Symptomatic sinus bradycardia, due to either sick sinus syndrome or vagotonia, can be familial, affecting several members of a family. We report an 18-year-old male patient with palpitations and limited exercise capacity who was noted to have severe sinus bradycardia. His resting heart rate was 40/min, with normal PR and corrected QT intervals, and sinus pauses up to 6 seconds during sleep. Exercise treadmill test and pharmacologic autonomic blockade during electrophysiologic studies abolished the bradycardia, suggestive of vagotonia rather than intrinsic sinus node dysfunction. This patient's father and a female cousin had a similar clinical history but associated with syncope and severe sinus bradycardia. The mode of transmission appeared to be autosomal dominant. All three have permanent demand pacemakers implanted and are asymptomatic.

Our objective was to determine whether atrial fibrillation (AF) results from excessive activation of intrinsic cardiac neurons (ICNs) and, if so, whether select subpopulations of neurons therein represent therapeutic targets for suppression of this arrhythmogenic potential. Trains of five electrical stimuli (0.3-1.2 mA, 1 ms) were delivered during the atrial refractory period to mediastinal nerves (MSN) on the superior vena cava to evoke AF. Neuroanatomical studies were performed by injecting the neuronal tracer DiI into MSN sites that induced AF. Functional studies involved recording of neuronal activity in situ from the right atrial ganglionated plexus (RAGP) in response to MSN stimulation (MSNS) prior to and following neuromodulation involving either preemptive spinal cord stimulation (SCS; T 1-T 3, 50 Hz, 200-ms duration) or ganglionic blockade (hexamethonium, 5 mg/kg). The tetramethylindocarbocyanine perchlorate (DiI) neuronal tracer labeled a subset (13.2%) of RAGP neurons, which also colocalized with cholinergic or adrenergic markers. A subset of DiI-labeled RAGP neurons were noncholinergic/nonadrenergic. MSNS evoked an ~4-fold increase in RAGP neuronal activity from baseline, which SCS reduced by 43%. Hexamethonium blocked MSNS-evoked increases in neuronal activity. MSNS evoked AF in 78% of right-sided MSN sites, which SCS reduced to 33% and hexamethonium reduced to 7%. MSNS-induced bradycardia was maintained with SCS but was mitigated by hexamethonium. We conclude that MSNS activates subpopulations of intrinsic cardiac neurons, thereby resulting in the formation of atrial arrhythmias leading to atrial fibrillation. Stabilization of ICN local circuit neurons by SCS or the local circuit and autonomic efferent neurons with hexamethonium reduces the arrhythmogenic potential.

No description available.

No description available.

