Balali_Pargol_MSc thesis_Neuroscience department_2023Sep / Background: Cerebral microbleeds are asymptomatic neuroimaging markers of small vessel disease (SVD), visualized as small hypointensities on blood-sensitive magnetic resonance imaging (MRI) sequences. Patients with ischemic stroke and microbleeds are at a higher risk of future ischemic stroke and intracranial hemorrhage. Antithrombotic therapies, the mainstay treatment of secondary stroke prevention, are associated with an increased risk of bleeding. This raises concerns surrounding the net benefit of antithrombotic therapies in these hemorrhage-prone patients. The overarching aim of this thesis is to determine the safety of antithrombotic treatments in patients with hemorrhage-prone SVD marked by microbleeds on MRI or prior intracerebral hemorrhage (ICH). I aimed to characterize the association between baseline microbleeds and the risk of future clinical outcomes in patients with ischemic stroke and whether there exists treatment effect modification of different anticoagulants on clinical outcomes according to microbleeds presence, location, and number. Methods: We performed post hoc analyses on two multicenter previously conducted randomized trials in patients with non-cardioembolic ischemic stroke. For the PACIFIC-STROKE trial, we used multivariable regression models to determine the contribution of microbleeds to the risk of new microbleeds, hemorrhagic transformation (HT), ischemic stroke, intracranial hemorrhage, and death. We assessed the treatment effect of asundexian, a factor XIa inhibitor, vs. placebo on these clinical outcomes, stratified by microbleeds presence, location, and number. I was trained on standardized rating of microbleeds on MRI, achieved excellent interrater reliability, and rated all DATAS-II participant MRIs. I used multivariable logistic regression models to identify the association between microbleeds and HT and 90-day excellent functional outcome. I assessed the interaction between treatment with dabigatran, a direct thrombin inhibitor, vs. aspirin and microbleeds for these outcomes. Separately, I performed a review of the literature and wrote an editorial discussing the optimum timing of antiplatelet re-initiation after ICH. Results: The PACIFIC-STROKE post hoc analyses showed that microbleeds are associated with a 1.6-fold and 4.4-fold higher risk of HT and new microbleeds, respectively. The DATAS-II exploratory analyses demonstrated no association between the risk of outcomes and microbleeds presence. We found no interaction between treatment assignment and microbleed presence for any of the clinical outcomes investigated in either of these studies. Based on the totality of evidence, we concluded that early resumption of antiplatelets in ICH survivors is likely to be safe. Conclusion: Our findings do not support existing concerns surrounding the use of anticoagulants in patients with acute ischemic stroke and microbleeds on MRI, nor for the early resumption of antiplatelets in ICH survivors. / Thesis / Master of Science (MSc) / Diseases of small brain blood vessels can lead to strokes due to blockage or bleeding. Small, asymptomatic brain bleeds on MRIs (microbleeds) are common among affected patients. Patients with clot-induced stroke and microbleeds have a higher risk of both types of strokes. Blood thinners are standard treatments to prevent future clotting events after clot-induced stroke. However, their potential to increase the risk of brain bleeding has raised concerns regarding their use in patients with microbleeds or bleeding-induced stroke. We assessed information from two large, previously completed randomized trials to evaluate the safety of strong blood thinners (anticoagulants) in patients with clot-induced stroke and microbleeds. Additionally, we evaluated the risk vs. benefit of restarting milder blood thinners (antiplatelets) early after bleeding-induced stroke. Bleeding was more prevalent in patients with microbleeds; however, the effect of the anticoagulants tested on bleeding outcomes was not modified by microbleed presence. Overall, our findings suggest that blood thinners are safe in patients with clot-induced stroke and microbleeds, and that early resumption of antiplatelets seems safe in patients with bleeding-induced stroke.

