Einleitung Der interventionelle Verschluß eines einfachen Vorhofseptumdefekts (ASD) vom Sekundumtyp und eines persistierenden Foramen ovale (PFO) ist zur Routinemethode gereift (1). Die Intervention wird unter Röntgendurchleuchtung (Strahlenexposition) durchgeführt. Sie ist wegen der geringen Invasivität auch bis ins hohe Alter mit deutlich niedrigerem Risiko als eine Operation durchführbar (2). Die hier vorgestellten Arbeiten haben systematisch untersucht, welche Möglichkeiten bestehen, bei der Intervention auf eine Strahlenexposition zu verzichten (3-6), welche interventionellen Möglichkeiten bei multiplen Defekten und Vorhofseptumaneurysmen bestehen (7,8) und welche Auswirkungen ein restriktiver linker Ventrikel auf die hämodynamische Adaptation nach Defektverschluß haben kann (9-11). Methodik Alle Untersuchungen wurden im Rahmen der klinischen Routine im Herzkatheterlabor am sedierten Patienten mit Vorhofseptumdefekt vom Sekundumtyp, persistierendem Foramen ovale, perforiertem Vorhofseptumaneurysma oder multiperforiertem Vorhofseptum durchgeführt. 1. Es wurde eine Methode zum Verschluß von Vorhofseptumdefekten unter alleiniger Ultraschallkontrolle entwickelt, d.h. unter vollständigem Verzicht auf die sonst notwendige Röntgenstrahlung. 2. Die Morphologie von Vorhofseptumaneurysmen und multiperforierten Vorhofsepten wurde analysiert und im Hinblick auf die interventionellen Verschlußmöglichkeiten klassifiziert. Dabei wurde auch die Möglichkeit der simultanen Implantation mehrerer Okkluder mit einbezogen. 3. Zur Erkennung von Patienten mit einem restriktiven linken Ventrikel, der unmittelbar nach ASD-Verschluß insuffizient werden könnte, wurde eine Methode der präinterventionellen hämodynamischen Evaluation etabliert. Dazu wird die Vorlast und die diastolische Funktion des linken Ventrikels unter temporärem Verschluß des ASD mit einem Okklusionsballon untersucht. Demaskiert sich eine linksventrikuläre Restriktion, so wird als Therapiekonzept der Ventrikel auf den interventionellen Verschluß durch eine prophylaktische 'Konditionierung' mittels Diuretika und Inotropika vorbereitet. Resultate 1. Interventioneller ASD-Verschluß ohne Strahlenexposition Wir konnten zeigen, daß der interventionelle ASD-Verschluß ohne Einsatz von Röntgenstrahlung durchführbar ist (3). Dies gilt für die präinterventionelle Diagnostik, die invasive Größenmessung (Ballonsizing) (6) und den interventionelle Verschluß selbst (4). Als einziges bildgebendes Verfahren für die Intervention dient die Echokardiographie. Im Vergleich zum Standardprocedere waren beim Verzicht auf eine Strahlenexposition gleich gute Ergebnisse zu erzielen, die Prozedurdauer war vergleichbar. Beim spontan atmenden Patienten sind für diese Methode höhere Dosen an Sedierung erforderlich, um die längere Verweilzeit der transösophagealen Echokardiographiesonde zu ermöglichen (5). Der Amplatzer Occluder ist wegen seiner guten Sichtbarkeit im transösophagealen Ultraschall, seiner Rotationssymmetrie und seiner einfachen Plazierung für diese neue Methode des ASD-Verschlusses ohne Röntgenstrahlung besonders geeignet. 2. Verschluß morphologisch komplexer Vorhofseptumdefekte Auch multiperforierte Vorhofsepten können interventionell erfolgreich verschlossen werden. Bei dicht nebeneinander liegenden Defekten ist dies mit einem Occluder, der alle Defekte abdeckt, möglich, bei weiter auseinanderliegenden Defekten ist die simultane Implantation zweier Occluder sinnvoll. Zwei Occluder führen mit größerer Sicherheit zu einem Verschluß ohne Restshunt (7). Multiple Defekte sind häufig mit einem Vorhofseptumaneurysma vergesellschaftet. Im Hinblick auf die Interventionsmöglichkeiten läßt sich diese Anomalie in vier Gruppen unterteilen: Aneurysma mit PFO (Typ A), mit ASD (Typ B), mit mehreren dicht nebeneinander liegenden Defekten (Typ C) und große Aneurysmen mit einer Vielzahl irregulär verteilter Perforationen (Typ D). Die ersten drei Formen lassen sich interventionell verschließen. Dabei gelingt zumindest eine Teilstabilisierung der Aneurysmen (8). 3. Vorhofseptumdefekte und restriktiver linker Ventrikel Wir konnten zeigen, daß insbesondere bei älteren Patienten mit ASD eine verdeckte linksventrikuläre Restriktion vorliegen kann. Ein interventioneller ASD-Verschluß kann bei diesen Patienten zur akuten kardialen Dekompensation führen (9). Als Hinweis auf eine gestörte linksventrikuläre Compliance fanden wir bei temporärer Okklusion des Defekts einen deutlichen Anstieg des linksatrialen Drucks und einen gestörten Mitralklappeneinstrom (10). Nach einer prophylaktischen 'Konditionierung' des linken Ventrikels mittels vorlastsenkenden und inotropiesteigernden Medikamenten (Diuretika, Phosphodiesterasehemmer, Katecholamine) gelang bei fast allen Patienten der interventionelle ASD-Verschluß mit guter Adaptation des Ventrikels, ohne daß es zur kardialen Dekompensation kam (11). Schlußfolgerungen Die in dieser Habilitationsschrift ausgeführten Arbeiten haben weiterführende Fragestellungen und Grenzbereiche des interventionellen Verschlusses von ASD und PFO aufgezeigt und neue interventionelle Therapiestrategien dargestellt. Dadurch