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Fetal neuroprotection

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Arne Jensen
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Das vorliegende Buch ‚The Cord Blood Story VIII’ gibt einen Überblick über die von uns erreichten Ziele auf dem Wege zur Einführung der autologen Stammzelltherapie zur Behandlung Frühkindlicher Hirnschäden im Jahr 2021, wobei die Entscheidung eine Aktiengesellschaft zu gründen und einen Börsengang zu erwägen ein wirklicher Durchbruch war. Auslöser war, daß der Managing Director der Nasdaq Nordic in Stockholm Kontakt mit uns über LinkedIn aufnahm, weil er unseren Therapieansatz und das Geschäftsmodell hoch spannend fand. Er organisierte eine Online-Konferenz mit dem ‚Head of Listings’, auf der wir und die Nasdaq Nordic sich vorstellten und das weitere Vorgehen besprachen. Die folgende Resonanz per Email war außergewöhnlich positiv („Congratulations on a fantastic company! I believe this would be a great fit and look forward to working with you to explore this further.”), so daß wir gut motiviert die Mammutaufgabe in Angriff nahmen. Die vielfältigen Aktivitäten erforderten mehrere Online-Sitzungen pro Woche, um die Aktiengesellschaft ‚BrainRepair AB (Aktiebolag)’ zu gründen und das ‚Information Memorandum (IM)’ vorzubereiten. Die juristische Begleitung übernahm die Großkanzlei Baker McKenzie, die global aufgestellt ist und vor wenigen Jahren noch von Christine Lagarde, der EZB Präsidentin, verantwortlich geleitet wurde. Als Wirtschaftsprüfungsgesellschaft unterstützt uns KPMG und als Investmentbank Carlsquare GmbH, die in Skandinavien und Deutschland an mehreren Standorten tätig ist.
Arne Jensen
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Kreißsaalführungsseminar B-O-C-H-U-M: B - BEL-Entbindung (A.Feige) O - Organisation und Dokumentation im Kreißsaal (W. Müller, M. Kumbartski) C - CTG-Kurs und Risikomanagement (R. Berger, J. Middelanis) H - Hands on am Phantom: Glocke-ZangeSchulterdystokie (K. Marschner, B. Holmer, B. Karbowski) U - Untersuchung und Reanimation des Neugebornen (N. Teig) M - Maternaler Notfall (A. Keck, G. Lincke)
Arne Jensen
added 2 research items
A MODEL OF NEONATAL CEREBRAL ISCHEMIA IN RATS (‘LEVINE’) TO STUDY NEUROPROTECTION AND NEUROREGENERATION J. MIDDELANIS1, H.-M. VAIHINGER1; Y. GARNIER1, K. GOTTMANN2, H. DINSE3, A. JENSEN1 1 Department of Obstetrics & Gynecology, University of Bochum 2 Institute of Cell Physiology, University of Bochum 3 Department of Neuroinformatics, University of Bochum Experimental evidence has shown that neuroprotective strategies using pharmacologic agents or moderate cerebral hypothermia may alleviate perinatal brain damage. Using the neonatal rat model we tested the neuroprotective effects of creatine against hypoxic-ischemic injury in the immature brain. We measured neuronal cell damage in 7-day-old rat pups that had undergone unilateral carotid artery occlusion followed by 80 min of hypoxia. Neuronal cell injury was significantly lower in the cortex of the neonatal rats that received creatine (3 g/kg) s.c. This was also true for the evaluated subfields in the hippocampus. From these results we conclude that creatine protects the immature brain from hypoxic-ischemic injury. Though neuroprotection by pharmacologic agents is possible, so far no convincing strategies are available for regeneration of damaged nervous structures in the perinatal period. Therefore we will now study the potential of cord blood derived stem cells to reconstitute brain damage caused by a hypoxic-ischemic insult in the perinatal period in the ‘Levine-model’. Seven–day-old Wistar rat pups are exposed to ischemia by ligation of the left common carotid artery and subsequent hypoxia will be induced by exposure to a hypoxic gas mixture (8% oxygen, 92% nitrogen) for 80 min. Seven days after the insult, rat pups will receive a transplantation of mononuclear cells prepared from human umbilical cord blood by density gradient centrifugation or in vitro pre-differentiated cells from the same source. Cells will be applied by stereotactically controlled intraventricular injection (either contra- or ipsilateral to the ischemic insult) or, alternatively, by intraperitoneal injection. At various timepoints after transplantation (7 d, 14 d, 28 d, 3 month, 6 month, 12 month) the rats will be examined for the fate of the transplanted cells. Evaluation of 'homing' and differentiation will be perfomed by immunohistochemical analysis. The restoration of physiological functions will be investigated by movement tests. (PDF) Middelanis et al., 2002 Abstract Symposium 2002, p. 9. Available from: https://www.researchgate.net/publication/282847357_Middelanis_et_al_2002_Abstract_Symposium_2002_p_9 [accessed Sep 24 2020].
