Direct in vivo cellular reprogramming offers the potential for local neural replacement to promote post-stroke neural regeneration and recovery. Pericytes are perivascular cells involved in blood-brain barrier maintenance under physiological conditions but are reprogrammed into multipotent induced neural progenitor cells (i-NPCs) in response to ischemia. The atypical protein kinase C (aPKC)-CREB binding protein (CBP) pathway regulates ischemia-activated pericyte (a-pericyte) reprogramming and neuronal differentiation. Our previous work showed that the pathway inhibitor compound C (CpdC) facilitated a- pericyte reprogramming into i-NPCs in culture, and that monoacylglycerol lipase (Mgll) inhibitor JZL184 was able to promote NPC differentiation to generate newborn neurons by mimicking pathway activation. In this regard, we propose to use acute CpdC treatment followed by chronic JZL184 treatment to enhance reprogramming of a-pericytes into i-NPCs and subsequently promote their neuronal differentiation, ultimately improving post-stroke functional recovery. Using the endothelin-1 (ET-1)/L-NAME ischemic stroke model in a pericyte lineage tracing transgenic mouse line, I characterized the ability of a-pericytes in the ischemic lesion site to generate neural (i-NPC, newborn neurons) and non-neural (microglia and fibroblasts) cell types. The CpdC+JZL184 treatment had early effects on enhancing a- pericyte reprogramming efficiency to produce i-NPCs at 7 days post-stroke and promoting their differentiation to generate neuroblasts at 14 days post-stroke. However, it did not affect stroke volume and produced minimal alterations to the pattern of post-stroke motor function recovery. Interestingly, I discovered a novel role of tamoxifen treatment prior to stroke in regulating reprogramming of a-pericytes and efficacy of compound C treatment. These studies inform the necessity of optimization of drug delivery for better control over the timing and duration to directly target in vivo i-NPC reprogramming and reveal a novel pharmacological paradigm to control the aPKC-CBP pathway.

Stroke är den näst vanligaste dödsorsaken i världen och den tredje vanligaste orsaken till funktionshinder. I Sverige drabbas cirka 25 000 personer årligen. Patienter med stroke är den enskilda sjukdomsgrupp som står för flest vårddagar på svenska sjukhus. I akut behandling av stroke används termen ”Time is Brain”, då det dör cirka två miljoner hjärnceller vid varje minuts fördröjning. Det har utförts stora ansträngningar i två decennier för att effektivisera akuta vårdkedjan vid stroke. Endast två till 13 procent av patienterna får möjlighet till behandling på sjukhus med trombolys och antalet trombektomi är mycket lägre. Av de patienter som får trombolys är det cirka en till tio procent som får trombolys inom en timme efter symtomdebut. Främsta orsaken till underbehandling är att patienter inte når sjukhuset tillräckligt snabbt för att undersökas och behandlas inom det smala terapeutiska fönstret. I Sverige år 2016 anlände 33 procent av patienterna med stroke inom tre timmar till sjukhus och antalet har inte ökat sedan 2011. Det var angeläget att beskriva befintlig kunskap om hur ambulanspersonal kan påskynda behandlingen för patienter med stroke. Syftet var att belysa ambulansteamets betydelse för att minska tiden från symtomdebut till behandling av stroke Metoden för studien var en litteraturöversikt med 16 vetenskapliga artiklar publicerade mellan åren 2012 och 2017. Artiklarna söktes i databaserna PubMed och Cinahl. Resultatet som framkom av de valda artiklarna kunde sammanställas genom två huvudkategorier och fem underkategorier. Den ena huvudkategorin handlade om ambulanspersonalens omhändertagande av patienter med stroke. Den andra huvudkategorin handlade om ambulanspersonalens kunskap. Resultatet visade att ambulanspersonal kunde genom teamarbete i ett ambulansfordon med en inbyggd röntgenapparat, kallad Mobile Stroke Unit (MSU), förkorta tiden från symtomdebut till behandling. MSU var mellan 25 till 81 minuter snabbare, jämfört med konventionell ambulans. Dörr-till-nål tiderna (tiden från det att patient ankommer till sjukhus till start av trombolys) förbättrades med fem minuter