Postpartumblödning utgör den främsta anledningen till mödradödlighet globalt med en tendens till att öka i både låg- och höginkomstländer. Det är viktigt att vården besitter god kunskap och förståelse för hur en postpartumblödning upplevs och dess konsekvenser för de födande kvinnorna för att på bästa sätt kunna förebygga och hantera en postpartumblödning. För att få en bredare bild och skapa förståelse för hur en postpartumblödning kan påverka födande kvinnor var syftet med denna litteraturstudie att belysa kvinnors erfarenheter av en postpartumblödning. En litteraturstudie användes som metod där dataanalysen utfördes med hjälp av en integrerad analys. Databassökning genomfördes i databaserna PubMed, CINAHL och PsycINFO och resulterade i att 18 vetenskapliga artiklar publicerade 2011 till 2022 inkluderades. Resultatet visar att det finns ett tydligt samband mellan postpartumblödning och en påverkan på förlossningsupplevelsen samt den efterföljande tiden. Resultatet redovisas i två huvudkategorier: Förlossningsupplevelser vid en postpartumblödning och Konsekvenser efter en postpartumblödning. Majoriteten av kvinnorna beskriver postpartumblödningen som en traumatisk upplevelse som påverkade deras förlossningsupplevelse negativt. Konsekvenserna av blödningen hade en negativ inverkan på den psykiska och fysiska hälsan. Slutsatsen av litteraturstudien visar på att postpartumblödning ökar risken för en traumatisk förlossningsupplevelse samt efterföljande fysisk och psykisk problematik. För en positiv förlossningsupplevelse krävs en god kommunikation och ett gott bemötande från vårdpersonal. Därtill behöver vården identifiera kvinnor som drabbats av postpartumblödning i ett tidigt skede och rutinmässigt erbjuda stöd för att på sikt minska sexuell och reproduktiv ohälsa. / Postpartum hemorrhage, in connection with childbirth, is the main reason for global maternal mortality with a tendency to increase in both low- and high-income countries. Care must possess good knowledge and the understanding of how a postpartum hemorrhage is experienced and its consequences, to help reduce and prevent illness, in particular in areas of sexual and reproductive health. To get a broader picture and create an understanding of how a postpartum hemorrhage can affect the women giving birth, this study aimed to shed light on experiences of postpartum hemorrhage. The method used is a literature study where the data analysis was performed using integrated analysis. Database searches were performed in the databases PubMed, CINAHL and PsycINFO and resulted in the inclusion of 18 scientific articles published from 2011 to 2022. The results demonstrate that there is a connection between postpartum hemorrhage and an impact on childbirth experience and the subsequent postpartum period. The results are reported in two main categories: childbirth experiences when suffering a postpartum hemorrhage and consequences after a postpartum hemorrhage. The majority of women describe a postpartum hemorrhage as a traumatic experience that negatively affected their childbirth experience and where the consequences mostly had a negative impact on mental and physical health. The conclusion of the literature study shows that postpartum hemorrhage increases the risk of a traumatic childbirth experience and subsequent physical and mental problems. A positive childbirth experience requires good communication and a good response from healthcare staff. In addition, healthcare needs to pay attention to women who have suffered from postpartum hemorrhage at an early stage, where they are offered routine support in order to reduce sexual and reproductive illness in the long run.

Background Aneurysmal subarachnoid hemorrhage can lead to multi-organ disturbances as a result of central and autonomic nervous system injuries. Alterations in the brain-body interface associated with this cerebrovascular disorder have significant impact on patient morbidity and mortality. Knowledge of the most pertinent brain-body associations, as well as demographic, systemic and neurological prognostic factors on hospital admission, along with their progression during hospitalization can assist the clinician and patient family in the process of treatment decision making. Objectives The goals of this dissertation are to: (1) synthesize and critically appraise the methodologic quality of existing studies that derive clinical predictor tools and clinical predictors used to determine outcome prognosis in patients with aneurysmal subarachnoid hemorrhage (SAH), (2) synthesize and critically appraise the methodologic quality of existing studies that derive pathophysiologic mechanisms of brain-body associations in aneurysmal SAH, (3) provide new insights into the significance of brain-body associations that are essential in influencing outcome in aneurysmal SAH, and (4) create a decision making algorithm for aneurysmal SAH patients that is useful in bedside prognostication and clinical treatment decision making. Methods Existing prospective and retrospective cohort studies and randomized controlled trials were included in the systematic review investigating prognostic factors and clinical prediction tools associated with determining the neurologic outcome in adults patients with aneurysmal SAH. Existing prospective and retrospective cohorts were included in the systematic