CEREBRAL ISCHEMIA AND UMBILICAL STEM CELL TRANSPLANTATION IN CHRONICALLY PREPARED FETAL SHEEP Y. GARNIER1, H.-M. VAIHINGER1, J. MIDDELANIS1, O. BRÜSTLE2, A. JENSEN1 1Department of Obstetrics & Gynecology, University of Bochum 2Institute of Reconstructive Neurobiology, University of Bonn Objective: Hypoxic-ischemic cerebral damage is an important contributor to perinatal mortality and morbidity including long-term neurological sequalae in term and preterm fetuses. Hypoxic-ischemic insults are usually causing parasagittal brain lesions and affect the parietal and occipital regions in particular. This form of damage has been reproduced in the chronically prepared fetal sheep model, which has been in use for years in Bochum. Experimental evidence has shown that neuroprotective strategies using pharmacologic agents may alleviate perinatal brain damage. However, so far no convincing strategies are available for regeneration of damaged nervous structures in the perinatal period. Therefore, one of the most urgent tasks for scientists and clinicians will be to explore the enormous potential of cell replacement therapies using stem cells in general and umbilical cord blood stem cells in particular to provide a future therapeutic approach for perinatal neuronal repair. Material and Methods: Fetal sheep will be chronically instrumented at 0.7 of gestation. The ewe will be anesthetized by subarachnoid injection of 0.75% bupivacaine at the lower spine, and will be operated under sterile conditions. The fetal hindlimbs will be exposed through a small incision of the uterus. Using local anesthesia polyvinyl catheters will be inserted into the inferior vena cava of the fetus. Furthermore, a catheter will be placed in a cotyledonary vein and its tip will be advanced to the umbilical vein. The uterine incision will be closed and a second uterine incision will be performed over the fetal snout in order to exteriorize the head and neck of the fetus. Catheters will be inserted into the fetal ascending aorta via the right brachial artery. Furthermore, both fetal common carotic arteries will be prepared. After measurements of blood gases and acid base balance global cerebral ischemia will be induced by bilateral occlusion of the carotid arteries for 30 min. All catheters will be filled with heparin, plugged, and passed subcutaneously to the ewe’s flank, where they will be exteriorized and protected by a pouch sewn to the skin. Sampling of fetal blood and flushing of the catheters will be repeated daily. At +24 h, approx. 1-2 x 107 mononuclear cells prepared from human umbilical cord blood will be intravenously transfused to the fetus at a rate of 0.5 ml/min (10 ml total volume). The delay between the ischemic insult and the transplantation of cells will be extended up to two weeks in further experiments. At the end of the experiment (at +120 h or later in further experiments) the ewe will be anaesthetized for perfusion fixation. The brain will be dissected and immediately placed in ice-cold fixative without removal of the meninges. Furthermore, organ samples will be taken from spleen, liver, lung, bone marrow and cotyledons. Results: In a promising pilot experiment, cerebral ischemia was induced by occlusion of both carotid arteries in utero in chronically prepared fetal sheep. One day after the insult, mononuclear cells from human umbilical cord blood were applied to the fetus via the umbilical vein. Three days after transplantation, the fetal brain was examined for both damage and evidence of incorporated human cells. Preliminary evaluation indicates Page 2 severe parasaggital neuronal degeneration in the host cortex. DNA in situ hybridization detecting a human alu-repeat element revealed numerous labeled cells, some of which also expressed the neural progenitor specific marker glial fibrillary acidic protein (GFAP). Conclusion and Outlook: Our preliminary results point to the migration of transplanted cells and, furthermore, indicate that differentiation commences in vivo. Thus, the planned series of studies is essential to solve important questions regarding therapeutical approaches using umbilical cord blood derived stem cells for the regeneration of damage of the nervous system. (PDF) Garnier et al., 2002 Abstract Symposium 2002, p. 7 and 8. Available from: https://www.researchgate.net/publication/282847423_Garnier_et_al_2002_Abstract_Symposium_2002_p_7_and_8 [accessed Sep 24 2020].