när ambulanspersonal förvarnade sjukhusen med strokelarm. Ambulanspersonal förbättrade inte akuta vårdkedjan med hjälp av telemedicin. Patienter med stroke i bakre cirkulationen hade en timmes prehospitala fördröjningar jämfört med patienter med stroke i främre cirkulationen. Akuta vårdkedjan förbättrades inte när ambulanspersonal fick en timmes föreläsning om stroke. Slutsatsen var att ambulansteamet förkortade tiden från symtomdebut till behandling genom teamarbete i Mobile Stroke Unit. Ambulansteamet förbättrade inte akuta vårdkedjan med hjälp av telemedicin. Det skedde prehospitala fördröjningar för patienter med stroke i bakre cirkulationen. Ytterligare forskning av MSU behövs. Framtida randomiserade studier bör undersöka kliniskt utfall och kostnadseffektivitet. Det bör även forskas i området om hur ambulansteamet kan minska tiden från symtomdebut till behandling av stroke i en konventionell ambulans. Nyckelord: stroke, ambulanspersonal, tid, prehospital trombolys, Mobile Stroke Unit. / Stroke is the second most common cause of death in the world and the third most common reason cause for disability. In Sweden approximately 25000 people are affected annually. Patients whit stroke are the group that accounts for most care days in Swedish hospitals. In acute stroke treatment, the term "Time is Brain" is used, as about two million brain cells die at every minute delay. Despite two decades of substantial efforts to streamline systems of care in stroke, only two to 13 percent of patients receive the treatment thtombolysis in a hospital and the rates of delivery of thrombectomy are far lower. Of the patients who are treated with thrombolysis, approximately one to ten percent receives thrombolysis within one hour after symptom on set. The main reason for such undertreatment is that patients do not reach the hospital quickly enough to be assesed and treated within the narrow therapeutic window. In Sweden 2016, only 33 percent of patients with stroke arrived to the hospital within three-hours after symptom on set and the rates has not increased since 2011. It was important to describe existing knowledge about how the ambulance staff can shorten the time from symptom on set to treatment for stroke patients. The aim was to highlight the importance of the ambulance staff to reduce the time from symptom on set to stroke treatment. The method of the study was a literature review of 16 scientific articles published between the years 2012 and 2017. The articles were searched in the PubMed and Cinahl databases. The results obtained from the selected articles were compiled by two main categories and five subcategories. One main category was about the care of ambulance staff in patients with stroke. The second main category was about the ambulance staff's knowledge. The result showed that ambulance staff can shorten the time from symptom on set to treatment though teamwork in an ambulance with an inbuilt CT-scan, called Mobile Stroke Unit (MSU). MSU was between 25 minutes and 81 minutes faster, compared to conventional ambulance. Door-to-Needle time (time from patient arriving to hospital until start of thrombolysis) improved with five minutes when ambulance staff warned the hospital with a strokealarm. Ambulance staff did not improve the system of care using telemedicine. Patients with stroke in the posterior circulation had one hour of prehospital delays compared with patients with stroke in the anterior circulation. The system of care did not improve when ambulance staff received an hour's lecture on stroke. The conclusion was that ambulance staff shortened the time from symptom on set to treatment through teamwork in the Mobile Stroke Unit. Ambulance staff did not improve the system of care using telemedicine. There where prehospital delays for patients with stroke in the posterior circulation. Further research of MSU is required. Further randomized studies should investigate clinical outcome and cost-effectiveness. It should also be researched in the area of how the ambulance staff can shorten the time from symptom on set to treatment in a conventional ambulance Keywords: stroke, emergency medical service, time, prehospital thrombolysis, Mobile Stroke Unit.

