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In Drosophila melanogaster, the genes of the spitz group and of the DER signaling pathway function together to communicate localized developmental signals to the cells of many tissues. The embryonic midline glia (MG), a mesectodermal lineage essential to proper morphogenesis of the axon tracts of the ventral nerve cord (VNC), depend on spitz group signaling for survival and differentiation. Loss of function of any of the spitz group genes or of DER results in a decrease in the number of MG and subsequent defects in the formation of the axon tracts. These defects include a medial collapse of the longitudinal axons and fusion of the posterior and anterior commissures. Ectopic expression of Rhomboid, a putative seven pass transmembrane protein which is a member of the spitz group, generates supernumerary glia. Directed expression of DER^AB87T, an activated form of the Drosophila EGF receptor, sSpi, a diffusible ligand, or Ras^v12, a constitutively activated variant of a monomeric G-protein, have the same effect on MG number. It is proposed that the spitz group/DER signaling pathway act to promote survival of MG precursor cells. In addition, expression of Draf and pntP1 are found to increase the number of surviving supernumerary MG, however these signaling molecules are determined to be less effective at promoting the survival of the MG, based on their decreased ability to generate supernumerary MG. Furthermore, a subset of the supernumerary MG created in embryos in which Draf has been misexpressed appear to be incompletely differentiated or insulated from normal programmed cell death (PCD) by expression of this transgene. The effect of multiple cytoplasmic signaling pathways, activated by spitz group/DER signaling, on MG survival and differentiation is examined and discussed. Ectopic expression of rhomboid generates supernumerary MG. This process is suppressed by mutation of genes of the spitz group or of DER. Evidence that Rho functions upstream of Spi, Star and DER is presented. The implications of these data and their relevance to previously published models which propose the molecular actions of the spitz group/DER pathway genes are discussed. Finally, the role of spitz group/DER signaling in the activation of downstream target genes is explored. Overexpression of these genes results in increased expression of pointed, argos, and rhomboid. A model for spitz group function in signal amplification is proposed. / Thesis / Master of Science (MSc)

It is a commonly held belief that a repeat caesarean section through a low vertical scar provides easier access and fewer complications than an operation through a previous Pfannenstiel incision. To test this hypothesis the records of one hundred and twenty one repeat caesarean sections were retrospectively reviewed by the author. These records were reviewed at the two large teaching hospitals of the University of the Witwatersrand, Chris Hani Baragwanath and Johannesburg General Hospital. Statistically significant findings were that older women were more likely to have had an initial midline incision. Incision to delivery times were faster via the midline (4 min) than the Pfannenstiel incision (5.5 min). Total operating times did not differ significantly. The findings do show that repeat midline incisions are faster (1.5 min) to deliver, but do not address the patient’s need for a cosmetically pleasing wound scar.

