Einleitung Erkrankungen des Bewegungsapparates haben bei Milchkühen eine hohe wirtschaftliche Bedeutung sowie enorme Auswirkungen auf das Tierwohl. Etwa 90 % der Lahmheiten beim Rind werden durch Klauenerkrankungen hervorgerufen. Die Ursachen dieser Klauenerkrankungen sind multifaktoriell und umfassen tier- und umweltassoziierte Faktoren. Die Pododermatitis aseptica diffusa ist eine der wichtigsten Ursachen für die Entstehung von umschriebenen Klauenlederhautentzündungen. In ihrer Pathogenese spielen Veränderungen der Zehendurchblutung eine zentrale Rolle. Die Pulsed-Wave (PW)-Dopplersonographie ist eine nicht invasive Technik zur Beurteilung des Blutflusses an Gefäßen und zur Untersuchung der Durchblutung von Organen. Jedoch liegen keine PW-Dopplersonographischen Untersuchungen an der Zehe des Rindes in der Literatur vor. Ziele der Untersuchungen Ziel der Untersuchungen war es, die Zehendurchblutung bei Rindern, die an einer Pododermatitis circumscripta solearis oder parietalis litten, im Milchviehbetrieb zu erfassen. Dazu wurde in einem ersten Schritt die Methodik der PW-Dopplersonographie an der Zehe der Hintergliedmaßen von gesunden Kühen etabliert. In einem zweiten Schritt wurden Blutflussmerkmale an den Hintergliedmaßen lahmer Kühe, die an einer Pododermatitis circumscripta solearis oder parietalis litten, erfasst, um Auswirkungen der Entzündung sowie weiterer als relevant erscheinender Einflussfaktoren für die Zehendurchblutung zu untersuchen. Material und Methoden In der Publikation 1 wurden 22 gesunde Deutsch Holstein Kühe einbezogen. Die Versuchstiere wurden im Betrieb einer klinischen Untersuchung inklusive einer Lahmheitsbeurteilung sowie einer Klauenpflege aller Gliedmaßen unterzogen. Am zweiten Versuchstag wurde eine sonographische Untersuchung beider Hintergliedmaßen am stehenden Tier durchgeführt. Zur sonographischen Untersuchung wurde das MyLab One (Esaote Deutschland GmbH) mit einem Linearschallkopf (10 MHz) ohne Vorlaufstrecke verwendet. Mittels Brightness(B)-Mode wurden Weichteilgewebe, synoviale Einrichtungen und Blutgefäße distal des Tarsus untersucht. In der Arteria (A.) interdigitalis wurde der Blutfluss mittels PW-Dopplersonographie beurteilt. Die Auswertung der Daten erfolgte mit dem Programm MyLap Desk auf einem Laptop. In die Publikation 2 wurden 33 lahme und 11 gesunde Deutsch Holstein Kühe einbezogen. Die lahmen Kühe litten an einer superfiziellen bis profunden Pododermatitis an der Außenklaue einer Hintergliedmaße. Die klinische und sonographische Untersuchung erfolgte wie in der Publikation 1 beschrieben. Für die statistische Bearbeitung der Daten wurde die procedure mixed (SAS, Version 9.4) verwendet. Ergebnisse In den Publikationen 1 und 2 konnte an 112 von 132 Hintergliedmaßen bei 66 Kühen ein auswertbares PW-Doppler-Signal gemessen werden. Bei 17 der 20 nicht auswertbaren Hintergliedmaßen lag nur eine mäßige B-Mode-Bildqualität vor. Die lahmen Kühe trippelten bei der sonographischen Untersuchung mehr als die gesunden Kühe. Blutflusskurventypen mit einem niedrigen peripheren Gefäßwiderstand liegen vor allem an den Hintergliedmaßen lahmer Kühe und Kurventypen mit einem hohen Widerstand am häufigsten bei gesunden Kühen vor. Lahme Kühe haben im Vergleich zu nicht-lahmen Kühen einen erhöhten Gefäßdurchmesser (D) und eine gesteigerte Blutflussrate (BF) sowie enddiastolische Blutflussgeschwindigkeit. Es bestehen keine Unterschiede zwischen der betroffenen Gliedmaße und der Gegengliedmaße lahmer Kühe. Ein numerisch höherer D, eine höhere BF sowie maximale systolische und maximale mittlere Blutflussgeschwindigkeit liegen bei Kühen mit einer mittelgradigen Lahmheit vor. Schlussfolgerungen Die PW-Dopplersonographie in Kombination mit dem in der Studie verwendeten Untersuchungsgang ist für die Messung des Blutflusses in der A. interdigitalis an den Hintergliedmaßen des Rindes sehr gut geeignet. Sowohl die bei den Kühen gefundenen Blutflusskurvenprofile als auch die quantitativen Blutflussmerkmale sind mit Werten von Pferden vergleichbar. Es liegt eine gesteigerte Durchblutung an den betroffenen Zehen und denen der Gegengliedmaße von lahmen Kühen im Vergleich zu gesunden Kühen vor. Nicht nur das Vorliegen einer umschriebenen Klauenlederhautentzündung, sondern auch ihr zeitlicher Verlauf, die Auswirkungen einer aktivierten Entzündungskaskade, das Vorliegen einer chronischen Klauenrehe und vor allem die Gewichtsbelastung und die Gewichtsverschiebung zwischen den Hintergliedmaßen müssen in die Beurteilung des digitalen Blutflusses einbezogen werden. Die erstmalig an der Rinderzehe ermittelten Blutflussdaten stellen eine gute Grundlage für weitere Forschungen auf dem Gebiet der Klauenrehe-Pathogenese dar.:Inhaltsverzeichnis 1 Einleitung 