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Stroke är en världsomfattande sjukdom som orsakar många dödsfall men leder även till funktionsnedsättningar. Att drabbas av stroke innebär för de flesta att deras livs-kvalité försämras. Forskning visar att livskvalitén kan öka, genom stöd från den stro-kedrabbades omgivning, som består av anhöriga och vänner men inkluderar även vårdpersonalen. Syftet med studien är att få kunskap om hur vårdpersonalen inom akut och hemsjukvården upplever att de kan stödja strokepatienten samt vilken funk-tion stödjandet kan ha. Till detta finns ett delsyfte angående någon specifik omvård-nadsmodell som kan tänkas användas inom vården av strokepatienter. Studien genomfördes med en kvalitativ ansats där fyra respondenter inom vården svarade på semistrukturerade frågor angående studiens syfte tillika frågeställning. Genom att intervjua vårdpersonal ur olika yrkesroller knutna till strokesjukvården fanns en för-hoppning om att kunna urskilja olikheter men även se likheter i deras arbetssätt samt uppgifter vilket kunde berika studien än mer. Resultatet visar att genom den inlärda kunskap som fanns hos respondenterna, tillsammans med de riktlinjer som finns, an-gående strokesjukvård så upplevde vårdpersonalen att de kunde stödja patienterna. Stödjandet är kompatibelt med copingstrategier och empowerment, vilka förklarar patientens möjligheter att återfå kontrollen över sitt liv och att vara delaktig i sin re-habilitering. Delaktigheten innebär att patienten är med i vårdplaneringen innan ut-skrivning sker och där själva planeringen bidrar till att vårdkedjan hålls obruten, vil-ket anses vara en viktig komponent för patientens livskvalité.Nyckelord: Delaktighet, Livskvalité, Stroke, Stödjande / Stroke is a world wide-spread disease that causes many deaths but also brings on dis-abilities. To be affected by stroke for most of the individuals means an impairment of their quality of life. Science reveals that quality of life can increase through support from their surroundings of relatives, family, friends and the health personnel. The purpose of this study is to find knowledge about if health personnel in both emer-gency – and home care service, feels that they can support the persons that suffered from stroke and trough support give the person their quality of life back. A partial purpose of the study was to find out if there are any guide lines for stroke medical care. The study was made by a qualitative approach where four respondents in the health personnel and home care answered a semi structured questionnaire. By includ-ing respondents from different professions involved in the stroke medical care there was an expectation to enrich the study to discern differences but also detect similari-ties in their way of working and assignments. The result indicate that through the learned skills within the respondents altogether with the guidelines for stroke medical care the health personnel experienced that they could support their patients. The sup-port consist in strategies to cope and empowerment which allows the patient to regain the control of his or hers life as well as for taking part in the rehabilitation. The par-ticipation in planning the treatment before being discharged from hospital treatment and the planning itself contributes to the unbroken chain of care which is important for the stroke patient’s quality of life.Keywords: Coping, Participation, Stroke, Quality of life

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In this project stroke data were analyzed with the use of survival techniques and incomplete principal component cox analysis. The data set resulted from a multi-center randomised controlled trial coordinated by investigators from the Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton with 438 patients. It was found that among stroke survivors, congestive heart failure along with other cardiac impairments post the major risks. Other factors found to be important were patient age, previous TIAs, presence of ulcers, diabetes and sex. / Thesis / Master of Science (MS)