ist es möglich, im klinischen Alltag weniger Röntgenstrahlung und Röntgenkontrastmittel zu verwenden, auch morphologisch komplexe Defekte standardisiert zu behandeln und selbst im hohen Alter bei Vorliegen einer linksventrikulären restriktiven Dysfunktion Defekte mit geringem Risiko zu verschließen. / Introduction Interventional closure of the simple secundum type atrial septal defect (ASD) and of persistent foramen ovale (PFO) has developed into a routine procedure (1). The intervention is carried out under X-ray monitoring (X-ray exposure). Since it is minimally invasive it can be carried out even in patients of advanced age with significantly less risk than an operation (2). The work presented here investigates systematically the possibilities of carrying out the intervention without X-ray exposure (3-6) and in the case of multiple defects and atrial aneurysms (7, 8). It also looks at the effects of a restrictive left ventricle on hemodynamic adaptation after closure of the defect (9-11). Methods All examinations were carried out as part of the clinical routine of the heart catheter laboratory in sedated patients with a secundum type atrial septal defect, persistent foramen ovale, perforated atrial aneurysms or multiply perforated atrial septum. 1. A method was developed whereby the closure of atrial septal defects can be carried out solely under echocardiographic monitoring, i.e. completely without X-ray exposure. 2. The morphology of atrial septal aneurysms and multiply perforated atrial septum was analyzed and classified with regard to the possibilities of interventional closure. The possibility of simultaneous implantation of several occluders was also considered. 3. To recognize patients with a restrictive left ventricle, which might become insufficient directly after ASD closure, a method of preinterventional hemodynamic evaluation was established. This involves examining preload and the diastolic function of the left ventricle during temporary closure of the ASD with an occlusion balloon. If this procedure reveals left ventricular restriction, the ventricle is prepared for interventional closure by prophylactic conditioning by means of diuretics and inotropes. Results 1. Interventional ASD Closure without X-Ray Exposure We were able to show that interventional ASD closure is possible without the use of X-rays (3). This applies to the preinterventional diagnostic procedures, invasive size measurement (balloon sizing) (6) and the interventional closure itself (4). The sole imaging procedure used for the intervention is echocardiography. In comparison with the standard procedure, the results are equally good and the duration of the procedure is comparable. In the spontaneously breathing patient higher sedative doses are necessary so that the transesophageal echocardiography tube can remain in place throughout (5). The Amplatzer occluder is particularly suitable for this new method because it is easily viewed in transesophageal echocardiographic imaging, rotationally symmetrical and easily positioned. 2. Closure of Morphologically Complex Atrial Septal Defects Multiple perforations of the atrial septum can also be successfully closed by intervention. If the defects are close together, one occluder can be used to cover all the defects; if they are further apart, the simultaneous implantation of two occluders is indicated. Two occluders are more likely to achieve occlusion without residual shunt (7). Multiple defects are often associated with an atrial septal aneurysm. With regard to the interventional possibilities these anomalies can be divided into four groups: aneurysm with PFO (type A), with ASD (type B), with several defects situated close together (type C) and large aneurysms with a number of irregularly distributed perforations (type D). The first three types may be closed by intervention, which mostly achieves partial stabilization of the aneurysms (8). 3. Atrial Septal Defects and Restrictive Left Ventricle We showed that, in particular in older patients with ASD, left ventricular restriction may be concealed. In these patients interventional ASD closure can lead to acute cardiac decompensation (9). A sign of disruption of left ventricular compliance was a marked rise in the left atrial pressure and disturbance of the mitral valve inflow during temporary occlusion of the defect (10). Following prophylactic 'conditioning' of the left ventricle by drugs that reduce the preload and increase inotropism (diuretics, phosphodiesterase inhibitors, catecholamines), interventional ASD closure succeeded in almost all patients with good adaptation of the ventricle and without cardiac decompensation occurring (11). Conclusion The work reported here addresses complex questions and frontier areas of the interventional closure of ASDs and PFO and presents new interventional strategies. It enables less X-ray exposure and less X-ray contrast medium to be used in clinical practice. Morphologically complex defects can be treated by standard procedures and with a small risk, even in patients with advanced age and left ventricular restrictive dysfunction.