1 2 Literaturübersicht 3 2.1 Pododermatitis aseptica diffusa beim Rind 3 2.1.1 Definition 3 2.1.2 Symptomatik 3 2.1.2.1 Klinisches Stadium 3 2.1.2.1.1 Akute Form 3 2.1.2.1.2 Subakute Form 4 2.1.2.1.3 Chronische Form 4 2.1.2.2 Subklinisches Stadium 5 2.1.3 Ätiologie 5 2.1.3.1 Fütterung 5 2.1.3.1.1 Zusammenhang zwischen Fütterung und Dysfunktion des Blutgefäßsystems der Zehe 5 2.1.3.1.2 Kohlenhydrate 7 2.1.3.1.3 Proteine und Aminosäuren 9 2.1.3.1.4 Lipide 10 2.1.3.1.5 Spurenelemente 10 2.1.3.1.5.1 Kupfer 10 2.1.3.1.5.2 Zink 10 2.1.3.1.5.3 Mangan 11 2.1.3.1.5.4 Selen 11 2.1.3.1.6 Vitamine 11 2.1.3.1.6.1 Biotin 11 2.1.3.1.6.2 Vitamine A, D, E 12 2.1.3.1.7 Toxine 12 2.1.3.1.8 Bewertung der Versorgung mit Mineralstoffen, Spurenelementen und Vitaminen für die Klauengesundheit 12 2.1.3.2 Mechanische Faktoren 13 2.1.3.2.1 Digitales Fettpolster 13 2.1.3.2.2 Hypertrophie der Außenklaue an den Hintergliedmaßen 14 2.1.3.2.3 Dünne Sohlen 14 2.1.3.3 Hormonelle Veränderungen während der Transitphase 15 2.1.3.4 Haltung 17 2.1.4 Pathogenese 18 2.1.5 Reheassoziierte Klauenlederhautentzündungen 19 2.2 Anatomie des Blutgefäßsystems beim Rind 20 2.2.1 Arterien der Hintergliedmaße 20 2.2.1.1 Arterien am Ober- und Unterschenkel 20 2.2.1.2 Arterien an Mittelfuß und Zehen 21 2.2.1.2.1 Plantares System 21 2.2.1.2.2 Dorsales System 21 2.2.2 Venen der Hintergliedmaße 21 2.2.2.1 Venen am Ober- und Unterschenkel 21 2.2.2.2 Venen an Mittelfuß und Zehen 22 2.2.2.2.1 Plantares System 22 2.2.2.2.2 Dorsales System 22 2.2.3 Blutgefäßsystem der Klauen 23 2.2.3.1 Arterien 23 2.2.3.2 Venen 23 2.2.3.3 Arterio-venöse Anastomosen 24 2.3 Bildgebende Verfahren zur Darstellung des Gefäßsystems 24 2.3.1 Allgemein 24 2.3.2 Brightness Mode Sonographie 25 2.3.2.1 Prinzip 25 2.3.2.2 Allgemeine Anwendung an der Gliedmaße 25 2.3.2.3 Spezielle Anwendung zur Untersuchung des Blutgefäßsystems an der Gliedmaße distal des Tarsus 26 2.3.3 Pulsed-Wave-Dopplersonographie 27 2.3.3.1 Prinzip 27 2.3.3.2 Merkmale 29 2.3.3.3 Allgemeine Anwendung 30 2.3.3.4 Anwendung an der Gliedmaße 30 2.3.4 Weitere bildgebende Verfahren 33 2.3.4.1 Angiographie 33 2.3.4.1.1 Prinzip 33 2.3.4.1.2 Anwendung an der Gliedmaße 34 2.3.4.2 Szintigraphie 34 2.4 Zusammenfassende Schlussfolgerungen aus dem Literaturstudium 35 3 Publikation 1 37 4 Publikation 2 47 5 Diskussion 59 5.1 Auswahl des Messpunktes und Messbarkeit des Blutflusses 59 5.2 Verhalten 60 5.3 Gliedmaßenstellung 60 5.4 Qualitative Blutflussmerkmale 61 5.5 Quantitative Blutflussmerkmale 62 6 Zusammenfassung 66 7 Summary 68 8 Literaturverzeichnis 70 9 Danksagung 96 / Introduction Diseases of the locomotor system in dairy cattle have a huge economic and welfare importance. Nearly 90 % of lameness in cattle is caused by claw disease. The reasons are multifactorial and include animal as well as environmental factors. Claw horn disruption is the main cause for the development of claw horn lesions. Changes in the blood circulation of the toes play an essential role in their pathogenesis. Pulsed-Wave (PW)-Doppler ultrasonography is a non-invasive technique to evaluate the flow in blood vessels and to examine the blood circulation of an organ. However, there have not been any PW-Doppler ultrasonographical investigations for the bovine limb in the literature yet. Aims The objective of this investigation is to measure the blood flow of the toes in dairy cattle suffering from sole ulcer or white line disease in dairy farms. In a first step the PW-Doppler ultrasonography was established at the toe of hindlimbs in healthy dairy cattle. In a second step blood flow variables in the hindlimbs of lame cows affected by a sole ulcer or white line disease were recorded to evaluate the consequence of inflammation as well as to examine further factors seem to influence the blood flow of the toes. Material and Methods Twenty-two German Holstein cows were included in the first publication. The cows were examined clinically in the farm including an evaluation of the lameness score as well as a claw trimming of all limbs. One day after an ultrasonography was performed in standing position in both hind limbs. For the examination a MyLabOne (Esaote Deutschland GmbH) with a linear transducer without a standoff pad was used. Soft tissue, synovial structures and blood vessels distal of the tarsal region were examined by using a Brightness (B)-mode ultrasonography. In the interdigital arteria the blood flow was measured by PW-Doppler ultrasonography. The analysis of the data was carried out by the program MyLabDesk on a laptop. The second publication included 33 lame and 11 healthy German Holstein cows. The lame cows suffered from a superficial too profound sole ulcer or white line disease at the outer