The Involvement of Iron in Traumatic Brain Injury and Neurodegenerative Disease

Traumatic brain injury (TBI) consists of acute and long-term pathophysiological sequelae that ultimately lead to cognitive and motor function deficits, with age being a critical risk factor for poorer prognosis. TBI has been recently linked to the development of neurodegenerative diseases later in life including Alzheimer’s disease, Parkinson’s disease, chronic traumatic encephalopathy, and multiple sclerosis. The accumulation of iron in the brain has been documented in a number of neurodegenerative diseases, and also in normal aging, and can contribute to neurotoxicity through a variety of mechanisms including the production of free radicals leading to oxidative stress, excitotoxicity and by promoting inflammatory reactions. A growing body of evidence similarly supports a deleterious role of iron in the pathogenesis of TBI. Iron deposition in the injured brain can occur via hemorrhage/microhemorrhages (heme-bound iron) or independently as labile iron (non-heme bound), which is considered to be more damaging to the brain. This review focusses on the role of iron in potentiating neurodegeneration in TBI, with insight into the intersection with neurodegenerative conditions. An important implication of this work is the potential for therapeutic approaches that target iron to attenuate the neuropathology/phenotype related to TBI and to also reduce the associated risk of developing neurodegenerative disease

Anti-Lysophosphatidic Acid Antibodies Improve Traumatic Brain Injury Outcomes

BACKGROUND: Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury. FINDINGS: Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes. CONCLUSIONS: This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction

The tissue-type plasminogen activator-plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans

The neurovascular unit provides a dynamic interface between the circulation and central nervous system. Disruption of neurovascular integrity occurs in numerous brain pathologies including neurotrauma and ischaemic stroke. Tissue plasminogen activator is a serine protease that converts plasminogen to plasmin, a protease that dissolves blood clots. Besides its role in fibrinolysis, tissue plasminogen activator is abundantly expressed in the brain where it mediates extracellular proteolysis. However, proteolytically active tissue plasminogen activator also promotes neurovascular disruption after ischaemic stroke; the molecular mechanisms of this process are still unclear. Tissue plasminogen activator is naturally inhibited by serine protease inhibitors (serpins): plasminogen activator inhibitor-1, neuroserpin or protease nexin-1 that results in the formation of serpin:protease complexes. Proteases and serpin:protease complexes are cleared through high-affinity binding to low-density lipoprotein receptors, but their binding to these receptors can also transmit extracellular signals across the plasma membrane. The matrix metalloproteinases are the second major proteolytic system in the mammalian brain, and like tissue plasminogen activators are pivotal to neurological function but can also degrade structures of the neurovascular unit after injury. Herein, we show that tissue plasminogen activator potentiates neurovascular damage in a dose-dependent manner in a mouse model of neurotrauma. Surprisingly, inhibition of activity following administration of plasminogen activator inhibitor-1 significantly increased cerebrovascular permeability. This led to our finding that formation of complexes between tissue plasminogen activator and plasminogen activator inhibitor-1 in the brain parenchyma facilitates post-traumatic cerebrovascular damage. We demonstrate that following trauma, the complex binds to low-density lipoprotein receptors, triggering the induction of matrix metalloproteinase-3. Accordingly, pharmacological inhibition of matrix metalloproteinase-3 attenuates neurovascular permeability and improves neurological function in injured mice. Our results are clinically relevant, because concentrations of tissue plasminogen activator: plasminogen activator inhibitor-1 complex and matrix metalloproteinase-3 are significantly elevated in cerebrospinal fluid of trauma patients and correlate with neurological outcome. In a separate study, we found that matrix metalloproteinase-3 and albumin, a marker of cerebrovascular damage, were significantly increased in brain tissue of patients with neurotrauma. Perturbation of neurovascular homeostasis causing oedema, inflammation and cell death is an important cause of acute and long-term neurological dysfunction after trauma. A role for the tissue plasminogen activator-matrix metalloproteinase axis in promoting neurovascular disruption after neurotrauma has not been described thus far. Targeting tissue plasminogen activator: plasminogen activator inhibitor-1 complex signalling or downstream matrix metalloproteinase-3 induction may provide viable therapeutic strategies to reduce cerebrovascular permeability after neurotraum

