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  • Disputas: 2018-02-27 09:00 80127, Uppsala
    Hettiarachchi, Pasan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Elektricitetslära.
    Measurements of X-Ray Emission from Laboratory Sparks and Upward Initiated Lightning2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In 1925 Nobel laureate R. C. Wilson predicted that high electric fields of thunderstorms could accelerate electrons to relativistic energies which are capable of generating high energetic radiation. The first detection of X-rays from lightning was made in 2001 and from long sparks in 2005. Still there are gaps in our knowledge concerning the production of X-rays from lightning and long sparks, and the motivation of this thesis was to rectify this situation by performing new experiments to gather data in this subject.

    The first problem that we addressed in this thesis was to understand how the electrode geometry influences the generation of X-rays. The results showed that the electrode geometry affects the X-ray generation and this dependency could be explained using a model developed previously by scientists at Uppsala University. The other missing information was the distribution of energy. Using a series of attenuators, we observed how the X-ray photons were attenuated as a function of barrier thickness and using a simple model we obtained the average and the maximum energy of X-rays. 

    All the studies conducted previously was based on the lightning impulses, but in switching impulses, the voltage waveform rises very slowly compared to lightning impulses, and according to some scientists the rate of rise is an important parameter in X-ray development. Our study showed that the switching impulses were as efficient as lightning impulses in generating X-rays even though the rate of rise of voltage in switching impulses was hundreds of times slower.

    All the observations on X-ray generation from lightning by other scientists were based on either natural downward lightning flashes or triggered lightning in Florida. The first experiments to study the X-ray generation from upward lightning flashes systematically was conducted within this thesis work at Gaisberg Tower in Austria. The results showed that the X-ray emissions from these flashes were much weaker than the ones produced by either natural downward or triggered lightning. An attempt was made to explain this observation by invoking the possible differences in the charge distribution of leaders associated with the triggered lightning flashes in Florida and upward initiated lightning flashes at Gaisberg tower.

    Delarbeid
    1. X-rays from negative laboratory sparks in air: Influence of the anode geometry
    Åpne denne publikasjonen i ny fane eller vindu >>X-rays from negative laboratory sparks in air: Influence of the anode geometry
    2017 (engelsk)Inngår i: Journal of Atmospheric and Solar-Terrestrial Physics, ISSN 1364-6826, E-ISSN 1879-1824, Vol. 154, s. 190-194Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In this experimental work, the influence of the grounded anode geometry is studied on the X-ray production from the laboratory sparks in air at atmospheric pressure when a negative impulse voltage is applied to a high voltage rod which served as a cathode. The result shows that the smaller the diameter of the anode, the higher the energy of X-ray bursts. This observation can be explained by the mechanism that the encounter of negative and positive streamer fronts just before the final breakdown is the event that accelerates electrons to X-ray generating energies, but may not be the only mechanism that generates X-rays.

    Emneord
    X-rays, laboratory sparks, electrodes, runaway electrons
    HSV kategori
    Forskningsprogram
    Teknisk fysik med inriktning mot atmosfäriska urladdningar
    Identifikatorer
    urn:nbn:se:uu:diva-268859 (URN)10.1016/j.jastp.2016.07.012 (DOI)000395952000019 ()
    Forskningsfinansiär
    Swedish Research Council, 621-2012-3300
    Tilgjengelig fra: 2015-12-10 Laget: 2015-12-10 Sist oppdatert: 2018-01-08bibliografisk kontrollert
    2. Energy Distribution of X-rays Produced by Meter-long Negative Discharges in Air
    Åpne denne publikasjonen i ny fane eller vindu >>Energy Distribution of X-rays Produced by Meter-long Negative Discharges in Air
    2017 (engelsk)Inngår i: Atmosphere, ISSN 2073-4433, E-ISSN 2073-4433, Vol. 8, nr 12, artikkel-id 244Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The energy deposited from X-rays generated by 1 m long laboratory sparks in air created by 950 kV negative lightning impulses on scintillated detectors was measured. Assuming the X-ray energy detected in such sparks results from the accumulation of multiple photons at the detector having a certain energy distribution, an experiment was designed in such a way to characterize their distribution parameters. The detector was screened by a copper shield, and eight series of fifteen impulses were applied by stepwise increasing the copper shield thickness. The average deposited energy was calculated in each series and compared with the results from a model consisting of the attenuation of photons along their path and probable photon distributions. The results show that the energy distribution of X-ray bursts can be approximated by a bremsstrahlung spectrum of photons, having a maximum energy of 200 keV to 250 keV and a mean photon energy around 52 keV to 55 keV.

