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Allerdings merken Zihl und Cramon , S. Babinsky ; Poetzl ; Barkman McDaniel, McDaniel Es wurde nach Anton benannt, der eine Frau beschrieb, die ihre Blindheit nicht bemerkte.

Beck et al. Hartmann et al. Walsh, Hoyt Sie lassen sich je nach Schweregrad, ihrer Lage, Form und Ausdehnung einteilen. Tabelle 1.

Jan, Groenveld ; s. Foley, Gordon ; Merrill, Kewman ; Ronen et al. Gloning, Tschabitscher ; Ritter et al. Alexandridis et al.

Unterschiedliche Begrifflichkeiten entstehen jedoch, indem einige vgl. Baillet et al. Pschyrembel , S. Foley, Gordon ; Merrill, Kewman ; Celesia et al.

Auch Ronen et al. Barnet et al. Weiskrantz et al. Ter Braak et al. Denny- Brown, Chambers ; Keating Obwohl sie behaupteten, dass ein solcher Versuch aussichtslos sei, stellte sich heraus, dass sie mit einer erstaunlich hohen Trefferquote die verschiedenen Richtungen der Stimuli auseinander halten konnten.

Auch dieser Patient versicherte ihm, ebenso wie die anderen Betroffenen, nichts zu sehen, sondern lediglich zu raten, obwohl er eine Vielzahl visueller Reize auseinander halten konnte vgl.

Campion et al. Nach Stoerig und Cowey , S. Stoerig et al. Weiskrantz ; Morland et al. Blythe et al.

Barbur et al. Stoerig ; Stoerig, Cowey ; Brent et al. Perenin et al. Obwohl auch Perenin et al.

Jan et al. Aufgrund dieser weiter gefassten Definition kann nach Jan et al. Henrich in der Literatur finden. Hertz et al.

Porro et al. Tabelle 2. Snelling et al. Aldrich et al. Casanova et al. Whiting et al. Hochstetler, Beals ; Gospe bis hin zu einem bzw.

Thomas, Troost ; Parry et al. Gjerris, Mellemgaard ; Prakash et al. Truwit et al. Antonellis et al.

Grimes et al. Ichikawa et al. Levavi et al. Lambert et al. Eldridge, Punt ; Singh bzw. Felber et al.

Memon et al. Merimsky et al. Nakajo et al. Chew bzw. Coughlin et al. Chew ; van Nieuwenhuizen, Willemse ; Wong ; Chen et al. Ceccaldi et al.

Sadeh et al. Ronen et al. Auch Good et al. Balzar et al. Kraus et al. Akute Kortikale Blindheit kann in kritischen Situationen, wie z.

Garty et al. Ein Hydrozephalus kann sowohl akute als auch chronische CVI verursachen vgl. Lorber ; Arroyo et al. Tabelle 3. Anton ; Gerlach et al.

Henrich Obwohl der Begriff der Blindheit auch heute noch von verschiedenen Autorinnen und Autoren verwendet wird, ist er aufgrund der verschiedenen Beobachtungen und Tests vgl.

Kapitel 3. Cytowic et al. Nieuwenhuys et al. Cytowic , S. Groenveld et al. In den Studien von Huo et al. Von insgesamt 76 untersuchten Kindern, diagostizierten Lanners et al.

Quelle: nach Lanners et al. Van Hof- van Duin et al. Sie setzen stattdessen korrektive Augenbewegungen ein, um ein Objekt zu fixieren.

Dieses Verhalten kann ebenfalls bei angeborener homonymer Hemianopsie beobachtet werden. Nystagmus Lanners et al. Es ist daher wahrscheinlich, dass bei den Kindern, die einen Nystagmus aufweisen, zumindest kleine Teile des striaten Kortex erhalten geblieben sind.

Huo et al. Jan, Groenveld , S. Bei Huo et al. Kolobome im Zusammenhang mit CVI auftreten. Infolge koexistierender Verletzungen der Augen bzw.

Good et al. So konnten Lanners et al. Wong , S. Bei Groenveld et al. Lanners et al. Castano et al. Quelle: Lanners et al.

In der Studie von Huo et al. Wieser , S. Ahmed und Dutton berichten z. Es wird vermutet, dass das Ziel von Stimulationen immer darauf ausgerichtet ist, den visuellen Kortex zu stimulieren vgl.

Wenn Licht die Retina erreicht, entsteht eine photochemische Reaktion, welche die Nervenbahnen vom Auge erregt. Diese Aktionspotentiale werden zum visuellen Kortex transportiert.

Nach Jan et al. Daher vermuten Jan et al. Light gazing Jan et al. Tso, La Piana ; Guerry et al. Desmond et al. Da alle drei Verhaltensweisen der Stimulation des visuellen Kortex dienen sollen vgl.

Auch bei Kindern mit Photophobien kann light gazing auftreten vgl. Bei Kindern mit starken Photophobien empfehlen Lanners et al.

Dadurch kann sich eine Art zentraler Photophobie entwickeln, die als "thalamic glare" bezeichnet wird. Der Thalamus spielt u.

Wiesel ; Groenveld ; Dutton et al. Porro et a. Nach Porro et al. Overlooking Jan et al. Bei Lanners et al. Taylor et al. Nach Good et al.

Jedem Kind sollte daher 18 Benton et al. Devinsky und Good et al. Auch in der Studie von Jan et al. Die 2 Kinder von den 16 untersuchten Personen mit kortikaler Blindheit, die Dutton et al.

Einige Autoren vgl. Segrares et al. Rizzo, Hurtig Identifikation von Objekten Jan et al. Diese Kinder konnten z. Auch Kivlin , S. Morse , S.

Identifikation von Gesichtern Verschiedene Autoren vgl. Kivlin ; Whiting et al. Bei der Studie von Whiting et al.

Kivlin , S. Entfernungs- und Tiefenwahrnehmung Die Ergebnisse verschiedener Studien vgl. Abschnitt Identifikation von Objekten.

Kosslyn et al. Die Autorinnen und Autoren konnten dementsprechend bei mentalen visuellen Bildern keine Aktivierung des visuellen Kortex nachweisen vgl.

Rowe, Kahn nach Chatterjee, Southwood Chatterjee, Southwood , S. Chatterjee und Southwood , S. Auch Devinsky , S. Devinsky , S. Goldenberg et al.

Goldenberg ; Redlich, Bonvicini nach Goldenberg et al. Die Autoren gehen daher davon aus, dass die Verneinung der Blindheit dadurch entsteht, dass die betroffenen Personen ihre mentalen visuellen Bilder mit der realen Wahrnehmung verwechseln.

Die Ergebnisse von Goldenberg et al. In der Diskussion geht es vor allem um autistische Symptome wie z. Humphries , S.

Diagnostiziert wird Autismus jedoch aufgrund des Verhaltens und nach speziellen Kriterien. Ek et al. Jordan Internet Adresse; Garreau et al.

Fraiberg ; Gense, Gense Jordan Internet Adresse. Dzikowski , S. Solche Empfindungen werden durch Bewegungen im visuellen Feld und bei schnellen Bewegungen im peripheren Bereich hervorgerufen Flickering vgl.

Auch schauen sie Objekte oder Personen selten direkt an, auch wenn sie versuchen diese zu erreichen und schenken einem einzelnen Spielzeug mehr Aufmerksamkeit als einer breiten Auswahl von Spielzeugen vgl.

Frith ; Grandin ; Jordan, Riding Tabelle 5. Dutton et al. Ogden Munk unterscheidet die Seelenblindheit als Verlust der visuellen Vorstellung von der Rindenblindheit als Verlust der visuellen Wahrnehmung.

Stoerig und Cowey , S. Stoerig , S. WHO Die vorhandenen Registrierungen orientieren sich zudem an unterschiedlichen Definitionen von Blindheit bzw.

Pfau et al. Hochrechnungen angewiesen vgl. Die wichtigsten vorhandenen Angaben sollen im Folgenden kurz dargestellt werden.

Steinkuller , S. Foster, Gilbert ; Gilbert et al. Mai und dem Uganda In Uganda wurden zwischen und in Schulen und zwischen und in communities 44 Regionen insgesamt Kinder unter 15 Jahren untersucht.

Waddell Im Zeitraum zwischen Februar und Dezember konnten so 45 Kinder, die zwischen einem und sechs Jahren alt waren, beobachtet werden.

Olurin , S. Bei drei anderen Kindern manifestierte sich die kortikale Blindheit als Folge einer Enzephalitis und bei drei weiteren Kindern aufgrund von schweren Kopfverletzungen.