review investigating the pathophysiologic mechanisms of brain-body associations in patients with ruptured brain aneurysms. The multicenter Tirilazad database (3551 patients) was used to create the aneurysmal SAH prognostic model, in order to elucidate significant brain-body associations. Traditional binary logistic regression models were used. The classification and regression tree analysis technique is applied to the multicenter Tirilazad database in order to create a decision making algorithm. Results Systematic review of the literature confirmed the most frequently retained clinical outcome predictors, namely, age, neurological grade, aneurysm size and blood clot thickness. Systematic review of the literature clarified currently known pathophysiologic mechanisms of brain-body associations in aneurysmal SAH, specifically, sympathetic activation of the cardiopulmonary system with subsequent delayed activation of neuro-cardio-endocrinological responses as part of the secondary injury cascade in response to the primary ictus of aneurysmal SAH. Logistic regression models found the significance of hepatic disease and hypertension in development of brain edema, and the negative consequences of seizures in those with history of myocardial infarction and post admission fever worsening neurological outcome. A clinically useful classification and regression tree revealed prognostic subgroups with important explanatory nodes including neurological grade, age, post admission fever and post-admission stroke. Discussion This dissertation clarified existing information on clinical predictors and pathophysiologic mechanisms of brain-body associations in aneurysmal SAH. It also provides novel information on brain-body associations that are essential in influencing outcome in aneurysmal SAH patients despite scarce existing literature on such important relationships. A clinically useful classification and regression tree was generated to guide both bedside prognostication and clinical treatment decision making in aneurysmal SAH patients. / Thesis / Doctor of Philosophy (PhD)

Le troisième trimestre de grossesse est une période-clé du développement cérébelleux. L’extrême prématurité et les lésions cérébelleuses (LCb) associées prédisposent ces enfants à des déficits moteurs, sociaux, comportementaux et cognitifs. Nos objectifs étaient de décrire les déficits neurocomportementaux associés à long-terme aux LCb, et d’explorer le rôle des microglies cérébelleuses dans leur survenue. À 3 jours de vie, des LCb ont expérimentalement et aléatoirement été induites chez des souriceaux transgéniques (B6.129P2(Cg)-Cx3Cr1 CreERT2-EYFP/iDTR), présentant ou non, une déplétion microgliale cérébelleuse transitoire : contrôle, hémorragies cérébelleuses, état inflammatoire systémique précoce et association des deux lésions. Une évaluation neurocomportementale a été réalisée à l’aveugle en période juvénile et à l’âge adulte. En présence de microglies cérébelleuses, les souris mâles adultes ayant souffert de LCb présentaient une diminution des comportements liés à l’anxiété (test du labyrinthe en croix surélevé) et les souris femelles juvéniles ayant souffert de LCb une augmentation des comportements d’investigation sociale (test de reconnaissance sociale) en comparaison des groupes contrôles. Vis-à-vis d’un état inflammatoire systémique précoce, la déplétion microgliale cérébelleuse assurait une récupération fonctionnelle du phénotype anxieux masculin et social féminin. Ce constat suggérait l’implication d’une activation microgliale délétère à la suite de LCb. Des études complémentaires permettront de préciser les sous-domaines neurocomportementaux affectés et d’investiguer les conséquences d’une activation microgliale (altération de l’élagage synaptique et/ou de la myélinogénèse cérébelleuse). / The third trimester of pregnancy is a key period for cerebellar development. Extreme prematurity and cerebellar injuries (CBI) predispose ex-preterm infants to long-term motor, social, behavioral, and cognitive deficits. Our objectives were to describe the long-term neurobehavioral deficits associated with CBI, and to determine if cerebellar microglia play a pathological role in these induced neurobehavioral deficits. At 3 days of life, CBI were experimentally and randomly induced in transgenic mice (B6.129P2(Cg)-Cx3Cr1 CreERT2-EYFP/iDTR), with or without transient cerebellar microglial depletion: control, cerebellar hemorrhages, early systemic inflammatory state, and association of these 2 injuries. A blinded neurobehavioral assessment was performed in juvenile and adult age. In the presence of cerebellar microglial cells, CBI adult male mice exposed to CBI showed a decrease in anxiety-related behaviors (elevated plus maze test), and CBI juvenile female mice exposed to CBI showed an increase in social investigation behaviors (social recognition test) compared to control groups. Cerebellar microglial depletion ensured a functional recovery of these anxiety-related and social investigation behaviors in mice exposed to an early systemic inflammatory state. This finding was consistent with a deleterious role of microglial activation. Further studies will precise the neurobehavioral subdomains affected and investigate the consequences of microglial activation (alteration of synaptic pruning and/or cerebellar myelinogenesis).

