contraction. But only a small number of patients needed the upgradation

Quantitative Comparison of Abundance Structures of Generalized Communities: From B-Cell Receptor Repertoires to Microbiomes

The \emph{community}, the assemblage of organisms co-existing in a given space and time, has the potential to become one of the unifying concepts of biology, especially with the advent of high-throughput sequencing experiments that reveal genetic diversity exhaustively. In this spirit we show that a tool from community ecology, the Rank Abundance Distribution (RAD), can be turned by the new MaxRank normalization method into a generic, expressive descriptor for quantitative comparison of communities in many areas of biology. To illustrate the versatility of the method, we analyze RADs from various \emph{generalized communities}, i.e.\ assemblages of genetically diverse cells or organisms, including human B cells, gut microbiomes under antibiotic treatment and of different ages and countries of origin, and other human and environmental microbial communities. We show that normalized RADs enable novel quantitative approaches that help to understand structures and dynamics of complex generalize communities

Statistische Analyse von Sequenzpopulationen in der Virologie und Immunologie

In this thesis I have examined various topics regarding the relationship between viruses and the human immune system. I expanded and refined a tool (which can now be found as R-package SeqFeatR on C-RAN) for the analysis of sequence data and features of this sequences like HLA type or tropism (see chapter 4) and checked with this tool if there are differences between some multiple correction approaches for sequence data, and how Bayesian inference could be used in this context (see chapter 5). It could be shown that Bayesian inference is superior to the frequentistic methods for this kind of problem, because multiple correction approaches ignore the fact that different positions in a sequence alignment may be connected in the protein product of this sequence and are therefor not independent. Furthermore, I have examined sequences from HCV with a form of bootstrap algorithm to find sequence areas which can be used in unknown transmission cases in court. Two areas were found, one in the hypervariable region and the other at the end of the non-structural protein NS5B (see chapter 9). Proteasomal cleavage of alien amino acid sequences inside human cells leads to a presentation of fragments of these sequences on the surface of the cell as epitopes. To present such a fragment, not only must it bind to the MHC, but also needs to be in the correct length to be presented. Therefore viral evolution should favor those viruses, which cannot be cut into presentable epitopes. With epitope data from IEDB and predicted viral sequences which bind the MHC, I searched for amino acids inside the flanking regions around the epitope that may indicate a possible escape mutation against the proteasomal cleavage processes. Fourteen such amino acids and positions were found (see chapter 7). I created a model of HBV reverse transcriptase to check if mutations in certain positions could influence binding with the nucleotide analogue reverse transcriptase inhibitor Tenofovir. Mutations which were inside the binding pocket for Tenofovir showed, in an experimental design by the group of Mengji Lu, a decreased affinity towards the drug (see chapter 10). Together with Ralf Küppers group I examined NGS from different types of B cells to search for almost identical sequences between those. We found similar to identical sequences from two, three and even four kinds of cells in the blood samples of both donors (see chapter 6).In dieser Dissertation bearbeitete ich verschiedene Themen aus dem Bereich der humanpatho-genen Viren und des menschlichen Immunsystems. Zu diesem Zweck entwarf ich ein Programm (welches auf dem R-Archiv C-RAN unter dem Namen SeqFeatR zu finden ist) mit dem sich der Zusammenhang zwischen Sequenzdaten und spezifischen Eigenschaften, wie etwa HLA Typ oder Tropismus, analysieren läßt (s.h Kapitel 4). Mit diesem Programm untersuchte ich ob ein Unterschied zwischen den Verfahren zur Korrektur von Alphafehler-Kumulierung bei Sequenzdaten besteht und in welchem Maße die Verfahren der Bayesschen Statistik besser für diese geeignet sind (s.h. Kapitel 5). Dabei stellte sich heraus, dass letztere für diese Klasse von Problemen eher verwendet werden sollten, da Alphafehler-Kumulierungskorrekturen möglichen Abhängigkeite zwischen verschiedenen Sequen-zpositionen, welche sich unter Umständen erst im fertigen Protein offenbaren, ignorieren. Weiterhin untersuchte ich HCV Sequenzen mittels einer Variante des Bootstrap-Algorithmus um jene Sequenz-Bereiche zu finden, die im Falle von ungeklärten Übertragungswegen zur Identifizierung dieser genutzt werden können. Dabei stellten sich zwei Bereiche als besonders geeignet heraus: Die hypervariable Region sowie ein Bereich am Ende des Nicht-Struktur Protein NS5B (s.h. Kapitel 9). Die Spaltung von fremden Aminosäuresequenzen innerhalb von menschlichen Zellen durch das Proteasom kann zu einer Präsentation dieser Fragmente auf der Zelloberfläche als Epitope führen. Um solche Fragmente präsentieren zu können, müssen diese nicht nur an das spezifische MHC Molekül binden, sondern auch eine optimale Länge besitzen. Daher sollte der evolutionäre Prozess solche Viren fördern, deren Sequenzen sich nicht in entsprechende Stücke zerteilen lassen. Durch eine Kombination von Epitopdaten aus der IEDB und vorhergesagten viralen Sequenzen, welche sicher an MHC Moleküle binden, untersuchte ich, ob innerhalb der flankierenden Regionen um das jeweilige Epitop Sequenzpositionen existieren, welche auf eine Mutation hinweisen, die den Schnittmechanismus der Zelle verhindert. Ich fand vierzehn Aminosäuren und Positionen, die einen solchen Zusammenhang besitzen können (s.h. Kapitel 7). Um heraus zu finden ob es in der reversen Transkriptase von HBV Positionen gibt, welche die Bindung mit dem nukleotidischen Reverse-Transkriptase-Inhibitor Tenofovir beeinflussen, erstellte ich ein Modell dieses Enzyms. Mutationen, die innerhalb der Bindetasche für Tenofovir lagen, führten in einer Versuchsreihe von der Gruppe von Mengji Lu zu einer verringerten Affinität zw ischen Enzym und Medikament (s.h. Kapitel 10). Zusammen mit der Gruppe von Ralf Küppers untersuchte ich Hoch-Durchsatz-Sequenzdaten von verschiedenen Arten von B Zellen um ähnliche Sequenzen zu finden. Wir fanden ähnliche und sogar identische Sequenzen zwischen zwei, drei und sogar allen vier Arten von Zellen jeweils innerhalb der Blutproben jedes der beiden Spender (s.h Kapitel 6)