Das Alter der Betroffenen reichte von einem Monat bis zu 76 Jahren. Foster, Gilbert ; Eckstein et al.

Tirosh et al. Texas Williamson et al. Tielsch et al. Steinkuller et al. Jan, Robinson ; Jan et al.

Nach der nordamerikanischen Definition wird partially seeing Sehbehinderung von Blindheit legally blind unterschieden. Legally blind beschreibt dabei Kinder von einem Visus von 0,1 bis zum Fehlen von Lichtscheinwahrnehmung und umfasst damit einen wesentlich breiteren Bereich als der deutsche Begriff der Blindheit vgl.

Hudelmayer Mets , S. Schweden Am Dezember geboren wurden. Bei sechzehn Kindern wurde cortical blindness, bei neun Kindern cortical visual impairment, diagnostiziert vgl.

Ducrey et al. Estimation of visual function is difficult owing to communication problems: A Infants and young children deemed by refering clinicians to have poor vision.

B Multiply handicapped children. Bei Kindern bis zum Rath, Hudelmayer , S. In einer Studie von Hansen et al.

Hansen et al. Waddell ; Dandona et al. Meremikwu et al. Rosenberg et al. Kommt es im Zusammenhang mit CVI z.

Da CVI meist mit mehrfachen Behinderungen s. Einige Autorinnen und Autoren erfassen sowohl Kinder als auch Erwachsene vgl. Doch auch bei diesen Studien variiert das Altersspektrum deutlich.

So gibt es Autorinnen und Autoren vgl. Bayce, Alemayece , andere Kinder bis 9 Jahren vgl. Arnaud et al. Williamson et al.

Trosh et al. Dandona et al. Bohme, Tonnquvist Wesentlich geringer fallen die Populationen in der Untersuchung von Meremikwu et al.

Im VIP werden z. Trotz der differierenden Erhebungs- bzw. Foster, Gilbert ; Thylefors ; Eckstein et al.

Ferrell , Whiting et al. Seit ca. Robertson et al. Nach Wieser , S. Shibata et al. Yuen ; Kasahata et al.

Psatta, Matei ; Lambert et al. DeVolder et al. Price et al. Patronas, Argyopoulou , Embolien vgl.

Heeney, Koo ; Acolovschi et al. Lebedeva, Kanevskaia ; Howard et al. Tsutsui et al. Murayama et al. Sanin, Mathew ; Ogden ; Milandre et al.

Man nimmt an, dass der zugrunde liegende Mechanismus Infarkte an den arteriellen Grenzzonen der Wasserscheidengebiete, den sogenannten parietookkipital und parasagittalen Regionen, sind vgl.

Volpe et al. Hoyt, Walsh ; Benton et al. Das Erscheinungsbild bzw. In den Untersuchungen von Flodmark et al. Pape, Wigglesworth Casteels ; s.

Shuman, Selednik ; Roland et al. Uggetti et al. Flodmark et al. So war auch in den Untersuchungen von Groenveld et al.

Hoyt, Walsh ; Weinberger et al. Casteels et al. Haas, Souner Griffith, Dodge ; Drymalski Auch Palinopsien 26 konnten beobachtet werden vgl.

Singh Der Sehverlust nach weniger schweren Traumata kann sich ca. Han, Wilkinson Tabelle 7. Hier manifestiert sich die Blindheit sofort oder innerhalb einiger Minuten nach dem Unfall.

Das adoleszente Muster, bei dem die Betroffenen zwischen 8 bis zu 14 Jahren alt sind, wird von Greenblatt als das Paradigma des Syndroms verstanden.

Gjerris und Mellemgaard betonen, dass Erwachsene wesentlich mehr verschiedene und schwerere Symptome haben.

Es kann sich dabei iktal Zung, Margalith ; Joseph, Louis oder postiktal vgl. Skolik et al. Kosnik et al. Barry et al.

Verdile, Verdile ; Chew ; Lau et al. Die Mehrheit der Betroffenen war zehn oder zwanzig Jahre alt, und der Sehverlust dauerte einige Minuten bis zu einer halben Stunde.

Der Sehverlust manifestierte sich entweder iktal oder postikatal. Postiktale Blindheit kann u. Olurin ; Fiume Aldrich, Vanderzant Daher ist nach Good et al.

Helmchen et al. Kinn, Breisblatt ; Kermode et al. Horwitz, Wener ; Good et al. Wesentlich seltener wird es nach Aortographie vgl. Johnson, Moss 32 und nach Myelographie vgl.

Smirniotopoulos et al. Kinn, Breisblatt ; Rama et al. Studdard et al. Manifestation Der Sehverlust als Folge der Infusion von Kontrastmitteln manifestiert sich innerhalb von ein paar Minuten bis zu 12 Stunden nach einer Angiographie.

Fast alle Betroffenen regenerieren sich nach und nach innerhalb von zwei bis zu sieben Tagen vgl. Brewster et al. Lawrence et al.

Kabra et al. Waldron, Stallworth 36 oder als Komplikation einer Nephritis vgl. Devathasan et al. Drymalski Ackroyd Tepperberg et al.

Gado et al. Katafuchi et al. Es lassen sich auch Berichte von Neurotoxikosen nach einem Kobrabiss vgl. Berger, Brook , einer Quecksilbervergiftung vgl.

Davis et al. Gospe oder einer Toxoplasmose vgl. Wilson et al. Cyclosporin-A, Interleukin 2 vgl. Cisplatin berichtet vgl.

Higley et al. Das Kokain diffundiert sehr schnell durch die Plazentaschranke. Dixon , S. Kupferschmidt et al. Craigen et al.

Brown et al. Amano et al. Servidei et al. Kormguth et al. Connolly et al. Hagerty et al. Mathe et al. Durand et al.

Tsutsumi et al. Burke et al. Marsh, Hurst ; Hayashi et al. Goldberg, Custis 52, Leigh-Syndrom vgl. Morris, Harbord ; Donovan ; Oldfors et al.

MacDonald ; Markowitz et al. Schonlein-Henoch Syndrom vgl. Benhamou et al. Schimmelpfennig-Feuerstein-Mims-Syndrom vgl. Hager 56, Creutzfeld-Jakob Krankheit Pinto et al.

Carney, Anderson a,b 58, Mumps vgl. Ohama et al. Hahn et al. Fanton et al. Payton, Jones 61, Multiple Sclerose vgl.

Castaigne et al. Constantinou et al. Assadi et al. Opitz et al. Ikeda et al. Elner et al. Sahota et al. Es kann aber auch verschiedene neurodegenerative Erkrankungen z.

Estbe ; Jin et al. Krimmel, Reinert ; Okamoto et al. Hydrozephalus kann akute, aber auch chronische CVI bedingen. Corbett Sekhar et al.

Hochwald, Sahar ; Saher Osher et al. Keane ; Drymalski , aber auch schwerer bilateraler Sehverlust kann beobachtet werden vgl.

Keen ; Wybar ; Jan et al. Der Sehverlust kann abrupt auftreten und von einer Reihe visueller Symptome begleitet werden vgl.

Hayreh und Okkipitalinfarkte aufgrund der Kompression der hinteren Zerebralarterie vgl. Arroyo et al. Moore, Sterm Erstmals von zerebraler Blindheit in Folge einer Bestrahlung haben Pomeranz et al.

In dieser haben sie drei Kinder untersucht. Das Absterben eines Zwillings geschieht teilweise unbemerkt, so dass Good et al. Angeborene Hirnfehlbildungen s.

Bei 14 Kindern waren die zerebralen Anomalien unspezifisch. Barkovich, Norman a und der Abwesenheit des Septum Pellukidum vgl.

Barkovich, Norman b verbunden. Barkovich et al. Fantz Teller et al. Birch und Bane , S. McDonald et al.

Good ; Jan et al. Allen et al. Meienberg et al. Das Suchmuster kann dann als grobes Muster benutzt werden, um das visuelle Feld zu messen vgl.

Van Hof-van Duin, Mohn Manchmal erlaubt auch ein Goldmann Perimeter ein genaues Messen des Gesichtsfeldes s. Akiyama et al. Danach werden differente Elektroden, die in Kontaktlinsen eingearbeitet sind, auf die Hornhaut gesetzt.

Nickel, Hoyt Bei dieser Methode werden an der Kopfhaut der Patientinnen und Patienten Kontaktelektroden angebracht, die die Potentialschwankungen des Gehirns registrieren.

Der Alpharhythmus entwickelt sich im Alter von drei Monaten und stabilisiert sich mit dem ersten Lebensjahr. Er wird durch psychosensorische Reizung z.

