Generation of cells for cell-replacement therapy: Specification of neural precursors in vivo and in neural stem cell cultures

Cell replacement therapy of neurodegenerative disorders aims to substitute the degenerating cells with new functional neurons. Clinical trails with patients suffering from Parkinson’s or Huntington’s disease have generated proof-of-principle results that neural precursors taken from the developing human brain can survive upon grafting to the diseased brain and provide long-lasting symptomatic relief. However, further development of this type of therapy critically depends on the generation of an unlimited and standardized source of neural precursors that after transplantation differentiate into the proper neuronal subtypes. This requires knowledge on the molecular mechanisms responsible for the specification of neurons during development, and how cells with the potential for regional specific neuronal differentiation can be expanded in culture. The work of this thesis has focused on the role of the proneural gene Neurogenin2 in specification of the midbrain dopaminergic (mesDA) neurons, the cell population that degenerate in Parkinson’s disease. Additionally, we have studied to what extent neural stem cells isolated from the developing brain and expanded under growth-factor stimulation in culture maintain their regional specification. We show that Neurogenin2 is required in vivo for proper development of the mesDA neuron system, more specifically for the immature mesDA neuron precursors to adopt a neuronal fate. Furthermore, we successfully applied a new culture system for expansion of neural stem cells, the neural stem cell (NS cell) cultures, to neural precursors from different regions of the developing brain. We showed that even after extensive expansion cells in the NS cell cultures retain their capacity to form neurons. Furthermore, the expanded cells harbor regional differences in their growth properties and to some extend in their gene expression profile. This show that the NS cell culture is an attractive alternative to the traditionally and more commonly used neurosphere culture system for expansion of fetal neural stem cells. Unfortunately, our investigations also showed that neither in the neurosphere nor in the NS cell culture system cells with the characteristic of mesDA neuron precursors are expandable. These results are valuable for further progression in neural stem cell research and particular for improvement of the existing protocols for generating mesDA neurons from expanded neural stem cells

Trauma Severity at Level 2 Trauma Center – Attainability of Retrospective Documentation on Severity

Abstract Background: Centralizing and specializing in Danish health care is ongoing. Around the country Mobile Emergency Care Units (MECU) are introduced during the past years. Pre-hospital triage is important to evaluate at which trauma level the severely injured patients must be received. The aim of our study was to evaluate changes in the severity in adult traffic related high injury traumas admitted to a level 2 trauma center at Odense University Hospital, Svendborg Hospital (OUH-SH) during the last decade and before and after the introduction of the local MECU through the years 2007-2009. Methods: The study was a retrospective study covering an eleven-year period from 2002-2012. All admissions from traffic accidents to OUH, SH were extracted from the hospital inpatient registry for patients aged 18+. The study was performed as a pilot study including only patients born 1st-6th in every month. Based on clinical record reviews and radiology findings, we decided if the patient was Multi Trauma (MT) defined as received by trauma response team and/or CT trauma scanned. Diagnoses were evaluated and maximum Abbreviated Injury Score (mAIS) was assigned dividing patients in severe injured with mAIS ≥ 3 and less injured with mAIS < 3. Data was compared as proportions and confidence intervals and furthermore data before and after the launching of the MECU was dichotomized. Results: A total of 363 traffic injury patients were identified. Five were undeterminable in MT status and 137 non-MT patients were excluded, giving 221 adult MT cases for analysis. Forty-one patients (19%, CI: 14-24) had mAIS ≥ 3. Percentages varied with year from 0-29% with no up- or downwards trend throughout the decade. Proportion of mAIS ≥ 3 in the years before implementing the MECU in Svendborg was 17.1% (CI: 10.2-24.0) versus 23.9% (CI: 11.1-36.7) in the years after the implementation (p = 0.32). The admission rate on MT’s dropped from 24 to 15 and for mAIS ≥ 3 from 4 to 3.5. Conclusions: There was no significant change in the proportion of severely injured patients admitted to this level 2 trauma center during the last decade or after implementation of the local MECU in this study. However, a reduction in admission rate for MT’s might suggest a reduction in overtriage. Keywords: Multi trauma; Severity of trauma; Level trauma center; Medical emergency care unit; Prehospital emergency car

Trauma Severity at Level 2 Trauma Center – Attainability of Retrospective Documentation on Severity