Investigating the acute and long-term effects of traumatic brain injury on the immune and fibrinolytic system

Traumatic brain injury is a serious condition that results in long-term disability in most patients. This thesis investigated the early and long-term effects of the immune and fibrinolytic response (blood clot breakdown), and the link between these two systems after brain injury in mice. A unique discovery was that the chronic immune response, over a period of 8 months, directly contributes to a worse outcome after brain injury. We also found gender-specific differences occurring at the early stage of injury, that influence recovery, brain-related pathology and the immune response after brain injury, mediated by components of the fibrinolytic system

Bioethical decisions applied to neonatal care during perinatal period: views of health professionals in Greece

The rapid advancement of medical knowledge and technology in the field of neonatal care along with the improvement of living standards in recent decades have brought significant, positive changes to epidemiological indicators of neonatal survival at the international level. However, perinatal complications such as prematurity, intrauterine growth disorders of the fetus, congenital and perinatal infections, congenital anomalies and hypoxic–ischemic stroke inevitably lead to the birth of diseased and extremely/very premature infants, with extremely/low birth weight. These infant categories show low survival rates and suffer from severe disorders, which prevent their social and professional integration and adaptation in later life. So far, international epidemiological data are not encouraging with regard to these categories of infants and, in particular, infants born before completing the 24th week of pregnancy. Survival rates for this category of infants do not seem to increase, while no encouraging changes have been recorded with regard to the rate of occurrence of physical or mental disabilities in early childhood or adulthood. Intensive care is available and is often provided to these infants. However, serious bioethical questions arise in respect of the use and feasibility of intensive care in such clinical cases, in view of its reduced efficacy in preventing death and achieving the full recovery of those children. This has lead to the emergence of a broader bioethical dilemma, namely of whether human life must be saved at any cost and with any consequence by using intensive care, life-support practices, or whether limits must be put in place with regard to the provision of invasive, life-saving techniques and medicines, so that the course of the disease and the health status of the newborn may evolve naturally, without interventions.Three different approaches and strategies for managing the provision of intensive care to extremely/very premature and diseased infants may be found in international literature: (a) the ‘interventionist approach’ or ‘wait until certainty strategy’, which consists in offering ‘aggressive’ intensive care and treatment to all newborns from the outset; (b) the ‘statistic approach’ or ‘statistical prognostic strategy’, which sets limits to the intensive care provided from the outset, according to the gestational age and weight of the newborn, based on statistical probabilities for an unfavorable diagnosis or bad outcome of the incident; and (c) the ‘individualized approach’ or ‘individual prognostic strategy’, according to which intensive care must be initiated for almost every newborn and must be thereafter reassessed on a regular basis, according to the severity of the damages suffered.These different approaches for managing the intensive care services provided to infants, reveal that different, or at least differentiated, criteria are used when it comes to making critical ethical decisions, such as the ones mentioned above. However, international literature and practice tend to converge towards a specific decision-making criterion with regard to ethical questions, namely that of the infant’s ‘best interest’. On the one hand, this criterion seems to be increasingly applied in clinical practice and, on the other hand, it is increasingly recommended by international guidelines and instructions, as well as by scientific organizations. Indeed, in spite of all the criticism which has been leveled at it, the ‘best interest’ approach is highly recommended in cases where decisions concern newborns, infants and children, as well as other persons who lack the capacity of making such decisions for themselves. According to this approach, the criterion for providing intensive care or for defining the care to be provided is the infant’s quality of life, both during hospitalization and in the long run. As an alternative to this criterion, Wilkinson (2011) has recently proposed the ‘Threshold View’, according to which it is not obligatory to continue providing life-support to infants where it is expected that their wellbeing will be extremely restricted in the future. Crucial moral dilemmas arising in clinical practice and the variety of approaches towards managing intensive care for extremely/very premature infants, with extremely/low birth weight, as well as diseased infants, combined with the fact that the relevant legal framework is quite limited and varies between different countries, have put forward the need to establish a regulatory framework for making such decisions and have lead to the introduction of guidelines and recommendations. Despite the lack of consensus, international guidelines and recommendations agree in that there is no hope of survival for newborns with a gestational