Jan, Wong Ackroyd , Tepperberg et al. Bodis- Wollner et al. Reim , S. Kupersmith, Nelson Jan, Wong ; Whiting et al.

So stellten auch Whiting et al. Bowerman et al. Mohn et al. Von pathologischen Strukturen wie z.

Weindling et al. PVL ist daher in der subakuten Phase mit Sonographie nur schwer zu diagnostizieren.

Bosley et al. Gottlob , S. Die visuellen Funktionen sollen sich bei diesen Kindern erst zwischen dem zweiten und vierten Lebensjahr verbessern.

Innerhalb der ersten zwei Jahre soll es bei dieser Gruppe zu einer Verbesserung des Visus kommen, selbst wenn die zugrundeliegende Augenkrankheit nicht behandelt werden kann.

Sie zeigen keine visuelle Aufmerksamkeit und fixieren oder folgen auch keinen hellen Objekten vgl.

Lancet Fielder, Mayer ; Wieser Vielmehr konnten auch visuelle Antworten bei Kindern ohne visuellen Kortex beobachtet werden vgl.

Aylward et al. So beschreiben Aykward et al. Lambert Nach Flodmark et al. Smythies , S. Griffith, Dodge Drymalski ; Ramani ; Beck et al.

Faust Viele Kinder haben Schwierigkeiten mit ganz spezifischen visuellen Stimuli vgl. Morse , die sich z. Daher kann nach Groenveld et al.

Diese Faktoren werden daher mit bestimmten Prognoseaussichten verbunden. Dabei gehen Flodmark et al. Auch Lambert et al. Wong ; Foley, Gordon ; Hoyt ; Wunderlich et al.

Erwachsene mit erworbenem CVI vgl. Wong, ; Foley, Gordon , Wong ; Casteels et al. Kennard ; Stewart, Riesen Janowsky, Finley ; Pilar et al.

Blakemore Wunderlich et al. Der These von Tresidder et al. Wong ; Foley, Gordon Wong So stellen van Hof- van Duin , S.

Beneveto, Fallon ; Mauguiere, Ballydier Arnott ; Braddick et al. Islands of preserved residual vision Andere Autorinnen und Autoren vgl.

Kasten et al. Chow et al. Provis et al. Frotscher Internet Adresse. Die Autorinnen und Autoren vermuten daher, ebenso wie Rausch et al.

Baskin, Hosobuchi Die Patientinnen und Patienten werden hierbei aufgefordert einen roten Lichtpunkt in der Mitte eines homogen beleuchteten Gebietes zu fixieren.

Dieser rote Lichtpunkt wird ca. Balliet et al. Auch Kasten et al. Unter diesen Kindern waren auch neun, bei denen cortical visual impairment diagnostiziert worden ist.

Sonksen et al. Auf einem Computermonitor werden verschiedene visuelle Stimuli dargeboten, die individuell an den entsprechenden Patienten angepasst werden.

Am Ende der Therapie werden die verschiedenen Stimuli gemischt angeboten. Diese Verbesserungen sollen sich sowohl in den Testsituationen als auch im Alltag gezeigt haben.

Tegenthoff Hoyt ; Foley, Gordon Wong und Hoyt konnten z. Ferner werden die Prognoseaussichten infolge von Traumata von Drymalski et al.

Fitzhardinge et al. Vielmehr beurteilen u. Dubowitz et al. So kamen Balliet et al. Durch die physiologische Reifung der Zapfen der Netzhaut, des Sehnerven, des Thalamus, des visuellen Kortex sowie der visuellen Koordinationszentren s.

Roland , S. Dazu wurden mit Hilfe von Bildertechniken sowie elektrophysiologischer Verfahren s. Der WHO , S.

Es fehlen daher Aussagen, anhand deren beurteilt werden kann, welcher Vorgang als Sehvorgang interpretiert wird.

Engelhardt, Schipperges , S. Baillet , der Heidelberger Pupillograph vgl. Duchowny et al. Eken et al. Teilweise war ein Elternteil anwesend, welches das Kind in den Situationen festhielt und passend positionierte vgl.

Birch, Bane ; Porro et al. He was reminded to avoid searching for the target beyond the first saccade, regardless of his success in localisation.

Verschiedene Autorinnen und Autoren vgl. Ross et al. Bronfenbrenner , S. Balgo , S. Desinteresse bedingen. Dementsprechend wird bei der Gegenstandskonstruktion der Untersuchung die Zielsetzung, der theoretische Bezugsrahmen, sowie das Untersuchungsdesign festgelegt.

Alle Dimensionen stehen in Wechselbeziehung mit Kontextfaktoren, die personenbezogene Faktoren und Umweltfaktoren umfassen.

Wenn das Behindernde erst im Umgang entsteht vgl. Simon , S. Werbik ; Eckensberger, Meacham Ihnen liegen bestimmte individuelle und subjektive Motive, Interessen und Bedeutungsdimensionen zugrunde, so dass sie als intentional verstanden werden vgl.

Groeben et al. Groeben , S. Den Ideen autopoietischer Prozesse zufolge ist Verhalten von dem operationalen Kontext bedingt, in dem es stattfindet.

Diesem Kontext entsprechend bildet das Individuum vor dem Hintergrund seiner eigenen Kriterien und Erfahrungen selbstbestimmt sinnvolle Verhaltensstrukturen s.

Aebli ; Alisch ; v. Cranach ; v. Cranach et al. Schimank , S. Der Begriff der Alltagswelt ist in der Entwicklungspsychologie und der Sozialisationsforschung relativ neu.

Engelbert ; Herlth, Schleimer ; Mundt Kinder nehmen ihre Umwelt selektiv wahr und greifen aktiv und sinnvoll in sie ein.

Das elementare Verstehen, d. Lamnek , S. In diesem Sinne halte ich das Sinnverstehen, d. Ferner gehe ich davon aus, dass sich die Diskrepanzen auf der Sinnebene durch die Anwendung hermeneutischer Zirkel reduzieren lassen.

Das Verstehen- Wollen der Verhaltensweisen basiert auf der prinzipiellen Annahme, dass diese Auseinandersetzung des Kindes mit seiner Umwelt sinnvoll und bedeutsam ist.

Bronfenbrenner ; Engelbert ; Geulen ; Hurrelmann et al. Entwicklung wird als Interaktion in sozialen Systemen, als Wechselwirkung zwischen dem Kind und seiner Umwelt verstanden Bronfenbrenner , so dass der Untersuchungsgegenstand weder das Individuum noch die Umwelt als solche ist, sondern vielmehr die Wechselwirkung zwischen beiden Schmidt- Denter , S.

Es betont die Notwendigkeit einer systematischen Untersuchung der unmittelbaren und mittelbaren Lebensbereiche, d.

Walter Barker , Wright ; ; Wright ; Barker ; Dies kann z. Mesosysteme beschreiben die wechselseitigen Beziehungen von Lebensbereichen, an denen die Person aktiv und direkt beteiligt ist.

Hiermit kann z. Kaminski , S. Kaminski Das Problem der Identifizierung und Beschreibung solcher Umwelten menschlichen Handelns wurde als ein empirisches betrachtet.

Wesentliche Elemente des Konzeptes stellen die Synomorphie, das Behavior Setting sowie das darin ablaufende Programm dar.

Fuhrer , S. Zwischen dem nonpsychologischem Milieu und dem Verhaltensmuster besteht in der Regel eine Art Passung matching.

Gump, Ross Die Synomorphie stellt den Grundbaustein jedes Behavior Settings dar. Einen solchen Kontext stellt z.

Diese Kontexte werden als Behavior Settings vgl. Dieser Begriff wird auch in der deutschsprachigen Literatur unter nonpsychologischem Milieu verstehen Barker und Wright die Ort- Zeit- Konstellation, in die ein konstantes Verhalten eingebettet ist.

Unterschiedliche Standpunkte werden jedoch in Bezug auf das verhaltensdeterminierende Moment deutlich. Sie verstehen Handlungen nicht als kontextsondern als strukturdeterminiert.

Bei den Interaktionen zwischen dem Lebewesen und der Umgebung determinieren daher Pertubationen der Umgebung nicht, wie Barker es beschreibt, was dem Lebewesen geschieht, es ist vielmehr die Struktur 3 Gegenstandskonstruktion der Untersuchung des Lebewesens, die determiniert, zu welchem Wandel es infolge der Pertubationen kommt.

No modelling has been undertaken to determine the threshold population size needed to maintain viruses associated with respiratory presentations.

