Model prediction of subendocardial perfusion of the coronary circulation in the presence of an epicardial coronary artery stenosis

The subendocardium is most vulnerable to ischemia, which is ameliorated by relaxation during diastole and increased coronary pressure. Recent clinical techniques permit the measuring of subendocardial perfusion and it is therefore important to gain insight into how measurements depend on perfusion conditions of the heart. Using data from microsphere experiments a layered model of the myocardial wall was developed. Myocardial perfusion distribution during hyperemia was predicted for different degrees of coronary stenosis and at different levels of Diastolic Time Fraction (DTF). At the reference DTF, perfusion was rather evenly distributed over the layers and the effect of the stenosis was homogenous. However, at shorter or longer DTF, the subendocardium was the first or last to suffer from shortage of perfusion. It is therefore concluded that the possible occurrence of subendocardial ischemia at exercise is underestimated when heart rate is increased and DTF is lower

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Challenges to economic integration and social inclusion of Syrian refugees in Turkey

Purpose: The following question drove this research: Would the pursuit of a rights-based approach, one that considers local dynamics and political sensitivities result in greater economic integration and social inclusion of Syrian refugees in Turkey? The paper aims to discuss this issue. Design/methodology/approach: This piece draws on independent research the author conducted in Turkey and other frontline states to the war in Syria from 2016 to 2018. Findings: Despite a shift in government policy toward Syrian refugees, without an overarching rights-based approach that includes the participation of all stakeholders and considers local dynamics and political sensitivities, enhancing the livelihood security of Syrian refugees and vulnerable members of host communities remains bleak in Turkey. Originality/value: This original paper closely examines the Government of Turkey’s response to the humanitarian crisis that was precipitated by the armed conflict in Syria. The paper also examines the socioeconomic dynamics and increased tensions between the Syrian refugee and host communities

Entwicklung eines Tests zur Ablösung von Tierversuchen beim Nachweis von Pertussis-Toxin