The halt of deep convection in the Greenland Sea: A natural experiment for the study of their causes and effects

There are only a few sites where the deep ocean is ventilated from the surface. The responsible process known as deep convection is recognized to be a key process on the Earth’s climate system, but still it is scarcely observed, and its good representation by global oceanographic and climate models remains unclear. In the Arctic Ocean, the halt of deep convection in the Greenland Sea during the last three decades serves as a natural experiment to study: (1) the conditions that drive the occurrence or not of deep convection and (2) the effects of the halt of deep convection on the thermohaline properties of the deep water masses and circulation both locally and in adjacent ocean basins. Combining oceanic and atmospheric in-situ data together with reanalysis data, we observe that not only on average the winter net heat losses from the ocean to the atmosphere (Qo) have decreased during the last three decades in the Greenland Sea ( Qo (before the 1980s- after the 1980s) = 25 Wm-2) but the intensity and number of strong cooling events (Qo 800Wm-2). This last value for convection reaching 2000 m in the Greenland Sea seems critical to make the mixed layer deepening from being a non-penetrative process to one arrested by baroclinic instabilities. Besides, changes in the wind stress curl and preconditioning for deep convection have occurred, hindering also the occurrence of deep convection. Concerning the effects of the halt of deep convection, hydrographic data reveal that the temperature between 2000 meters depth and the sea floor has risen by 0.3 C in the last 30 years, which is ten times higher than the temperature increase in the global ocean on average, and salinity rose by 0.02 because import of relatively warm and salty Arctic Ocean deep waters continued. The necessary transports to explain the observed changes suggest an increase of Arctic Ocean deep water transport that would have compensated the decrease in deep water formation rate after the 1980s. The effects of these changes in adjacent basins remain unstudied, but the bottom waters seem to be upwelled towards the slope and the Jan Mayen ridge, being an exit for the Greenland Sea deep waters.0,000

Strong-mixing induced deep ocean heat uptake events in the North Atlantic.