Rare lipoprotein A (RlpA) has been studied previously only in Escherichia coli, where it localizes to the septal ring and scattered foci along the lateral wall, but mutants have no phenotypic change. In this thesis, we show rlpA mutants of Pseudomonas aeruginosa form chains of short, fat cells when grown in media of low osmotic strength. These morphological defects indicate RlpA is needed for efficient separation of daughter cells and maintenance of rod shape. Analysis of peptidoglycan sacculi from a ΔrlpA mutant revealed increased tetra and hexasaccharides that lack stem peptides (hereafter called "naked glycans"). Incubation of these sacculi with purified RlpA resulted in release of naked glycans containing 1,6-anhydro N-acetylmuramic acid ends. RlpA did not degrade sacculi from wild-type cells unless the sacculi were subjected to a limited digestion with an amidase to remove some of the stem peptides. Collectively, these findings indicate RlpA is a lytic transglycosylase with a strong preference for naked glycan strands. We propose that RlpA activity is regulated in vivo by substrate availability, and that amidases and RlpA work in tandem to degrade peptidoglycan in the division septum and lateral wall. Our discovery that RlpA from P. aeruginosa is a lytic transglycosylase motivated us to reinvestigate RlpA from E. coli. We confirmed predictions that RlpA of E. coli is an outer membrane protein and determined its abundance to be about 600 molecules per cell. However, multiple efforts to demonstrate that E. coli RlpA is a lytic transglycosylase were unsuccessful and the function of this protein in E. coli remains obscure.

No description available.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 6 uppsatser.

Thesis (doctoral)--Rijksuniversiteit te Groningen.

Made available in DSpace on 2016-06-02T19:22:49Z (GMT). No. of bitstreams: 1 1829.pdf: 1302384 bytes, checksum: f53ef9f9cd782da76b146d55e3808620 (MD5) Previous issue date: 2008-04-30 / Universidade Federal de Minas Gerais / Peripheral injection of pilocarpine (PILO, 1 mg/Kg of body weight), muscarinic cholinergic agonist, induce salivation, water intake and pressor response. The medial septal area (MSA) is an important brain area involved in cardiovascular regulation and hydroelectrolytic control. In this present study, we investigated: 1) the effect of MSA electrolytic lesion or the blockade of muscarinic cholinergic receptors into MSA on salivation, water intake and cardiovascular responses induced by peripheral pilocarpine; 2) the role of the sympathetic nervous system and/or vasopressin on the cardiovascular responses induced by peripheral pilocarpine; 3) the effect of injection of pilocarpine into MSA on salivation, water intake and cardiovascular responses. Male Holtzman rats weighing 280 to 320 g were submitted to 1 or 15 days MSA electrolytic lesion (2 mA x 5 s) or stainless steel guide cannulas were stereotaxically implanted into the MSA. We observed that peripheral pilocarpine (1 mg/kg of body weight) induces salivary secretion, water intake and an increase in mean arterial pressure (MAP) . This increase in MAP is due to an activation of simpathetic nervous system, since it was significantly reduced by previous treatment with prazosin (1 mg/kg of body weight), but not by vasopressin V1a receptor antagonist (10 µg/kg of body weigh). The salivary secretion and dipsogenic response induced by peripheral pilocarpine was reduced by MSA eletrolytic lesion or MSA muscarinic cholinergic blockade. Nonetheless, the pressor response induced by peripheral pilocarpine was not depend of MSA, since MSA eletrolytic lesion or muscarinic cholinergic receptors blockade did not change this response. Pilocarpine injection into MSA induced water intake (200 e 500 nmol/0,5 µL), salivary secretion (500 nmol/0,5 µL) and MAP increase (500 nmol/0,5 µL). Our results show that peripheral or MSA injection of pilocarpine induce salivary secretion, water intake and pressor response. The pressor response induced by peripheral pilocarpine is due to sympathetic activation. The MSA and its muscarinic cholinergic receptors are involved in the salivary secretion and water intake, but not in the control of pressor response induced by peripheral pilocarpine, suggesting that MSA has a differencial control on the responses induced by peripheral pilocarpine. / A injeção periférica de pilocarpina (PILO, 1 mg/kg de peso corporal), agonista colinérgico muscarínico, induz salivação, ingestão de água e resposta pressora. A área septal medial (ASM) é uma importante área cerebral envolvida com a regulação cardiovascular e com o controle do balanço hidroeletrolítico. No presente estudo, investigamos: 1) o efeito da lesão eletrolítica da ASM ou do bloqueio dos receptores colinérgicos muscarínicos