Search

Here we report the results of a retrospective germline analysis of 6941 individuals fulfilling the criteria necessary for genetic testing of hereditary breast- and ovarian cancer (HBOC) according to the German S3 or AGO Guidelines. Genetic testing was performed by next-generation sequencing using 123 cancer-associated genes based on the Illumina TruSight® Cancer Sequencing Panel. In 1431 of 6941 cases (20.6%) at least one variant was reported (ACMG/AMP classes 3–5). Of those 56.3% (n = 806) were class 4 or 5 and 43.7% (n = 625) were a class 3 (VUS). We defined a 14 gene HBOC core gene panel and compared this to a national and different internationally recommended gene panels (German Hereditary Breast and Ovarian Cancer Consortium HBOC Consortium, ClinGen expert Panel, Genomics England PanelsApp) in regard of diagnostic yield, revealing a diagnostic range of pathogenic variants (class 4/5) from 7.8 to 11.6% depending on the panel evaluated. With the 14 HBOC core gene panel having a diagnostic yield of pathogenic variants (class 4/5) of 10.8%. Additionally, 66 (1%) pathogenic variants (ACMG/AMP class 4 or 5) were found in genes outside the 14 HBOC core gene set (secondary findings) that would have been missed with the restriction to the analysis of HBOC genes. Furthermore, we evaluated a workflow for a periodic re-evaluation of variants of uncertain clinical significance (VUS) for the improvement of clinical validity of germline genetic testing.

In this document, we outline the challenges faced by patients and clinicians in heart failure, specifically centered around the needed coordination of care among the various subspecialties within cardiovascular medicine. We call for a more organized and collaborative effort among clinicians in primary care, general cardiology, electrophysiology, interventional cardiology, cardiothoracic surgery, cardiac imaging, and heart failure—all caring for mutual patients. Care is contextualized within the framework of two phases: a cardiomyopathy phase and an advanced heart failure phase, each of which lends to different considerations in therapy. Ultimately multidisciplinary coordinated care within cardiovascular medicine may lead to greater patient and clinician satisfaction as well as improved outcomes, but this remains to be investigated.

Im Rahmen der chirurgischen Versorgung aortaler Pathologien (z. B. Dissektion, Aneurysma) kann es durch Abklemmen der Aorta oder Uberstenten kritischer Segmentarterien zu einer Ischamie mit odembedingter Ruckenmarkschadigung bis hin zur Paraplegie kommen. Der Spinalkatheter stellt durch Kontrolle des Liquordrucks ein wirksames Verfahren zur Prophylaxe und Therapie der Ruckenmarkischamie dar. Eine ausfuhrliche Risiko-Nutzen-Abwagung ist in Anbetracht der hohen Komplikationsrate des Spinalkatheters obligat: Neben Liquorleckagen, Postpunktionskopfschmerzen und lokalen Infektionen konnen auch gefurchtete Komplikationen wie intrakranielle Blutungen, Meningitiden und neuraxiale Hamatome, zum Teil mit deutlicher Latenz nach Beendigung des Verfahrens, auftreten. Eine adaquate Schulung des Personals im perioperativen Umgang mit Spinalkathetern und das penible Einhalten der Drainageparameter stellen wichtige Saulen zur Erhohung der Verfahrenssicherheit dar. Dies gilt insbesondere auch angesichts dessen, dass sich die Klinik der katheterassoziierten Komplikationen von derjenigen der ischamischen Ruckenmarkschadigung nur unwesentlich unterscheidet.

Collagen XIII is a non-fibrillar transmembrane collagen which has been long recognized for its critical role in synaptic maturation of the neuromuscular junction. More recently, biallelic COL13A1 loss-of-function mutations were identified in three patients with congenital myasthenic syndrome (CMS), a rare inherited condition with defective neuromuscular transmission, causing abnormal fatigability and fluctuating muscle weakness and often successfully treated with acetylcholinesterase inhibitors. Here we report six additional CMS patients from three unrelated families with previously unreported homozygous COL13A1 loss-of-function mutations (p.Tyr216*, p.Glu543fs and p.Thr629fs). The phenotype of our cases was similar to the previously reported patients including respiratory distress and severe dysphagia at birth that often resolved or improved in the first days or weeks of life. All individuals had prominent eyelid ptosis with only minor ophthalmoparesis as well as generalized muscle weakness, predominantly affecting facial, bulbar, respiratory and axial muscles. Response to acetylcholinesterase inhibitor treatment was generally negative while salbutamol proved beneficial. Our data further support the causality of COL13A1 variants for CMS and suggest that this type of CMS might be clinically homogenous and requires alternative pharmacological therapy.

