Coming dissertations at Uppsala university
-
Translational Aspects of Brain-Specific Drug Delivery by Targeting Active Uptake at Brain Barriers
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-540918
Challenges in central nervous system (CNS) drug development often arise from difficulties in achieving safe and effective brain drug delivery. Key to addressing this issue is ensuring sufficient drug concentrations at the CNS target site. This requires efficient drug transport across brain barriers and reliable translation of preclinical findings to clinical settings. The proton-coupled organic cation (H+/OC) antiporter, associated with blood-brain barrier (BBB) uptake of several marketed CNS drugs, has emerged as a promising target in this regard. However, several critical questions are unresolved for fully leveraging this system in drug development. The studies in this thesis investigated key translational pharmacokinetic questions of the CNS delivery of antiporter substrates. This included characterization of the uptake across several CNS barriers, potential sex and species differences, the impact of inflammation, in vitro-in vivo correlations, and regional CNS distribution. Oxycodone served as the primary model substrate across in vitro and in vivo studies, including microdialysis, the Combinatory Mapping Approach for Regions of Interest, and in vitro BBB cell models. Active uptake was confirmed at the BBB and revealed at the blood-cerebrospinal fluid barrier (BCSFB) and blood-spinal cord barrier in rats. Novel evidence of active uptake at the pig BBB and BCSFB was presented, suggesting potential translatability to humans. Cerebrospinal fluid, often used as a proxy for brain concentrations in the clinic, underestimated antiporter substrate exposure, necessitating caution in its use as a surrogate for brain interstitial fluid. Importantly, no sex-related differences were observed in BBB uptake, supporting the antiporter as a viable target in CNS drug development. Lipopolysaccharide-induced inflammation significantly reduced the uptake. Although the active uptake was reduced, net uptake was still present during inflammation. In vitro BBB models of various origins (mouse, rat, pig, human) reflected in vivo findings, supporting the utility of these models for verification of active uptake. A consistent net uptake, with minor regional differences, was observed in the CNS delivery of antiporter substrates. These findings contribute to advancing CNS drug development by highlighting the significance of active uptake transporters and the necessity for comprehensive neuropharmacokinetic evaluations both in vitro and in vivo.
-
Regulation of Lymphatic Development and (Dys)Function : A Matter of Cellular Competition and Dynamics
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-540956
Lymphatic vessels are essential for maintaining fluid homeostasis, immune cell trafficking and lipid absorption in the gut. Postnatal expansion of the lymphatic vasculature occurs through sprouting lymphangiogenesis from pre-existing lymphatic networks, which is regulated primarily by vascular endothelial growth factor C (VEGF-C) and its receptors, VEGFR2 and VEGFR3. While the role of VEGFR3 in lymphangiogenesis is well established, the function of VEGFR2 remains less understood. In Paper I, we use high-fidelity conditional genetics for VEGFR2 deletion and adeno-associated viruses (AAVs) overexpressing selective VEGFR2 and VEGFR3 ligands to reveal a critical role of VEGFR2 in lymphatic biology. In Paper II, we extend our studies to the mature lymphatic vasculature, composed of specialized lymphatic capillaries and collecting vessels. Fluid absorption occurs in lymphatic capillaries, which are composed of oak leaf shaped lymphatic endothelial cells (LECs) connected by discontinuous junctions. However, it is unclear how these capillaries maintain endothelial integrity while taking up fluid from the interstitial space. We show that capillary LECs dynamically remodel their shape during homeostasis and in response to increased interstitial fluid in a process driven by cytoskeletal actin remodelling. We further identify isotropic stretch as an upstream regulator of LEC cell shape and use mathematical modelling to show that the oak leaf cell shape provides increased resilience, preventing luminal collapse upon increased pressure on the vessel wall. While the development of blood and lymphatic vasculature is tightly controlled, certain pathologies are associated with aberrant expansion of these vessels. In Paper III and IV, we investigate the mechanisms underlying vascular malformations, which are a spectrum of diseases characterised by focal lesions of malformed blood or lymphatic vessels. The majority of vascular malformations are caused by somatic activating mutations in genes involved in (lymph-)angiogenesis, leading to ectopic growth of endothelial cells. Using genetic mouse models of vascular malformations, Paper III characterized organ-specific responses of LECs driving lymphatic malformations, while Paper IV identified a venous-specific feedback loop that amplifies upstream growth factor signalling, promoting venous malformations. These results illustrate that the same activating mutations can elicit distinct responses in endothelial cells depending on the organs or vessel type involved. In summary, by using various in vivo genetic models coupled with advanced imaging techniques, this thesis work uncovers critical new molecular mechanisms and the underlying cellular dynamics involved in the development, maintenance and pathological expansion of the blood and lymphatic vasculature.
-
Co-creating Respectful Maternity Care Intervention to Improve Perinatal Mental Health in Nepal
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-540880
Background: Mistreatment during institutional childbirth is a global health concern, with 80% of births taking place in hospitals. Postpartum depression remains inadequately addressed in many maternal health settings. There is an urgent need for research to investigate mistreatment during childbirth as exposure and its linkage with postpartum depression.
Aims: The overarching aim was to investigate mistreatment during institutional childbirth in Nepal and to co-design intervention prototypes for respectful maternity care. The specific objectives were: to assess mistreatment during childbirth in tertiary care facilities (Paper I), to measure its association with postpartum depressive symptoms (Paper II), to explore mistreatment from women’s perspectives (Paper III), and to co-design early-stage respectful maternity care interventions (Paper IV).
Methods: Prospective cohort design was employed in paper I to measure the prevalence of mistreatment during childbirth in 11 hospitals and in Paper II to assess its association with postpartum depressive symptoms in one hospital. Paper III involved 16 in-depth interviews to explore women’s lived experiences of mistreatment during childbirth. Paper IV adopted a human-centered co-design process involving 28 midwives to develop prototypes of respectful care.
Results: Altogether, 84.3% (n = 53,047) of women had no opportunity to discuss their concerns; 80.4% (n = 50,593) were not adequately informed; 42.1% (n = 26,492) did not receive breastfeeding counselling; 1.5% (n = 944) were refused postpartum care for inability to pay. Women aged 30–34 years old (β,− 0.38013; p-value, 0.000) were less likely to expereince mistreatment compared to women aged 18 years or younger. Furthermore, women from relatively disadvantaged (Dalit) ethnic groups were more likely to experience mistreatment (β, 0.29596; p-value, 0.000) than women from more advantaged (Chettri) ethnic groups. Paper II found that a third of women (n = 360, 29.5%) experienced mistreatment during childbirth and these women were almost 50% more likely (cRR 1.47; 95% CI 1.14, 1.89; p = 0.003) to experience postpartum depressive symptoms compared to those who did not report mistreatment. Paper III identified adverse hospital culture, systemic constraints and territorial behavior as perceived drivers of mistreatment during childbirth. Paper IV codesigned respectful care prototypes: bottom-up communication system, communication skills for midwives, and community-based health education for clients.
Conclusion: Thesis demonstrates high burden of mistreatment during childbirth and its potential linkage to postpartum depression, and highlight the capacity of co-designed interventions to address the root causes of mistreatment. Personalized care with effective communication in a supportive hospital environment, is essential for positive health outcomes.