age equal to or lower than 22 weeks and that the threshold of human survival lies between the beginning and end of the 22nd week of pregnancy. Offering palliative care and comfort is the only indicated treatment for infants of this age. With regard to treating infants born between the 23rd and the 24th (or, for others, the 25th) week of pregnancy, a period characterized as the ‘gray area’, it is recommended to take seriously into account the opinion of parents, in view of the existing uncertainties. In the light of the above and despite international efforts, the regulatory framework for managing neonatal intensive care remains rather unclear and ambiguous. On the other hand, the challenges and dilemmas arising from clinical practice tend to increase with the advancement and progress of available means and techniques. It is therefore necessary to investigate both the decision-making process with regard to ethical questions, such as those involving intensive neonatal care, as well as the framework (clinical, social, cultural, etc) in which such decisions are made and implemented. This situation is particularly exacerbated in countries like Greece, where there are no guidelines and recommendations by scientific organizations, the relevant legislative framework is extremely limited, and, unlike the situation in other countries, the actual conditions of decision-making on ethical issues concerning infants are not being recorded. The purpose of this thesis is to fill this gap.In particular, this PhD thesis focuses on assessing the ethical appropriateness of crucial clinical decisions setting ethical limitations and constraints to the application of life-support and life-saving invasive practices in infants, and investigates the criteria used to justify such decisions. The first objective is approached through international literature. The second objective is approached by conducting a critical analysis of international guidelines and recommendations. The particular empirical goals of this thesis are: (a) making an assessment of the ethical acceptability of posing restrictions to neonatal care by Greek health care professionals, through investigating the degree of acceptance or rejection of specific clinical behaviors that put ethical limits to the provision of neonatal intensive care; and (b) investigating the factors that shape the assessment framework of the ethical acceptability of applying restrictions to neonatal care. The survey was conducted on a sample of 251 Greek health care professionals (physicians, midwives, nurses) working in 15 public hospitals in Greece. Data was collected through international weighted questionnaires (partially differentiated per professional group), which were translated and adjusted to the Greek reality and conditions. The questionnaires used were initially developed in the context of the European program ‘Euronic’ and they have been used in a large number of similar surveys throughout the world ever since. As a consequence, for the first time, the empirical research carried out in the context of this thesis records and brings to the fore the opinions and behaviors of Greek health care professionals (physicians, midwives, nurses) in relation to decision-making on ethical issues when it comes to providing intensive care to exceptionally/very premature infants, with very/extremely low birth weight and diseased infants. In addition, by using this specific research tool, this survey achieves yet another empirical goal, namely to produce data on Greece which are comparable to data from other countries. According to the survey results, Greek health care professionals, both in general and as individual professional groups, tend to attribute an intrinsic value to human life. Hence, for the majority of Greek health care professionals of the sample, the beginning and continuation of neonatal intensive care, regardless of its result or other qualitative criteria, is regarded as ethically justifiable. On the other hand, health care professionals who prioritize quality of life are more likely to believe that it is ethically justifiable to withhold the health care services provided, as well as to implement the relevant practices. However, the above two findings highlight the importance of the attitude of health-care professionals towards human life, given that this attitude conditions their behavior. The views of health care professionals with regard to the ethical appropriateness of restricting invasive practices, even for near-death infants or infants with a highly unfavorable neurological prognosis, range between full acceptance, reservation and full rejection. The vast majority of health care professionals in Greece believe that the most ethically acceptable practice is to restrict intensive care only in the case of anencephaly. In the same context, ‘mild’ intensive care restriction practices also tend to be regarded as ethically justifiable, including the continuation of ongoing treatment without adding any new treatments and administering sedatives and/or analgesics in order to address the pain suffered by newborns, even if these substances may lead to death. The vast majority of Greek health care professionals (87.7%) state that the decision to limit neonatal intensive care is not made very often in Greek Neonatal Intensive Care Units (NICU), whereas a large majority of Greek health care professionals (66.1%) state that some infants are subjected to excessive intensive care. Nevertheless, one third of Greek physicians state that they have made the decision to restrict intensive care at least once during the exercise of their clinical work, in