The most relevant analogy can be drawn from comparison with measles virus, which probably emerged at least two thousand years ago Sharp, To sustain itself, measles virus requires a population size of which supports a maintained susceptible pool of Black, Critically, measles is transmitted by the respiratory route, causes non-persistent infections and does not survive for any length of time in the environment.

Measles infection induces life long immunity, which is likely the result of the systemic nature of MV infections and its antigenically monotypic nature, contrasting with the plethora of respiratory virus strains generated through antigenic drift.

It follows that the population size required for maintenance of respiratory viruses such as HRSV may be smaller than that needed for measles, and so other respiratory viruses may have been circulating for substantially longer.

Recombination events create new viruses by capturing genes or gene segments from other viruses or from the host cell genome , can occur in both segmented and non-segmented viruses, and can be homologous or heterologous.

Homologous recombination occurs between parental RNAs of the same virus species with crossovers occurring at homologous sites in the genome, and does not necessarily occur during virus replication.

Coronavirus progeny of the same infection have been demonstrated to undergo homologous recombination Keck, Heterologous recombination may occur between different virus species via the copy choice mechanism first proposed for polio virus Cooper, , wherein during replication the viral RNA-dependent RNA polymerase switches templates to create a hybrid virus.

Heterologous recombination occurs between strains of the same species General Introduction - 29 - e. Reassortment involves the mixing of virus genome segments between strains of multipartite viruses during virion assembly to yield a novel virus, and is most widely associated with influenza virus discussed in more detail subsequently.

Independent circulation in humans To illustrate, rabies reaches stage two, causing sporadic human cases; ebola virus causes limited outbreaks in people, attaining stage three; dengue causes long outbreaks in humans before returning to the sylvatic host, thereby reaching stage four; and HIV-1 clade M has successfully established itself in humans to attain stage five.

The ability of respiratory viruses to re-infect hosts is widely thought to be a product of immune-driven adaptive evolution, facilitated by the RNA-dependent RNA polymerase which does not, unlike DNA-dependent RNA polymerase, have proofreading activity.

Frequent errors during RNA replication result inevitably in the production of some progeny viruses with deleterious mutations, which are removed from the population by purifying selection.

Recombinant and zoonotic respiratory viruses Historically, rhinoviruses and coronaviruses have been considered separately from other respiratory viruses, conceptually segregated as common cold viruses, which is in part attributable to the excellent epidemiologic studies of respiratory viruses conducted in the mid twentieth century Table 7.

Much of the understanding of respiratory virus epidemiology today is drawn from the results of these classic studies.

Rhinoviruses are the most common cause of acute infectious illness in humans. The mean infection rate in the Seattle study was 0.

Young adult females experience more rhinovirus infections and illnesses than their male peers, due to their increased contact with young children, though this is redressed in later years when illness rates are higher among males Gwaltney Jr, General Introduction - 31 - Table 7.

Nasopharyngeal swabs on respiratory and COPD in later life presentation General Introduction May - Jun Families observed for one year - 32 - Rhinovirus immunogenicity is poor, and varies greatly with serotype Fox, ; an increasing number of serotypes are being reported, with over of species A and B, and 61 of species C to date.

It is this diversity which permits re-infection with rhinoviruses year after year, and on which the presumption that there will never be a vaccine for the common cold is based.

Rhinovirus and enterovirus species group within the Enterovirus genus of the Picornaviridae, and undertake recombination as a mechanism to produce novel strains McIntyre, ; McWilliam Leitch, , ; Santti, ; Savolainen, Enteroviruses undergo periodical turnover and replacement of contemporary clades by a rapidly disseminating recombinant form with striking regularity.

This remarkably high frequency of recombination provides some insight into the tremendous success of rhinoviruses to circumvent population immunity and re-infect individuals frequently throughout life.

Coronaviruses have a longer incubation period than rhinoviruses, though the duration of illness is generally shorter and symptoms are indistinguishable.

The classic epidemiologic studies of coronaviruses were of course limited to HCoVE and HCoV-OC43, though recent studies of the four coronaviruses together including the results presented here do not imply any deviating trends for the newly discovered coronaviruses2.

Antibody to coronaviruses appears in early childhood and increases in prevalence rapidly with age McIntosh, , with seroconversion in most occurring for HCoVE and HCoV-NL63 by the age of 3 and a half Dijkman, The development of a cell culture system for HCoV-HKU1 is only very recently reported Pyrc and serosurveillance was undertaken using a baculovirus expression system incorporating nucleocapsid gene.

HCoV-HKU1 comprises three genotypes Woo , the serologic determinants of which are poorly defined, and so this result is highly subjective in light of current understanding, especially when one considers the epidemiologic traits of other coronaviruses and other respiratory viruses in general.

General Introduction - 33 - rhinovirus antibody Callow, Recombination has played an intrinsic role in the evolution of the coronaviruses.

Group two, but not group one coronaviruses express a haemagglutinin esterase HE protein, acquired through a historical recombination event with an ancestral influenza C virus.

This remarkable acquisition provided the group two coronaviruses with a protein which mediates a reversible attachment to O-acetylated sialic acids Zeng, , through activity as a receptor destroying enzyme.

The emergence of SARS-CoV provides an excellent illustrative example of zoonotic transfer of a virus from an animal host into man, giving rise to a novel virus in humans.

The virus emerged in southern China with the first case reports in late and spread as far as Canada, altogether detected in 37 countries.

The species from which SARS-CoV was transferred to man will remain unknown; it is thought that frequent and close contact between humans and any of the species in which SARS-CoV infection has been demonstrated in live animal markets may have been instrumental in the zoonotic transfer of the virus.

Influenza viruses are the only viruses to repeatedly cause pandemics of respiratory disease, and a great deal of interest has been taken in the evolutionary mechanisms pervading to this feature.

Influenza viruses can circulate in a range of hosts, including human, avian, and swine species. The host specificity of the influenza virus is determined by the conformation of the host sialic acid receptor, which in the upper respiratory tract General Introduction - 34 - of human and avian hosts is distinct.

However, pigs abundantly express sialic acids of both conformations, meaning they can be infected with influenza viruses of both human and avian origin.

If a pig is infected with a human and avian virus simultaneously, the two strains are free to reassort, producing a novel virus with genomic regions of both human and avian origin.

If the haemagglutinin attachment protein is specific for the human sialic acid, a novel influenza variant with human infectivity is born.

This circumstance is the usual origin of pandemic influenza strains arising every thirty or forty years.

The reassortant pandemic strain of influenza which emerged in in Mexico incorporated genes of swine, human and avian influenza origin Novel Swine-Origin Influenza A H1N1 Virus Investigation Team, The pandemic strain has now ceased to circulate in humans due to rapidly acquired global herd immunity through both natural and artificial means.

The pandemic potential of a novel influenza variant is of course dependent on successful zoonotic transfer of viruses. While this is frequently observed for influenza viruses rendering this event seemingly unremarkable, other respiratory viruses are very rarely seen to have this ability, usually limited to occasional reports of transfer between humans and chimps.

Just eight years ago, influenza would have been the only example of a contemporary zoonotic respiratory virus; the emergence of SARS-CoV serves as a reminder that respiratory viruses are not so predictable, and the inter-continental dissemination of the virus touches on the effects of changing human demography on the potential for virus emergence.

Seasonal influenza A epidemics are caused by viruses with novel genomic and immunologic traits generated by host-population driven selection acting on the haemagglutinin and neuraminidase surface proteins.

The influenza epidemic peak can be identified by an increase in school absenteeism soon followed by an excess mortality in the infected population.

The General Introduction - 35 - characteristic winter seasonality of influenza virus arises through the optimal air humidity at this time of year, which facilitates virus spread as virus respiratory droplets containing virions do not be come so dense as to settle Hemmes, ; Schaffer, , and at lower temperatures respiratory mucosa are thicker, so viruses stick in the respiratory tract better Palese, Humans are the sole host of influenza B viruses, which provides the likely explanation for the lack of pandemic strains.

Influenza B comprises several co-circulating lineages Bao-Lan, ; Oxford, which are not susceptible to immunologically driven evolutionary selection pressures Air, ; Oxford, , but do undergo recombination.

An evolutionary rate for influenza B was estimated at 1. Influenza C causes mild respiratory infections in children and the elderly Katagiri, , though the epidemiologic traits of the virus are less widely defined than for other influenza viruses.

The classic studies of respiratory virus epidemiology Table 7 did not report on the characteristics of the virus for a variety of reasons.

