| 61. |
- Abu Hamdeh, Sami, 1982-
(författare)
-
Clinical Consequences of Axonal Injury in Traumatic Brain Injury
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Traumatic brain injury (TBI), mainly caused by road-traffic accidents and falls, is a leading cause of mortality. Survivors often display debilitating motor, sensory and cognitive symptoms, leading to reduced quality of life and a profound economic burden to society. Additionally, TBI is a risk factor for future neurodegenerative disorders including Alzheimer’s disease (AD). Commonly, TBI is categorized into focal and diffuse injuries, and based on symptom severity into mild, moderate and severe TBI. Diffuse axonal injury (DAI), biomechanically caused by rotational acceleration-deceleration forces at impact, is characterized by widespread axonal injury in superficial and deep white substance. DAI comprises a clinical challenge due to its variable course and unreliable prognostic methods. Furthermore, axonal injury may convey the link to neurodegeneration since molecules associated with neurodegenerative events aggregate in injured axons.The aim of this thesis was to study clinical consequences of axonal injury, its detection and pathological features, and potential link to neurodegeneration in severe TBI patients treated at the neurointensive care unit at Uppsala University Hospital. In paper I and IV DAI patients were studied for the relation of elevated intracranial pressure (ICP) and poor outcome to axonal injury on magnetic resonance imaging. In paper II, soluble amyloid-beta aggregates (oligomers and protofibrils), characteristic of AD pathology, were investigated in surgically resected brain tissue from severe TBI patients, using highly-selective Enzyme-Linked ImmunoSorbent Assays. In paper III, brain tissue biopsy samples from TBI patients with either focal injury or DAI were examined for differential proteome profiles using mass spectrometry-based proteomics.The results provide evidence that axonal injury, located in the central brain stem, in substantia nigra and the mesencephalic tegmentum, is particularly related to poor outcome and increased ICP during neurointensive care of DAI patients. A novel classification system for prognostication after DAI is proposed. Furthermore, the thesis shows that severe TBI induces rapid accumulation of neurotoxic soluble amyloid-beta oligomers and protofibrils. In addition, DAI initiates unique proteome profiles different from that of focal TBI in structurally normal-appearing brain. These findings have implication for the clinical management of DAI patients, and provide new insight in the neuropathological consequences of axonal injury.
|
|
| 62. |
- Abu Sabaa, Amal
(författare)
-
Clinical and Molecular Studies of Diffuse Large B-cell Lymphoma
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The general aim of this thesis was to study the prognostic clinical and biological markers of Diffuse Large B-cell Lymphoma (DLBCL).Paper I: Utilizing population-based data for patients with DLBCL in Sweden, the study aimed to establish whether event free survival at 24 months (EFS24) was a reproducible milestone. The disease-free survival for lymphoma patients was compared with that of age and sex matched Swedish general population. We demonstrated that overall survival was similar to age and sex matched general population only for younger patients (<60 years of age) achieving ES24. Patients older than that had worse prognosis. Death was mainly linked to cardiovascular disease and secondary malignancies.Paper II: Plasma samples collected via the bio bank U-CAN were analyzed using multiplex extension assay (PEA) utilizing preselected protein panels to examine the possibility of distinguishing lymphomas, leukemias and controls. The study confirmed that PEA technology could be used not only to effectively screen for large number of plasma protein biomarkers in low plasma sample volumes (1 µL), but even to discriminate between controls and different haematological malignancies. Paper III: Plasma protein pattern evolution in DLBCL patients was highlighted by PEA analysis of plasma proteins at different time points under treatment with Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Significant distinctions in protein patterns at diagnosis compared to controls and striking differences in protein levels before and after treatment in patient who responded to treatment were evident. The three top proteins were TCL1A, CXCL13 and IL2RA. Paper IV: An interesting protein that emerged from the above studies was TCL1A. This plasma protein was analyzed in plasma samples by PEA. Validation by plasma enzyme immunosorbent assay (ELISA) was attempted. The cytoplasm and nucleus bound form of TCL1A were analyzed with the help of immunohistochemistry in tissue microarray samples. The study included 178 patients of which 125 received R-CHOP. Clinical risk factor analysis showed no significant correlation with tissue IHC. Significantly higher levels of plasma TCL1A were seen in male patients (measured by ELISA and PEA) and in patients with Ann Arbor stages II-IV (measured by PEA). Survival analysis showed no statistical significance.