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No description available.

<p><strong>BACKGROUND</strong></p> <p>Amiodarone is believed to inhibit the hepatic metabolism of warfarin, potentiating its hypoprothrombinemic effect and increasing the risk of hemorrhage. The consequences of this drug interaction on important clinical outcomes are unknown.</p> <p><strong>METHODOLOGY</strong></p> <p>Using linked health administrative databases, we conducted a population-based retrospective cohort study among Ontario residents aged 66 years or older who had been treated with warfarin therapy for at least 6 months. Within this group, we identified subjects who initiated amiodarone while on warfarin. Each of these subjects was matched to a subject not treated with amiodarone on age, sex, year of cohort entry, and a high dimensional propensity score. The primary outcome was a hospitalization due to a hemorrhagic event within 30 days of follow-up. In a secondary analysis, we examined in-hospital mortality following hospitalization for major hemorrhage.</p> <p><strong>RESULTS</strong></p> <p>We identified 60,497 eligible patients between July 1, 1994 and March 31, 2009. Of these, 11,665 (19.3%) received a new prescription for amiodarone while receiving ongoing warfarin therapy and 7,124 (61.1%) of these were matched to a subject who was not exposed to amiodarone while receiving warfarin therapy. The median age at cohort entry of the matched cohort was 76 years, 51.6% in the cohort were male, 14.5% lived in a rural location, 2.8% had a bleed in the past year, and 21.6% had a diagnosis of congestive heart failure in the past year. Fifty-six amiodarone recipients experienced a hemorrhagic event (0.8%) as compared to 23 individuals (0.3%) in the non-exposed group at 30 day follow-up (adjusted hazard ratio (HR) = 2.45; 95% CI, 1.49 to 4.02). Seven patients in the amiodarone group died after hospitalization for a hemorrhage versus four in the non-exposed group (adjusted HR = 1.74; 95% CI, 0.25 to 12.24).</p> <p><strong>CONCLUSION</strong></p> <p>Initiation of amiodarone in patients on chronic warfarin therapy was associated with a two-fold increase in the risk of hospitalization due to a hemorrhagic event. Physicians should closely monitor the response to warfarin following initiation of amiodarone.</p> / Master of Science (MSc)

The regulation of surface tension (ST) by surfactants plays an important role in the human respiratory system but is largely unexplored in brain homeostasis. The aim of this study was to evaluate changes in ST in relation to surfactant proteins (SPs) in children with intraventricular hemorrhage (IVH). CSF samples from 93 patients were analyzed for ST with a force tensiometer and SP-A-D and -G with ELISA assays. Patients belonged to six groups: (i) IVH before primary intervention (PI), (ii) IVH 4–28 days after PI, (iii) IVH 44–357 days after PI, (iv) hydrocephalus, (v) sepsis and (vi) controls. We found indirect correlations and significant differences in ST and SPs (all p < 0.001; except for SP-C, p = 0.007). Post hoc analyses showed significantly decreased ST in IVH patients before PI compared with patients with hydrocephalus, sepsis or controls (p < 0.001), but it increased in IVH patients over time. All SPs were significantly elevated when comparing IVH patients before PI with controls (all p < 0.001; except for SP-C, p = 0.003). Children suffering from IVH displayed an increase in SPs and a decrease in ST as coping mechanisms to preserve CSF flow. The increase in ST over time could serve as prognostic marker for the healing process.