The Cleveland study was undertaken prior to the discovery of the virus, the Seattle virus watch did not recover the virus Kim, , and the Tecumseh study was limited to retrospective determination of seroconversion rates, which were highest in the age bracket of years Troisi, Influenza C viruses, like the other influenza viruses, comprise several cocirculating lineages which undergo reassortment Buonagurio, a; Peng, , and are, like influenza B viruses, not responsive to immunologic selection pressures - the nonstructural gene of two strains isolated 19 years apart showed no nucleotide differences Buonagurio, a , and the haemagglutinin genes of two strains isolated 31 years apart differed only by two nucleotides Buonagurio, Influenza C evolves more slowly than influenza viruses A and B Buonagurio, a , and naturally infects swine Guo, General Introduction - 36 - 1.

Infection rates with parainfluenza viruses are estimated at Maternal antibodies elicit protective immunity to PIV-1 and PIV-2 in the first four months of life, but despite the presence of PIV-3 maternal antibody in this age group, the protective effect is less.

PIV-3 generally infects all individuals in a semi-closed population e. Host immunity to parainfluenza viruses is dependent on high serum antibody, and so when humoral immunologic responses wane, the host is once again susceptible to infection Ray, PIV-4 also circulates at highest frequency in late autumn or early winter, but no cyclicity is apparent Laurichesse, During this study conducted over 22 years, The incubation period for parainfluenza viruses is between two and six days Chanock, ; Kapikian, ; Smith, During primary infection with PIV-3, virus is shed for three to ten days, and shedding is of shorter duration during subsequent infections Chanock, Prolonged shedding is observed in immunocompromised individuals Gross, Parainfluenza viruses do not persist long in the environment Ansari, and transmission occurs primarily via respiratory droplet rather than through fomites.

Both viruses comprise two genogroups, A and B, distinguishable genetically and serologically Anderson, ; Mufson, ; van den Hoogen, which co-circulate with fluctuating frequencies.

The two HRSV genogroups are referred to as subgroups; these comprise genotypes distinguished on the basis of antibody cross reactivity McGill, or phylogeny Venter, Each of the two HMPV genogroups are referred to, somewhat paradoxically, as genotypes, and each genotype comprises two sub-genotypes A1, A2, B1 and B2 ; genotypes are distinguishable serologically and sub-genotypes are differentiated phylogenetically van den Hoogen, HRSV subtype A is more prevalent than subtype B Zlateva, , and whether clinical differences between the two subtypes exist is still debated, though HRSV-A has been associated with higher morbidity outcomes Taylor, Re-infections with HRSV occur throughout life, and many re-infections with the same subtype are observed, even in infancy Mufson, Re-infections in all ages are usually symptomatic Hall, HRSV epidemics occur every winter, and sporadically a particularly bad season arises Taylor, ; the reasons underlying this are unknown.

Stockton et al reported a 2. HMPV can cause asymptomatic infections Falsey, ; Williams, , though how often these occur is not established.

The only epidemiologic study of sub-clinical infection with HMPV in the community determined a 4. General Introduction - 39 - Reports contradict as to whether mixed infection with these two viruses causes exacerbated disease Caracciolo, ; Greensill, ; McNamara, ; van Woensel, ; Wilkesmann, Nonstructural proteins common to both viruses are invariably highly conserved and include the matrix protein M , the second matrix protein M2 , the phosphoprotein P , the polymerase L , and the nucleocapsid N , which tightly encapsidates genomic RNA.

The fusion F protein mediates fusion of viral and cell membranes and is highly conserved. Anti-HRSV antibody directed against F protein is cross-reactive for strains of both subtypes Anderson, ; Hendry, ; Mufson, ; Olmsted, , and studies on HMPV using human sera and animal models have indicated similar antibody reactivity patterns Endo, ; Herfst, ; Skiadopoulos, ; van den Hoogen, General Introduction - 40 - The attachment G glycoprotein of pneumoviruses conversely exhibits several characteristics expressly for immune evasion.

In both viruses the G protein is extensively glycosylated with both N- and O-linked sugars and a high proportion of proline residues Ishiguro, ; Johnson, b; Zlateva, , thought to reduce ordered secondary structure of the protein.

It is hypothesized that switching of the predominant circulating subtype of HRSV is brought about by short-lived subtype-specific herd immunity in a population generated over one or two seasons probably against the G protein, which favours dissemination of the alternate subtype in a subsequent season Botosso, ; Scott, ; White, ; this suggestion has been borrowed to explain HMPV genotype switching also Agapov, Adenoviruses Adenoviruses are somewhat of a misfit in the respiratory virus group, as they are predominantly transmitted by the faecal-oral route Fox, Initial spread may occur via the respiratory route, but prolonged carriage of adenoviruses in the gut makes it such that faecal oral transmission is more widely observed both during the acute phase of illness and during intermittent recurrences of viral shedding in persistent infections.

Adenoviruses can persist in healthy adults for a duration of 24 months Fox, , and documented survival of adenovirus for ten years in a tear film was documented in patients with recurrent conjunctivitis Kaye, Zoonotic transmission of bovine, simian and feline adenoviruses to humans has been demonstrated by seroconversion General Introduction - 41 - Afshar, ; Phan, ; Xiang, , though infections were asymptomatic.

Recently it has been demonstrated that adenoviruses are able to undergo recombination Halstead, Postinfection, the host usually develops type-specific antibodies which may protect against disease or re-infection, but do not resolve the carrier state.

Asymptomatic adenovirus infection is frequent Fox, , Adenoviruses may circulate in both endemic and epidemic forms.

Adenoviruses follow no seasonal trends, and are serotype specific in their predilections for the age-profile of the host infected Schmitz, Epidemiologic relationships between respiratory viruses That respiratory viruses might facilitate bacterial infections was first suggested in the literature in the s, when it was demonstrated that during URTI, H.

The predisposing factors which turn asymptomatic carriage of common bacteria such as S. Excess mortality during influenza pandemics has been attributed to S.

There are two mechanisms suggested by which prior virus infection might facilitate bacterial adhesion. Physical damage to the respiratory epithelia, possibly including ciliostasis, may prevent host clearance of invading bacteria and so aid in establishment of infection.

Alternatively, viral glycoproteins expressed on the surface of General Introduction - 42 - an infected cell could act as receptors for invading bacteria.

For example, the HRSV G protein is inserted into the membrane of the infected cell, and this expression increases binding of N.

Surprisingly, neither of these mechanisms has been put forward to suggest that primary infection with a virus may facilitate secondary viral infection, nor has it been suggested that HRSV might use commensal N.

Virus-virus interactions are documented in the form of antibody-dependent enhancement ADE , whereby viruses use heterologous anti-virus antibody to mediate attachment and entry into target cells.

ADE during HRSV infection in infants has been suggested in explanation of the exacerbated morbidity seen during infections in those under 6 months of age Osiowy, , though this idea has not been followed up in the literature.

Conversely, infection with one respiratory virus may protect from infection with other viruses. It has been noted that rhinoviruses were less likely than expected to be found in mixed infections Greer, , and this relationship has been reported more specifically for HRSV and HRV-C Wisdom, a , when an unexpectedly low mixed infection frequency with these two viruses was observed.

It is suggested that the innate immune response to one of these infections is protective from a secondary infection with the alternate virus.

Another study which was undertaken during an interval of concurrent high circulation of both HRSV and rhinoviruses observed high mixed infection frequencies Richard, , and so these observations may have been a coincidental occurrence of differing virus seasonalities.

Nevertheless, the suggestion that innate immunity stimulated during one virus infection might be protective from infection with another respiratory virus is interesting.

General Introduction - 43 - 1. Analyses of virus evolution at the genomic level RNA viruses are the most rapidly evolving entities known; the lack of proofreading activity of the RNA polymerase augments the potential for transcriptional errors.

Nucleotide substitutions may or may not result in an amino acid change, and may or may not become fixed in the virus population.

Some residues are functionally conserved and so substitutions at these sites produce non-selected changes, and the likelihood of detecting such changes in a sampled virus population is minimal.

Other changes are inconsequential; their occurrence in such a large virus population renders the chances of them coming to predominance in the virus population low.

These are neutral or nearly neutral changes. Some mutations may be advantageous, for example by increasing receptor affinity or subverting host immune responses, and so the change is selected for by the host population rather than the virus.

Such changes usually occur at specific residues, and convergence of the virus population at these residues occurs. Statistical analyses of sequence datasets can be undertaken to detect residues which are under this positive selection.

Virus evolution can be captured by observing changes in residues at both neutral and positively selected sites, visualised by phylogenetic analyses.

Phylogenetic reconstruction models the diversification events in the history of a virus population which gave rise to the sample population, and it is possible to estimate when such events occurred.

The number of years since the root of a phylogenetic tree i. Evolutionary modelling of several respiratory viruses has been undertaken.