Left ventricular assist devices (LVAD) have been increasingly used in the treatment of end-stage heart failure. While warfarin has been uniformly recommended in the long-term as anticoagulation strategy, no clear recommendation exists for the post-operative period. We sought to evaluate the feasibility of enoxaparin in the immediate and early postoperative period after LVAD implantation.This is a two-center, retrospective analysis of 250 consecutive patients undergoing LVAD implantation between January 2017 and December 2018. Patients were bridged postoperatively to therapeutic INR by either receiving unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Patients were followed while inpatient and for 3 months after LVAD implantation. The efficacy outcome was occurrence of first and subsequent cerebrovascular accident while safety outcome was the occurrence of bleeding events. Length of stay (LOS) was also assessed.Two hundred fifty and 246 patients were analyzed for index admission and 3-month follow up respectively. No statistically significant differences were found between the two groups in CVA (OR = 0.67; CI = 0.07-6.39, P = 0.73) or bleeding events (OR = 0.91; CI = 0.27-3.04, P = 0.88) during index admission. Similarly, there were no differences at 3 months in either CVAs or bleeding events (OR = 0.85; 0.31-2.34; p = 0.76). No fatal events occurred during the study follow-up period. Median LOS was significantly lower (4 days; p = 0.03) in the LMWH group.LMWH in the immediate and early postoperative period after LVAD implantation appears to be a concurrently safe and efficacious option allowing earlier postoperative discharge and avoidance of recurrent hospitalizations due to sub-therapeutic INR.

Kongenitale myasthene Syndrome (CMS) stellen eine heterogene Gruppe von Erkrankungen dar, die mit einem breiten Spektrum von Phanotypen einhergehen, aber alle auf vererbte Defekte an der motorischen Endplatte zuruckzufuhren sind. Auch wenn einige Patienten bisher (noch) nicht genetisch charakterisiert werden konnen, hat die zunehmende Identifizierung ursachlicher Gene in den letzten Jahren neue Einblicke in die Funktionalitat von Strukturproteinen der neuromuskularen Endplatte ermoglicht. Die Erstmanifestation der meisten CMS geschieht im Neugeborenen- bzw. Kleinkindesalter. Im Falle einer spateren Manifestation, oder wenn die Diagnose (z. B. aufgrund einer atypischen Manifestation) im Kleinkindesalter nicht gestellt wurde, ist die Diagnosestellung im Erwachsenenalter oft schwierig. Die Definition der zugrunde liegenden Mutation hat jedoch unmittelbare Therapierelevanz. In dieser Ubersicht sollen ausgehend von charakteristischen Patientenbeispielen wesentliche klinische und zusatzdiagnostische Befunde verschiedener CMS-Subtypen dargestellt werden. Es wird insbesondere auch auf die differenzialdiagnostische Abgrenzung des CMS-Erkrankungsspektrums von Muskelerkrankungen im engeren Sinn, insbesondere von Muskeldystrophien, eingegangen. Zur Veranschaulichung geschieht dies einerseits mithilfe charakteristischer Patientenbeispiele und andererseits der Darstellung der wesentlichen klinischen und zusatzdiagnostischen Befunde verschiedener CMS-Subtypen sowie spezieller diagnostischer Hinweise.