    HSV kategori
    Forskningsprogram
    Teknisk fysik med inriktning mot atmosfäriska urladdningar
    Identifikatorer
    urn:nbn:se:uu:diva-335142 (URN)10.3390/atmos8120244 (DOI)000419179200014 ()
    Tilgjengelig fra: 2017-11-30 Laget: 2017-11-30 Sist oppdatert: 2018-02-14bibliografisk kontrollert
    3. X-ray observations at Gaisberg Tower
    Åpne denne publikasjonen i ny fane eller vindu >>X-ray observations at Gaisberg Tower
    Vise andre…
    2018 (engelsk)Inngår i: Atmosphere, ISSN 2073-4433, E-ISSN 2073-4433, Vol. 9, nr 1, artikkel-id 20Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    We report the occurrence of X-rays at ground level due to cloud-to-ground flashes of upward initiated lightning from Gaisberg Tower in Austria which is located at a 1300 m altitude.  This is the first time that the X-rays from upward lightning from a tower top located in high altitude is observed. Measurement was carried out using scintillation detectors installed close to the tower top in two phases from 2011 to 2015. X-rays were recorded in three subsequent strokes of three flashes out of the total of 108 flashes recorded in the system during both phases. In contrast to the observations from downward natural or triggered lightning, X-rays were observed only within 10 µs before the subsequent return stroke. This shows that X-rays were emitted when the dart leader is in the vicinity of the tower top and hence during the most intense phase of the dart leader. Both the detected energy and the fluence of X-rays are far lower compared to X-rays from downward natural or rocket-triggered lightning. In addition to above 108 flashes, an interesting observation of X-rays produced by a nearby downward flash is also presented. The shorter dart-leader channels length in Gaisberg is suggested as a possible cause of this apparently weaker X-ray production.

    HSV kategori
    Forskningsprogram
    Teknisk fysik med inriktning mot atmosfäriska urladdningar
    Identifikatorer
    urn:nbn:se:uu:diva-338132 (URN)10.3390/atmos9010020 (DOI)
    Forskningsfinansiär
    Swedish Research Council, 2015-05026
    Tilgjengelig fra: 2018-01-08 Laget: 2018-01-08 Sist oppdatert: 2018-01-26bibliografisk kontrollert
    4. X-ray observations from laboratory sparks in air at atmospheric pressure under negative switching impulse voltages
    Åpne denne publikasjonen i ny fane eller vindu >>X-ray observations from laboratory sparks in air at atmospheric pressure under negative switching impulse voltages
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    We present for the first time detection of X-rays from laboratory sparks created in air at atmospheric pressure by applying an impulse voltage with slow rise time. X-ray production from three different electrode configurations were studied. The results confirm, for the first time, the production of X-rays in gaps excited by switching impulses. Results also show that the slow rate of rise of the voltage from switching impulses does not have a significant influence on the production of X-rays. Additionally, the timing of the X-ray occurrence strengthens the possibility that the mechanism of X-ray production is related to the encounter between streamers of opposite polarity.

    HSV kategori
    Forskningsprogram
    Teknisk fysik med inriktning mot atmosfäriska urladdningar
    Identifikatorer
    urn:nbn:se:uu:diva-338135 (URN)
    Forskningsfinansiär
    The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IG2004-2031Swedish Research Council, 621-2009-2697Swedish Research Council, 621-2006-4299Swedish Research Council, 621-2012-3300
    Tilgjengelig fra: 2018-01-08 Laget: 2018-01-08 Sist oppdatert: 2018-01-08
  • Disputas: 2018-02-28 09:00 Rosénsalen, Uppsala
    Nazir, Madiha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Drug Repositioning for Cancer Treatment: Novel Candidate Identification Strategies2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Regardless of the enormous investments in cancer research and drug development, the proportion of approved drugs in oncology is low compared to other indications, and new avenues are needed. One attractive approach in this regard is drug repositioning where new uses outside the scope of the original medical indications for existing drugs are identified. It offers the advantages of reduced development risks, time and cost over de novo drug discovery pathways.