Zusammenfassung Hintergrund Die Interscalenäre Blockade des Plexus brachialis (ISB) ist ein weit verbreitetes regionalanästhesiologisches Verfahren zu postoperativen Schmerzkontrolle bei Operationen an der Schulter. Ungeachtet der suffizienten Analgesie kommt es bei der ISB fast immer zur akzessorischen Blockade des Nervus phrenicus mit konsekutiver Lähmung des Zwerchfells sowie zu einer motorischen Blockade der betroffenen Extremität. Eine nebenwirkungsärmere Alternative könnte die ultraschallgestützte anteriore Blockade des Nervus suprascapularis (NSSB) darstellen. Methoden 55 für eine ambulante arthroskopische Schulteroperation vorgesehene Patienten wurden nach dem Zufallsprinzip der Gruppe ISB oder NSSB zugeteilt. Für beide Verfahren wurden jeweils 10 ml 1 %iges Ropivacain verwendet. Primärer Endpunkt war die prozentuale Lungenventilation auf der zu operierenden Seite, welche mittels Elektrischer Impedanz-Tomographie (EIT) gemessen wurde. Zur Beurteilung der hemidiaphragmatischen Parese erfolgte zusätzlich die sonographische Darstellung des Zwerchfells auf der ipsilateralen Seite im M-Mode. Als sekundäre Endpunkte wurden der postoperative Schmerzmittelverbrauch, Schmerz-Scores, die Handkraft, die sensorische Blockade der Hand sowie die Patientenzufriedenheit untersucht. Ergebnisse Insgesamt konnten die Daten von 48 Patienten analysiert (24 NSSB, 24 ISB, durchschnittliches Alter 51 Jahre, 22 Frauen, 26 Männer) werden. Technische Probleme bei der Durchführung der EIT-Messung sowie die fehlerhafte Aufzeichnung der EIT-Daten führten zum Ausschluss von 7 Patienten. Vor der Nervenblockade wurde die zu untersuchende Lungenhälfte mit durchschnittlich 51 % des gesamten Lungenvolumens belüftet. Postoperativ fielen die Werte auf 34 % (NSSB) vs. 10 % (ISB) ab, dies entsprach einer Differenz von 23 % (95 % KI = 13 bis 34 %, p < 0,001). Eine Zwerchfellparese wurde bei 21 % (NSSB) vs. 88 % (ISB) der Patienten nachgewiesen (p < 0,001). Die Handkraft war bei der NSSB um 11,2 kg (95 % KI = 3,6 bis 18,9 kg, p = 0,0024) höher und eine eingeschränkte Sensorik der Hand wurde bei 0 % (NSSB) vs. 46 % (ISB) der Patienten beobachtet (p < 0,001). Die angegebenen Schmerzen waren in den ersten 6 h nach der Operation in beiden Gruppen niedrig, mit leichtem Vorteil zugunsten der ISB. Hinsichtlich des postoperativen Opioid-Verbrauchs und der Patientenzufriedenheit zeigten sich keine signifikanten Unterschiede. Schlussfolgerung Die anteriore Blockade des Nervus suprascapularis führt zu einer weniger ausgeprägten postoperativen Ventilationseinschränkung und geht seltener mit einer Parese des Zwerchfells einher. In Bezug auf Analgesie, Schmerzmittelverbrauch und Patientenkomfort ist sie der Interscalenären Blockade gleichwertig.:Inhaltsverzeichnis Abkürzungsverzeichnis 1 1 Einleitung 3 1.1 Anatomie 4 1.1.1 Schultergelenk 4 1.1.2 Plexus brachialis 5 1.1.3 Nervus suprascapularis 9 1.1.4 Innervation der Schulter 10 1.2 Regionalanästhesie 11 1.2.1 Geschichte der Regionalanästhesie 11 1.2.2 Verfahren der Regionalanästhesie 12 1.2.3 Periphere Nervenblockaden des Plexus brachialis 15 1.3 Die Elektrische Impedanz-Tomographie (EIT) 25 1.3.1 Technisches Prinzip 26 1.3.2 Einsatzmöglichkeiten der EIT im klinischen Alltag 27 1.4 Ambulante Operationen 28 1.4.1 Entwicklung des tagesklinischen Bereiches 28 1.4.2 Vorteile ambulanter Operationen 30 1.4.3 Voraussetzungen für einen ambulanten Eingriff 30 1.4.4 Anforderungen an das Anästhesieverfahren 31 2. Zielsetzung der Doktorarbeit 33 3. Material und Methoden 34 3.1 Studie 34 3.1.1 Stichprobenberechnung, Gruppeneinteilung und Randomisierung 34 3.1.2 Einschluss- und Ausschlusskriterien 35 3.2 Punktionsprozedere und -technik 36 3.2.1 Durchführung der Interscalenären Blockade 37 3.2.2 Durchführung der anterioren N. suprascapularis Blockade 38 3.2.3 Rescue-Medikation, Procedere bei unzureichender Analgesie sowie Verfahrensweise bei Verdacht auf neurologische Schäden 40 3.3 EIT-Messung und sonographischen Darstellung des Zwerchfells 41 3.3.1 Durchführung der EIT-Messung 41 3.3.2 Sonographie des Zwerchfells 42 3.4 Datenerhebung 44 3.5 Studienendpunkte 46 3.6 Statistik 47 4. Ergebnisse 48 4.1 Demographische Daten 48 4.2 OP-Indikationen und Nebendiagnosen 51 4.2.1 OP-Indikationen 51 4.2.2 Komorbiditäten 51 4.3 OP-Daten, Anästhesieverfahren und Punktionsdaten 53 4.3.1 OP-Daten 53 4.3.2 Anästhesieverfahren und intraoperativer Medikamentenverbrauch 54 4.3.3 Punktionsdaten 54 4.4 EIT-Messung und Zwerchfellsonographie 56 4.5 Evaluation der Schmerzintensität und postoperativer Schmerzmittelverbrauch 60 4.5.1 Schmerzintensität 60 4.5.2 Postoperativer Analgetikaverbrauch 61 4.6 Daten zur Handkraftmessung, Blockadequalität, Blockadedauer, Nebenwirkung und Komplikationen sowie Patientenzufriedenheit 63 4.6.1 Bestimmung der Handkraft, sensorische Blockadequalität und Blockadedauer 63 4.6.2 Nebenwirkungen und Komplikationen 65 4.6.3 Patientenzufriedenheit 66 5 Diskussion 68 5.1 Zusammenfassung der Hauptergebnisse 68 5.2 Diskussion der Ergebnisse 69 5.2.1 EIT und Sonographie zur Detektion der N. phrenicus Parese 69 5.2.2 Parese des N. phrenicus und Zwerchfellparese 71 5.2.3 Schmerztherapie und periphere Nervenblockaden bei ambulanten Operationen 73 5.2.4 Sensomotorische Blockadequalität 75 5.2.5 Blockadedauer 76 5.2.6 Methodenimmanente Nebenwirkungen und Komplikationen 77 5.2.7 Patientenzufriedenheit und erneute Entscheidung 77 5.2.8 Limitationen 77 5.2.9 Ausblick 78 Zusammenfassung 80 Literaturverzeichnis 82 Abbildungsverzeichnis 93 Tabellenverzeichnis 95 Anhang 96 Eigenständigkeitserklärung 98 Publikationen 99

