Topical Review: Animal Models of Germinal Matrix Hemorrhage

Balasubramaniam, Janani; Bigio, Marc R. Del

doi:10.1177/08830738060210050201

Cited by 61 publications

(62 citation statements)

References 82 publications

(78 reference statements)

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“…These include studies of needle injected blood or collagenase into the cerebral intraventricular space or alterations in haemodynamic parameters, i.e. blood pressure, circulating blood volume, serum osmolarity, partial carbon dioxide or oxygen levels [36]. None of these animal models can be considered ideal, but in combination each of them aid in obtaining a better understanding of the underlying pathophysiological mechanisms of IVH.…”

Section: Aetiology and Studies Of Hb-related Brain Damage In Animal Mmentioning

confidence: 99%

Pathophysiology of extracellular haemoglobin: use of animal models to translate molecular mechanisms into clinical significance

Smeds

Romantsik

Jungner

et al. 2016

ISBT Science Series

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Pathophysiology of extracellular haemoglobinuse of animal models to translate molecular mechanisms into clinical significance Smeds, Emanuel; Romantsik, Olga; Jungner, Åsa; Erlandsson, Lena; Gram, Magnus General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. AbstractThe blood's major gas-exchange is carried out by haemoglobin, a heme-protein that binds iron and oxygen and can have potentially dangerous side effects due to redox reactions.Haemoglobin is a very abundant molecule with a concentration of 150 g/L in whole blood, resulting in almost one kg haemoglobin in an adult human body. Normal turn-over of red blood cells results in significant haemoglobin release, and pathological conditions that involve haemolysis can lead to massive haemoglobin levels. To control for the potential threat of extracellular haemoglobin, several protective defence systems have evolved.Many pathological conditions, diseases as well as iatrogenic conditions, such as infusion of haemoglobin-based oxygen carriers, cerebral intraventricular haemorrhage, extracorporeal circulation and the pregnancy complication preeclampsia, involve abnormal levels of haemolysis and extracellular haemoglobin. Although quite different aetiology, the haemoglobin-induced damage often cause similar clinical sequelae and symptoms. Here we will give an overview of the pathophysiological mechanisms of extracellular haemoglobin and its metabolites. Furthermore, we will highlight the use of animal models in advancing the understanding of these mechanisms and discuss how to utilize the knowledge in the development of new and better pharmaceutical therapies.

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Section: Aetiology and Studies Of Hb-related Brain Damage In Animal Mmentioning

confidence: 99%

Pathophysiology of extracellular haemoglobin: use of animal models to translate molecular mechanisms into clinical significance

Smeds

Romantsik

Jungner

et al. 2016

ISBT Science Series

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“…Furthermore, typical GMH among premature infants primarily occurs in the caudate nucleus, the floor of the lateral ventricle, and the caudothalamic groove, in which germinal matrix is abundant. 2,4,12 Thus, there may be a possibility that previously reported cases were also cases of MIPH rather than delayed GMH. We assume that this phenomenon occurs when a sudden environmental transition takes place in the immature but rapidly growing brains of infants.…”

Section: Discussionmentioning

confidence: 95%

Multifocal intraparenchymal hemorrhages after ventriculoperitoneal shunt surgery in infants

Choi¹,

Kim²,

Wang³

et al. 2014

PED

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Object Ventriculoperitoneal (VP) shunt surgery is the most common treatment for hydrocephalus. In certain situations, uncommon complications can occur after shunting procedures. The authors undertook this study to analyze the clinical characteristics of pediatric patients who developed multifocal intraparenchymal hemorrhages (MIPHs) as a complication of shunt surgery. The authors also analyzed the risk factors for MIPH in a large cohort of patients with hydrocephalus. Methods This study included all pediatric patients (age < 18 years) who underwent VP shunt surgery at the authors' institution between January 2001 and December 2012. During this period, 507 VP shunt operations were performed in 330 patients. Four of these patients were subsequently diagnosed as having MIPH. The authors analyzed the clinical characteristics of these patients in comparison with those of the entire group of shunt-treated patients. Results The incidence of MIPH was 1.2% (4 of 330 cases) for all pediatric patients who underwent VP shunt placement but 2.9% (4 of 140 cases) for infants less than 1 year old. When the analysis was limited to patients whose corrected age was less than 3 months, the incidence was 5.3% (4 of 76 cases). Of the 4 patients with MIPH, 2 were male and 2 were female. Their median age at surgery was 54 days (range 25–127 days), and in all 4 cases, the patients' corrected age was less than 1 month. Three patients were preterm infants, whereas one patient was full-term. None of these patients had a prior history of intracranial surgery (including CSF diversion procedures). All showed severe hydrocephalus during the preoperative period. Their clinical courses as patients with MIPH were comparatively favorable, despite the radiological findings. Conclusions MIPH is a rare but not negligible complication of VP shunt surgery. This complication might be a unique phenomenon in infants, especially young, preterm infants with severe hydrocephalus. Moreover, the absence of previous intracranial procedures might be one of the risk factors for this complication. The rapid alteration of brain conditions in the setting of immaturity might cause MIPH. To prevent this complication, the authors recommend that pressure settings of programmable valves should be gradually adapted to the target pressure.