A well conducted analysis which identified positively selected sites and the evolutionary characteristics of HRSV was undertaken in two parts corresponding with the two subtypes A and B Zlateva, , The most recent common ancestor of HMPV and avian metapneumovirus, the most closely related virus to HMPV identified to date, was estimated to have existed de Graaf, or Yang, years ago; the former study analysed data from sequences spanning twelve years, whereas the latter study analysed sequence data generated from samples collected over twenty years.

Sensitivity of the evolutionary analyses to the input sequence data is demonstrated by the disparity in the estimates of divergence times indicated by the species level and inter-species level tMRCAs.

This exemplifies the risk inherent in modelling evolutionary events with sequence data for less than ten percent of the predictive period.

Disease burden of respiratory viruses A tremendous ethical debate ensues on publication of any method which attempts to quantify the burden of any disease, yet the value of such studies in providing indications of where limited resources should be diverted to maximize their return in terms of human life validates the dogged pursuit of acceptable methodologies.

QALYs were used to identify where resources should be diverted in order to maximize a social utility outcome, that is, where people perceive the greatest benefits to quality of General Introduction - 45 - life are to be gained, and are utilitarian in their aim to do the greatest good for the greatest number of people.

QALYs identify Health Related Quality of Life HRQL weightings on a scale between zero and one, where zero is death and one is full health, without specific linkages to diseases, conditions or disabilities, but rather directed by the values of individuals and how they perceive their own health state.

A variety of methods to standardise perceptions of health across ages, cultures and genders while including considerations of physical, psychological, and social parameters have been described.

One of the most common used is asking respondents what they would be willing to sacrifice in terms of risk of death or time in order to return from their current status to perfect health.

This is nevertheless inevitably subject to variability inherent between sampling populations. Health professionals have been found to provide lower values than others when scoring illnesses.

To overcome the practical difficulties associated with collecting comparable primary data on a global scale and the concerns raised over self-assessments of health by using QALYs, the need for a new way of quantifying disease burden was identified.

Quantification of the global burden of premature death, disease and injury in order to identify optimum strategies for improvement of health globally was undertaken in a collaborate effort by the World Bank and the World Health Organization, which in heralded the introduction of the Disability Adjusted Life Year DALY model.

This, for the first time, provided the means to assess whether one intervention or another for two different diseases would provide the greatest benefit e.

Reviews of this approach have nevertheless often been critical with inferences made that panelists were led in their scoring.

The practical drawback of this approach in comparison with QALYs is the inability to account for co-morbidities.

In conclusion, both QALYs and DALYs strive to produce summary measures of population health which combine the effects of morbidity and mortality for simultaneous consideration.

Notwithstanding, such calculations currently represent the most sophisticated means with which to directly compare health outcomes, and without strategies for quantification of disease, policy makers are left in the dark when making decisions on the optimal way to allocate finite resources.

Quantification of the global burden of disease has been undertaken for HRSV using the DALY model Nair, , and the study concluded the tremendous value of General Introduction - 47 - development of vaccines, prophylaxes and treatments to reduce the morbidity and mortality caused by this virus.

HRSV is widely purported as the single greatest cause of viral ARTI regardless of sampled population, yet without some form of direct comparison between respiratory viruses the value of this study serves only to emphasise the importance of HRSV without making clear the need for investment into researching interventions for this virus rather than other respiratory viruses.

General Introduction - 48 - 2. Materials and Methods This chapter contains general descriptions of the materials, methods and software used during the course of study, and is divided into three sections.

The first describes the samples used, and the second outlines the laboratory methods and materials employed.

Computational techniques are detailed in the third section. Retained information recorded in an Excel database included patient age Figure 3 and sex, month and origin of sample collection Figure 4, Figure 5 , clinical information recorded on referral forms, and routine diagnostic screening results.

Figure 3. Patient ages were recorded on a banded basis in accordance with ethical restrictions, corresponding with the ranges indicated.

Methods - 50 - Samples collected between July and June were anonymised using sequential ascending integers3. A nucleic acid archive complementary to the sample archive comprising nucleic acids extracted from samples during diagnostic testing was also assembled.

Figure 4. Between 1 patients and 80 1 3 There were two good reasons for terminating epidemiologic studies from this time.

Primarily, the influenza pandemic changed the sampling frame from around this time, with GPs sending an increased proportion of samples and some samples were taken for screening of asymptomatic contacts.

Additionally, the ethical requirement for anonymisation of all samples and nucleic acids became overwhelming for one individual due to the increased influx of samples it took a day to re-label around a thousand samples or fifteen hundred nucleic acids.

Methods - 51 - patient samples were collected from each patient. Repeat samplings from the same patient arose through both re-sampling during one illness, and sampling from temporally discrete illnesses.

In all, referral sites were recorded. Most samples were hospital referred Figure 5. Origin of all samples collected between July and June total Methods - 52 - Figure 6.

The proportion of samples in each group in which at least one virus from the routine panel described in 2. Nasal secretions, nasal swab and perinasal swab were grouped under nasal.

Oral included oral secretions, saliva, and mouth swab. Tracheal consisted of tracheal aspirate, endotracheal tube, endotracheal secretions, tracheal secretions, throat swab, and tracheal ring.

Samples for which the origin was not clear e. Breakdown of the physiological origin of samples collected over the three year study period is indicated Figure 6.

Diagnostic testing For respiratory virus diagnosis, respiratory samples are typically screened by molecular amplification methods such as the polymerase chain reaction PCR for a panel Methods - 53 - of viruses which varies between diagnostic laboratories.

Figure 7. Number of samples and proportion for which a virus included in the routine panel was detected is indicated at the head of each column.

Only a fraction of the samples were tested for these viruses, so the results could not be included in epidemiologic study.

Methods - 54 - 2. Clinical data Clinical information reported on referral forms was recorded in the respiratory database and divided into seven categories.

These were: 1. Included samples collected from patients with neoplasia, a known immunosuppressive disorder and transplant patients.

Samples collected from patients with chronic respiratory conditions such as asthma and cystic fibrosis.

Lower respiratory tract infection LRTI. Samples taken from patients with pneumonia, bronchiolitis, bronchitis, influenza-like illness ILI , tested for HRSV using a near-patient test NPT 5 Mackenzie, , chest infection, shortness of breath, atypical pneumonia, acute respiratory distress syndrome ARDS , difficulty breathing, community acquired pneumonia, cough, wheeze and respiratory failure if a sample number from the same patient preceding this clinical report was associated with URTI or LRTI.

Upper respiratory tract infection URTI. Tonsillitis, coryza, rhinorrhoea and sore throat were classified as URTI.

Clinical evidence for respiratory tract infection was indeterminate e. No data. No data was recorded for Clinical data relating to some samples could be assigned to more than one category, and so categories were treated in a hierarchical fashion with precedent given in the order as above.

The relative frequency of the described clinical categories is indicated Figure 7. Infants presenting with symptoms of lower respiratory tract infection requiring hospitalization are tested for HRSV using a point of care test to guide cohorting.

Methods: Laboratory based techniques Laboratory techniques were undertaken at two sites. Automated nucleic acid extraction 2.

At both research sites, a one way flow through laboratory system is operational to reduce risk of contamination. These were replenished by sample re-extraction using the same protocol used for diagnostics of automated BioRobot MDx extraction for continuity.

Extraction of nucleic acids from specimens used in studies of molecular evolution or as positive controls where a standardised approach to extraction was not essential was undertaken using Qiagen Southampton, UK viral RNA mini kit following the protocol for purification of viral RNA from sample fluid by centrifugation, with a double elution step.

Methods - 56 - 2. Pooling of respiratory RNA To maximize the number of samples tested, screening of pooled nucleic acids was undertaken during epidemiologic studies.

Pooling has previously been demonstrated as an effective technique for efficient screening of respiratory samples for viruses circulating at sufficiently low frequency e.

Reverse transcription To enable amplification of viral nucleic acids by nested PCR, single nucleic acids and RNA pools were converted to cDNA by reverse transcription RT using Promega Southampton, UK A kit according to manufacturers instructions for use of random primers, modified to incorporate an extended elongation step of 55 minutes.

Successful amplification of the target region was confirmed by agarose gel electrophoresis 2. This enzyme metabolises X-Gal.

One culture was selected and plasmid was extracted using Qiagen Crawley, UK miniprep kit according to manufacturer instructions.

Polymerase Chain Reaction PCR techniques The polymerase chain reaction PCR amplifies nucleic acids by a cyclic chain of DNA denaturation, primer annealing and nucleotide extension events, each of which occur optimally at different temperatures.