    The main focus of this thesis was to explore and employ different strategies to identify repurposable drug candidates for treatment of cancer. Aiming for this, in the first project we followed a bioinformatics approach to evaluate PDE3A as a drug target and biomarker. We showed that subgroups of tumors, within many different cancer types, overexpress PDE3A (mRNA and protein) and that PDE3A can predict sensitivity to the clinically tested phosphodiesterase inhibitors zardaverine and quazinone (Paper I). In the second project, a novel automated image based microscopy assay was developed and used for detection of apoptotic cells. In a screen the method was successfully used to identify apoptosis inducing compounds. Two of these apoptosis inducers were found to have repurposing potential (Paper II). Moreover, high-throughput combination screening was performed using different cell models. In paper III, monolayer cell cultures were used as cell model to search for combination partners for the anti-parasitic compound mebendazole (a repurposing candidate). As a result, the antipsychotic drug thioridazine was found to have synergistic effect when combined with mebendazol. Finally, a novel drug-combination platform for three-dimensional cell culture based screening, in 384 well formats, was developed. This assay was used to search for combination partners to the anti-parasitic compound nitazoxanide (a repurposing candidate), which was previously reported to specifically target quiescent cancer cells. The screen identified the antifungal agent ketoconazole as selectively toxic to hypoxic and nutrient deprived cancer cells when combined with nitazoxanide (Paper IV). Thus, we have developed/explored several methodological approaches and identified drugs that potentially can be repurposed for treatment of cancer. 

    Delarbeid
    1. Targeting tumor cells based on phosphodiesterase 3A expression
    Åpne denne publikasjonen i ny fane eller vindu >>Targeting tumor cells based on phosphodiesterase 3A expression
    Vise andre…
    2017 (engelsk)Inngår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 361, s. 308-315Artikkel i tidsskrift, Meeting abstract (Fagfellevurdert) Published
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-338321 (URN)
    Tilgjengelig fra: 2018-01-08 Laget: 2018-01-08 Sist oppdatert: 2018-01-09
    2. Label free high throughput screening for apoptosis inducing chemicals using time-lapse microscopy signal processing
    Åpne denne publikasjonen i ny fane eller vindu >>Label free high throughput screening for apoptosis inducing chemicals using time-lapse microscopy signal processing
    Vise andre…
    2014 (engelsk)Inngår i: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 19, nr 9, s. 1411-1418Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Label free time-lapse microscopy has opened a new avenue to the study of time evolving events in living cells. When combined with automated image analysis it provides a powerful tool that enables automated large-scale spatiotemporal quantification at the cell population level. Very few attempts, however, have been reported regarding the design of image analysis algorithms dedicated to the detection of apoptotic cells in such time-lapse microscopy images. In particular, none of the reported attempts is based on sufficiently fast signal processing algorithms to enable large-scale detection of apoptosis within hours/days without access to high-end computers. Here we show that it is indeed possible to successfully detect chemically induced apoptosis by applying a two-dimensional linear matched filter tailored to the detection of objects with the typical features of an apoptotic cell in phase-contrast images. First a set of recorded computational detections of apoptosis was validated by comparison with apoptosis specific caspase activity readouts obtained via a fluorescence based assay. Then a large screen encompassing 2,866 drug like compounds was performed using the human colorectal carcinoma cell line HCT116. In addition to many well known inducers (positive controls) the screening resulted in the detection of two compounds here reported for the first time to induce apoptosis.