Bakgrund: Barn som vårdas på sjukhus är ofta i behov av någon form av venaccess. På flera platser i Sverige finns enbart perifiera venkatetrar att tillgå när en central infart ej är aktuellt. För barn med långvarigt behov av intravenösa läkemedel kan detta orsaka upprepade stick och kateterbyten. Midline är en perifer venaccsess med längre hållbarhet som nyligen börjat användas inom pediatrisk vård. Syfte: Studiens syfte är att undersöka sjuksköterskors erfarenheter av att vårda barn med Midline. Metod: Studien genomfördes med kvalitativ metod genom semistrukturerade intervjuer.Därefter utfördes en innehållsanalys för att besvara studiens syfte. Deltagarna var nio sjuksköterskor vid fyra olika sjukhus i mellersta och södra Sverige. Resultat: Analysen resulterade i kategorierna: En ny typ av infart, En vårdupplevelse med barnet i fokus samt Att företräda barnen. Tillgång till en infart som var säker och hade längre hållbarhet än andra perifiera venkatetrar uppskattades av deltagarna. Tydliga instruktioner och rutiner ansågs viktiga. En stor fördel med Midline ur ett barnperspektiv var färre stick i samband med långvarigt behov av venaccsess. Samt vikten av det interprofessionella samarbetet som krävs för att få inläggning av katetern att bli så bra som möjligt. Slutsats: Deltagarna såg Midline som ett bra alternativ till andra perifiera infarter i vården av barn med behov av långvarig venaccess. Detta då det minskade lidandet för barnen samt att det gav en möjlighet till lek och vistelse utanför sjukhus som annars hade varit svårt att tillgodose. / Background: Children in hospital care may need venous access. In many places in Sweden the only type of access available is peripheral venous catheter or central lines. For children with a long need of intravenous treatment this can cause repeated procedures and pain.Midline is a peripheral venousacsess with longer durability that recently has been introduced in pediatric care. Aim: To explore nurses experience of using Midline in paediatric care. Method: The method used was a qualitative design with a content analysis. Semistructured interviews were conducted with nine nurses from four different hospitals in the middle and southern parts of Sweden. Results: The participants’ experiences were categorized in three main categories: A new type of venous access, A care experience with the child in focus and To represent the child. To have a secure access with a longer durability compared to a regular venous catheter was highly appreciated by the participants. Instructions and routines where essential for the catheter to work properly. Fewer painful procedures was seen as an advantage with the Midline catheter through the children's perspective. Conclusion: The participants saw the Midline catheter as a good alternative to the regular peripheral venous catheter in the paediatric care. It was seen to decrease childrens suffering and gave a better opportunity to play and spend time outside of the hospital.

Central line-associated bloodstream infections (CLABSIs) are responsible for 100,000 patient deaths per year, creating a critical need for prevention of these deadly infections that occur with central venous lines (CVLs). Alternative forms of IV access such as midline catheters (MLCs) may offer lower rates of infection than those seen with CVLs. MLCs were implemented at the practice setting in 2016; however, no evaluation of their effectiveness had been conducted. The purpose of this project was to evaluate the effectiveness of MLCs using a retrospective, pre- post- comparison of CLABSI rates and device utilization rates (DUR) obtained from the practice setting before and after implementation of MLCs. Infection control and Lewin's change theories were used to provide a foundation for the project. This retrospective, pre-post comparison of CLABSI and DUR 6 months before and after introduction of MLCs sought to determine if MLC use affected either rate. Results of a Wilcoxon signed-rank test showed no statistical differences (p > .05) in CLABSI rates and DUR when comparing the rates from the specified 6 month periods. A secondary purpose was to identify the characteristics and conditions in which MLCs were used. Patients with cardiovascular, neuro, and infection diagnoses constituted 43% of the 262 MLC placements. No statistically significant improvement in infection rates was demonstrated by this project; however, these findings illuminate the types of patients or conditions where MLCs are a viable alternative for IV access, and this knowledge may assist providers in options for patient care. This project promotes positive social change by raising awareness of potential strategies for reducing infections in patients when they are at their most vulnerable.