Introduction The joint dysfunction of the spine in the sense of functional blockade is connected with corresponding painful condition, reflex contraction of the surrounding muscles and restriction of mobility in the spinal segment. Joint block has its mechanical context, which need not be accompanied by a structural disturbance but it's affecting the biomechanical properties of the spine. Several theories exist how the joints become restricted. Scientific evidence highly supports the meniscoid entrapment theory. Purposes The aim of the study was to identify the meniscoids of the cervical spine using in- vivo MRI imaging and to determine their potential role in the development of functional joint blocks of the axial system (AS). Another objective was to find out how the articular blocks affect the rheological properties of the spine by the Transfer Vibration through the Spine (TVS) method. Patient sample The MRI study was conducted on a research file of 12 subjects - two anatomical preparations and ten in vivo. Two subjects were examined in TVS experiment. Methodology Two anatomical preparations were investigated on MRI to find the appropriate sequence for imaging of meniscoids, three subjects for identification of meniscoids in vivo. Seven subjects underwent initial investigation, manipulation of...

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This thesis presents a computational study of water and ion dynamics in modified hydrophobic silicon nitride (Si3N4) nanopores, aimed at enhancing protein sequenc- ing technologies. By employing molecular dynamics (MD) simulations, the research investigates the wetting-dewetting behavior within nanopores as an indirect measure of amino acid residue hydrophobicity, focusing on how post-translational modifications (PTMs) of lysine, particularly the acetylation of lysine residues, influence nanopore hydrophobicity and ionic conductance. The study reveals that nanopore radius and hydrophobicity significantly affect water and ion permeation, with smaller nanopores oscillating between open and closed states, while larger ones remain open.  Using umbrella sampling and the Weighted Histogram Analysis Method (WHAM), the potential of mean force (PMF) for potassium (K+), chloride (Cl−), and water within the nanopores was determined, showing distinct PMF profiles based on lysine and acetyl- lysine presence. The modulation of ionic currents as a tool for protein sequencing was explored, demonstrating that different amino acid residues affect ionic currents by par- tially blocking the pore and altering local permeability, thereby enabling differentiation based on size, shape, charge, and hydrophobicity.  The findings suggest that silicon nitride pore hydrophobicity can be tailored for nanopore sequencing, correlating changes in ionic currents with amino acid residue translocation. This research enhances the understanding of interactions within nanopore environments, potentially leading to more precise nanopore-based sequencing methods.