cases of near-death infants (37.7%) or infants with unfavorable neurological prognosis (30.8%). The practices reported by health care professionals with regard to putting ethical limits to the intensive care provided to infants are coherent with their views on ethical acceptability. Therefore, the usual practice is to avoid intensifying the health care services provided, by continuing current treatment without adding new treatments (73.9%), and without using emergency nursing/medical procedures (58.3%). Based on the statements made by health care professionals of the sample, it appears that the initial withholding of life-saving interventions and treatments immediately after childbirth tends to be avoided in Greece, whereas the practice of treatment withdrawal is disapproved.This survey also investigated Greek health care professionals attitude towards the introduction of legislative arrangements on withholding and withdrawing neonatal intensive care. According to the survey, only a small percentage of health care professionals (21.3%) agree with the introduction of legislative arrangements, which would set detailed rules for the limitation and discontinuation of intensive care. Despite the fact that a significant percentage of health care professionals (42.4%) are in favor of legalizing palliative care, which may lead to death, there are certain reservations with regard to establishing a legal framework allowing for the restriction of intensive care. Furthermore, the survey reveals significant reactions with regard to introducing a legal framework which would allow professionals to refuse to conduct resuscitation, while seven out of ten health care professionals (68.4%) declared categorically that they are against a potential legal framework allowing for active euthanasia. Physicians are partially differentiated from other professional groups as they tend to be more positive towards a potential legalization of discontinuing intensive care and not performing resuscitation to infants. On the other hand, they tend to be more negative towards a legislative framework that would allow for active euthanasia, as compared to midwives and nurses.Η ραγδαία εξέλιξη της ιατρικής γνώσης και τεχνολογίας στον τομέα της νεογνικής φροντίδας καθώς και η βελτίωση του βιοτικού επιπέδου κατά τις τελευταίες δεκαετίες έχουν επιφέρει σημαντικές, θετικές αλλαγές στους επιδημιολογικούς δείκτες που σχετίζονται με τη νεογνική επιβίωση σε διεθνές επίπεδο. Ωστόσο, περιγεννητικές επιπλοκές όπως η προωρότητα, οι διαταραχές της ενδομήτριας ανάπτυξης του εμβρύου, οι συγγενείς και περιγεννητικές λοιμώξεις, οι συγγενείς ανωμαλίες και το υποξαιμικό-ισχαιμικό επεισόδιο συμβάλλουν, αναπόφευκτα, στη γέννηση νοσούντων νεογνών και εξαιρετικώς/πολύ πρόωρων νεογνών, με εξαιρετικά ή πολύ χαμηλό βάρος γέννησης. Αυτές οι κατηγορίες νεογνών εμφανίζουν χαμηλή επιβίωση και σοβαρές διαταραχές που εμποδίζουν την κοινωνική και επαγγελματική ένταξη και προσαρμογή στη μετέπειτα ζωή. Μέχρι σήμερα, η διεθνής επιδημιολογική πραγματικότητα δεν είναι ενθαρρυντική για τις παραπάνω κατηγορίες νεογνών και ιδίως για όσα νεογνά γεννιούνται πριν την συμπλήρωση της 24ης εβδομάδας κύησης. Τα ποσοστά επιβίωσης αυτής της κατηγορίας νεογνών δεν φαίνεται να αυξάνουν, ενώ δεν καταγράφεται καμιά ενθαρρυντική μεταβολή στο ρυθμό εμφάνισης των σωματικών ή νοητικών αναπηριών στην πρώιμη παιδική ηλικία ή την ενηλικίωση. Για τα νεογνά αυτά είναι διαθέσιμη και συχνά παρέχεται εντατική φροντίδα. Με δεδομένη όμως, την περιορισμένη αποτελεσματικότητά της στην αντιμετώπιση του θανάτου και στην προσπάθεια πλήρους αποκατάστασης της υγείας αυτών των παιδιών εγείρονται έντονα βιοηθικά ερωτήματα για τη χρήση και τη σκοπιμότητα παροχής εντατικής φροντίδας σε τέτοιες κλινικές περιπτώσεις. Κατά συνέπεια, αναδεικνύεται το ευρύτερο βιοηθικό δίλημμα της διατήρησης της ανθρώπινης ζωής με κάθε κόστος και συνέπεια, με την εφαρμογή υποστηρικτικών για τη ζωή πρακτικών εντατικής φροντίδας ή της εφαρμογής ορίων στην παροχή των επεμβατικών και σωτήριων για τη ζωή τεχνικών και φαρμάκων, προκειμένου η πορεία της νόσου και η κατάσταση της υγείας του νεογέννητου να εξελιχθεί με φυσικό τρόπο, χωρίς παρεμβάσεις.Στη διεθνή βιβλιογραφία καταγράφονται τρεις διαφορετικές προσεγγίσεις και στρατηγικές φροντίδας των εξαιρετικώς/πολύ πρόωρων και νοσούντων νεογνών: α) η «παρεμβατική προσέγγιση» (‘interventionist approach’) ή «στρατηγική του να περιμένει κανείς μέχρι να βεβαιωθεί» (‘wait until certainty strategy’), η οποία συνίσταται στην παροχή «επιθετικής» εντατικής φροντίδας και θεραπείας εξ αρχής σε όλα τα νεογνά, β) η «στατιστική προσέγγιση» (‘statistic approach’) ή «στρατηγική των στατιστικών προγνωστικών» (‘statistical prognostic strategy’), που θέτει εξ αρχής ηθικά όρια στην παρεχόμενη εντατική φροντίδα, ανάλογα με την ηλικία κύησης και το βάρος του νεογνού, βασιζόμενη στις στατιστικές πιθανότητες για μια δυσμενή διάγνωση ή κακή έκβαση του περιστατικού και γ) η «εξατομικευμένη προσέγγιση» (‘individualized approach’) ή «εξατομικευμένη προγνωστική στρατηγική» (‘individual prognostic strategy’), που προτείνει την έναρξη της εντατικής φροντίδας σχεδόν σε κάθε νεογνό και την τακτική επανεκτίμηση της στη συνέχεια, σύμφωνα με την σοβαρότητα των προκληθεισών βλαβών.