Ventral body wall closure (VBW) defects are amongst the most common human congenital anomalies. They represent a wide and heterogeneous group of phenotypic defects that can present in isolation or as a component in a larger syndromic anomaly. In addition, the incidence of associated anomalies is high and reaches 75% of fetuses in some types of VBW closure defects. Nevertheless, the embryonic origin and the underlying cellular and molecular mechanisms between ventral closure defects and their associated congenital anomalies remain poorly characterised. This is in part due to the poor understanding of the physiological mechanisms that regulate the development of ventral organs and the lack of representative transgenic animal models allowing detailed in vivo analysis of defect formation. Transforming growth factor beta (TGF-ÃŽÂ2) signalling is essential for VBW closure and vascular and cardiac development. Yet, its mechanism of action and the responding cell(s) in the body wall remain largely unknown. In addition, in various cells TGF-B can induce the expression of Tagln, encoding for a cytoskeleton associated protein that enhances cell migration. No function has been ascribed to TAGLN in body wall development. I define here a role of TGF-B during a critical time window in embryonic development to fashion the ventral body wall, anterior diaphragm and parts of the circulatory system. I identify a population of TAGLN+ myofibroblasts that respond to a temporally regulated TGF-B signalling originating from the epithelium of the primary body wall. Deletion of TGF-B receptor in TAGLN+ cells leads to failure of ventral body wall closure, anterior diaphragmatic hernia, cardiac and outflow tract anomaly. Nevertheless, the descending aorta and the large aortic branches are spared. By using advanced transgenic methodology, I generated novel transgenic mouse lines that enabled me to fate map the cells that initiate the formation of important mesenchymal tissues. These studies revealed that the origin of aortic vascular smooth muscle cells can be traced back to a group of progenitor cells that reside in the wall of the dorsal aorta before the VBW closure. My studies provide intriguing evidence for spatially restricted role for TGF-B signalling in ascending but not descending aorta morphogenesis. I used a variety of techniques to characterise, analyse and quantify important mechanisms during mesenchymal and vascular development, their response to injury and repair. This thesis has been written in an alternative format, comprising the different areas which have been investigated. Collectively, the results presented here provide new insights into the role of migratory and mechanically stabilising cells in the development and maintenance of critical structures in the body and their common role in the development of concurrent congenital anomalies. A detailed understanding of the molecular signalling pathways and cells that drive VBW closure raises the hope that the related birth defects can in the future be treated by precise gene and cell therapies.

Several cell lineages derived from the mesectoderm occupy and contact axons in the midline of the developing Drosophila CNS. Which of these midline cell lineages contribute to commissural axon morphogenesis? In the absence of the midline cells as in mutant embryos of the single-minded gene, the longitudinal axons collapse at the midline and commissural axons are absent. Despite the similarity in axon tract phenotype, the midline cells in slit mutant embryos survive but are displaced. Correct cytoarchitecture of the midline cells is therefore dependent on the activity of Sli protein which is in turn necessary for commissure formation. In mutant embryos displaying a fused commissure phenotype (rhomboid and Star), the anterior and middle midline glia cells failed to migrate and died by apoptosis after commissure development. In these mutants the number of cells in midline neuronal lineages was reduced before defects in midline glia were apparent. In wildtype embryos approximately 50% of cells in three midline glia lineages died by apoptosis after commissure separation as shown by ultrastructural and enhancer trap analysis. Midline glia lineages died by apoptosis as shown morphologically and by their survival in embryos deficient in the cell death gene reaper. Quantitative analysis revealed variable survival of cells in the anterior, middle and posterior midline glial lineages during embryogenesis suggesting heterogeneity among these cells. The presence of extra anterior, middle and posterior midline glial lineages relative to wildtype numbers in reaper mutant embryos suggested that cell death regulates either midline glial proliferation or cell fate determination during wildtype embryogenesis. Alterations in axon-glia contact correlated with changes in midline glia survival. What happens to apoptotic cells in the Drosophila embryonic central nervous system? A variety of glia in the nervous system were capable of phagocytic activity including midline glia, longitudinal tract glia, nerve root glia and subperineurial glia, revealed by electron microscopy. However, the majority of apoptotic cells in the central nervous system were engulfed by subperineurial glia. In the absence of phagocytic haemocytes in embryos mutant for the Bicaudal-d gene, most apoptotic cells were retained in subperineurial glia at the outer edges of the central nervous system. Apoptotic cells were expelled from the central nervous system of Bicaudal-d mutant embryos suggesting that phagocytic haemocytes participate in the removal of apoptotic cells from the central nervous system but are not essential for this process. / Thesis / Doctor of Philosophy (PhD)