Der plotzliche Herztod (PHT) ist ein tragisches, seltenes Ereignis. Fur die Altersgruppe bis zu 35 Jahren wurde eine Haufigkeit von 1,3/100.000 Personenjahren berechnet. Obwohl kardiovaskulare Veranderungen den grosten Teil der PHT-Falle erklaren, ist in 10–30 % dieser Falle die Ursache durch eine konventionelle Autopsie nicht geklart. Fur mindestens ein Drittel dieser Todesfalle konnen kardiale Ionenkanalerkrankungen verantwortlich sein, die mithilfe der molekularen Autopsie identifiziert werden konnen. Die parallele Sequenzierung mehrerer Gene tragt entscheidend zur Diagnosesicherung bei. Durch die Identifikation der zugrunde liegenden Erkrankung kann nahen Verwandten eine gezielte Diagnostik angeboten werden. Der Befundinterpretation kommt zentrale Bedeutung zu. Darauf aufbauend konnen Empfehlungen fur praventive Masnahmen und die Meidung spezifischer Ausloser lebensbedrohlicher Rhythmusstorungen ausgesprochen werden, um das PHT-Risiko erheblich zu senken.

Background Congenital myasthenic syndrome with episodic apnoea (CMS-EA) is a rare but potentially treatable cause of apparent life-threatening events in infancy. The underlying mechanisms for sudden and recurrent episodes of respiratory arrest in these patients are unclear. Whilst CMS-EA is most commonly caused by mutations in CHAT, the list of associated genotypes is expanding. Methods We reviewed clinical information from 19 patients with CMS-EA, including patients with mutations in CHAT, SLC5A7 and RAPSN, and patients lacking a genetic diagnosis. Results Lack of genetic diagnosis was more common in CMS-EA than in CMS without EA (56% n = 18, compared to 7% n = 97). Most patients manifested intermittent apnoea in the first 4 months of life (74%, n = 14). A degree of clinical improvement with medication was observed in most patients (74%, n = 14), but the majority of cases also showed a tendency towards complete remission of apnoeic events with age (mean age of resolution 2 years 5 months). Signs of impaired neuromuscular transmission were detected on neurophysiology studies in 79% (n = 15) of cases, but in six cases, this was only apparent following specific neurophysiological testing protocols (prolonged high-frequency stimulation). Conclusions A relatively large proportion of CMS-EA remains genetically undiagnosed, which suggests the existence of novel causative CMS genes which remain uncharacterised. In light of the potential for recurrent life-threatening apnoeas in early life and the positive response to therapy, early diagnostic consideration of CMS-EA is critical, but without specific neurophysiology tests, it may go overlooked.

In this Letter, Mayuko Kurome and Valeri Zakhartchenko have been added to the author list (affiliated with Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany). The author list and 'Author contributions' section have been corrected online; see accompanying Amendment.

Durch eine fruhere Diagnosestellung und verbesserte Therapie wurden die Mortalitat und der Verlauf einer erworbenen neuromuskularen Ubertragungsstorung deutlich verbessert. Trotzdem bleiben die Erkennung und die Aufklarung der Pathogenese neuromuskularer Transmissionsstorungen eine klinische und wissenschaftliche Herausforderung. Die Abgrenzung seronegativer erworbener Myasthenien gegenuber den kongenitalen myasthenen Syndromen (CMS) ist im Hinblick auf eine differenzierte Therapie und zur Vermeidung einer nichtindizierten immunsuppressiven Therapie bei Patienten mit kongenitalen Formen wichtig. An ein CMS sollte insbesondere immer dann gedacht werden, wenn bei Patienten mit seronegativer Myasthenie die Anamnese einer belastungsabhangigen Muskelschwache bis in die Kindheit oder Jugendzeit zuruckreicht oder aber eine Spatmanifestation mit einem Gliedergurtelphanotyp oder klinischen Besonderheiten eines autosomal-dominanten „Slow-channel“-Syndroms vorliegt, hier mit selektiven Paresen der zervikalen Muskulatur sowie der Finger- und Unterarmstreckermuskulatur. Die Familienanamnese bei den zumeist rezessiv vererbten CMS ist nicht immer wegweisend. Daher kann eine molekulargenetische Untersuchung zur Diagnosesicherung oder auch zum Ausschluss von haufigeren, potenziell symptomatisch behandelbaren CMS hilfreich sein.