Οι διαφορετικές προσεγγίσεις στην παροχή της εντατικής φροντίδας σε αυτά τα νεογνά υποδεικνύουν την ύπαρξη και εφαρμογή διαφορετικών ή έστω διαφοροποιημένων κριτηρίων, που εφαρμόζονται στη λήψη κρίσιμων αποφάσεων ηθικού περιεχομένου, όπως οι εν προκειμένω αποφάσεις. Στη διεθνή βιβλιογραφία και πρακτική ωστόσο, καταγράφεται μια τάση σύγκλισης προς ένα συγκεκριμένο κριτήριο λήψης αποφάσεων ηθικού περιεχομένου, το κριτήριο του «βελτίστου συμφέροντος» (‘best interest’) του νεογνού. Το κριτήριο αυτό από τη μια φαίνεται να εφαρμόζεται συχνότερα στην κλινική πρακτική και από την άλλη τείνει να προτείνεται συχνότερα, τόσο από διεθνείς κατευθυντήριες οδηγίες και συστάσεις, όσο και από επιστημονικούς φορείς. Μάλιστα, η προσέγγιση του «βελτίστου συμφέροντος», παρά τις επικρίσεις που έχει δεχτεί, συνιστάται ιδιαίτερα, στις περιπτώσεις που οι αποφάσεις αφορούν νεογέννητα, βρέφη και παιδιά, αλλά και άλλα πρόσωπα που στερούνται της ικανότητας λήψης μιας τέτοιας απόφασης για τον εαυτό τους. Με βάση αυτή την προσέγγιση, κριτήριο για την παροχή εντατικής φροντίδας ή για την οριοθέτηση της παρεχόμενης φροντίδας αποτελεί η ποιότητα ζωής του νεογνού, τόσο κατά τη διάρκεια της νοσηλείας του, όσο και μακροπρόθεσμα. Ως εναλλακτική αυτού του κριτηρίου προτάθηκε πρόσφατα η «Άποψη των ορίων» (‘The Threshold View’) του Wilkinson (2011), σύμφωνα με την οποία δεν θεωρείται υποχρεωτικό να συνεχιστεί η υποστήριξη της ζωής των νεογνών που αναμένεται να έχουν πολύ χαμηλά επίπεδα ευημερίας στο μέλλον. Τα κρίσιμα ηθικά διλήμματα που αναδεικνύονται κατά την κλινική πρακτική, οι ποικίλες προσεγγίσεις στην οργάνωση και ρύθμιση της εντατικής φροντίδας των εξαιρετικώς/πολύ πρόωρων νεογνών, με εξαιρετικά/πολύ χαμηλό βάρος γέννησης και των νοσούντων νεογνών, η διαπίστωση ότι το σχετικό νομοθετικό πλαίσιο είναι και περιορισμένο και διαφοροποιείται μεταξύ των χωρών ανέδειξαν την ανάγκη για τον προσδιορισμό ρυθμιστικού πλαισίου, εντός του οποίου λαμβάνονται τέτοιες αποφάσεις και οδήγησαν στη διαμόρφωση κατευθυντηρίων οδηγιών και συστάσεων. Παρά την έλλειψη ομοφωνίας, στις διεθνείς κατευθυντήριες οδηγίες και συστάσεις καταγράφεται συμφωνία ότι δεν υπάρχει καμιά ελπίδα επιβίωσης στα νεογνά με ηλικία κύησης ίση ή μικρότερη των 22 εβδομάδων και ότι το κατώτατο όριο της ανθρώπινης βιωσιμότητας εντοπίζεται μεταξύ της αρχής και του τέλους της 22ης εβδομάδας κύησης. Για τα νεογνά αυτών των ηλικιών συνιστάται μόνο η προσφορά παρηγορητικής φροντίδας και άνεσης. Για την αντιμετώπιση των νεογνών που γεννιούνται στη χρονική περίοδο μεταξύ της 23ης και 24ης (ή αλλού 25ης) εβδομάδας κύησης, περίοδος η οποία και χαρακτηρίζεται ως «γκρίζα ζώνη», συνιστάται να λαμβάνεται σοβαρά υπόψη η γνώμη των γονέων, εξαιτίας της επικρατούσας αβεβαιότητας. Όπως προκύπτει από τα παραπάνω, το ρυθμιστικό πλαίσιο της νεογνικής εντατικής φροντίδας, στις περιπτώσεις των εξαιρετικώς/πολύ πρόωρων και νοσούντων νεογνών, παραμένει, παρά τις διεθνείς προσπάθειες, μάλλον ασαφές και αμφισβητούμενο. Από την άλλη μεριά, οι προκλήσεις και τα διλήμματα που προκύπτουν κατά την κλινική πρακτική μάλλον εντείνονται παρά μειώνονται με την πρόοδο και την εξέλιξη των διαθέσιμων μέσων και τεχνικών. Καθίσταται λοιπόν επιτακτική η ανάγκη διερεύνησης τόσο των κριτηρίων λήψης αποφάσεων ηθικού περιεχομένου, όπως αυτών που αφορούν την εντατική φροντίδα νεογνών, όσο και του πλαισίου (κλινικού, κοινωνικού, πολιτισμικού, κτλ) εντός του οποίου λαμβάνονται και υλοποιούνται τέτοιες αποφάσεις. Η κατάσταση αυτή είναι ιδιαίτερα έντονη σε χώρες όπως η δική μας, που δεν υπάρχουν κατευθυντήριες οδηγίες και συστάσεις από επιστημονικούς φορείς, το σχετικό νομοθετικό πλαίσιο είναι εξαιρετικά περιορισμένο, ενώ, σε αντίθεση με την κατάσταση σε άλλες χώρες, ανύπαρκτη είναι η καταγραφή της πραγματικότητας της λήψης τέτοιων αποφάσεων ηθικού περιεχομένου στα νεογνά. Η παρούσα διατριβή επιχειρεί να καλύψει αυτό το κενό. Συγκεκριμένα η παρούσα διδακτορική διατριβή εστιάζει στην αξιολόγηση της ηθικής ορθότητας των κρίσιμων κλινικών αποφάσεων που θέτουν όρια και περιορισμούς στην εφαρμογή των υποστηρικτικών και σωτήριων για τη ζωή επεμβατικών πρακτικών στη νεογνική ηλικία και διερευνά τα κριτήρια δικαιολόγησης αυτών των αποφάσεων. Ο πρώτος από τους παραπάνω στόχους προσεγγίζεται μέσα από τη διεθνή βιβλιογραφία. Για τη διερεύνηση του δεύτερου στόχου αναλύεται κριτικά το περιεχόμενο διεθνών κατευθυντηρίων οδηγιών και συστάσεων. Ειδικότερους εμπειρικούς στόχους της παρούσας διατριβής αποτελούν τα παρακάτω: α) αξιολόγηση του ηθικά αποδεκτού της εφαρμογής περιορισμών στη νεογνική φροντίδα από Έλληνες επαγγελματίες υγείας, μέσω της διερεύνησης του βαθμού αποδοχής ή απόρριψης συγκεκριμένων κλινικών συμπεριφορών που θέτουν ηθικά όρια στην παροχή νεογνικής εντατικής φροντίδας και β) διερεύνηση των παραγόντων που διαμορφώνουν το πλαίσιο αξιολόγησης του ηθικά αποδεκτού της εφαρμογής περιορισμών στη νεογνική φροντίδα. Η έρευνα διεξήχθη σε δείγμα 251 Ελλήνων επαγγελματιών υγείας (ιατρών, μαιών, νοσηλευτριών) που εργάζονται σε 15 Δημόσια Νοσοκομεία της Ελλάδας. Για τη συλλογή των δεδομένων χρησιμοποιήθηκαν διεθνή σταθμισμένα ερωτηματολόγια (μερικώς διαφοροποιημένα ανά επαγγελματική ομάδα), τα οποία μεταφράστηκαν και προσαρμόστηκαν στην ελληνική πραγματικότητα και συνθήκες. Τα ερωτηματολόγια που χρησιμοποιήθηκαν αναπτύχθηκαν αρχικά στο πλαίσιο του Ευρωπαϊκού προγράμματος ‘Euronic’ και έκτοτε χρησιμοποιήθηκαν σε σημαντικό αριθμό παρόμοιων ερευνών σε διάφορες χώρες στον κόσμο. Κατά συνέπεια, η εμπειρική έρευνα στο πλαίσιο της παρούσας διατριβής για πρώτη φορά, καταγράφει και φέρνει στο προσκήνιο απόψεις, στάσεις και συμπεριφορές των Ελλήνων επαγγελματιών υγείας (ιατρών, μαιών και νοσηλευτριών) που σχετίζονται με τη λήψη αποφάσεων ηθικού περιεχομένου κατά την παροχή της εντατικής φροντίδας στα εξαιρετικώς/πολύ πρόωρα, με εξαιρετικά/πολύ χαμηλό βάρος γέννησης νεογνά και νοσούντα νεογνά. Παράλληλα, και εξαιτίας της χρήσης του συγκεκριμένου ερευνητικού εργαλείου επιτυγχάνεται ένας ακόμη εμπειρικός στόχος, αυτός της παραγωγής δεδομένων για την Ελλάδα που είναι συγκρίσιμα με δεδομένα άλλων χωρών. Σύμφωνα με την παρούσα έρευνα οι Έλληνες επ