Evidence in older adults suggest that the benefits of exercise on cognition may be moderated by sex. To our knowledge, no studies have examined this relationship in individuals with stroke. This thesis investigated whether there were sex differences in the effect of exercise on cognition post-stroke. The first study was a systematic review of the literature on exercise and cognition in individuals with stroke. The second study was a secondary analysis of data from a randomized controlled trial comparing the effect of aerobic vs. balance and flexibility exercise on cognition. Findings from the systematic review revealed no differences between studies of higher and lower female proportions with respect to memory (Verbal Digit Span Forward, Memory Domain of Stroke Impact Scale and Wechsler Memory Scale III - Verbal Pairing Domain: Chi2 =1.52, p=0.22), executive function (Stroop Test: Chi2 = 0.56, p=0.45; Trail Making Test B: Chi2 = 0.00, p=0.98), language (Communication Domain of Stroke Impact Scale: Chi2 = 3.17, p=0.08) or global cognition (Montreal Cognitive Assessment, Cognitive Domain of Functional Independence Measure and Addenbrooke’s Cognitive Examination-Revised: Chi2 = 0.88, p=0.35). Findings from the secondary analysis indicated that there was a group x time interaction in females (effect size 0.28, p=0.03) that was not observed in males (effect size 0.01, p=0.62). Females demonstrated a Stroop Colour-Word Interference test change of -2.3 seconds, whereas males demonstrated a change of +5.5 seconds following AE. There were no differences between exercise groups in either sex for any of the other outcomes (working memory and set-shifting/ cognitive flexibility). Together, these studies suggest that there is a clear need for future clinical trials that incorporate sex-based analysis to adequately investigate sex-dependent effects of interventions. / Thesis / Master of Science Rehabilitation Science (MSc)

Background. Stroke affects over 80 million individuals worldwide. Elevated arterial stiffness has emerged as a novel independent risk marker for stroke. While arterial stiffness is improved after chronic aerobic training, a single bout of aerobic exercise leads to transient increases that typically resolve within 5 minutes of recovery. Elevated arterial stiffness may persist for up to 30 minutes following exercise in populations with cardiovascular disease. However, no study has examined the effect of acute aerobic exercise on arterial stiffness and central hemodynamics in individuals with stroke. Moreover, no study has explored the clinical significance of these responses. Objectives. The primary objective of this thesis was to characterize the response and recovery of arterial stiffness and central hemodynamics to peak aerobic exercise in individuals ≥ 6 months post-stroke. The secondary objective was to explore the relationships between the exercise response and recovery of arterial stiffness and central hemodynamics, with cardiorespiratory fitness and walking ability. Results. This cross-sectional study recruited 10 adults with stroke (mean ± SD age=56.9 ± 11.8; median [IQR]= 2.9 [1.9] years post-stroke; n=4 females). After peak aerobic exercise, cfPWV increased from rest and remained elevated for 20 minutes (p<0.05). Heart rate increased and remained elevated for 10 minutes post-exercise (p<0.05), while systolic blood pressure decreased and remained reduced for 15 minutes (p<0.05). Positive associations were found between cardiorespiratory fitness and heart rate reserve (r=0.74, p=0.02), and with each phase of heart rate recovery (HR60s r=0.80, p=0.005, HR120s r=0.79, p=0.006; HR300s r=0.72, p=0.02; and HR600s r=0.75, p=0.01). There were no relationships between response and recovery of hemodynamic variables with walking ability. Conclusion. Individuals with chronic stroke may have impaired arterial stiffness and heart rate recovery following peak aerobic exercise. Moreover, heart rate reserve and all phases of heart rate recovery were related to cardiorespiratory fitness, but not walking ability. / Thesis / Master of Science Rehabilitation Science (MSc) / Arterial stiffness has been recently identified as an important risk marker for stroke. Aerobic exercise reduces the risk of stroke by lowering arterial stiffness. But during exercise, there is an increase in arterial stiffness that usually subsides by 5 minutes. Lengthy exposure to arterial stiffness can cause damage to organs like the kidneys and liver. The purpose of this thesis was to measure the arterial stiffness and cardiovascular response to exercise in people with stroke. We also studied the relationship between the responses, fitness and walking ability. Ten people with stroke participated in this study. After aerobic exercise, arterial stiffness stayed high above resting levels and did not recover after 20 minutes. Also, heart rate recovery was related to fitness but not walking ability. This study tells us that people with stroke have an weakened ability to recover from aerobic exercise and that higher fitness levels can improve exercise recovery.