    Emneord
    Apoptosis, high throughput screening, cancer
    HSV kategori
    Forskningsprogram
    Bioinformatik
    Identifikatorer
    urn:nbn:se:uu:diva-229069 (URN)10.1007/s10495-014-1009-9 (DOI)000340518000010 ()
    Forskningsfinansiär
    Swedish Society for Medical Research (SSMF)
    Tilgjengelig fra: 2014-07-29 Laget: 2014-07-29 Sist oppdatert: 2018-01-09bibliografisk kontrollert
    3. Drug combination screening for mebendazole for the treatment of colorectal cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Drug combination screening for mebendazole for the treatment of colorectal cancer
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Klinisk farmakologi
    Identifikatorer
    urn:nbn:se:uu:diva-336682 (URN)
    Tilgjengelig fra: 2017-12-15 Laget: 2017-12-15 Sist oppdatert: 2018-01-09
    4. Drug combination screening in multicellular tumor spheroids identifies synthetic lethalities in quiescent cancer cells
    Åpne denne publikasjonen i ny fane eller vindu >>Drug combination screening in multicellular tumor spheroids identifies synthetic lethalities in quiescent cancer cells
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-336689 (URN)
    Tilgjengelig fra: 2017-12-15 Laget: 2017-12-15 Sist oppdatert: 2018-01-09
  • Disputas: 2018-03-01 13:15 Rosénsalen, Uppsala
    Al-Mashhadi, Ammar Nadhom Farman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    High Blood Pressure in Children with Hydronephrosis2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The most common cause of secondary hypertension is intrinsic renal disease, but little is known about the influence of hydronephrosis on blood pressure. In this thesis, the risk of development of hypertension in children with hydronephrosis was studied.

    Experimental and clinical studies were combined in order to investigate the risk of developing elevated blood pressure following conservative treatment of hydronephrosis, and to further explore underlying mechanisms. We started with a clinical study in children (study I), which in agreement with previous experimental studies, showed that blood pressure was lowered by surgical management of hydronephrosis. In parallel, an experimental study was conducted (study II) to investigate the involvement of renal sympathetic nerve activity in development of hypertension following induction of hydronephrosis caused by pelvo-ureteric junction obstruction. Renal denervation of the obstructed kidney attenuated hypertension and restored the renal excretion pattern, effects that were associated with reduced activity of both renal NADPH oxidase derived oxidative stress and components of the renin-angiotensin-aldosterone system.

    Based on the findings in studies I and II, we continued our studies in children with hydronephrosis, and including two control groups as comparisons with the hydronephrotic group (study III). In the same study, we further investigated potential mechanism(s) of hypertension by analyzing markers of oxidative stress and nitric oxide homeostasis in both urine and blood samples. We demonstrated increased arterial pressure and oxidative stress in children with hydronephrosis compared with healthy controls, which was restored to normal levels by surgical correction of the obstruction. Finally, in a retrospective cohort study, blood pressure of adult patients undergoing surgical management of hydronephrosis due to pelvo-ureteric junction obstruction was assessed (study IV). Similar to that demonstrated in the pediatric hydronephrotic population, blood pressure was significantly reduced by relief of the obstruction. In addition, blood pressure was increased again if the hydronephrosis recurred, and was reduced again following re-operation.

    It is concluded that conservative management of hydronephrosis in children is associated with a risk for development of high blood pressure, which can be reduced or even normalized by relief of the obstruction. The mechanism(s), at least in part, is coupled to increased oxidative stress.