|
|
| 63. |
|
|
| 64. |
|
|
| 65. |
- Acharya, Parag, 1972-
(författare)
-
Studies on the Non-covalent Interactions (Stereoelectronics, Stacking and Hydrogen Bonding) in the Self-assembly of DNA and RNA
- 2003
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is based on ten publications (Papers I-X). The phosphodiester backbone makes DNA or RNA to behave as polyelectrolyte, the pentose sugar gives the flexibility, and the aglycones promote the self-assembly or the ligand-binding process. The hydrogen bonding, stacking, stereoelectronics and hydration are few of the important non-covalent forces dictating the self-assembly of DNA/RNA. The pH-dependent thermodynamics clearly show (Papers I and II) that a change of the electronic character of aglycone modulates the conformation of the sugar moiety by the tunable interplay of stereoelectronic anomeric and gauche effects, which are further transmitted to steer the sugar-phosphate backbone conformation in a cooperative manner. 3'-anthraniloyl adenosine (a mimic of 3'-teminal CCAOH of the aminoacyl-tRNAPhe) binds to EF-Tu*GTP in preference over 2'-anthraniloyl adenosine, thereby showing (Paper III) that the 2’-endo sugar conformation is a more suitable mimic of the transition state geometry than the 3’-endo conformation in discriminating between correctly and incorrectly charged aminoacyl-tRNAPhe by EF-Tu during protein synthesis. The presence of 2'-OH in RNA distinguishes it from DNA both functionally as well as structurally. This work (Paper IV) provides straightforward NMR evidence to show that the 2'-OH is intramolecularly hydrogen bonded with the vicinal 3'-oxygen, and the exposure of the 3'-phosphate of the ribonucleotides to the bulk water determines the availability of the bound water around the vicinal 2'-OH, which then can play various functional role through inter- or intramolecular interactions. The pH-dependent 1H NMR study with nicotinamide derivatives demonstrates (Paper V) that the cascade of intramolecular cation (pyridinium)-π(phenyl)-CH(methyl) interaction in edge-to-face geometry is responsible for perturbing the pKa of the pyridine-nitrogen as well as for the modulation of the aromatic character of the neighboring phenyl moiety, which is also supported by the T1 relaxation studies and ab initio calculations. It has been found (Papers VI-IX) that the variable intramolecular electrostatic interaction between electronically coupled nearest neighbor nucleobases (steered by their respective microenvironments) can modulate their respective pseudoaromatic characters. The net result of this pseudoaromatic cross-modulation is the creation of a unique set of aglycones in an oligo or polynucleotide, whose physico-chemical properties are completely dependent upon the propensity and geometry of the nearest neighbor interactions (extended genetic code). The propagation of the interplay of these electrostatic interactions across the hexameric ssDNA chain is considerably less favoured (effectively up to the fourth nucleobase) compared to that of the isosequential ssRNA (up to the sixth nucleobase). The dissection of the relative strength of basepairing and stacking in a duplex shows that stability of DNA-DNA duplex weakens over the corresponding RNA-RNA duplexes with the increasing content of A-T/U base pairs, while the strength of stacking of A-T rich DNA-DNA duplex increases in comparison with A-U rich sequence in RNA-RNA duplexes (Paper X).