Polymerase gamma 1 (POLG) mutations are a frequent cause of both autosomal dominant and recessive complex neurological phenotypes. In contrast, only a single pathogenic mutation in one patient was reported in POLG2 so far. Here we describe a 62-year-old woman, carrying a novel heterozygous sequence variant in the POLG2 gene. She developed bilateral ptosis at 30 years of age, followed by exercise intolerance, muscle weakness and mild CK increase in her late forties. Muscle histology and respiratory chain activities were normal. Southern blot and long range PCR detected multiple mtDNA deletions, but no depletion in muscle DNA. Sequencing of POLG, PEO1, ANT1, OPA1 and RRM2B showed normal results. A novel heteroallelic 24 bp insertion (c.1207_1208ins24) was detected in POLG2. This 24 bp insertion into exon 7 causes missplicing and loss of exon 7 in myoblast cDNA. We did not detect POLG2 mutations in 62 patients with multiple mtDNA deletions in muscle DNA, suggesting that POLG2 mutations may represent a rare cause of autosomal dominant PEO.

Das naturliche Tibiofemoralgelenk (TFG) funktioniert nach einem Roll-Gleit-Mechanismus: In der Standphase (0–20° Beugung) rollt das Femur auf dem Tibiaplateau nach hinten, bei weiterer Beugung kommt es zu einem zunehmenden Gleiten. Dieser Kinematik liegt das Prinzip des Viergelenks zugrunde. Die 4 morphologischen Drehachsen sind dabei jeweils die Krummungsmittelpunkte der medialen und lateralen Femurkondyle sowie des medialen und das lateralen Tibiaplateaus. Zusatzlich sind das mediale und das laterale Kompartiment wenige Millimeter sagittal versetzt, das mediale Tibiaplateau ist konkav und das laterale konvex geformt. Die meisten derzeit verwendeten Kniegelenkendoprothesen berucksichtigen diese Gegebenheiten nicht, sondern besitzen medial und lateral symmetrische Gelenkflachen. Dadurch bildet sich sowohl femoral als auch tibial eine gemeinsame Rotationsachse, welche keinen physiologischen Roll-Gleit-Mechanismus zulasst. Ziel der vorliegenden Arbeit ist es, biomechanische Grundlagen des Kniegelenks hinsichtlich der Endoprothetik darzulegen und die Entwicklung einer neuartigen Kniegelenkendoprothese auf mathematisch-physikalischer Basis vorzustellen. Das Design der strukturell neuartigen Kniegelenkendoprothese AEQUOS zeigt lateral eine konvexe Formung der tibialen Gelenkflache im sagittalen Schnitt und erfullt weitere oben genannte physiologische Eigenschaften. Das Problem der Reibung dieser Endoprothese soll dadurch weiter verbessert werden. Wahrend des Gehens in der Standphase sollen die kunstlichen Gelenkflachen zu mehr als 95% aufeinander abrollen und erst bei weiterer Beugung gleiten. Im Rahmen der Zulassungstests wurde die Endoprothese nach ISO/WC 14243 im Kniesimulator getestet. Die Abriebraten waren dabei kleiner oder mindestens gleich gut wie bei konventionellen Endoprothesen. Die geschilderten Daten zeigen ein vollig neues Konzept in der Knieendoprothetik, welches im klinischen Langzeitverlauf jedoch noch evaluiert werden muss.