    Delarbeid
    1. Surgical treatment reduces blood pressure in children with unilateral congenital hydronephrosis
    Åpne denne publikasjonen i ny fane eller vindu >>Surgical treatment reduces blood pressure in children with unilateral congenital hydronephrosis
    Vise andre…
    2015 (engelsk)Inngår i: Journal of Pediatric Urology, ISSN 1477-5131, E-ISSN 1873-4898, Vol. 11, nr 2, s. 91.e1-91.e6Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Objective Renal disorders can cause hypertension, but less is known about the influence of hydronephrosis on blood pressure. Hydronephrosis due to pelvo-ureteric junction obstruction (PUJO) is a fairly common condition (incidence in newborns of 0.5-1%). Although hypertensive effects of hydronephrosis have been suggested, this has not been substantiated by prospective studies in humans [1-3]. Experimental studies with PUJO have shown that animals with induced hydronephrosis develop salt-sensitive hypertension, which strongly correlate to the degree of obstruction [4-7]. Moreover, relief of the obstruction normalized blood pressure [8]. In this first prospective study our aim was to study the blood pressure pattern in pediatric patients with hydronephrosis before and after surgical correction of the ureteral obstruction. Specifically, we investigated if preoperative blood pressure is reduced after surgery and if split renal function and renographic excretion curves provide any prognostic information. Patients and methods Twelve patients with unilateral congenital hydronephrosis were included in this prospective study. Ambulatory blood pressure (24 h) was measured preoperatively and six months after surgery. Preoperative evaluations of bilateral renal function by Tc99m-MAG3 scintigraphy, and renography curves, classified according to O'Reilly, were also performed. Results As shown in the summary figure, postoperative systolic (103 +/- 2 mmHg) and diastolic (62 +/- 2 mmHg) blood pressure were significantly lower than those obtained preoperatively (110 +/- 4 and 69 +/- 2 mmHg, respectively), whereas no changes in circadian variation or pulse pressure were observed. Renal functional share of the hydronephrotic kidney ranged from 11 to 55%. There was no correlation between the degree of renal function impairment and the preoperative excretory pattern, or between the preoperative excretory pattern and the blood pressure reduction postoperatively. However, preoperative MAG3 function of the affected kidney correlated with the magnitude of blood pressure change after surgery. Discussion Correction of the obstruction lowered blood pressure, and the reduction in blood pressure appeared to correlate with the degree of renal functional impairment, but not with the excretory pattern. Thus, in the setting of hypertension, it appears that the functional share of the hydronephrotic kidney should be considered an indicator of the need for surgery, whereas the renography curve is less reliable. The strength of the present study is the prospective nature and that ambulatory blood pressure monitoring was used. Future longitudinal prolonged follow-up studies are warranted to confirm the present findings, and to understand if a real nephrogenic hypertension with potential necessity of treatment will develop. Conclusion This novel prospective study in patients with congenital hydronephrosis demonstrates a reduction in blood pressure following relief of the obstruction. Based on the present results, we propose that the blood pressure level should also be taken into account when deciding whether to correct hydronephrosis surgically or not.

    Emneord
    Hydronephrosis, Hypertension, Pelvo-ureteric junction obstruction, Pyeloplasty, Renal function
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-257044 (URN)10.1016/j.jpurol.2015.01.008 (DOI)000355333400035 ()
    Tilgjengelig fra: 2015-06-29 Laget: 2015-06-29 Sist oppdatert: 2018-01-11
    2. Renal denervation attenuates NADPH oxidase-mediated oxidative stress and hypertension in rats with hydronephrosis
    Åpne denne publikasjonen i ny fane eller vindu >>Renal denervation attenuates NADPH oxidase-mediated oxidative stress and hypertension in rats with hydronephrosis
    Vise andre…
    2016 (engelsk)Inngår i: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 310, nr 1, s. F43-F56Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Hydronephrosis is associated with development of salt-sensitive hypertension. Studies suggest that increased sympathetic nerve activity (SNA) and oxidative stress play important roles in renovascular hypertension. This study aimed to investigate the link between renal SNA and NADPH oxidase (NOX) regulation in the development of hypertension in rats with hydronephrosis. Hydronephrosis was induced by partial unilateral ureteral obstruction (PUUO) in young rats. Sham surgery or renal denervation was performed at the same time. Blood pressure was measured during normal, high and low salt diets. Renal excretion pattern, NOX activity and expression, as well as components of RAAS were characterized. On normal salt diet, PUUO rats had elevated blood pressure compared with controls (115±3 vs 87±1 mmHg), and displayed increased urine production and lower urine osmolality. Blood pressure change in response to salt loading (salt-sensitivity) was more pronounced in the PUUO group compared with controls (15±2 vs 5±1mmHg). Renal denervation in PUUO rats attenuated hypertension (97±3mmHg) and salt-sensitivity (5±1mmHg), and normalized renal excretion pattern, whereas the degree of renal fibrosis and inflammation was not changed. NOX activity and expression, as well as renin and AT1A receptor expression, were increased in renal cortex from PUUO rats, and normalized by denervation. Plasma sodium and potassium levels were elevated in PUUO rats and normalized after renal denervation. Denervation in PUUO rats was also associated with reduced NOX expression, superoxide production and fibrosis in the heart. This study emphasizes a link between renal nerves, NOX function, and development of hypertension.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-267780 (URN)10.1152/ajprenal.00345.2015 (DOI)000366593500007 ()26538440 (PubMedID)
    Merknad

    De två första författarna delar förstaförfattarskapet.