PCR played a dual role in this work, used for virus detection and sequence analysis. Primer design Design of primers was undertaken by downloading available target region sequences from Genbank and aligning in Simmonics software www.

The primer pair was inputted into the search, and the results returned for products complementary to these primers were checked to ensure they matched the target product, and that no undesired targets were amplified.

The positive control was usually a clinical specimen. All PCR reactions comprised the same basic reagents.

Methods - 60 - Figure 8. The algorithmic process of PCR protocol design. PCR protocol variables are described in white boxes which follow the chain of events in setting up a PCR reaction.

Questions to determine the next stage of optimization are in grey boxes. Decisions are in black boxes. Methods - 61 - 2.

Virus detection was by direct visualization of fluorescence emitted by virus-specific probes on ABI bioluminescence machines Applied Biosystems technologies.

Probes bound to a specific nucleotide sequence were cleaved on complementary DNA binding, releasing the probe to emit fluorescence, and so the more DNA amplified the stronger the fluorescence refer to 1.

Amplified nucleic acid was detected directly using Bioluminescence ABI machine. Negative control product from automated extraction was used as negative control.

Component samples of coronavirus positive pools in this group were screened using the 7 Dr Kate Templeton who supervised this project previously worked at Leiden University Medical Centre, Leiden, The Netherlands.

With a colleague there, Dr Eric Claas, Kate designed but did not publish this protocol. Methods - 62 - same four way multiplex assay to detect constituent positive samples.

Additionally, components of nine coronavirus negative pools were screened by the multiplex assay. Table 9. Primers are described in Table 8.

IS, inner sense; IAS, inner antisense. Synthesis of high copy number coronavirus RNA and multiplex assay sensitivity To assess the sensitivity of the multiplex assay, a standard curve was constructed using ten-fold serially diluted coronavirus RNA of known copy number, and the limit of detection was assumed to be the RNA copy number theoretically detectable after 50 PCR cycles.

PCR product was cloned into pCR2. Methods - 63 - transformation of electrocompetent E. Blue colonies were picked and success of transformation was confirmed by sequence analysis.

Table PCR product was quantified and checked for purity by spectrophotometry using nanodrop testing for absorbance at wavelengths of A and A These RNA standards were subject to the multiplex assay in triplicate to construct a standard curve.

Second round PCR was then undertaken as previously described. This method successfully amplified HRSV RNA in around half of cases and so the insufficiencies of the PCR techniques were attributed to RNA degradation, possibly 10 Platinum Taq polymerase is a recombinant Taq polymerase complexed with an activity blocking antibody at room temperature.

At high temperatures, antibody is denatured and polymerase activity is restored. This prevents non-specific annealing of the polymerase, thereby increasing sensitivity and reducing the need for PCR optimization.

Methods - 65 - arising due to the inevitable freeze-thaw associated with repeatedly moving RNA within and between sites.

Agarose gel electrophoresis PCR positive samples were detected by visualization of reaction product by agarose gel electrophoresis.

Loading dye adds colour and density to the sample for ease of loading and is negatively charged, so will migrate unidirectionally with DNA.

Gels were immersed in tanks containing 1xTAE solution at volts for minutes, and visualized using a UV transilluminator. Sequencing reaction Nucleotide sequencing was undertaken using the Sanger method of a cyclic reaction wherein at each stage one fluorescently tagged nucleotide is knocked off the transcript and detected.

To prepare transcripts comprising fluorescent signals, DNA was amplified using fluorescently tagged nucleotides For each amplicon this reaction was undertaken twice, once in the sense and once in the antisense direction with inner primers used accordingly.

This removed free dNTPs and primers to improve accuracy of sequencing. Methods: Computational analyses 2. Sequence alignment Sequences generated during the course of this study were used for molecular epidemiologic and evolutionary analyses.

Nucleotide sequencing results were returned from the Genepool sequencing service by email, and were imported into the most contemporary version of the in-house sequence alignment and analysis software program Simmonics www.

Phylogenetic analyses Phylogenetic reconstruction produces a topography representative of modeled ancestral relationships for a taxonomic group.

There are several software packages available for phylogenetic reconstruction, which use a variety of techniques for establishing the tree which best fits input sequence data.

The most widely used models for phylogenetic reconstruction are briefly summarized Table Phylogenetic analyses were conducted by nearest neighbour joining from samplings of maximum composite likelihood Methods - 67 - MCL distances with pair-wise deletions for missing nucleotides and gamma distributed rates among sites to allow variability in substitution rates between nucleotide positions.

Neighbour joining trees are constructed iteratively whereby all branches are initially connected by one internal node to give a star-like tree.

A pairwise distance matrix is calculated representing the sum of the branch lengths across the tree if each pair of taxa was joined.

An internal branch is added to join the pair of taxa giving the smallest sum of branch lengths. Neighbour joining trees are computationally efficient and so can be used on large datasets, do not assume all lineages evolve at the same rate and produce an unrooted tree.

However NJ assumes that no backward or parallel substitutions occur. Neighbour joining trees are exposed to Long Branch Attraction LBA Felsenstein, , whereby differentially evolving lineages may be subject to multiple substitutions at specific sites, thereby increasing likelihood that the neighbour joining model will predict that two strains are more closely related than they actually are.

As such, NJ trees are not ideal for sequence sets under positive selection. Maximum composite likelihood is ideal for phylogenetic reconstruction of rapidly evolving sites as it corrects for multiple mutational events at the same site.

MCL modifies the estimate of evolutionary distances between sequences in a pairwise fashion by fitting common parameters for nucleotide substitution events to every sequence pair.

Different transition purine to purine or pyrimidine to pyrimidine substitutions and transversion purine to pyrimidine or pyrimidine to purine substitutions ratios are modeled, reflecting the observation that transitions occur more readily than transversions.

Estimation of pairwise evolutionary distances by maximum composite likelihood overcomes any exposure to LBA. Trees were rooted using an outlier e.

Methods - 68 - Table Summary of models commonly cited for phylogenetic tree construction. Detailed in 2. Reference source not found..

Bootstrap values A phylogenetic tree gives the best estimate of the relationship between groups of sequences. Bootstrapping is a statistical technique to establish how well the model used supports each of the relationships represented on the tree.

Random re-sampling of the input dataset and evolutionary reconstruction is undertaken usually or times. How frequently the relationships on the original tree are supported by the randomly resampled datasets is indicated by the bootstrap value.

A low bootstrap value indicates that a grouping is sensitive to the exact combination of isolates and sites that were sequenced. However, this does not necessarily mean the relationship is accurate, for example, in a tree exposed to LBA.

Bootstrapping, while invaluable for interpreting phylogenetic trees, is of significant computational burden as the original analysis must be repeated or times.

Bayesian Evolutionary Analysis of Sampling Trees BEAST is a software package which uses a Bayesian maximum likelihood technique to calculate the evolutionary rate and time since the most recent common ancestor tMRCA of a set of sequences with known isolation dates.

Millions of phylogenetic reconstructions are modeled by step-wise variations of input parameters. A conceptual algorithmic chain links the steps which each propose a new location in parameter space.

The next step is usually similar to the current step as it is generated by random disturbance of a few parameters in the current step.

The relative posterior probability density of the new step is calculated, and if it is higher than the current step the move is accepted.

Thus, slight drops in posterior probability are tolerated whereas big drops are discouraged. If the proposed location is rejected, the present location is accepted as the next step in the chain and so two identical steps in the chain exist.

Repeating this process millions of times creates a long chain of locations in parameter space. Chains tend to stay in regions of high posterior probability, and the proportion of time the chain spends in any region of parameter space is used to estimate the posterior probability of that region.

BEAUti allows the user to define the substitution model of input sequence data Hasegawa-Kishino-Yano HKY85 , General Time Reversible GTR or Tamura-Nei, 93 TN93 , base frequencies empirical, estimated or all equal , site heterogeneity none, gamma distributed or gamma distributed with invariant sites , and if using gamma or gamma and invariant sites the number of gamma categories GTR comprises a 4x4 matrix of substitution rates with each nucleotide pair represented.

The GTR model assumes that the base frequencies remain constant over time, and the rate of change from base i to base j is equal to the rate of change from base j to base i i.

The TN93 or TrN model limits the six rate Methods - 71 - parameters to three, one for transversions and two for transitions.

The HKY85 model incorporates only two rate parameters, one each for transitions and transversions. The first and second bases of a codon were assumed to have the same evolutionary rate.

The third base of a codon was modeled to have an independent evolutionary rate due to the redundancy associated with this coding position.