claw of one hind limb. The clinical and ultrasonographical examination took place analogically to the first publication. For the statistical analyses the MIXED procedure (SAS, version 9.4) was used. Results Combining both publications in 112 of 132 hindlimbs a usable PW-Doppler signal was generated. Seventeen of the 20 not usable signals the B-mode quality was moderate. During the ultrasonography lame cows pattered their limbs more often than healthy cows. Blood flow profiles with a low peripheral resistance are more common in the hindlimbs of lame cows and profiles with a high peripheral resistance are most frequent in healthy cows. Lame cows have a higher vessel diameter (D), blood flow rate (BF) and end-diastolic blood flow velocity compared to healthy cows. There was no difference in the affected compared to the opposite limbs of lame cows. A numerical higher D, BF as well as maximum systolic and maximum time-averaged mean blood flow velocity occurred in moderate lame cows compared to mild lame cows. Conclusions The PW-Doppler ultrasonography is well suited for the evaluation of the blood flow in the bovine interdigital artery at the hindlimbs. The observed blood flow profiles as well as quantitative blood flow parameters are comparable to data in horses. There is an increased blood circulation in the affected and the opposite limb of lame cows compared to healthy cows. Not only the existence of the claw horn lesions but also their chronological progress, the influence of the inflammatory cascade, the availability of chronic claw horn disruption and especially weight bearing and weight shifting between hindlimbs have to be considered in the assessment of the blood flow of toes. The for the first-time generated blood flow parameters provide a good basis for further investigations in the topic of claw horn disruption pathogenesis.:Inhaltsverzeichnis 1 Einleitung 1 2 Literaturübersicht 3 2.1 Pododermatitis aseptica diffusa beim Rind 3 2.1.1 Definition 3 2.1.2 Symptomatik 3 2.1.2.1 Klinisches Stadium 3 2.1.2.1.1 Akute Form 3 2.1.2.1.2 Subakute Form 4 2.1.2.1.3 Chronische Form 4 2.1.2.2 Subklinisches Stadium 5 2.1.3 Ätiologie 5 2.1.3.1 Fütterung 5 2.1.3.1.1 Zusammenhang zwischen Fütterung und Dysfunktion des Blutgefäßsystems der Zehe 5 2.1.3.1.2 Kohlenhydrate 7 2.1.3.1.3 Proteine und Aminosäuren 9 2.1.3.1.4 Lipide 10 2.1.3.1.5 Spurenelemente 10 2.1.3.1.5.1 Kupfer 10 2.1.3.1.5.2 Zink 10 2.1.3.1.5.3 Mangan 11 2.1.3.1.5.4 Selen 11 2.1.3.1.6 Vitamine 11 2.1.3.1.6.1 Biotin 11 2.1.3.1.6.2 Vitamine A, D, E 12 2.1.3.1.7 Toxine 12 2.1.3.1.8 Bewertung der Versorgung mit Mineralstoffen, Spurenelementen und Vitaminen für die Klauengesundheit 12 2.1.3.2 Mechanische Faktoren 13 2.1.3.2.1 Digitales Fettpolster 13 2.1.3.2.2 Hypertrophie der Außenklaue an den Hintergliedmaßen 14 2.1.3.2.3 Dünne Sohlen 14 2.1.3.3 Hormonelle Veränderungen während der Transitphase 15 2.1.3.4 Haltung 17 2.1.4 Pathogenese 18 2.1.5 Reheassoziierte Klauenlederhautentzündungen 19 2.2 Anatomie des Blutgefäßsystems beim Rind 20 2.2.1 Arterien der Hintergliedmaße 20 2.2.1.1 Arterien am Ober- und Unterschenkel 20 2.2.1.2 Arterien an Mittelfuß und Zehen 21 2.2.1.2.1 Plantares System 21 2.2.1.2.2 Dorsales System 21 2.2.2 Venen der Hintergliedmaße 21 2.2.2.1 Venen am Ober- und Unterschenkel 21 2.2.2.2 Venen an Mittelfuß und Zehen 22 2.2.2.2.1 Plantares System 22 2.2.2.2.2 Dorsales System 22 2.2.3 Blutgefäßsystem der Klauen 23 2.2.3.1 Arterien 23 2.2.3.2 Venen 23 2.2.3.3 Arterio-venöse Anastomosen 24 2.3 Bildgebende Verfahren zur Darstellung des Gefäßsystems 24 2.3.1 Allgemein 24 2.3.2 Brightness Mode Sonographie 25 2.3.2.1 Prinzip 25 2.3.2.2 Allgemeine Anwendung an der Gliedmaße 25 2.3.2.3 Spezielle Anwendung zur Untersuchung des Blutgefäßsystems an der Gliedmaße distal des Tarsus 26 2.3.3 Pulsed-Wave-Dopplersonographie 27 2.3.3.1 Prinzip 27 2.3.3.2 Merkmale 29 2.3.3.3 Allgemeine Anwendung 30 2.3.3.4 Anwendung an der Gliedmaße 30 2.3.4 Weitere bildgebende Verfahren 33 2.3.4.1 Angiographie 33 2.3.4.1.1 Prinzip 33 2.3.4.1.2 Anwendung an der Gliedmaße 34 2.3.4.2 Szintigraphie 34 2.4 Zusammenfassende Schlussfolgerungen aus dem Literaturstudium 35 3 Publikation 1 37 4 Publikation 2 47 5 Diskussion 59 5.1 Auswahl des Messpunktes und Messbarkeit des Blutflusses 59 5.2 Verhalten 60 5.3 Gliedmaßenstellung 60 5.4 Qualitative Blutflussmerkmale 61 5.5 Quantitative Blutflussmerkmale 62 6 Zusammenfassung 66 7 Summary 68 8 Literaturverzeichnis 70 9 Danksagung 96