da ASM na salivação, na ingestão de água e nas respostas cardiovasculares induzida pela pilocarpina periférica; 2) a participação do sistema nervoso simpático e da vasopressina sobre as respostas cardiovasculares induzidas pela pilocarpina periférica; 3) os efeitos da injeção de pilocarpina na ASM sobre a salivação, ingestão de água e respostas cardiovasculares. Ratos Holtzman (280 - 320 g), foram submetidos à lesão eletrolítica (2 mA x 5 s) da ASM (1 ou 15 dias) ou ao implante de cânula-guia de aço inoxidável na ASM. Verificamos que a injeção periférica de pilocarpina (1 mg/kg de peso corporal) produz secreção salivar, ingestão de água e aumento da pressão arterial média (PAM). Este aumento da pressão arterial é decorrente da ativação do sistema nervoso simpático, pois foi reduzida significantemente pelo tratamento prévio com prazosin (1 mg/kg de peso corporal), mas não pelo antagonista do receptor V1a de vasopressina (10 µg/kg de peso corporal). A salivação e a resposta dipsogênica induzidas pela pilocarpina periférica foram reduzidas pela lesão eletrolítica ou pelo bloqueio colinérgico muscarínico da ASM. Entretanto, a resposta pressora induzida pela pilocarpina periférica não depende da ASM, já que a lesão eletrolítica ou o bloqueio de receptores colinérgicos muscarínicos da ASM não alteraram esta resposta. A injeção de pilocarpina na ASM induz resposta dipsôgenica (200 e 500 nmol/0,5 µL), salivação (500 nmol/0,5 µL) e resposta pressora (500 nmol/0,5 µL). Nossos resultados mostram que a pilocarpina periférica ou na ASM induz salivação, ingestão de água e resposta pressora. A resposta pressora induzida pela pilocarpina periférica é decorrente de um aumento na atividade simpática. A ASM e seus receptores colinérgicos muscarínicos participam do controle da secreção salivar e ingestão de água, mas não da resposta pressora induzida pela pilocarpina periférica, sugerindo um controle diferencial da ASM nas respostas induzidas pela administração periférica de pilocarpina.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13331号 / 論医博第2199号 / 新制||医||1044(附属図書館) / (主査)教授 湊谷 謙司, 教授 横出 正之, 教授 戸口田 淳也 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introduction: Transseptal puncture (TSP) is challenging in patients with prior percutaneous atrial septal defect (ASD) occluder. We aimed to perform a systematic review and meta-analysis of the safety and efficacy of catheter ablation for atrial fibrillation (AF) in patients with percutaneous ASD occluder. Methods: We searched PubMed, Medline, Embase, Ovid, and Cochrane for studies reporting results of AF ablation (freedom from AF, fluoroscopy/procedure time, and complications) in patients with percutaneous ASD occluders. Results: Three studies with a total of 64 patients met inclusion criteria. The success rate of TSP was 100%. All patients (but one) underwent TSP under fluoroscopic and intracardiac echocardiography guidance. Freedom from AF was achieved in 77.7% (95% confidence interval [CI]: 65.7–86.3) patients. In the subgroup analysis, comparing septal versus device puncture, no significant difference in recurrence of AF was observed (23.07% vs. 16.66%; risk ratio: 1.18; 95% CI: 0.35–4.00; p =.79, respectively). The total fluoroscopy time was not significantly different in patients with TSP via native septum or device (43.50 vs. 70.67 min; p =.44), total procedural time was significantly longer with TSP via the closure device (237.3 vs. 180 min; p =.004) compared with the native septum. There were no device dislodgement or residual interatrial shunt during the follow-up period. Conclusion: Catheter ablation for AF in patients with prior percutaneous ASD closure device is feasible and safe with favorable long-term outcomes.

The physiological significance of noradrenergic sympathohabenular ingrowth following medial septal lesions was investigated. Following septal lesions, sympathetic fibers originating in the superior cervical ganglia are known to sprout into the medial habenular nuclei, and into the hippocampal formation. Previous work involving sympathohippocampal ingrowth showed that firing rates in septal animals with no ingrowth showed that firing rates in septal animals with no ingrowth were higher than rates of septal animals with ingrowth and controls. Those results suggested that sympathetic ingrowth in the hippocampus had some functional capability in a modulatory manner. The primary aim of the present study was to determine if the peripheral sympathetic ingrowth into the medial habenular nuclei following a septal lesion is functionally significant. The results showed that firing rates of neurons of the medial habenulae in animals receiving septal lesions were significantly higher than rates of control animals and septal lesioned + ganglionectomized animals.