|
|
| 66. |
- Acharya, Sandipta, 1972-
(författare)
-
Some Aspects of Physicochemical Properties of DNA and RNA
- 2006
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is based on nine research publications (I – IX) on structure and reactivity of RNA vis-à-vis DNA. The DNA and RNA are made of flexible pentose sugar units, polyelectrolytic phosphodiester backbone, and heterocyclic nucleobases. DNA stores our genetic code, whereas RNA is involved both in protein biosynthesis and catalysis. Various ligand-binding and recognition properties of DNA/RNA are mediated through inter- and intra-molecular H-bonding and stacking interactions, beside hydration, van der Waal and London dispersion forces. In this work the pH dependant chemical shift, pKa values of 2'-OH group as well as those the nucleobases in different sequence context, alkaline hydrolysis of the internucleotidic phosphodiester bonds and analysis of NOESY footprints along with NMR constrained molecular dynamics simulation were used as tools to explore and understand the physico-chemical behavior of various nucleic acid sequences, and the forces involved in their self-assembly process. Papers I – II showed that the ionization of 2'-OH group is nucleobase-dependant. Paper III showed that the chemical characters of internucleotidic phosphate are non-identical in RNA compared to that of DNA. Papers IV – VI show that variable intramolecular electrostatic interactions between electronically coupled nearest neighbor nucleobases in a ssRNA can modulate their respective pseudoaromatic character, and result in creation of a unique set of aglycons with unique properties depending on propensity and geometry of nearest neighbor interaction. Paper VII showed that the cross-modulation of the pseudoaromatic character of nucleobases by the nearest neighbor is sequence-dependant in nature in oligonucleotides. Paper VIII showed that the purine-rich hexameric ssDNA and ssRNA retain the right-handed helical structure (B-type in ssDNA and A-type in ssRNA) in the single-stranded form even in absence of intermolecular hydrogen bonding. The directionality of stacking geometry however differs in ssDNA compared to ssRNA. In ssDNA the relatively electron-rich imidazole stacks above the electron-deficient pyrimidine in the 5' to 3' direction, in contradistinction, the pyrimidine stacks above the imidazole in the 5' to 3' direction in ssRNA. Paper IX showed that the pKa values of the nucleobases in monomeric nucleotides can be used to show that a RNA-RNA duplex is more stable than a DNA-DNA duplex. The dissection of the relative strength of base-pairing and stacking showed that the relative contribution of former compared to that of the latter in an RNA-RNA over the corresponding DNA-DNA duplexes decreases with the increasing content of A-T/U base pairs in a sequence.
|
|
| 67. |
- Achermann, Sheila
(författare)
-
Prediction in Typical and Atypical Development
- 2020
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Forming predictions about what is going to happen next is a crucial ability that develops early in life. Theory and some empirical evidence suggest that predictive abilities may be impaired in Autism Spectrum Disorder (ASD). The overarching aim of this thesis is to investigate early measures of prediction in relation to concurrent and later outcomes in typical and atypical development, with a particular focus on ASD and related behavioral problems.In Study I, we used motion capture technology to examine prospective motor control and its relationship to executive functions in typically developing 18-month-olds. Our findings showed that motor control is associated with executive functioning in infancy.Study II investigated motor control in infants at low and elevated likelihood for ASD and examined how these measures relate to later development. We found group differences as well as similarities in motor control in 10-months-olds with and without a familial history of ASD. Early motor measures were related to general developmental level, but not ASD symptomatology in toddlerhood.Using eye tracking, Study III examined how infants with later ASD and neurotypical infants form predictions about visual object motion. Our findings indicated that infants with later ASD were able to form predictions about object motion and adapt to simple changes in motion patterns, and that their performance did not differ from the performance of neurotypical infants.In Study IV, we surveyed parents about their experiences during participation in an infant sibling study of ASD as a first step to understanding the benefits and risks associated with this type of research. Parents were generally positive about their experiences both from their own perspective as well as, the child’s perspective.This thesis illustrates the potential of using advanced technology, such as motion tracking and eye tracking, to study and compare prediction in typical and atypical development. It points to the important role of prediction and motor control for child development, but fails to find a specific link to ASD.
|
|
| 68. |
- Ackermann-Boström, Constanze
(författare)
-
Gelebte Mehrsprachigkeit im Plattenbau : Untersuchungen von Narrativen und Praktiken russlanddeutscher junger Erwachsener
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on the lived multilingualism of a group of young Russian-German adults who as children migrated together with their families from post-Soviet states to the Federal Republic of Germany during the 1990s. Today these adults live in a ‘Plattenbau’ housing estate in a small town in one of the new federal states of Germany. The large pre-fabricated concrete-slab system-built housing estates that were built during the GDR-era are today generally considered as deprived areas due a combination of decreasing population and high unemployment.This thesis shows how young Russian-Germans create a multilingual community of practice and use various aspects of language and non-linguistic resources for identity construction. The data analysed in this thesis comes from ethnographic studies conducted during three phases of fieldwork between Spring 2011 and Spring 2012. The data was collected at a youth centre where the group of young Russian-German adults regularly met.Combining intensive participant observation, field notes, photos, and narrative interviews the thesis is a mixed-method investigation. Underpinning the analysis of the research data are theoretical models of the relationship between language, identity, and space. Methodologically this study combines linguistic ethnography, narrative analysis, and membership categorization analysis.The thesis argues that an ethnographical-narrative approach is a powerful tool that is able to highlight the role of language(s) and non-linguistic resources for identity construction in social spaces, illustrates how young Russian-Germans construct a web of multilingual identities by using social categories to position themselves and others, and shows how the lived multilingualism of young Russian-German adults influences all aspects of their social lives. For example, the thesis shows the maintenance of Russian as a heritage language within Russian-German families, yet and an avoidance of visible signs of the Russian-German heritage in public spaces.