Alterations in iron content, iron-regulatory proteins and behaviour without tau pathology at one year following repetitive mild traumatic brain injury

Abstract Repetitive mild traumatic brain injury (r-mTBI) has increasingly become recognised as a risk factor for the development of neurodegenerative diseases, many of which are characterised by tau pathology, metal dyshomeostasis and behavioural impairments. We aimed to characterise the status of tau and the involvement of iron dyshomeostasis in repetitive controlled cortical impact injury (5 impacts, 48 h apart) in 3-month-old C57Bl6 mice at the chronic (12-month) time point. We performed a battery of behavioural tests, characterised the status of neurodegeneration-associated proteins (tau and tau-regulatory proteins, amyloid precursor protein and iron-regulatory proteins) via western blot; and metal levels using bulk inductively coupled plasma-mass spectrometry (ICP-MS). We report significant changes in various ipsilateral iron-regulatory proteins following five but not a single injury, and significant increases in contralateral iron, zinc and copper levels following five impacts. There was no evidence of tau pathology or changes in tau-regulatory proteins following five impacts, although some changes were observed following a single injury. Five impacts resulted in significant gait deficits, mild anhedonia and mild cognitive deficits at 9–12 months post-injury, effects not seen following a single injury. To the best of our knowledge, we are the first to describe chronic changes in metals and iron-regulatory proteins in a mouse model of r-mTBI, providing a strong indication towards an overall increase in brain iron levels (and other metals) in the chronic phase following r-mTBI. These results bring to question the relevance of tau and highlight the involvement of iron dysregulation in the development and/or progression of neurodegeneration following injury, which may lead to new therapeutic approaches in the future