The evolutionary clock model can take the form of strict or relaxed. A strict clock does not allow variability in the evolutionary rate between branches of the phylogenetic tree, whereas the relaxed clock does.

The F gene was selected for evolutionary analysis as it is phylogenetically informative and sequence data spanning 20 years is available for HMPV despite its only recent discovery in While the same is true for the G gene, this region is under considerable positive selection.

Positively selected sites phylogenetically converge to an optimally selected residue, whereas neutral or nearly neutral sites are subject to drift, which is non-convergent.

Positively selected sites therefore violate the concept of time reversible models of substitution through a tendency to unidirectionally converge.

It was therefore decided that positively selected should be identified and removed from sequence alignments prior to evolutionary analyses.

Phylogenetic analyses of all available sequences were then used to incorporate monophyletic sequences with older isolation dates within lineages, and the monophyletic groups were defined as clades.

A genetic variability of 1. Evolutionary analyses were restricted to clades comprising a minimum of 15 sequences.

A strict evolutionary clock was used under the assumption that the evolutionary rate within a monophyletic clade would not vary.

Preliminarily, all models were run using a strict clock as recommended. A strict clock assumes the substitution rate substitutions per site per unit time between branches does not vary.

Subsequently, datasets were analysed using a relaxed clock model as recommended. When using a relaxed clock, BEAST models a distribution of variation in substitution rate over a phylogeny.

If there is no variation in the substitution rate between branches of the phylogenetic tree, the coefficient of variation will be zero.

A histogram representative of the posterior probability distribution of values of the coefficient of variation is provided in the data output when using a relaxed clock.

It was expected that the strict model should not be rejected, as monophyletic lineages should not return a model with rate variation.

Detection of residues under positive selection Several software packages and web services are available for analysis of nucleotide sequences to detect positively selected sites.

Both packages were investigated. Datamonkey was very user-friendly with results returned rapidly. However, the results did not inspire confidence; they were returned too quickly for robust analyses to have been undertaken, no understanding whatsoever was required to produce a discernibly meaningful result, and when several models were tested using HRSV sequence data, none were able to detect the cysteines which are absolutely conserved even in bovine RSV as negatively selected sites.

PAML v. Sequence alignments were exported from Simmonics into Phylip v3. Neighbor Phylip was then run using the distance matrix to produce a Neighbour-Joining starting tree for the sequence alignment, and this was copied into the PAML work directory.

As this was simply a starting tree, the computationally efficient methods of calculation of a distance matrix using JC, rapid phylogenetic reconstruction by NJ, and lack of bootstrapping were sufficient.

Codeml is the PAML software which detects positively selected sites in a nucleotide alignment. The codeml control file was edited to change the sequence alignment and starting tree file names to correspond with those produced, then codeml was run using command prompt to detect positively selected sites.

NEB uses maximum likelihood estimates MLE of parameters, without accounting for sampling errors, which may be introduced by small sample sets.

Methods - 74 - recommended combination of models 1 and 2 Yang, was used to yield satisfactory results, and so PAML was selected as the program for detection of positively selected sites.

It was considered that detection of positively selected sites within HRSV should be undertaken at the subtype level, as considerable divergence between the subtype attachment proteins was sufficient for breakdown of the analyses in the ectodomain such that all sites were identified as positively selected.

For HMPV, the optimal strategy of sub-genotype level analyses was undertaken. Methods: Relative quantification of the disease burden of ten respiratory viruses using the Disability Adjusted Life Year DALY model The clinical significance of recently discovered and lower prevalence respiratory viruses has not been systematically quantified.

The Disability Adjusted Life Year DALY model was embraced by the World Health Organization in as a methodology for prioritizing interventions in the health sector based on their potential to reduce burden of disease and the cost effectiveness of such interventions.

DALYs combine time lost due to morbidity and mortality to attribute a single numerical value as a measure of the associated burden caused by a disease outcome.

DALYs are founded on the concept that like health outcomes should be treated as like, so a 30 year old woman living in a slum in Bogota losing a leg would be equivalent to a 30 year old woman losing a leg in New York.

While the ethical implications of this are debatable, literature consensus is that a social discount rate should be incorporated to reflect the dependency of the young and elderly on adults and is justified in detail elsewhere Murray, The DALY model has been used to directly compare the disease burden associated with a panel of the most commonly detected respiratory viruses to provide an indication of where resources should be diverted in terms of diagnostics, patient management and treatment.

Methods - 75 - 2. Sampled population The time frame of study was established between 1 July and 30 June Samples testing positive for more than one of the viruses included in the study were considered separately as mixed infections.

Due to the differences in sampling strategy from different patient populations, it was appropriate to undertake analyses in an age-stratified way and to consider immunocompromised patients separately.

Clinical outcomes and estimates of morbidity scores The DALY model quantifies morbidity associated with different clinical outcomes by assigning morbidity scores on a scale between 0 and 1, whereby 0 is no morbidity and 1 is death.

The clinical categories described 2. Review of the clinical correlates of respiratory viruses highlighted the need to include further clinical categories for which rates were estimable.

Seven patients in the study had single adenovirus infection and gastrointestinal presentations. As adenoviruses are the respiratory viruses most strongly associated with GI symptoms, it was decided to not include this presentation in morbidity calculations.

Combined with the results of the published study, over a thousand samples were tested for rhinoviruses. Neurological manifestations were not included in analyses as the causal association between respiratory virus infection and presentation is most unclear.

Samples from eighteen patients were referred due to apnoeic presentations, in six of which a respiratory virus was detected interestingly, three of these were coronaviruses.

This was insufficient to justify inclusion in morbidity analyses. A virus was detected in samples from fourteen patients with sepsis, thirteen of which were single infections.

This infrequent association without causality justified the exclusion of sepsis from morbidity calculations. In the study population, LRTI was assumed to be the cause of hospitalization, and so a higher morbidity score was deemed appropriate Table The range in morbidity scores considered to reflect the possible implications of hospitalization due to LRTI fell between 0.

A score of 0. The morbidity score attributed to LRTI was assigned on a virus-dependent basis in the range of 0. For example, Definitions of disability weighting.

From Murray, Disability Description class Class 1 Limited ability to perfom at least one activity in one of the following areas: recreation, education, procreation and occupation.

Class 2 Limited ability to perfom most activities in one of the following areas: recreation, education, procreation and occupation.

Class 3 Limited ability to perfom activities in two or more of the following areas: recreation, education, procreation and occupation.

Class 4 Limited ability to perfom most activities in all of the following areas: recreation, education, procreation and occupation.

Class 5 Need assistance with instrumental activities of daily living such as meal preparation, shopping or housework. Class 6 Need assistance with activities of daily living such as eating, personal hygiene or toilet use.

Methods Disability weight 0. The first is from the literature. The second is using the rates observed in otherwise healthy individuals in Edinburgh.

The latter approach has been chosen: the Edinburgh archive may not reflect other sampled populations in terms of the criteria for sample testing, the viruses present and clinical definitions.

Morbidity scores for LRTI calculated in otherwise healthy patients were applied to the immunocompromised population.

ITU admission of an immunocompromised patient could not be assumed to be due to respiratory infection and so this method was preferred to a distinct morbidity score calculation in this group.

Estimates of case fatality rates for each virus infection were made using literature based meta-analyses appendices I, II and III. For other sequelae such as infection as a cause of asthma, Reyes syndrome and Goodpastures syndrome, incidence estimates were made by literature review.

Only estimated rates of asthma were sufficient for inclusion in study Goodpastures and Reyes are so uncommon it could not be assumed that any cases would have occurred in the sampling frame and World Bank study disability score of 0.

Immunocompromised patients DALYs are founded on the concepts that the characteristics of the individual affected by a health outcome considered in calculating the associated burden of disease should be restricted to age and sex, and that like health outcomes should be treated as like Murray, Differing values and conceptions of social justice may result in differing conclusions about the correct approach to this issue.

Using the assumptions described by Murray Murray, , application of the same social and life expectancy parameters to immunocompromised individuals as otherwise healthy individuals was considered the most ethically viable approach for the purpose of this study verified by Dr Claudia Stein, WHO pers.

Adjustment for age of onset, severity of disability, length of disability, and social value are incorporated in the DALY model.

The DALY model regards life expectancy as the maximum achievable length of life, and in DALY models used to estimate global burden of disease a Japanese life expectancy is used.

Sex specific mean life expectancies in Scotland between and as described by the Office for National Statistics were used here.

DALYs were calculated in an age stratified manner to reflect the different sampling strategies in place for patients of different ages, with immunocompromised patients considered separately.

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