Abstract Background: Centralizing and specializing in Danish health care is ongoing. Around the country Mobile Emergency Care Units (MECU) are introduced during the past years. Pre-hospital triage is important to evaluate at which trauma level the severely injured patients must be received. The aim of our study was to evaluate changes in the severity in adult traffic related high injury traumas admitted to a level 2 trauma center at Odense University Hospital, Svendborg Hospital (OUH-SH) during the last decade and before and after the introduction of the local MECU through the years 2007-2009. Methods: The study was a retrospective study covering an eleven-year period from 2002-2012. All admissions from traffic accidents to OUH, SH were extracted from the hospital inpatient registry for patients aged 18+. The study was performed as a pilot study including only patients born 1st-6th in every month. Based on clinical record reviews and radiology findings, we decided if the patient was Multi Trauma (MT) defined as received by trauma response team and/or CT trauma scanned. Diagnoses were evaluated and maximum Abbreviated Injury Score (mAIS) was assigned dividing patients in severe injured with mAIS ≥ 3 and less injured with mAIS < 3. Data was compared as proportions and confidence intervals and furthermore data before and after the launching of the MECU was dichotomized. Results: A total of 363 traffic injury patients were identified. Five were undeterminable in MT status and 137 non-MT patients were excluded, giving 221 adult MT cases for analysis. Forty-one patients (19%, CI: 14-24) had mAIS ≥ 3. Percentages varied with year from 0-29% with no up- or downwards trend throughout the decade. Proportion of mAIS ≥ 3 in the years before implementing the MECU in Svendborg was 17.1% (CI: 10.2-24.0) versus 23.9% (CI: 11.1-36.7) in the years after the implementation (p = 0.32). The admission rate on MT’s dropped from 24 to 15 and for mAIS ≥ 3 from 4 to 3.5. Conclusions: There was no significant change in the proportion of severely injured patients admitted to this level 2 trauma center during the last decade or after implementation of the local MECU in this study. However, a reduction in admission rate for MT’s might suggest a reduction in overtriage. Keywords: Multi trauma; Severity of trauma; Level trauma center; Medical emergency care unit; Prehospital emergency car

Trauma Severity at Level 2 Trauma Center – Attainability of Retrospective Documentation on Severity

Abstract Background: Centralizing and specializing in Danish health care is ongoing. Around the country Mobile Emergency Care Units (MECU) are introduced during the past years. Pre-hospital triage is important to evaluate at which trauma level the severely injured patients must be received. The aim of our study was to evaluate changes in the severity in adult traffic related high injury traumas admitted to a level 2 trauma center at Odense University Hospital, Svendborg Hospital (OUH-SH) during the last decade and before and after the introduction of the local MECU through the years 2007-2009. Methods: The study was a retrospective study covering an eleven-year period from 2002-2012. All admissions from traffic accidents to OUH, SH were extracted from the hospital inpatient registry for patients aged 18+. The study was performed as a pilot study including only patients born 1st-6th in every month. Based on clinical record reviews and radiology findings, we decided if the patient was Multi Trauma (MT) defined as received by trauma response team and/or CT trauma scanned. Diagnoses were evaluated and maximum Abbreviated Injury Score (mAIS) was assigned dividing patients in severe injured with mAIS ≥ 3 and less injured with mAIS < 3. Data was compared as proportions and confidence intervals and furthermore data before and after the launching of the MECU was dichotomized. Results: A total of 363 traffic injury patients were identified. Five were undeterminable in MT status and 137 non-MT patients were excluded, giving 221 adult MT cases for analysis. Forty-one patients (19%, CI: 14-24) had mAIS ≥ 3. Percentages varied with year from 0-29% with no up- or downwards trend throughout the decade. Proportion of mAIS ≥ 3 in the years before implementing the MECU in Svendborg was 17.1% (CI: 10.2-24.0) versus 23.9% (CI: 11.1-36.7) in the years after the implementation (p = 0.32). The admission rate on MT’s dropped from 24 to 15 and for mAIS ≥ 3 from 4 to 3.5. Conclusions: There was no significant change in the proportion of severely injured patients admitted to this level 2 trauma center during the last decade or after implementation of the local MECU in this study. However, a reduction in admission rate for MT’s might suggest a reduction in overtriage. Keywords: Multi trauma; Severity of trauma; Level trauma center; Medical emergency care unit; Prehospital emergency car

Konstruktioner mellem græcitet og modernitet

Thomas Hebsgaard Nielsen: Konstruktioner mellem græcitet og modernitet