Quantitative exakte morphologische Untersuchungen zu beiden Gelenkoberflachen des proximalen Interphalangealgelenkes (PIP) liegen bisher kaum vor. Die aus unseren anatomischen Daten sich ergebenden Einsichten uber Funktionsmechanismen des Fingermittelgelenks legten nicht nur die Entwicklung eines neuartigen Prothesendesigns, sondern auch die eines neuen apparativen Instrumentariums nahe. Von 40 PIP-Gelenken (anatomische Praparate) wurden mit den Prazisionsmethoden der Zahnmedizin 200 Abdrucke erstellt und die Krummungsradien und -mittelpunkte der Gelenkflachen vermessen. In Kenntnis dieser Daten wurde ein Prothesenprototyp entwickelt (Prothesenschaft titanlegiert, Gelenkflachenpaarung Titannitrid- Titannitrid) und eine neue instrumentelle Navigationshilfe (INA) konstruiert, um die Endoprothese mit groster Prazision einbringen zu konnen. Die morphologischen Ergebnisse belegen eine signifikante Inkongruenz der PIP-Gelenkflachen. In transversaler und sagittaler Richtung sind die Gelenkradien der Mittelgliedpfanne hoch signifikant groser als die des korrespondierenden Grundgliedkopfchens (p < 0.001). In transversaler Richtung kontaktieren die Gelenkflachen jeweils auf den medianen Abhangen der Kondylen des Grundgliedkopfchens. Der sagittale Sektor der von Knorpel bedeckten Gelenkoberflache der Mittelgliedpfanne betrug ca. 40 % der Gelenkflache des Grundgliedkopfchens, 64,3° (SD: 10,5°) vs. 166,9° (SD: 28,0°). Die neu entwickelte Prothese berucksichtigt die anatomisch funktionell gegebenen Eigenschaften bezuglich der Gelenkflachen des PIP-Gelenks. Da sie vom muskularen Apparat anatomiegerecht angesteuert werden kann, werden Zwangkrafte und eine unphysiologische Kinematik auf das Interface zwischen Prothesenschaft und Knochen vermieden. Die Kombination aus instrumentell unterstutzter Prothesenimplantation und neuem Prothesendesign lasst eine zuverlassige und reproduzierbare Prothesenimplantation am Fingermittelgelenk erwarten.

The formation of solid solutions of the type [Ba(HOC2H4OH)4][Ti1−xGex(OC2H4O)3] as Ba(Ti1−x/Gex)O3 precursors and the phase evolution during thermal decomposition of [Ba(HOC2H4OH)4][Ti0.9Ge0.1(OC2H4O)3] (1) are described herein. The 1,2-ethanediolato complex 1 decomposes above 589 °C to a mixture of BaTiO3 and BaGeO3. A heating rate controlled calcination procedure, up to 730 °C, leads to a nm-sized Ba(Ti0.9/Ge0.1)O3 powder (1a) with a specific surface area of S = 16.9 m2/g, whereas a constant heating rate calcination at 1,000 °C for 2 h yields a powder (1b) of S = 3.0 m2/g. The shrinkage and sintering behaviour of the resulting Ba(Ti0.9/Ge0.1)O3 powder compacts in comparison with nm-sized BaTiO3 powder compacts (2a) has been investigated. A two-step sintering procedure of nm-sized Ba(Ti0.9/Ge0.1)O3 compacts (1a) leads, below 900 °C, to ceramic bodies with a relative density of ≥90%. Furthermore, the cubic ⇆ tetragonal phase transition temperature has been detected by dilatometry, and the temperature dependence of the dielectric constant (relative permittivity) has also been measured.

In this paper, the results of a temperature dependent x-ray diffraction (XRD) study on BaTi0.95Sn0.05O3 (BTS-5) ceramics are compared with dielectric measurements. The orthorhombic-tetragonal phase transition at T2 = 306 K is found to proceed in a considerably wider temperature range than expected from the dielectric anomaly. Although the macroscopic properties of BTS-5 indicate a rather sharp ferroelectric phase transition at Tc = 358K, we observe anomalous XRD-patterns in a 25 K wide temperature range. This is interpreted in terms of mechanically clamped tetragonal and cubic phase, coexisting in the vicinity of Tc in grains with inhomogeneous Sn-distribution.

Donor-doped BaTiO3 ceramics (0–0.6 mol% Nb) were investigated during the sintering process at an oxygen partial pressure of 2.4 Pa and at a maximum temperature of 1430∘C. The occurring oxygen exchange with the ambient atmosphere was monitored quantitatively by oxygen coulometry. The coincidence between the grain growth behavior and the occurrence of distinct oxygen release peaks during the anomalous grain growth reveals that significant amounts of the donor are incorporated and charge-compensated by electrons only under the conditions of the anomalous grain growth. Quantitative analysis of the coulometric data shows that at a doping level of 0.2 mol% nearly all donors are charge-compensated by electrons. With increasing Nb concentration also Ti vacancies gradually begin to serve for compensation. At 0.5 mol% Nb their influence reaches 70 % of the electronic compensation.