|
|
| 69. |
- Acosta Ruiz, Vanessa, 1987-
(författare)
-
CT Guided Ablation of T1 Renal Tumors
- 2019
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The widespread use of medical imaging contributes to the increased detection of incidentally detected small renal tumors, a majority which are often indolent masses found in elderly patients with preexisting chronic kidney disease. In Sweden, partial nephrectomy with minimal invasive surgical approach is the current standard for removing these tumors, although another option is percutaneous image-guided tumor ablation that allows treatment of elderly patients with comorbidities for who surgery is a risk. Due to the lack of long-term follow-up studies and prospective randomized trials, ablation is still considered an alternative option to surgery in Sweden. The aim of this thesis was to evaluate treatment of T1 renal tumors with CT guided radiofrequency (RFA) and microwave ablation (MWA).Factors affecting the efficacy rate of complete tumor ablation with RFA after a single session were evaluated (Paper I). Optimal electrode placement and a long tumor distance to the collecting system were associated with an increased primary efficacy. Renal tumor RFA was compared with laparoscopic partial nephrectomy (LPN: Papers II-III): both methods had comparable secondary efficacy rates, but RFA involved several treatment sessions. Total session times and hospitalization times were shorter and complications less frequent for RFA than for LPN (Paper II). After treatment, renal function impact was assessed by evaluation of both renal function quantity and quality through determination of the split renal function (SRF: Paper III). Standard renal function measurements were assessed and both RFA and LPN were nephron sparing when treating small renal tumors and did not affect creatinine or GFR. However, LPN involved greater SRF reduction in the affected kidney than RFA. Initial experience with microwave ablation was evaluated and this new ablation technique demonstrated high efficacy rates with fewer complications, and was comparable with the mid-term results of now established ablation techniques (Paper IV).In conclusion, CT guided RFA and MWA are safe and effective treatments for the removal of T1 renal tumors. This thesis provides further insights into the field of thermal ablation of small renal masses, which can aid future treatment selection and patient management.
|
|
| 70. |
- Acosta, Stefan, 1967-
(författare)
-
On Acute Thrombo-Embolic Occlusion of the Superior Mesenteric Artery
- 2004
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acute thrombo-embolic occlusion of the superior mesenteric artery (SMA) with intestinal infarction is a lethal disease, difficult to diagnose in time, with unknown incidence and cause-specific mortality. The aim of this thesis was to characterize the disease and to develop diagnostic methods. Two laboratory studies were conducted on patients with suspected acute SMA occlusion. A pilot-study showed that the fibrinolytic marker D-dimer was elevated in six patients with the disease. In the subsequent study including 101 patients, D-dimer was the only elevated coagulation marker in nine patients with the disease. In a prospective study 24 patients (median age 84 years) were identified, of whom four were diagnosed at autopsy, despite an autopsy-rate of 10%. One-fourth were initially nursed in non-surgical wards. Length of the intestinal infarction was a predictor for death. An analysis of patients from the three studies showed that D-Dimer was elevated in all 16 tested patients with the disease.Sixty patients with acute SMA occlusion underwent intestinal revascularisation and were registered in the Swedish Vascular Registry (SWEDVASC). One-year survival-rate was 40%. Previous vascular surgery was a negative risk-factor.A population-based study was conducted in Malmö, based on an autopsy-rate of 87%. Among 270 patients with the disease, 2/3 were diagnosed only at autopsy and 1/2 were managed in non-surgical wards. The incidence was 8.6 per 100000 person years. The age-standardized incidence increased exponentially without gender differences. The diagnosis was the cause of death in 1.2% among octogenarians and beyond. Thrombotic occlusions were located proximally within the SMA and associated with extensive intestinal infarctions. Synchronous embolism, often multiple, occurred in 2/3 of the patients with embolic occlusions.Conclusions: A normal D-dimer at presentation most likely excludes the diagnosis. Acute SMA occlusion was more frequent than previously estimated from clinical series. The patients were often nursed in non-surgical wards.
|
|