Semiconductor–superconductor hybrid systems are promising candidates for the realization of Majorana fermions and topological order, i.e. topologically protected degeneracies, in solid state devices. We show that the topological order is mirrored in the excitation spectra and can be observed in nonlinear Coulomb blockade transport through a ring-shaped nanowire. Especially, the excitation spectrum is almost independent of magnetic flux in the topologically trivial phase but acquires a characteristic h/e magnetic flux periodicity in the non-trivial phase. The transition between the trivial and nontrivial phase is reflected in the closing and reopening of an excitation gap. We show that the signatures of topological order are robust against details of the geometry, electrostatic disorder and the existence of additional subbands and only rely on the topology of the nanowire and the existence of a superconducting gap. Finally, we show that the coherence length in the non-trivial phase is much longer than in the trivial phase. This opens the possibility to coat the nanowire with superconducting nanograins and thereby significantly reduce the current due to cotunnelling of Cooper pairs and to enhance the Coulomb charging energy without destroying the superconducting gap.

Cancer, historically considered a genetic disease, is currently acknowledged to affect the whole body. Our immune system is one key player that can elicit a response against malignant cells but can also promote tumorigenesis. Tumors avoid immune recognition by creating a suppressive microenvironment and inducing tolerance. T-cells are regarded a major effector cell type in tumor immunotherapy. An important ”switch” needed for T-cell activation involves so-called costimulatory and coinhibitory receptors. In this thesis, experimental tumor models were used to investigate the potential of immunomodulatory antibodies to stimulate immune cells and subsequently eliminate tumors. First, systemic antibody blockade of two negative checkpoint regulators (CTLA-4 and PD-1) present on T-cells was evaluated in combination with local CpG therapy or standard BCG treatment. Indeed, this combinatorial therapy with CpG augmented anti-tumor effects with increased levels of tumor-directed T-cells and reduced tumor-infiltrating Tregs. Secondly, as these immunomodulatory antibodies elicit severe side effects in patients, a local low-dose delivery regimen was explored as an alternative to systemic bolus treatment. Our results demonstrated that an approximately seven times lower dose of aCTLA-4, compared to systemic delivery, could eradicate both primary and distant tumors. CD40-expressing APCs are another potential target in antibody-mediated cancer therapy. CD40-stimulated dendritic cells (DCs) have the capability to activate tumor-directed T-cells to kill tumor cells. We next sought to investigate agonistic CD40 antibody efficacy and in vivo biodistribution when delivered locally compared to the equivalent systemic dose. Anti-tumor effects were dependent on CD8+ T-cells, host CD40 expression and the presence of tumor antigen at the injection site. CD40 antibodies were cleared from the circulation and accumulated in lymphoid organs, where, upon repeated aCD40 dosing, target APC populations increased in numbers and upregulated their surface CD40 expression. Lastly, CD40 agonist antibodies were mixed with nanoparticles to enhance their stimulatory properties. B-cells demonstrated increased proliferative capacity and DCs became more activated when exposed to the cocktail. Further, this combination reduced serum levels of pro-inflammatory cytokines compared to plain antibodies.       The results herein advocate further exploratory studies of the delivery of monoclonal antibodies at the tumor site in order to improve anti-tumor effects and reduce toxicity.