Perioperative hypotension corresponds to critically low blood pressure events during the pre, intra and postoperative periods. It is a common side effect of general anaesthesia and is strongly associated with an increased risk of postoperative complications, such as acute kidney injury, myocardial injury and in the worst case death. Early treatment of hypotension, preferably even before onset, is crucial in order to reduce the risk and severity of its associated complications. This work explores methods for predicting the onset of hypotension which could serve as a warning mechanism for clinicians managing the patient’s hemodynamics. More specifically, we present methods using only the arterial blood pressure curve to predict two different definitions of hypotension. The presented methods are based on a Convolutional Neural Network (CNN) trained on data from patients undergoing high-risk surgery. The experimental results show that our network can predict hypotension with 70% sensitivity and 80% specificity 5 minutes before onset. The prediction performance is then quickly reduced for longer prediction times, resulting in 60% sensitivity and 80% specificity 15 minutes before onset. / Perioperativ hypotension motsvarar perioder av kritiskt lågt blodtryck före, under och efter operation. Det är en vanlig bieffekt av generell anestesi och är starkt associerad med ökat risk av postoperativa komplikationer, så som akut leverskada, myokardskada och i värsta fall dödsfall. Tidig behandling av hypotension, helst innan perioden börjar, är avgörande för att minska risken och allvarlighetsgraden av postoperativa komplikationer. Det här arbetet utforskar metoder för att förutspå perioder av hypotension, vilket skulle kunna används för att varna vårdpersonal som ansvarar för patientens hemodynamiska övervakning. Mer specifikt så presenteras metoder som endast använder artärblodtryck för att förutspå två olika definitioner av hypotension. Metoderna som presenteras är baserade på ett Convolutional Neural Network (CNN) som tränats på data från patienter som genomgår högriskoperation. De experementella resultaten visar att våran modell kan förutspå hypotension med 70% sensitivitet och 80% specificitet 5 minuter i förväg. Förmågan att förutspå hypotension avtar sedan snabbt för längre prediktionstider, vilket resulterar i 60% sensitivitet och 80% specificitet 15 minuter i förväg.

Toxinas que atuam em canais para Na+ operados por voltagem são as principais responsáveis pelos efeitos tóxicos do envenenamento escorpiônico e podem ser divididas em duas classes: a- e b-neurotoxinas. TsTX-V e TsTX-I da peçonha de Tityus serrulatus (TsV) são, respectivamente, exemplos destas toxinas. Neste trabalho, foram avaliados os efeitos da TsV e destas toxinas sobre a pressão arterial média (PAM) e liberação de catecolaminas em ratos conscientes e não imobilizados, previamente cateterizados, bem como a captação de GABA, dopamina (DA) e glutamato (Glu) em sinaptosomas isolados de cérebro de ratos e a concentração citoplasmática de Ca+2 ([Ca+2 ]C) em células de músculo liso vascular de aorta de ratos. As toxinas foram isoladas por cromatografia de troca iônica (TsTX-I) seguida por CLAE de fase reversa (TsTX-V). As toxinas (15 e 30 g/kg) e TsV (50 e 100 g/kg) foram injetadas intravenosamente. A PAM foi monitorada continuamente através do cateter femoral. Os níveis plasmáticos de adrenalina (ADR) e noradrenalina (NA) foram determinados por CLAE de fase reversa com detector eletroquímico, em 10 min antes e 2,5, 30 e 90 min após os tratamentos. Efeitos pressores máximos foram observados em 2,5?3,5 min. TsV induziu um intenso aumento de longa duração na PAM, bem como a TsTX-I. A TsTX-V mostrou efeitos pressores menores. TsV mostrou os maiores efeitos sobre a liberação de catecolaminas, seguido pela TsTX-I e TsTX-V com um efeito máximo em 2,5 min, seguido por uma gradual redução, permanecendo, todavia, maior que os controles. Embora ambas as classes de toxinas atuem em canais para Na+, TsTX-I mostrou efeitos mais significantes e intensos sobre a liberação de catecolaminas e pressão arterial que a TsTX-V. Parece que a toxicidade da TsTX-V não está somente relacionada à sua capacidade de liberar catecolaminas, indicando que outros neutrotransmissores podem estar envolvidos em sua toxicidade. Nem a TsV ou suas toxinas foram capazes de afetar a captação de 3H-Glu. TsTXI inibiu somente a captação de 3H-DA (IC50 = 28,41 nM). Por outro lado, TsV (0,43ng/mL) inibiu a captação de 3H-GABA e 3H-DA (~50%). TsTX-V mostrou IC50 = 9,37 nM e 22,2 nM para a captação de 3H-GABA e 3HDA, respectivamente. Esses efeitos foram abolidos pelo pré-tratamento com TTX, indicando o envolvimento de canais para Na+ neste processo. Na ausência de Ca+2 e em baixas concentrações de toxinas, a redução não é tão singnificante como na presença de Ca+2. TsTX-V não reduziu a captação de 3H-GABA em células COS-7 expressando os transportadores de GABA, GAT-1 e GAT-3, sugerindo que esta toxina