[Recommendations of the S3 Guideline "Use of Extracorporeal Circulation (ECLS/ ECMO) for Cardiac and Circulatory Failure" of the Association of Scientific Medical Societies in Germany]. / Empfehlungen der S3-Leitlinie (AWMF) "Einsatz der extrakorporalen Zirkulation (ECLS/ECMO) bei Herz- und Kreislaufversagen".

In recent years, the use of mechanical support for patients with cardiac or circulatory failure has continuously increased, leading to 3,000 ECLS/ECMO (extracorporeal life support/extracorporeal membrane oxygenation) implantations annually in Germany. Due to the lack of guidelines, there is an urgent need for evidence-based recommendations addressing the central aspects of ECLS/ECMO therapy. In July 2015, the generation of a guideline level S3 according to the standards of the Association of the Scientific Medical Societies in Germany (AWMF) was announced by the German Society for Thoracic and Cardiovascular Surgery (GSTCVS). In a well-structured consensus process, involving experts from Germany, Austria and Switzerland, delegated by 16 scientific societies and the patients' representation, the guideline "Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure" was created under guidance of the GSTCVS, and published in February 2021. The guideline focuses on clinical aspects of initiation, continuation, weaning and aftercare, herein also addressing structural and economic issues. This article presents an overview on the methodology as well as the final recommendations.

[Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure : Short version of the S3 guideline]. / Einsatz der extrakorporalen Zirkulation (ECLS/ECMO) bei Herz- und Kreislaufversagen : Kurzversion der AWMF-S3-Leitlinie.

In Germany, a remarkable increase regarding the usage of extracorporeal membrane oxygenation (ECMO) and extracorporeal life support (ECLS) systems has been observed in recent years with approximately 3000 ECLS/ECMO implantations annually since 2015. Despite the widespread use of ECLS/ECMO, evidence-based recommendations or guidelines are still lacking regarding indications, contraindications, limitations and management of ECMO/ECLS patients. Therefore in 2015, the German Society of Thoracic and Cardiovascular Surgery (GSTCVS) registered the multidisciplinary S3 guideline "Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure" to develop evidence-based recommendations for ECMO/ECLS systems according to the requirements of the Association of the Scientific Medical Societies in Germany (AWMF). Although the clinical application of ECMO/ECLS represents the main focus, the presented guideline also addresses structural and economic issues. Experts from 17 German, Austrian and Swiss scientific societies and a patients' organization, guided by the GSTCVS, completed the project in February 2021. In this report, we present a summary of the methodological concept and tables displaying the recommendations for each chapter of the guideline.

[Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure : Short version of the S3 guideline]. / Einsatz der extrakorporalen Zirkulation (ECLS/ECMO) bei Herz- und Kreislaufversagen : Kurzversion der AWMF-S3-Leitlinie.

In Germany, a remarkable increase regarding the usage of extracorporeal membrane oxygenation (ECMO) and extracorporeal life support (ECLS) systems has been observed in recent years with approximately 3000 ECLS/ECMO implantations annually since 2015. Despite the widespread use of ECLS/ECMO, evidence-based recommendations or guidelines are still lacking regarding indications, contraindications, limitations and management of ECMO/ECLS patients. Therefore in 2015, the German Society of Thoracic and Cardiovascular Surgery (GSTCVS) registered the multidisciplinary S3 guideline "Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure" to develop evidence-based recommendations for ECMO/ECLS systems according to the requirements of the Association of the Scientific Medical Societies in Germany (AWMF). Although the clinical application of ECMO/ECLS represents the main focus, the presented guideline also addresses structural and economic issues. Experts from 17 German, Austrian and Swiss scientific societies and a patients' organization, guided by the GSTCVS, completed the project in February 2021. In this report, we present a summary of the methodological concept and tables displaying the recommendations for each chapter of the guideline.

Clinical variability and expression of the NBN c.657del5 allele in Nijmegen Breakage Syndrome.

Patients affected by the autosomal recessive Nijmegen Breakage Syndrome (NBS [MIM 251260]) have possibly the highest risk for developing a malignancy of all the chromosomal instability syndromes. This reflects the profound disturbance to genomic integrity and cellular homeostasis that is caused by the mutation of the essential mammalian gene, NBN. Whilst null-mutation of Nbn is lethal in the mouse, NBS patients survive due to the fact that the common human founder mutation, found in over 90% of patients, is in fact hypomorphic and leads, by alternative translation, to varying amounts of a partially functional carboxy-terminal protein fragment, p70-nibrin. The expression level of p70-nibrin correlates with cancer incidence amongst patients. Using real-time PCR we have now found that the variation in p70-nibrin expression cannot be attributed to differences in mRNA quantity and that nonsense-mediated mRNA decay is not responsible for the observed variation. We discuss an alternative explanation for p70-nibrin expression variation.