The deceleration of the upper ocean heat storage during the last decade has resulted in an active search for the ’missing heat’ in the deep ocean. Modeling work has provided new insights into the role of the central Pacific Ocean on the present hiatus in global warming and the efficient transfer of heat to the deep ocean, but recent studies have highlighted also the large contribution of the North Atlantic basin to these processes, mainly based on ocean observations. The deep ocean heat uptake (below 300 m) in the North Atlantic is not confined to the subpolar gyre region but extends to mid-latitudes of the Eastern North Atlantic (ENA), requiring an additional process for its explanation other than deep convection considered until now. Here, using oceanographic in-situ data, we describe a mechanism of heat and salt injection to the deep ocean after years of warming and saltening at the surface occurred both in regions of mode (43º-48ºN) and deep water (74º-76ºN) formation in the ENA. The mechanism, although punctual meditated by strong winter mixing events, is between 2 and 6 times higher than the 2000-2010 ocean heat uptake at depths of mode (300-700m) and deep water (>2000m) formation, contributing significantly to the observed deep ocean heat uptake in the North Atlantic. Nutrient, hydrographic and reanalysis data indicate that the strong mixing-induced deep ocean heat uptake events at areas of mode and deep water formation in the North Atlantic are connected through the northward propagation of salty ENA mode waters triggered by the contraction of the subpolar gyre reinforced by the occurrences of blocking anomalies in the ENA. Such connection is not unique of the last decade but observed also during the 1960s. Natural climate variability seems the ultimate driver of the strong mixing-induced deep ocean heat uptake events, although the anthropogenic global warming and its forcing on the Arctic sea-ice retreat and frequency of extreme weather events could modify their effects.0,000

Oceanic heat advection to the Arctic in the last Millennium

EGU2011-8738 At present, the Arctic is responding faster to global warming than most other areas on earth, as indicated by rising air temperatures, melting glaciers and ice sheets and a decline of the sea ice cover. As part of the meridional overturning circulation which connects all ocean basins and influences global climate, northward flowing Atlantic Water is the major means of heat and salt advection towards the Arctic where it strongly affects the sea ice distribution. Records of its natural variability are critical for the understanding of feedback mechanisms and the future of the Arctic climate system, but continuous historical records reach back only ca. 150 years. To reconstruct the history of temperature variations in the Fram Strait Branch of the Atlantic Current we analyzed a marine sediment core from the western Svalbard margin. In multidecadal resolution the Atlantic Water temperature record derived from planktic foraminifer associations and Mg/Ca measurements shows variations corresponding to the well-known climatic periods of the last millennium (Medieval Climate Anomaly, Little Ice Age, Modern/Industrial Period). We find that prior to the beginning of atmospheric CO2 rise at ca. 1850 A.D. average summer temperatures in the uppermost Atlantic Water entering the Arctic Ocean were in the range of 3-4.5°C. Within the 20th century, however, temperatures rose by ca. 2°C and eventually reached the modern level of ca. 6°C. Such values are unprecedented in the 1000 years before and are presumably linked to the Arctic Amplification of global warming. Taking into account the ongoing rise of global temperatures, further warming of inflowing Atlantic Water is expected to have a profound influence on sea ice and air temperatures in the Arctic

The prediction of ICD therapy in multicenter automatic defibrillator implantation trial (MADIT) II like patients: a retrospective analysis

Objectives MADIT II like patients have not been compared to patients without an electrophysiological study, patients in whom ventricular tachycardia or fibrillation were induced in an electrophysiological study (EPS) and patients without an inducibility in EPS in one study. Background The multicenter automatic defibrillator implantation trial (MADIT) II showed a benefit of ICD implantation in patients with ischemic heart disease.Methods We performed a retrospective analysis in 93 patients with an ischemic heart disease and an ejection fraction ≤30% who had an ICD implanted with a follow-up at least an 18 months. Patients were divided into 3 groups according to the primary indication for ICD implantation: without EPS (group I), patients in whom ventricular tachycardia or fibrillation were inducible in EPS (group II) or patients without an inducibility in EPS (group III). Results During the mean follow-up of 32.9 ± 16.1 months 289 appropriate ICD therapies and 10 deaths occurred. The incidence of appropriate ICD therapies did not differ significantly between the groups (group I 40%, group II 54% and group III 48% of patients). We found in group II a higher risk of appropriate ICD therapies with occurrence of a specific constellation of EPS values. These patients showed a 15-fold risk (P = 0.005) of an appropriate ICD therapy. Furthermore a brain natriuretic peptide value of 265 pg/ml also predicted an appropriate ICD therapy with a 3.5-fold risk (P = 0.017).Conclusion In the present retrospective study the results of MADIT II were affirmed in the case of incidence of ventricular arrhythmias in patients with an EF < 30% and coronary heart disease. The prediction of an appropriate ICD therapy with EPS was only achieved in patients with inducibility in the EPS