reduz indiretamente o transporte. A redução da captação de 3H-GABA pelos sinaptosomas pode ser devido a rápida e intensa despolarização celular, como revelado por microscopia confocal em células de glioma C6. Assim, TsTX-V causou redução da captação de 3H-GABA e 3H-DA de uma maneira independente de Ca+2, não afetando diretamente os transportadores de GABA, mas em consequencia da despolarização, envolvendo canais para Na+ operados por voltagem. TsV e suas toxinas foram capazes de aumentar a ([Ca2+ ]C , provavelmente por interargir com canais para Na+. Quando comparado aos efeitos despolarizantes do KCl 60 mM (100 %), TsV (100 e 500 g/mL) exibiu um aumento de 49,60 ± 2,58 % e 103,66 ± 5,17 %, respectivamente, enquanto que a TsTX-I e TsTX-V (50 e 100 g/mL de cada) exibiu 43,92 ± 3,06 % e 121,8 ± 8,9 %; 52,56 ± 8,33 % e 79,5 ± 6,1 % de aumento, respectivamente. TsTX-I (100 g/mL) mostrou-se mais potente nesta preparação, visto que uma dose de 100 g/mL causou efeito muito mais intenso do que a TsTX-V na mesma concentração. É possível que as diferenças observadas sobre os efeitos induzidos pela TsTX-I e TsTX-V sejam conseqüência de alterações estruturais entre canais para Na+ presentes em vários tipos de tecidos e inervações. / Voltage-gated Na+ channel toxins are mainly responsible for the toxic effects of scorpion envenoming and can be classified into two classes: a- and b-neurotoxins. TsTX-V and TsTX-I from Tityus serrulatus venom (TsV) are, respectively, examples of these toxins. In this work, were evaluate the effects of TsV and its toxins on mean arterial pressure (MAP) and catecholamines release in conscious unrestrained rats previously catheterized, as well as GABA, dopamine (DA) and glutamate (Glu) uptake in isolated rat brain synaptosomes and cytosolic Ca2+ concentration ([Ca2+ ]C) in vascular smooth muscle cells from rat aorta. Toxins were isolated by ion exchange chromatography (TsTX-I) followed by RP-HPLC (TsTX-V). The toxins (15 and 30 g/kg) and TsV (50 and 100 g/kg) were injected intravenously. MAP was continuously monitored through femoral catheter. Epinephrine (E) and norepinephrine (NE) plasma levels were determined by RP-HPLC with electrochemical detection, at 10 min before and 2.5, 30 and 90 min after treatments. Maximal pressor effects were observed at 2.5 3.5 min. TsV induced intense long lasting increase in MAP, as did TsTX-I. TsTX-V showed the lowest pressor effects. TsV showed the highest effects on catecholamines release, followed by TsTX-I and TsTX-V with maximal effect at 2.5 min, followed by a gradual reduction, however remaining higher than controls. Although both toxins act on Na+ channels, TsTX-I displayed significant and more intense effects on catecholamines release and blood pressure than TsTX-V. It seems that the toxicity of TsTX-V is not related only with its ability to release catecholamines, indicating that other neurotransmitters, may be involved in its toxicity. Neither the TsV or its toxins was capable to affect the 3H-Glu uptake. TsTX-I inhibited only 3H-DA uptake (IC50 = 28.41 nM). On the other hand, TsV (0.43ng/mL) inhibited both 3H-GABA and 3H-DA uptake (~50%). TsTX-V showed IC50 = 9.37 nM and 22.2 nM for 3H-GABA and 3H-DA uptake, respectively. These effects were abolished by pre-treatment with TTX, indicating the involvement of Na+ channels in this process. In the absence of Ca2+ and at low concentrations of toxin, the reduction is not as significant as in the presence of Ca2+. TsTX-V did not reduce 3H-GABA uptake in COS-7 cells expressing GABA transporters GAT-1 and GAT-3, suggesting that this toxin indirectly reduces the transport. The reduced 3H-GABA uptake by synaptosomes could be due to fast and intense cell depolarization as revealed by confocal microscopy of C6 glioma cells. Thus, TsTX-V causes reduction on 3H-GABA and 3H-DA uptake in a Ca2+-independent manner, not affecting directly GABA transporters, but, in consequence of depolarization, involving voltage-gated Na+ channels. TsV and its toxins were able to increase the ([Ca2+ ]C , probably by interact with Na+ channels. When compared to KCl 60 mM depolarizing effect (100 %), TsV (100 and 500 ?g/mL), showed an increase of 49.60 ± 2.58 % and 103.66 ± 5.17 %, respectively, whereas TsTX-I and TsTX-V (50 and 100?g/mL of each) showed 43.92 ± 3.06 % and 121.8 ± 8.9 %; 52.56 ± 8.33 % and 79.5 ± 6.1 %, respectively. TsTX-I (100 ?g/mL) showed most potent effects in this type of preparation, since induced most intense effect that TsTX-V in the same concentration. Thus, it is possible that the differences observed on the effects induced by both toxins are consequence of structural changes among Na+ channels present in several types of tissues and innervations .