Genital blood flow and endometrial gene expression during the preovulatory period after Prostaglandin F(2alpha)-induced luteolysis in different luteal phases in cows.

The aim of this study was to examine the hypothesis that follicular and uterine perfusion as well as endometrial gene expression during the ovulatory period differs after induction of luteolysis during the 1(st) follicular wave compared with the 2(nd) wave or in intact cycle. Nine healthy non-lactating Holstein-Friesian cows were examined during three estrous cycles. A prostaglandin F(2alpha) analogue (PGF) was administered randomly either on Day 7 (1(st) wave cycle) or Day 11 (2(nd) wave cycle) after detection of ovulation (=Day 1). No hormonal treatment was used in the intact cycle with spontaneous ovulation. Transrectal Doppler sonography was conducted daily after PGF injection and in the intact cycle beginning on Day 18 of the estrous cycle until ovulation. Follicular blood flow (FBF) was determined by measuring the maximum area of colour pixels on digitalized images of the follicles. Uterine blood flow was quantified by the time-averaged maximum velocity (UTAMV) and pulsatility index (PI) in both uterine arteries. Blood flow measurements were carried out on Days -1 and 0. Endometrial biopsy specimens were taken on Day 1 and analyzed for the gene expressions of estrogen, progesterone, oxytocin and VEGF receptors and eNOS and iNOS using RT-PCR. The interval from PGF injection to ovulation was shorter (P<0.05) in 1(st) wave cycles than in 2(nd) wave cycles. On Days 0 and -1, FBF was greater (P<0.05) in 1(st) wave cycles than in intact and 2(nd) wave cycles. On Day -1, UTAMV was greater (P<0.05) in 1(st) wave cycles than in intact and 2(nd) wave cycles. There were no differences (P>0.05) in FBF and UTAMV values between 2(nd) wave and intact cycles. No differences (P>0.05) were detected in the gene expressions of endometrial receptors and enzymes between intact, 1(st) and 2(nd) wave cycles. The results show that follicular and uterine perfusion during the ovulatory phase are higher after induction of luteolysis during the 1(st) follicular wave compared with the 2(nd) wave or intact cycle. There were no effects on endometrial gene expression.

Colour Doppler sonography of cystic ovarian follicles in cows.

The goals of the present study were to investigate whether colour Doppler sonography can be used to differentiate temporary from persistent ovarian follicles and follicles with luteal tissue from follicles without luteal tissue and to assess the response of follicular cysts to administration of a gonadotropin releasing hormone (GnRH) analogue. Fifty-four cows having ovarian follicular structures with a diameter of >15 mm but no corpus luteum were included. These cows were examined via B-mode and colour Doppler sonography. The same examinations were repeated 10 to 12 days later, and the cows with follicular cysts (n=17) received a GnRH analogue. Blood flow was measured before and 30 min after treatment. Ten to 12 days later, the response to treatment was assessed using B-mode sonography. While 31 of 54 follicles disappeared spontaneously (temporary follicles), 23 follicles persisted and were diagnosed as cystic ovarian follicles (COFs). There was no difference between temporary follicles and COFs in regard to total area, wall thickness or the perfused area. In the luteinized follicles (n=13), based on the plasma progesterone concentration, total area was twice as large, wall thickness was three times greater and the perfused area was 4.5 times larger than those of the non-luteinized follicles (n=41). The sensitivity of diagnosing luteinized follicles was 61.5% using B-mode sonography and 92.3% using colour Doppler sonography. Twelve cows responded to GnRH, and five cows did not. There was a trend (P=0.07) toward higher (59.3%) blood flow in the cyst wall 30 min after treatment in the responding cows compared with the non-responding cows. Our results showed that the perfused area more accurately reflects active luteal tissue than wall thickness. Thus, colour Doppler sonography is superior to B-mode sonography for differentiating follicular and luteal cysts and aids in the selection of treatment. However, exact prediction of COFs destined to regress or persist and the response of COFs to treatment with a GnRH analogue were not possible using colour Doppler sonography.

[Sonographic evaluation of the uterus in Holstein-Friesian cows without and with disturbances of the puerperium during the first 14 days postpartum]. / Sonographische Beurteilung des Uterus bei Holstein-friesian Kühen ohne und mit Puerperalstörungen in den ersten 14 Tagen post partum.