    Tilgjengelig fra: 2015-11-26 Laget: 2015-11-26 Sist oppdatert: 2018-01-22bibliografisk kontrollert
    3. Changes in arterial pressure and markers of nitric oxide homeostasis and oxidative stress following surgical correction of hydronephrosis in children
    Åpne denne publikasjonen i ny fane eller vindu >>Changes in arterial pressure and markers of nitric oxide homeostasis and oxidative stress following surgical correction of hydronephrosis in children
    Vise andre…
    2017 (engelsk)Inngår i: Pediatric nephrology (Berlin, West), ISSN 0931-041X, E-ISSN 1432-198XArtikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Objective Recent clinical studies have suggested an increased risk of elevated arterial pressure in patients with hydronephrosis. Animals with experimentally induced hydronephrosis develop hypertension, which is correlated to the degree of obstruction and increased oxidative stress. In this prospective study we investigated changes in arterial pressure, oxidative stress, and nitric oxide (NO) homeostasis following correction of hydronephrosis.

    Methods Ambulatory arterial pressure (24 h) was monitored in pediatric patients with hydronephrosis (n = 15) before and after surgical correction, and the measurements were compared with arterial pressure measurements in two control groups, i.e. healthy controls (n = 8) and operated controls (n = 8). Markers of oxidative stress and NO homeostasis were analyzed in matched urine and plasma samples.

    Results The preoperative mean arterial pressure was significantly higher in hydronephrotic patients [83 mmHg; 95% confidence interval (CI) 80–88 mmHg] than in healthy controls (74 mmHg; 95% CI 68–80 mmHg; p < 0.05), and surgical correction of ureteral obstruction reduced arterial pressure (76 mmHg; 95% CI 74–79 mmHg; p < 0.05). Markers of oxidative stress (i.e., 11- dehydroTXB2, PGF2α, 8-iso-PGF2α, 8,12-iso-iPF2α-VI) were significantly increased (p < 0.05) in patients with hydronephrosis compared with both control groups, and these were reduced following surgery (p < 0.05). Interestingly, there was a trend for increased NO synthase activity and signaling in hydronephrosis, which may indicate compensatory mechanism(s).

    Conclusion This study demonstrates increased arterial pressure and oxidative stress in children with hydronephrosis compared with healthy controls, which can be restored to normal levels by surgical correction of the obstruction. Once reference data on ambulatory blood pressure in this young age group become available, we hope cut-off values can be defined for deciding whether or not to correct hydronephrosis surgically.

    Keywords Blood pressure . Hydronephrosis . Hypertension . Nitric oxide . Oxidative stress . Ureteral obstruction 