Darbo tikslas. Ištirti slaugytojo vaidmenį prižiūrint centrinių venos kateterius reanimacijos ir intensyvios terapijos skyriuje. Darbo uždaviniai. Nustatyti centrinės venos kateterizacijos įtaką pagrindiniams pacientų gyvybinių funkcijų rodikliams. Ištirti, kokios dažniausiai pasitaiko centrinių venų komplikacijos ir jų priežastis. Išsiaiškinti slaugytojo veiksmus, padedančius sumažinti komplikacijų atsiradimo riziką. Ištirti reanimacijos ir intensyvios terapijos slaugytojų centrinių venų kateterių priežiūros žinias . Tyrimo medžiaga ir metodai. Teorinė mokslinės literatūros, leidinių, publikacijų apžvalga. Dokumentų analizės metodas (panaudotas pacientų su centrinių venų kateteriais tyrimui). Asmeninio stebėjimo metodas. Atliktas 97 pacientų po centrinių venų kateterizacijų, pagrindinių gyvybinių funkcijų stebėjimas reanimacijos ir intensyvios terapijos skyriuje. Reanimacijos ir intensyvios terapijos slaugytojų anketinė apklausa žinioms ištirti, dirbant su centrinių venų kateteriais. Gautų rezultatų aptarimas ir jų analizė. Statistinė analizė atlikta naudojant „Microsoft Office Excel 2003“ ir SPSS 16,0 for Windows versijos statistinę programą Tyrimo rezultatai ir išvados. Tam, kad būtų išsiaiškintas slaugytojos vaidmuo prižiūrint centrinius venos kateterius buvo atliktas stebėjimo tyrimas pacientų po centrinių venos kateterizacijų. Tyrimo metu Vilniaus Universiteto ligoninėje Santariškių klinikos I reanimacijos ir intensyvios terapijos skyriuje nustatyta, kad centrinių venos... [toliau žr. visą tekstą] / The goal of the study: to determine the role of a nurse in the maintenance of the central venous catheter (CVC) in the resuscitation and intensive care department. The objectives: to determine the influence of the central venous catheterization to the indexes of the main vital functions of the patients. To specify the most frequent venous complications and the reasons why they occur. To find out what nurses’ actions can reduce the risk of complications. To examine the professional knowledge of the nurses who work with central venous catheters in the resuscitation and intensive care departments. Research material and methods. Theoretical review of scientific literature, publications and articles. Document analysis method (utilized for the reasearch of patient’s with central venous catheters). Personal observation method. Observation of the main vital functions of 97 patients after central venous catheterization in the resuscitation and intensive care department. The questionnaire-based survey in order to examine the professional knowledge of the nurses who work with central venous catheters in the resuscitation and intensive care department. Discussion and analysis of the obtained results. Analysis of the statistical data using the Microsoft Office Excel 2003 and SPSS 16,0 for Windows software packages. The results and conclusions of the study. In order to determine the role of a nurse for the maintenance of central venous catheter, the observation research was conducted with... [to full text]

Toxinas que atuam em canais para Na+ operados por voltagem são as principais responsáveis pelos efeitos tóxicos do envenenamento escorpiônico e podem ser divididas em duas classes: a- e b-neurotoxinas. TsTX-V e TsTX-I da peçonha de Tityus serrulatus (TsV) são, respectivamente, exemplos destas toxinas. Neste trabalho, foram avaliados os efeitos da TsV e destas toxinas sobre a pressão arterial média (PAM) e liberação de catecolaminas em ratos conscientes e não imobilizados, previamente cateterizados, bem como a captação de GABA, dopamina (DA) e glutamato (Glu) em sinaptosomas isolados de cérebro de ratos e a concentração citoplasmática de Ca+2 ([Ca+2 ]C) em células de músculo liso vascular de aorta de ratos. As toxinas foram isoladas por cromatografia de troca iônica (TsTX-I) seguida por CLAE de fase reversa (TsTX-V). As toxinas (15 e 30 g/kg) e TsV (50 e 100 g/kg) foram injetadas intravenosamente. A PAM foi monitorada continuamente através do cateter femoral. Os níveis plasmáticos de adrenalina (ADR) e noradrenalina (NA) foram determinados por CLAE de fase reversa com detector eletroquímico, em 10 min antes e 2,5, 30 e 90 min após os tratamentos. Efeitos pressores máximos foram observados em 2,5?3,5 min. TsV induziu um intenso aumento de longa duração na PAM, bem como a TsTX-I. A TsTX-V mostrou efeitos pressores menores. TsV mostrou os maiores efeitos sobre a liberação de catecolaminas, seguido pela TsTX-I e TsTX-V com um efeito máximo em 2,5 min, seguido por uma gradual redução, permanecendo, todavia, maior que os controles. Embora ambas as classes de toxinas atuem em canais para Na+, TsTX-I mostrou efeitos mais significantes e intensos sobre a liberação de catecolaminas e pressão arterial que a TsTX-V. Parece que a toxicidade da TsTX-V não está somente relacionada à sua capacidade de liberar catecolaminas, indicando que outros neutrotransmissores podem estar envolvidos em sua toxicidade. Nem a TsV ou suas toxinas foram capazes de afetar a captação de 3H-Glu. TsTXI inibiu somente a captação de 3H-DA (IC50 = 28,41 nM). Por outro lado, TsV (0,43ng/mL) inibiu a captação de 3H-GABA e 3H-DA (~50%). TsTX-V