The aim of this study was to investigate if, compared with transrectal manual palpation, B-mode sonography provides additional information about the uterine structures and contents of Holstein-Friesian cows without and with disturbances during the early puerperal phase, that lead to a more precise diagnosis. The examinations were carried out once per cow either during the first four days p. p. (contraction phase, KPH) or on days 5 to 10 (desquamation phase, DPH) or on days 11 to 14 (regeneration phase, RPH) in 57 cows with undisturbed (UP) and 69 with disturbed puerperal phases (GP). The mean size of the uterus measured by transrectal palpation was 0.94 to 1.51 points (on a 6-point scale, p < 0.05) larger throughout the examination period and the fluctuation was 1.29 and 0.92 points (on a 4-point scale, p < 0.05) higher in GP cows compared with UP cows during the KPH and RPH, respectively. During the KPH, contractility of the uterus was 0.56 points (on a 3-point scale, p < 0.05) lower in GP cows compared with UP cows. Sonographically the cross sectional area of the most caudally located caruncle was 0.47 to 3.53 cm2 bigger (p < 0.05) in GP cows than in UP cows. The GP cows showed in the KPH a 0.21 cm thinner (p < 0.05) endometrium compared with the UP cows. In the DPH and RPH, the echogenicity was 1.63 and 1.04 points (on a 4-point scale, p < 0.05) higher and the intraluminal diameter of the uterine body was 0.49 to 0.67 cm greater (p < 0.05) in GP cows compared with UP cows, respectively. By means of dicriminant analysis 96.7% and 91.7% of the animals of the GP and UP group, respectively, where classified correctly during the DPH, whereas in the other two phases these proportions were between 70.0% and 87.5%. The results show that B-mode sonography is an additional valuable method for a more accurate differentiation of uterine involutionary processes between cows without and with disturbances of the puerperal phase.

Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein.

The human genetic disorder, Nijmegen breakage syndrome (NBS), is characterized by radiosensitivity, immunodeficiency and an increased risk for cancer, particularly B-cell non-Hodgkin lymphoma. The NBS1 gene codes for a protein, nibrin, involved in the processing/repair of DNA double-strand breaks and in cell cycle checkpoints. The majority of patients are homozygous for a founder mutation, a 5 bp deletion. This mutation is actually hypomorphic, since a functionally relevant truncated protein, of approximately 70 kDa, is produced by alternative translation. Null mutation of the homologous gene in mice is lethal; however, null-mutant murine cells can be rescued by a human NBS1 cDNA carrying the founder mutation. Clearly, the truncated p70-nibrin is able to sustain vital cellular functions of the full-length protein. We have used semi-quantitative immunoprecipitation to examine a panel of 26 lymphoblastoid B-cell lines from NBS patients for their level of p70-nibrin expression and correlate this with details of clinical phenotype provided by the two contributing centres. We find considerable variation in the amount of p70-nibrin in cell lines from different patients. Examination of clinical history indicated a clear and statistically significant correlation between p70-nibrin expression levels and lymphoma incidence. The variation in p70-nibrin levels between patients probably reflects the susceptibility of the alternative translation process to other genetic and non-genetic factors. Patients whose cells are able to maintain particularly high levels of the truncated p70-nibrin protein are at a lower risk for lymphoma than those patients with low levels of p70-nibrin in their cells.

Mild Nijmegen breakage syndrome phenotype due to alternative splicing.

Hypomorphic mutations of the NBS1 gene are responsible for Nijmegen breakage syndrome (NBS), characterized by microcephaly, chromosomal instability, radiosensitivity, immunodeficiency and high cancer predisposition. Over 90% of NBS patients are homozygous for the 657Delta5 mutation and are of Slavic origin; however, 10 further truncating mutations have been identified in patients of other ethnic origin. Partially functional proteins produced by alternative initiation of translation, and possibly diminishing the severity of the NBS phenotype, have been described for several NBS1 mutations. Here, we report a 53-year-old NBS patient, homozygous for the NBS1 mutation, 742insGG, in exon 7 and who presents with a particularly mild phenotype. In an attempt to find a potential molecular explanation for the mild phenotype observed, we carried out a conventional semi-quantitative and quantitative RT-PCR analyses which revealed two transcripts of almost equal amounts in the patient and her parents--the expected full-length transcript carrying the 742insGG mutation and a second transcript with deleted exons 6 and 7. The transcript was also observed in controls and other NBS patients, however, at quantities more than 100-fold lower than that in the patient described here. Because the skipping of exons 6 and 7 results in an internal in-frame deletion, which eliminates the truncating GG-insertion, we propose that this transcript may code for a partially functional protein of approximately 70 kDa that could be responsible for the unusually mild NBS phenotype observed in this patient. Indeed, complementation analysis of null-mutant mouse cells indicates that the alternatively spliced mRNA codes for a protein with significant functional capacity.