Presented dissertation deals with the problematics of optimal choice of venous access for each hospitalized patient at standard internal wards. Introduction of vascular access must be safe for the patient and must allow the fulfillment of all the goals for which it was indicated. In recent years, in addition to peripheral cannulas and non-tunneled central catheters, introduction of midline catheters and PICC gets into everyday practice. The choice of optimal vascular access device since adminition can bring benefit to the patients in the form of decline of complications. Goal: The goal of master thesis was to prove that the use of new types of vascular access devices has influence on the decline of vascular access devices related complication occurence. Methods: To reach the goal we used a quantitative method of data collection during certain time period using created collection protocols. Research investigation took place from November 2017 to February 2018 at two standard wards of Department of Internal Medicine FN Motol. Results: A total of 350 venous access devices (271 peripheral cannulas, 54 midline catheters, 35 PICC) in 187 hospitalized patients was monitored. Prevalence of complications, average length of placement and reasons for extraction of individual vascular access devices was...

Glutamate, the predominant excitatory neurotransmitter in the central nervous system, is involved in almost all aspects of neurological function including cognition, motor function, memory, learning, decision making, and neuronal plasticity. For normal neurological function, glutamate signaling must be properly regulated. Disrupted glutamate regulation plays a pivotal role in the acute pathophysiology of traumatic brain injury (TBI), disrupting neuronal signaling, initiating secondary injury cascades, and producing excitotoxicity. Increases in extracellular glutamate have been correlated with unfavorable outcomes in TBI survivors, emphasizing the importance of glutamate regulation. The aim of this thesis was to examine disruptions in the regulation of extracellular glutamate after experimental TBI. In these studies, we used glutamate-sensitive microelectrode arrays (MEAs) to examine the regulation of extracellular glutamate two days after diffuse brain injury. First, we examined which brain regions were vulnerable to post-traumatic increases in extracellular glutamate. We detected significant increases in extracellular glutamate in the dentate gyrus and striatum, which correlated to the severity of brain injury. Second, we examined the regulation of extracellular glutamate by neurons and glia to determine the mechanisms responsible for post-traumatic increases in extracellular glutamate. In the striatum of brain-injured rats, we detected significant disruptions in release of glutamate by neurons and significant decreases in the removal of glutamate from the extracellular space by glia. Third, we examined if a novel therapeutic strategy, a viral-vector mediated gene delivery approach, could improve the regulation of extracellular glutamate. Infusion of an adeno-associated virus expressing a glutamate transporter into the rat striatum produced significant improvements in glutamate clearance, identifying a novel strategy to reduce excitotoxicity. Lastly, we examined the translational potential of MEAs as novel neuromonitoring device for clinical TBI research. Overall, these studies have demonstrated the translational potential of MEAs to aid in the diagnosis and treatment of TBI survivors.

The severity of traumatic brain injury (TBI) is known to be characterized by the shift of the middle line in brain as the ventricular system often changes in size and position, depending on the location of the original injury. In this thesis, the focus is given to processing of the CT (Computer Tomography) brain images to automatically calculate midline shift in pathological cases and use it to predict Intracranial Pressure (ICP). The midline shift measurement can be divided into three steps. First the ideal midline of the brain, i.e., the midline before injury, is found via a hierarchical search based on skull symmetry and tissue features. Second, the ventricular system is segmented from the brain CT slices. Third, the actual midline is estimated from the deformed ventricles by shape matching method. The horizontal shift in the ventricles is then calculated based on the ideal midline and the actual midline in TBI CT images. The proposed method presents accurate detection of the ideal midline using anatomical features in the skull, accurate segmentation of ventricles for actual midline estimation using the information of anatomical features with a spatial template derived from a magnetic resonance imaging (MRI) scan, and an accurate estimation of the actual midline based on the robust proposed multiple regions shape matching algorithm. After the midline shift is successively measured, features including midline shift, texture information of CT images, as well as other demographic information are used to predict ICP. Machine learning algorithms are used to model the relation between the ICP and the extracted features. By using systematic feature selection and parameter selection of the learning model, promising results on ICP prediction are achieved. The prediction results also indicate the reliability of the proposed midline shift estimation.