mostrou IC50 = 9,37 nM e 22,2 nM para a captação de 3H-GABA e 3HDA, respectivamente. Esses efeitos foram abolidos pelo pré-tratamento com TTX, indicando o envolvimento de canais para Na+ neste processo. Na ausência de Ca+2 e em baixas concentrações de toxinas, a redução não é tão singnificante como na presença de Ca+2. TsTX-V não reduziu a captação de 3H-GABA em células COS-7 expressando os transportadores de GABA, GAT-1 e GAT-3, sugerindo que esta toxina reduz indiretamente o transporte. A redução da captação de 3H-GABA pelos sinaptosomas pode ser devido a rápida e intensa despolarização celular, como revelado por microscopia confocal em células de glioma C6. Assim, TsTX-V causou redução da captação de 3H-GABA e 3H-DA de uma maneira independente de Ca+2, não afetando diretamente os transportadores de GABA, mas em consequencia da despolarização, envolvendo canais para Na+ operados por voltagem. TsV e suas toxinas foram capazes de aumentar a ([Ca2+ ]C , provavelmente por interargir com canais para Na+. Quando comparado aos efeitos despolarizantes do KCl 60 mM (100 %), TsV (100 e 500 g/mL) exibiu um aumento de 49,60 ± 2,58 % e 103,66 ± 5,17 %, respectivamente, enquanto que a TsTX-I e TsTX-V (50 e 100 g/mL de cada) exibiu 43,92 ± 3,06 % e 121,8 ± 8,9 %; 52,56 ± 8,33 % e 79,5 ± 6,1 % de aumento, respectivamente. TsTX-I (100 g/mL) mostrou-se mais potente nesta preparação, visto que uma dose de 100 g/mL causou efeito muito mais intenso do que a TsTX-V na mesma concentração. É possível que as diferenças observadas sobre os efeitos induzidos pela TsTX-I e TsTX-V sejam conseqüência de alterações estruturais entre canais para Na+ presentes em vários tipos de tecidos e inervações. / Voltage-gated Na+ channel toxins are mainly responsible for the toxic effects of scorpion envenoming and can be classified into two classes: a- and b-neurotoxins. TsTX-V and TsTX-I from Tityus serrulatus venom (TsV) are, respectively, examples of these toxins. In this work, were evaluate the effects of TsV and its toxins on mean arterial pressure (MAP) and catecholamines release in conscious unrestrained rats previously catheterized, as well as GABA, dopamine (DA) and glutamate (Glu) uptake in isolated rat brain synaptosomes and cytosolic Ca2+ concentration ([Ca2+ ]C) in vascular smooth muscle cells from rat aorta. Toxins were isolated by ion exchange chromatography (TsTX-I) followed by RP-HPLC (TsTX-V). The toxins (15 and 30 g/kg) and TsV (50 and 100 g/kg) were injected intravenously. MAP was continuously monitored through femoral catheter. Epinephrine (E) and norepinephrine (NE) plasma levels were determined by RP-HPLC with electrochemical detection, at 10 min before and 2.5, 30 and 90 min after treatments. Maximal pressor effects were observed at 2.5 3.5 min. TsV induced intense long lasting increase in MAP, as did TsTX-I. TsTX-V showed the lowest pressor effects. TsV showed the highest effects on catecholamines release, followed by TsTX-I and TsTX-V with maximal effect at 2.5 min, followed by a gradual reduction, however remaining higher than controls. Although both toxins act on Na+ channels, TsTX-I displayed significant and more intense effects on catecholamines release and blood pressure than TsTX-V. It seems that the toxicity of TsTX-V is not related only with its ability to release catecholamines, indicating that other neurotransmitters, may be involved in its toxicity. Neither the TsV or its toxins was capable to affect the 3H-Glu uptake. TsTX-I inhibited only 3H-DA uptake (IC50 = 28.41 nM). On the other hand, TsV (0.43ng/mL) inhibited both 3H-GABA and 3H-DA uptake (~50%). TsTX-V showed IC50 = 9.37 nM and 22.2 nM for 3H-GABA and 3H-DA uptake, respectively. These effects were abolished by pre-treatment with TTX, indicating the involvement of Na+ channels in this process. In the absence of Ca2+ and at low concentrations of toxin, the reduction is not as significant as in the presence of Ca2+. TsTX-V did not reduce 3H-GABA uptake in COS-7 cells expressing GABA transporters GAT-1 and GAT-3, suggesting that this toxin indirectly reduces the transport. The reduced 3H-GABA uptake by synaptosomes could be due to fast and intense cell depolarization as revealed by confocal microscopy of C6 glioma cells. Thus, TsTX-V causes reduction on 3H-GABA and 3H-DA uptake in a Ca2+-independent manner, not affecting directly GABA transporters, but, in consequence of depolarization, involving voltage-gated Na+ channels. TsV and its toxins were able to increase the ([Ca2+ ]C , probably by interact with Na+ channels. When compared to KCl 60 mM depolarizing effect (100 %), TsV (100 and 500 ?g/mL), showed an increase of 49.60 ± 2.58 % and 103.66 ± 5.17 %, respectively, whereas TsTX-I and TsTX-V (50 and 100?g/mL of each) showed 43.92 ± 3.06 % and 121.8 ± 8.9 %; 52.56 ± 8.33 % and 79.5 ± 6.1 %, respectively. TsTX-I (100 ?g/mL) showed most potent effects in this type of preparation, since induced most intense effect that TsTX-V in the same concentration. Thus, it is possible that the differences observed on the effects induced by both toxins are consequence of structural changes among Na+ channels present in several types of tissues and innervations .