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-337796 (URN)10.1007/s00467-017-3848-4 (DOI)
    Tilgjengelig fra: 2018-01-04 Laget: 2018-01-04 Sist oppdatert: 2018-01-18bibliografisk kontrollert
    4. Reduction of arterial pressure following relief of obstruction in patients with hydronephrosis
    Åpne denne publikasjonen i ny fane eller vindu >>Reduction of arterial pressure following relief of obstruction in patients with hydronephrosis
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    blood pressure, hydronephrosis, hypertension, kidney, renal function, ureteral obstruction
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-338672 (URN)
    Tilgjengelig fra: 2018-01-11 Laget: 2018-01-11 Sist oppdatert: 2018-01-22
  • Disputas: 2018-03-02 09:00 A1:107a, Uppsala
    Kovachev, Petar Stefanov
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    The role of RNA in prion aggregation and disease2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    As humanity evolved to witness an exceptionally high standard of living, Alzheimer’s, cancer and diabetes gradually replaced infections as the main limiting factors in longevity. It is both disturbing and captivating that such degenerative conditions are caused by the most ubiquitous biomolecule – the protein. Indeed, proteins are not only the most functional, but also the least understood of the cellular biopolymers. It is then not surprising that many severe human ailments are associated with aberrant proteostasis. The key, causative mechanism of proteinopathy is protein aggregation. Naturally occurring and sometimes functional, aggregation is an auxiliary pathway in protein folding. In the context of a crowded cellular environment, folding and aggregation are the least and one of the least understood molecular processes, respectively. Unravelling one can help deconstruct the other and vice versa, but also can provide mechanistic insight on degenerative proteinopathies. A special class of proteins, which appear to propagate their own aggregation, occupy center-stage in the scientific field devoted to this goal. These proteins known as prions, can exist in at least two distinct forms. With the human prion, one of those is functional and benign and the other is infectious, aggregation prone, self-replicating and fatally pathogenic. As it happens, prion disease shares many of the descriptive features of other proteinaceous neuropathies. That, and the seductive idea that prions dwell in the twilight zone between folding and aggregation, have made the prion phenomenon a fixation for many molecular biologists. This thesis, although not the product of fixation, deals with one aspect of the prion process – the involvement of a molecular cofactor.

    Of all plausible adjuvants, RNAs have been proposed as likely participants in the prion process. Their prominent secondary structures and attractive polyanionic surfaces allow RNAs to freely engage in interactions, at times transmitting conformational information through induced fit effects. The present work summarizes the influence of various RNAs on the aggregation profiles of three prionogenic model systems. The produced results indicate a generic role for RNA in the molecular processes prion propagation and aggregation. Altogether, this study illustrates a previously overlooked RNA function, of potential relevance for protein-based disease. 

    Delarbeid
    1. Distinct modulatory role of RNA in the aggregation of the tumor suppressor protein p53 core domain.
    Åpne denne publikasjonen i ny fane eller vindu >>Distinct modulatory role of RNA in the aggregation of the tumor suppressor protein p53 core domain.
    Vise andre…
    2017 (engelsk)Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 292, nr 22, s. 9345-9357Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Inactivation of the tumor suppressor protein p53 by mutagenesis, chemical modification, protein-protein interaction, or aggregation has been associated with different human cancers. Although DNA is the typical substrate of p53, numerous studies have reported p53 interactions with RNA. Here, we have examined the effects of RNA of varied sequence, length, and origin on the mechanism of aggregation of the core domain of p53 (p53C) using light scattering, intrinsic fluorescence, transmission electron microscopy, thioflavin-T binding, seeding, and immunoblot assays. Our results are the first to demonstrate that RNA can modulate the aggregation of p53C and full-length p53. We found bimodal behavior of RNA in p53C aggregation. A low RNA:protein ratio (∼1:50) facilitates the accumulation of large amorphous aggregates of p53C. By contrast, at a high RNA:protein ratio (≥1:8), the amorphous aggregation of p53C is clearly suppressed. Instead, amyloid p53C oligomers are formed that can act as seeds nucleating de novo aggregation of p53C. We propose that structured RNAs prevent p53C aggregation through surface interaction and play a significant role in the regulation of the tumor suppressor protein.

    sted, utgiver, år, opplag, sider
    American Society for Biochemistry and Molecular Biology, 2017
    Emneord
    RNA, amyloid, domain V of 23S rRNA, fluorescence, kinetics, p53, p53C, prion, protein aggregation, protein folding
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-327976 (URN)10.1074/jbc.M116.762096 (DOI)000402538900028 ()28420731 (PubMedID)
    Tilgjengelig fra: 2017-08-14 Laget: 2017-08-14 Sist oppdatert: 2018-01-14
    2. Direct involvement of RNA in mammalian prion protein aggregation: Involvement of RNA in rPrP aggregation
    Åpne denne publikasjonen i ny fane eller vindu >>Direct involvement of RNA in mammalian prion protein aggregation: Involvement of RNA in rPrP aggregation
    Vise andre…
    (engelsk)Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351XArtikkel i tidsskrift (Annet vitenskapelig) Submitted
    Abstract [en]