A new procedure for the preparation of a core-shell-structured BaTiO(3) precursor (core=TiO(2); shell=BaCO(3)) will be described. The structure of this precursor is characterized by electron microscopy (environmental scanning electron microscopy; energy disperse X-ray spectroscopy), whereas the development of phases during thermal treatment is followed by X-ray powder diffraction.

The purpose of this work was to study the effect of CuO as a versatile sintering agent for BaTiO3 based ceramics. The response is shown to exist in three directions. Firstly, as liquid-phase former at comparatively low temperatures. Hence, the influence of various CuO-based flux formers on the shrinkage behaviour and the microstructure development of the ceramics was investigated. Secondly, the aptitude as an internal susceptor for secondary phase initiated microwave sintering. The use of CuO as a lossy secondary phase leads to an accelerated microwave heating of the ceramics. Thirdly, the addition of CuO to BaTiO3 powders with Ba-excess results in a phase transition cubic → hexagonal at about 1300°C, which is a indication for the incorporation of Cu2+ ions into the BaTiO3 lattice at Ti sites under this conditions.

Dependence of the composition of (100−x) BaTiO3 +xCaTiSiO5 precursor (x = 2–16 mol%) mixtures on calcination temperature was investigated by means of X-ray diffraction and differential scanning calorimetry. The formation of a secondary phase, fresnoite (Ba2TiSi2O8), starts at about 900 °C. The resulting Ba and O vacancies and the produced microstress stabilize the pseudocubic phase of BaTiO3 at room temperature. Temperatures higher than 1200 °C are necessary to incorporate Ca ions into the BaTiO3 crystals forming (Ba, Ca) TiO3 solid solutions. As a result the lattice becomes free of tension and the BaTiO3 based ceramics transform into thermodynamically stable tetragonal phases at room temperature.

BaTiO3 positive temperature coefficient of resistance ceramics were prepared with the general composition (La0.002Ca x Ba0.998−x ) (Ti1.01−y Mn y )O3 ·zSiO2 and sintered in air. The Ca content as well as the amount of doped Mn were varied ranging from 4–20 mol% and 0.02–0.04 mol%, respectively. Up to 4 mol% Si was added using a new method as well as by the classical means as solid silica. In the new method, the desired quantity of Si(OC2O5)4 (Si(OEt)4), contained in dry tetrahydrofurane (THF), was dropped under a slight stream of inert gas into the vigorously stirred aqueous slurry which was manufactured after the calcination process. The addition of Si by this technique was found to result in a homogenization of the microstructure and an improvement in electrical properties. The effect of Si on electrical properties is explained by the influence of the observed second phase on the equilibrium of Ba vacancies. The results of further variation of Ca and Mn contents are presented.

The aim of our study was to examine the cavernous smooth-muscle electric activity in normal and impotent patients as well as in those with (presumably) well-defined neurologic lesions. Single potential analysis of cavernous electric activity (SPACE) was done in 12 consecutive impotent patients, 34 normal patients, and 19 patients referred especially for SPACE. In the normal patients, similar potentials with a mean duration of 9.5 s, a mean amplitude of 153 μV and a mean polyphasity of 8.5 were recorded (cutoff frequencies, 2–2000 Hz), with cutoff frequencies set at 0.5–500 Hz, the mean duration was 12.8 s, amplitude was 444 μV and the mean polyphasity was 13.8 Upper spinal cord lesions showed potentials of long duration as well as whips and bursts. Patients with lower motor-neuron lesions showed either short potentials of high amplitude or potentials of small amplitude. In 49% of the impotent patients, abnormal SPACE was found. Our results suggest that SPACE is a reproducible and minimally invasive method for the diagnosis of autonomic neurogenic impotence.

The formation of fresnoite (Ba2TiSi2O8) from BaTi1.01O3.02 by addition of SiC was investigated in the temperature range from 700 to 1350 °C. Solid state reactions at the interface of grains indicate a formation of fresnoite below the temperature of liquid-phase-formation at about 1250 °C.