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Perioperative hypotension (PH), commonly a side effect of anesthesia,is one of the main mortality causes during the 30 posterior days of asurgical procedure. Novel research lines propose combining machinelearning algorithms with the Arterial Blood Pressure (ABP) waveform tonotify healthcare professionals about the onset of a hypotensive event withtime advance and prevent its occurrence. Nevertheless, ABP waveformsare heterogeneous among patients, consequently, a general model maypresent different predictive capabilities per individual. This project aimsat improving the performance of an artificial neural network (ANN) topredict hypotension events with time advance by applying personalizedmachine learning techniques, like data grouping and domain adaptation. Wehypothesize its implementation will allow us to cluster patients with similardemographic and ABP discriminative characteristics and tailor the modelto each specific group, resulting in a worst overall but better individualperformance. Results present a slight but not clinical significant improvementwhen comparing AUROC values between the group-specific and the generalmodel. This suggests even though personalization could be a good approach todealing with patient heterogeneity, the clustering algorithm presented in thisthesis is not sufficient to make the ANN clinically feasible. / Perioperativ hypotoni (PH), vanligtvis en sidoeffekt av anestesi, är en av dehuvudsakliga dödsorsakerna under de första 30 dagarna efter ett kirurgiskt ingrepp. Nya forskningslinjer föreslår att kombinera maskininlärningsalgo-ritmer med vågformen av det arteriella blodtrycket (ABP) för att förvarna sjukvårdspersonalen om uppkomsten av en hypotensiv episod, and därmedförhindra förekomsten. ABP-vågformen är dock heterogen bland patienter,så en allmän modell kan ha olik prediktiv förmåga för olika individer.I det här projektet används personaliserade maskininlärningstekniker, somdatagruppering och domänanpassning, för att försöka förbättra ett artificielltneuralt nätverk (ANN) som förutspår hytotensiva episoder. Vår hypotes är attimplementeringen kommer låta oss klustra patienter med liknande demografioch ABP-karakteristik för att skräddarsy modellen till varje specifik grupp,vilket leder till en sämre övergripande men bättre individuell prestanda. Resultaten visar små men inte kliniskt signifikanta förbättringar när AUROC-värden jämförs mellan den gruppspecifika och den allmänna modellen. Detta tyder på att även fast personalisering kan vara en bra tillnärmning till patientersheterogenitet, är inte klusteralgoritmen som presenteras här tillräcklig förklinisk användning av ANN.

Exploiting photoplethysmography signals (PPG) for non-invasive blood pressure (BP) measurement is interesting for various reasons. First, PPG can easily be measured using fingerclip sensors. Second, camera based approaches allow to derive remote PPG (rPPG) signals similar to PPG and therefore provide the opportunity for non-invasive measurements of BP. Various methods relying on machine learning techniques have recently been published. Performances are often reported as the mean average error (MAE) on the data which is problematic. This work aims to analyze the PPG- and rPPG based BP prediction error with respect to the underlying data distribution. First, we train established neural network (NN) architectures and derive an appropriate parameterization of input segments drawn from continuous PPG signals. Second, we use this parameterization to train NNs with a larger PPG dataset and carry out a systematic evaluation of the predicted blood pressure. The analysis revealed a strong systematic increase of the prediction error towards less frequent BP values across NN architectures. Moreover, we tested different train/test set split configurations which underpin the importance of a careful subject-aware dataset assignment to prevent overly optimistic results. Third, we use transfer learning to train the NNs for rPPG based BP prediction. The resulting performances are similar to the PPG-only case. Finally, we apply different personalization techniques and retrain our NNs with subject-specific data for both the PPG-only and rPPG case. Whilst the particular technique is less important, personalization reduces the prediction errors significantly.

Acid maltase deficiency (AMD) is a rare autosomal recessive genetic disorder that results in an accumulation of glycogen in the lysosomal storage vacuoles. It is classified as a glycogen storage disease (type II) and is also known as Pompe's disease. The prognosis of the patient with AMD is poor and the main cause of death is respiratory failure. We report a female patient whose respiratory insufficiency was documented to occur most severely during rapid eye movement sleep and who benefited clinically from the institution of nocturnal noninvasive bilevel positive airway pressure.