Arne Jensen
added a research item
As is likely true for most researchers, it was with utmost pleasure that I have read Talha Burki's expert interview of the 2019 Nobel Laureates for Physiology or Medicine. Their innate curiosity, reasoning, and deep understanding along with their joy of discovery comes to light in a most inspiring and instructive way. Their discovered cellular HIF oxygen sensing mechanism cannot be overestimated in its importance for living organisms - particularly for the beginning of life. At close look, the antecedents of the discovered HIF mechanism stem from foetal physiology since throughout intrauterine relative to post-natal life, oxygen is scarce. 1 It is an indispensable prerequisite for growth, undisturbed development, and wellbeing that metabolic drive of growing cells is sensibly adjusted to the oxygen available. Moreover, this physiologic concept has intact survival value when poor intrauterine oxygen supply is further reduced by deminished uterine and/or umbilical foetal oxygen delivery causing growth retardation, asphyxia, disability, or fatality. 1, 2 Therefore, not surprisingly, first observations that oxygen delivery determines oxygen consumption and hence metabolic drive were made during foetal life, in the conceptus, body parts, organs, and cells from foetal muscles, myocardium, and glia. 1, 2, 3, 4 This conclusive evidence pointed to oxygen itself being the regulator to reduce or increase the cells' metabolism, being particularly important during transition from intrauterine to post-natal life. It is utmost gratifying and rewarding that the actual mechanism based on HIF and its degradation through hydroxylating ambient oxygen atoms has been deciphered by the laureates as one of the fundamental mechanisms of life. References 1. Jensen A, Berger R (1991) Fetal circulatory responses to oxygen lack Journal of Developmental Physiology 16, 181-207 2. Jensen A, Hohmann M, Künzel W (1987) Dynamic changes in organ blood flow and oxygen consumption during acute asphyxia in fetal sheep Journal of Developmental Physiology 9, 543-559 3. Braems G, Jensen A (1991) Hypoxia reduces oxygen consumption of fetal skeletal muscle cells in monolayer culture Journal of Developmental Physiology 16(4):209-15 4. Jensen A, Roman C, Rudolph AM (1991) Effects of reducing uterine blood flow on fetal blood flow distribution and oxygen delivery Journal of Developmental Physiology 15, 309-323 - 5. Manuscript number: THELANCET-D-19-06784 Title: The Lancet Correspondence, Vol.394 | Number 10207 | Oct 19, 2019 2019 Nobel Prize awarded for work on oxygen regulation Oxygen delivery determines oxygen consumption Dear Professor Jensen, Thank you for submitting your Letter to The Lancet. Having discussed your Letter with the Editor-in-Chief, and weighing it up against other submissions we have under consideration, I am sorry to say that we are unable to accept it for publication. Please be assured that your Letter has been carefully read and discussed by the Editors. Thank you for your interest in The Lancet, I hope this decision does not deter you from considering us again in the future. Yours sincerely Josefine Gibson Senior Editor The Lancet
Arne Jensen
added a research item
This is a subsection from a review in which the concept that oxygen delivery determines cellular oxygen consumption was first presented before the cells' oxygen sensing discovery was made (HIF mechanism - Nobel Prize 2019). Fetal circulatory responses to oxygen lack. Jensen A, Berger R. J Dev Physiol. 1991 Oct;16(4):181-207. Department of Obstetrics and Gynaecology, University of Giessen, Germany. https://www.researchgate.net/publication/21344116_Fetal_circulatory_response_to_oxygen_lack - Abstract: The knowledge on fetal and neonatal circulatory physiology accumulated by basic scientists and clinicians over the years has contributed considerably to the recent decline of perinatal morbidity and mortality. This review will summarize the peculiarities of the fetal circulation, the distribution of organ blood flow during normoxemia, and that during oxygen lack caused by various experimental perturbations. Furthermore, the relation between oxygen delivery and tissue metabolism during oxygen lack as well as evidence to support a new concept will be presented along with the principal cardiovascular mechanisms involved. Finally, blood flow and oxygen delivery to the principal fetal organs will be examined and discussed in relation to organ function. The fetal circulatory response to hypoxemia and asphyxia is a centralization of blood flow in favour of the brain, heart, and adrenals and at the expense of almost all peripheral organs, particularly of the lungs, carcass, skin and scalp. This response is qualitatively similar but quantitatively different under various experimental conditions. However, at the nadir of severe acute asphyxia the circulatory centralization cannot be maintained. Then there is circulatory decentralization, and the fetus will experience severe brain damage if not expire unless immediate resuscitation occurs. Future work in this field will have to concentrate on the important questions, what factors determine this collapse of circulatory compensating mechanisms in the fetus, how does it relate to neuronal damage, and how can the fetal brain be pharmacologically protected against the adverse effects of asphyxia.