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“…Thus, in order to understand how GMH impacts NSPC and cortical development in the intermediate group, in whom outcomes appear to be most variable and who may have the most to gain from intervention, a more subtle injury model is needed. Currently available physiological techniques [52] cannot be used to model low-grade GMH as it causes widespread haemorrhage within the brain parenchyma [50] and may also be confounded by the use of glycerol, which has been shown to impact cortical development independently [54] . Similarly, the interpretation of results following the injection of collagenase into the SVZ [25] , whilst reducing bolus size, is significantly limited due to the potentially confounding affect of collagenase on the NSPC.…”

Section: Discussionmentioning

confidence: 99%

“…Given the clinical significance of GMH, numerous models in different animal species have been trialled [50] ; however, to date all models have focused on the severe end of the spectrum with extensive cortical injury where diffuse haemorrhage and marked disturbances in behaviour are seen [25,51,52] . It is well recognised that NSPC within the SVZ are exquisitely sensitive to microenvironmental cues [9,10] and further that haemorrhage within the ventricle alters the expression of NSC modulators, such as TGFβ [53] .…”

Section: Discussionmentioning

confidence: 99%

Moderate-Grade Germinal Matrix Haemorrhage Activates Cell Division in the Neonatal Mouse Subventricular Zone

et al. 2016

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Precise temporal and spatial control of the neural stem/progenitor cells within the subventricular zone (SVZ) germinal matrix of the brain is important for normal development in the third trimester and the early postnatal period. The high metabolic demands of proliferating germinal matrix precursors, coupled with the flimsy structure of the germinal matrix cerebral vasculature, are thought to account for the high rates of haemorrhage in extremely- and very-low-birth-weight preterm infants. Germinal matrix haemorrhage can commonly extend to intraventricular haemorrhage (IVH). Because neural stem/progenitor cells are sensitive to microenvironmental cues from the ventricular, intermediate, and basal domains within the germinal matrix, haemorrhage has been postulated to impact neurological outcomes through aberration of normal neural stem/progenitor cell behaviour. We developed an animal model of neonatal germinal matrix haemorrhage using stereotactic injection of autologous blood into the mouse neonatal germinal matrix. Pathological analysis at 4 days postinjury showed high rates of intraventricular extension and ventricular dilatation but low rates of parenchymal disruption outside the germinal zone, recapitulating key features of human “Papile grade III” IVH. At 4 days postinjury we observed proliferation in the wall of the lateral ventricle with significantly increased numbers of transient amplifying cells within the SVZ and the corpus callosum. Analysis at 21 days postinjury revealed that cortical development was also affected, with increased neuronal and concomitant reduced oligodendroglial differentiation. At the molecular level, we showed downregulation of the expression of the transmembrane receptor Notch2 in CD133^+ve cells of the SVZ, raising the possibility that the burst of precocious proliferation seen in our experimental mouse model and the skewed differentiation could be mediated by downregulation of the Notch pathway within the proximal/ventricular domain. These findings raise the possibility that Notch regulation plays a critical role in mediating the response of the neonatal SVZ to ischaemic and haemorrhagic insults.

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Topical Review: Animal Models of Germinal Matrix Hemorrhage

Cited by 61 publications

References 82 publications

Pathophysiology of extracellular haemoglobin: use of animal models to translate molecular mechanisms into clinical significance

Pathophysiology of extracellular haemoglobin: use of animal models to translate molecular mechanisms into clinical significance

Multifocal intraparenchymal hemorrhages after ventriculoperitoneal shunt surgery in infants

Moderate-Grade Germinal Matrix Haemorrhage Activates Cell Division in the Neonatal Mouse Subventricular Zone

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