Healthcare Professionals’ Attitudes and Practices According to Their Recommendations on Exercise during the First Trimester of Pregnancy: A Greek Cross-Sectional Study

Background: The aim of this study is to investigate healthcare professionals’ attitudes and practices when it comes to their recommendations on exercise during the first trimester of pregnancy and to highlight the factors that influence or predict these attitudes. Methods: This cross-sectional study was conducted between January 2022 and March 2023, on a sample of 237 Greek healthcare professionals (midwives and obstetricians) employed in healthcare settings in Attica/Greece. In the statistical analysis, eight independent models of multivariate analyses of variance were conducted. Results: Only half of the participants (54.89%) report that they recommend exercise to pregnant women in the first trimester of pregnancy. The majority do not routinely recommend a specific frequency and duration of exercise. Participants who believe that exercise during pregnancy is of little benefit to pregnant women were less likely to recommend the following, in the first trimester of pregnancy: (a) exercise in general (p = 0.002), (b) resistance/muscle strengthening exercises (p = 0.039), (c) relaxation exercises (p = 0.002), and (d) a specific exercise duration (p = 0.011). Those who report being very familiar with the international guidelines are (a) more likely to recommend exercise in general (p = 0.013), as well as aerobic exercises (p = 0.023); (b) less likely to not recommend a specific frequency (p = 0.027); and (c) more likely to recommend a duration of 30–45 min of exercise in the first trimester (p = 0.017). Conclusions: I this study, a significant proportion of health professionals’ attitudes appear to diverge from the recommendations set forth by international scientific bodies regarding exercise during pregnancy. Furthermore, health professionals’ beliefs regarding the benefits of exercise during pregnancy, along with their familiarity with international guidelines, appear to influence their usual practices in recommending exercise during the first trimester of pregnancy to pregnant women