Yves Garnier
added 2 research items
Objective: The aim of this study is to present the current state of neuroprotection for prematurely born infants.
Mit einem verfrühten vorzeitigen Blasensprung (PPROM) bei einer Frühgeburt gehen verschiedene maternale und fetale Komplikationen wie Infektion, pulmonale Hypoplasie, vorzeitige Plazentalösung und geburtswirksame Wehentätigkeit einher. Es werden Empfehlungen zum initialen und expektativen Management, abhängig von Alter und Lebensfähigkeit des Kindes, gegeben.
Yves Garnier
added 2 research items
Objective:We investigated the effects of magnesium on metabolic disturbances in hippocampal slices prepared from fetal guinea pigs after oxygen-glucose deprivation (OGD).
Objective:There is increasing evidence from animal experiments that mild hypothermia induced during or after cerebral ischemia might protect the immature brain from neuronal cell damage. However, the exact interrelation between the postischemic time delay and the degree of mild hypothermia by which to achieve neuroprotective effects on ischemic insults of different severity has not yet been elucidated systematically. To determine optimal neuroprotection, we studied the intention between these variables in a recently modified hippocampal slice model.
Yves Garnier
added 18 research items
Asphyxia is one of the major causes of perinatal brain damage and neuronal cell loss, which may result in psychomotor deficits during later development. It has been shown previously that the immature brain can be protected from ischemic injury by flunarizine, a class IV calcium antagonist. However, cardiovascular side-effects of flunarizine, when applied at the dosages used in those studies, have been reported. Recently, the present authors were able to demonstrate that even by injecting flunarizine at a far lower dosage (1 mg kg-1 estimated bodyweight) neuronal cell damage, caused by occlusion of both carotid arteries for 30 min, can be reduced in fetal sheep near term. The aim of the present study was, therefore, to examine whether low-dose flunarizine affects fetal cardiovascular responses to acute asphyxia in sheep near term. Ten fetal sheep were chronically instrumented at a mean gestational age of 132 +/- 1 days (term is at 147 days). Fetuses from the study group received a bolus injection of flunarizine (1 mg kg-1 estimated fetal weight) 60 min before asphyxia, whereas the solvent was administered to the fetuses from the control group. Organ blood flows, physiological variables and plasma concentrations of catecholamines were measured before, during and after a single occlusion of uterine blood flow for 2 min (i.e. at 0, 1, 2, 3, 4, and 30 min). Before asphyxia, the distribution of combined ventricular output and physiological variables, as well as concentrations of catecholamines, in fetuses from the control group were in the normal range for chronically prepared fetal sheep near term. During acute asphyxia there was a redistribution of cardiac output towards the central organs accompanied by a pronounced bradycardia and a rapid increase in arterial blood pressure. After asphyxia circulatory centralization did not resolve quite as rapidly as it developed, but was almost completely recovered at 30 min after the insult. There were nearly no differences in the time course of physiological and cardiovascular variables measured before, during and after acute intrauterine asphyxia between the control and study groups. From the present study it was concluded that low-dose flunarizine does not affect short-term fetal circulatory responses to acute asphyxia in sheep near term.