The regulation of surface tension (ST) by surfactants plays an important role in the human respiratory system but is largely unexplored in brain homeostasis. The aim of this study was to evaluate changes in ST in relation to surfactant proteins (SPs) in children with intraventricular hemorrhage (IVH). CSF samples from 93 patients were analyzed for ST with a force tensiometer and SP-A-D and -G with ELISA assays. Patients belonged to six groups: (i) IVH before primary intervention (PI), (ii) IVH 4–28 days after PI, (iii) IVH 44–357 days after PI, (iv) hydrocephalus, (v) sepsis and (vi) controls. We found indirect correlations and significant differences in ST and SPs (all p < 0.001; except for SP-C, p = 0.007). Post hoc analyses showed significantly decreased ST in IVH patients before PI compared with patients with hydrocephalus, sepsis or controls (p < 0.001), but it increased in IVH patients over time. All SPs were significantly elevated when comparing IVH patients before PI with controls (all p < 0.001; except for SP-C, p = 0.003). Children suffering from IVH displayed an increase in SPs and a decrease in ST as coping mechanisms to preserve CSF flow. The increase in ST over time could serve as prognostic marker for the healing process.:1. Einführung 3 1.1 Intraventrikuläre Hämorrhagie 3 1.1.1 Allgemeiner Überblick 3 1.1.2 Pathogenese 3 1.1.3 Risikofaktoren und Prävention 4 1.1.4 Klinik 5 1.1.5 Komplikationen 6 1.1.6 Behandlungsoptionen bei IVH und PHVD 7 1.1.6.1 Medikamente 7 1.1.6.2 Interventionen 7 1.2 Surfactant und Surfactant-Proteine 8 1.3 Zusammenfassung der IVH-Problematik und Fragestellungen der Dissertation 11 2. Publikationsmanuskript 13 3. Zusammenfassung der Arbeit 28 4. Literaturverzeichnis 32 5. Abkürzungsverzeichnis 39 6. Anlagen der Originalpublikation 41 7. Darstellung des eigenen Beitrags 48 8. Erklärung über die eigenständige Abfassung der Arbeit 49 9. Lebenslauf 50 10. Publikationen 51 11. Danksagung 52

<p>During brain activity neurons release the major excitatory transmitter glutamate, which is taken up by astrocytes and converted to glutamine. Glutamine returns to neurons for re-conversion to glutamate. This glutamate-glutamine cycle is energy demanding. Glutamate turnover in injured brain was studied using an animal iron-induced posttraumatic epilepsy model and using neurointensive care data from 33 patients with spontaneous subarachnoid hemorrhage (SAH). Immunoblotting revealed that the functional form of the major astrocytic glutamate uptake protein GLT-1 was decreased 1-5 days following a cortical epileptogenic iron-injection, presumably due to oxidation-induced aggregation. Using microdialysis it was shown that the GLT-1 decrease was associated with increased interstitial glutamate levels and decreased interstitial glutamine levels. The results indicate a possible posttraumatic and post-stroke epileptogenic mechanism. Analysing 3600 microdialysis hours from patients it was found that the interstitial lactate/pyruvate (L/P) ratio correlate with the glutamine/glutamate ratio (r =-0.66). This correlation was as strong as the correlation between L/P and glutamate (r=0.68) and between lactate and glutamate (r=0.65). Pyruvate and glutamine correlated linearly (r=0.52). Energy failure periods, defined as L/P>40, were associated with high interstitial glutamate levels. Glutamine increased or decreased during energy failure periods depending on pyruvate. Energy failure periods were clinically associated with delayed ischemic neurological deficits (DIND) or development of radiologically verified infarcts, confirming that L/P>40 is a pathological microdialysis pattern that can predict ischemic deterioration after SAH. DIND-associated microdialysis patterns were L/P elevations and surges in interstitial glutamine. Glutamine and pyruvate correlated with the cerebral perfusion pressure (r=0.25, r=0.24). Glutamine and the glutamine/glutamate ratio correlated with the intracranial pressure (r=-0.29, r=0.40). Glutamine surges appeared upon substantial lowering of the intracranial pressure by increased cerebrospinal fluid drainage. Increased interstitial glutamine and pyruvate levels may reflect augmented astrocytic glycolysis in recovering brain tissue with increased energy demand due to a high glutamate-glutamine turnover.</p>