Traumatic brain injury opens blood–brain barrier to stealth liposomes via an enhanced permeability and retention (EPR)-like effect

<div><p></p><p>The opening of the tight junctions in the blood–brain barrier (BBB) following traumatic brain injury (TBI) is hypothesized to be sufficient to enable accumulation of large drug carriers, such as stealth liposomes, in a similar manner to the extravasation seen in tumor tissue via the enhanced permeability and retention (EPR) effect. The controlled cortical impact model of TBI was used to evaluate liposome accumulation in mice. Dual-radiolabeled PEGylated liposomes were administered either immediately after induction of TBI or at increasing times post-TBI to mimic the likely clinical scenario. The accumulation of radiolabel in the brain tissue ipsilateral and contralateral to the site of trauma, as well as in other organs, was evaluated. Selective influx of liposomes occurred at 0–8 h after injury, while the barrier closed between 8 and 24 hr after injury, consistent with reports on albumin infiltration. Significantly enhanced accumulation of liposomes occurred in mice subjected to TBI compared to anaesthetized controls, and accumulation was greater in the injured versus the contralateral side of the brain. Thus, stealth liposomes show potential to enhance drug delivery to the site of brain injury with a wide range of encapsulated therapeutic candidates.</p></div

Additional file 1 of Alterations in iron content, iron-regulatory proteins and behaviour without tau pathology at one year following repetitive mild traumatic brain injury

Additional file 1: Figure S.1. Bulk metal analysis in mice receiving r-mTBI only. Figure S.2. Bulk metal analysis in mice receiving single mTBI only. Figure S.3. Swim speed of mice receiving a single or r-mTBI

Anti-lysophosphatidic acid antibodies improve traumatic brain injury outcomes

BACKGROUND:Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury.FINDINGS:Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes.CONCLUSIONS:This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]