Weltweit existiert keine zum Tierversuch alternative Methode, um adsorbierte Pertussis-Impfstoffe auf restliche Toxin-Aktivität hin zu untersuchen. Der im Europäischen Arzneibuch vorgeschriebene Tierversuch besitzt nach Erfahrungen der Industrie, internationaler Prüfbehörden sowie des Paul- Ehrlich-Institutes eine schlechte Aussagekraft. Er ist wenig standardisierbar und weist häufig ein zweifelhaftes Ergebnis auf, so dass Wiederholungen und damit einhergehend ein hoher Verbrauch an Versuchstieren unumgänglich sind. Enthält der Impfstoff Reste von nicht-inaktiviertem Pertussis-Toxin (PTx), muss mit schweren und schwersten Nebenwirkungen bei den Impflingen gerechnet werden. In dieser Arbeit wurde ein In vitro-Nachweis für aktives PTx entwickelt. rnAngeregt durch Publikationen, wonach Pertussis-Toxin humane Monozyten aktiviert, wurde zunächst versucht, diesen Effekt zum Toxin-Nachweis auszunutzen. Die vorliegende Arbeit zeigt jedoch eindeutig, dass Pertussis-Toxin selbst nicht zur Stimulation humaner Monozyten führt. Vielmehr konnte nachgewiesen werden, dass die Aktivierung dieser Immunzellen auf Kontaminationen durch Lipopolysaccharide zurückzuführen ist. Damit wurden die Aussagen in den oben erwähnten Veröffentlichungen widerlegt. Dieses Ergebnis wurde bereits zur Publikation eingereicht. rnNunmehr wurden verschiedene Ansätze zum Nachweis von Pertussis-Toxin entwickelt, welche seine enzymatischen Aktivitäten als NAD-Glycohydrolase und ADP-Ribosyltransferase ausnutzen. Zunächst wurde versucht, die Hydrolyse von NAD zu ADP-Ribose und Nicotinamid photometrisch nachzuweisen. Wegen unbefriedigender Sensitivität wurde dieses Verfahren zu einem fluorometrischen Nachweis weiterentwickelt. Verwendet wurde hier fluorogenes etheno-NAD, welches von Pertussis-Toxin als Substrat akzeptiert wird. Letzteres Prinzip ist zum In vitro-Nachweis von Pertussis-Toxin geeignet, wird jedoch durch das in Impfstoffen häufig verwendete Adsorbens Aluminiumhydroxid gestört. Deshalb wurde dieser Ansatz aufgegeben und ein neuer Weg verfolgt, welcher am Energiestoffwechsel von humanen Zellen ansetzt. Eine Konsequenz des Angriffs von Pertussis-Toxin auf seine Zielzellen im Respirationstrakt besteht – nach komplexen Reaktionen des Signaltransduktionsweges – im Absenken des ATP-Gehaltes. Als menschliche Surrogat-Zellen wurden frisch isolierte periphere mononukleäre Zellen (PBMCs) sowie die permanente Lymphozyten-Zelllinie Jurkat eingesetzt und deren ATP-Gehalt mittels Luziferin-Luziferase-Lumineszenz gemessen. Der Test wird nicht durch Lipopolysaccharid gestört und auch Aluminiumhydroxid übt erst nach mehreren Stunden Inkubation einen interferierenden Einfluss aus. Ebenso konnte aktives Pertussis-Toxin mit Hilfe kryokonservierter PBMCs detektiert werden, auch in orientierenden Versuchen mit komplexen Impfstoffen. Der Pertussis-ATP-Test kommt der In vivo-Situation in der Zelle sehr nahe, weil beide Untereinheiten des Toxins in einem Test überprüft werden. Demnach soll er Bestandteil einer geplanten internationalen Studie zu alternativen Pertussis-Toxin-Testungen sein.Worldwide no alternative method exists which is suitable to replace animal testing for residual Petussis Toxin activity in adsorbed pertussis vaccines. According to the opinion of industry, international authorities, and the Paul-Ehrlich-Institute, the animal test required by the European Pharmacopoeia exhibits, weak significance. This test is hard to standardise and is affected by inconsistencies, which make repetitions and accompanying use of high resources of animals inevitable. Residues of active Pertussis Toxin in the final products cause severe side effects. In this work an in vitro test for the detection of active Pertussis Toxin was developed. rnMotivated by publications describing how Pertussis Toxin activates human monocytes, it was attempted to exploit this effect. However, in this work it was clearly shown that Pertussis Toxin is not able to stimulate human monocytes. In fact, contaminating lipopolysaccharide caused the activation of these human immune cells. Therefore, the above mentioned publications were disproved. This result is submitted for publication.rnFor this reason, new principles of detection which utilise Pertussis Toxins enzymatic activity such as NAD-glycohydrolase and ADP-ribosyltransferase were investigated. At first it was attempted to take advantage of the hydrolysis of NAD to ADP-ribose by photometric measurement. Due to the need of improved sensitivity the objective method was altered to a fluorometric approach with fluorescent etheno-NAD as an accepted substrate of Pertussis Toxin. This principle is suitable as an in vitro method for detecting active Pertussis Toxin, but is interfered by the common used adjuvant aluminium hydroxide. Therefore this approach was abandoned and a new principle focusing on the energy turnover of human cells was established. As a consequence of being infected by Pertussis Toxin, respiratory tract cells showed a decrease in their ATP level as a consequence of the affected signal transduction pathway. As human surrogate-cells freshly isolated peripheral blood mononuclear cells (PBMCs) as well as the permanent lymphocyte cell line Jurkat were used and their ATP levels were monitored by luciferin luciferase luminescence. This test is not influenced by lipopolysaccharide and aluminium hydroxide disturbance does not occur until after several hours of incubation. In addition this test is even able to detect active Pertussis Toxin with cryopreserved PBMCs and orientative investigations of complex vaccines showed encouraging results. The Pertussis-ATP-Test is very similar to the in vivo situation of the cells, because both subunits of the Pertussis Toxin are examined in one test. Consequently this new method will be subject of a prospective international study for testing active Pertussis Toxin in alternative ways

Haploinsufficiency of CELF4 at 18q12.2 is associated with developmental and behavioral disorders, seizures, eye manifestations, and obesity

Only 20 patients with deletions of 18q12.2 have been reported in the literature and the associated phenotype includes borderline intellectual disability, behavioral problems, seizures, obesity, and eye manifestations. Here, we report a male patient with a de novo translocation involving chromosomes 12 and 18, with borderline IQ, developmental and behavioral disorders, myopia, obesity, and febrile seizures in childhood. We characterized the rearrangement with Affymetrix SNP 6.0 Array analysis and next-generation mate pair sequencing and found truncation of CELF4 at 18q12.2. This second report of a patient with a neurodevelopmental phenotype and a translocation involving CELF4 supports that CELF4 is responsible for the phenotype associated with deletion of 18q12.2. Our study illustrates the utility of high-resolution genome-wide techniques in identifying neurodevelopmental and neurobehavioral genes, and it adds to the growing evidence, including a transgenic mouse model, that CELF4 is important for human brain development