    Whether nucleic acids act as cofactors in the aggregation of prion proteins is still under debate. By employing RNAs of various source and size, we have studied the role of RNA in the aggregation of murine recombinant prion protein (rPrP23-231) using Rayleigh light scattering, dynamic light scattering, sedimentation, transmission electron microscopy, circular dichroism and isothermal titration calorimetry. We find that RNA modulates rPrP23-231 aggregation in a concentration dependent manner, affecting both the extent and rate of the process; the latter evident from fast kinetics measurements of rPrP23-231 aggregation using stopped-flow technique. At lower concentration, RNA stimulates amorphous aggregation of rPrP23-231, and at higher concentration it, instead, facilitates formation of oligomeric species capable of seeding de novo aggregation of rPrP23-231. Furthermore, RNA co-sediments with rPrP23-231. This leads to partial RNase resistance of RNA and secondary structure alterations in the protein, indicating a direct interaction between the two. Sequence analysis of the RNA co-aggregated with rPrP23-231 suggests that the interaction is not specific to RNA sequence. Alternatively, rPrP23-231 interaction with RNA appears site-specific and mediated by the N-terminus. Our study demonstrates the effective modulation of rPrP23-231 aggregation by RNA and puts forward the idea of the potential role of RNA in protein aggregation as a whole.

    Emneord
    prion, RNA, cofactor, RNA-protein interaction, aggregation, kinetics
    HSV kategori
    Forskningsprogram
    Molekylär cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-338856 (URN)
    Tilgjengelig fra: 2018-01-14 Laget: 2018-01-14 Sist oppdatert: 2018-01-14
    3. Intervention of ribosomal RNA in HET-s prion aggregation Intervention of ribosomal RNA in HET-s prion aggregation
    Åpne denne publikasjonen i ny fane eller vindu >>Intervention of ribosomal RNA in HET-s prion aggregation Intervention of ribosomal RNA in HET-s prion aggregation
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The role of nucleic acids in prion aggregation / disaggregation has remained unclear. Here, using HET-s prion from Podospora anserina as a model system, we have studied the role of RNA, particularly different domains of ribosomal RNA, in its aggregation process. Our results show that domain V rRNA, from the large subunit of the ribosome, substantially prevents amyloid aggregation of the HET-s prion in a concentration dependent manner. Instead, it promotes the formation of oligomeric seeds, which facilitate de novo HET-s aggregation. The interaction sites for the HET-s prion on domain V rRNA were also identified and shown to overlap with the sites previously found to responsible for the protein folding activity of the ribosome (PFAR). This study provides a missing link between the role of rRNA-based PFAR and prion propagation.

    HSV kategori
    Forskningsprogram
    Molekylär cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-338605 (URN)
    Tilgjengelig fra: 2018-01-14 Laget: 2018-01-14 Sist oppdatert: 2018-01-14
  • Disputas: 2018-03-02 09:15 Häggsalen, Uppsala
    Östman, Erik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi, Materialfysik.
    Collective properties of magnetic mesospins2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Mesoscopic spin systems consist of an ensemble of lithographically patterned nanomagnetic elements - mesospins. The interactions between the mesospins, can be designed at will by altering their lateral arrangement, enabling the study of collective magnetic order in a wide range of systems.          

      The spin dimensionality of a mesospin is controlled by its shape and form. Thin elongated elements are Ising-like, with only two possible magnetization directions. Disc shaped elements can be single domain and behave XY-like, with a magnetization direction free to rotate in the plane of the disc. Larger disc sizes result in magnetic vortices. Tuning the material parameters of the elements enables mesospin dynamics at and below room temperature. Combining all of the above, the magnetic state of a lattice is then defined by the mesospins lateral arrangement, their spin dimensionality, and the temperature.          

      In this Thesis we investigate the magnetic order and dynamic properties in a series of different configurations, where the nano-magnetic elements are in the vortex state, Ising-like mesospins or of mixed mesospin dimensionality. Chains of Ising-mesospins were investigated and shown to be successfully described by the Ising model. A lossless transition between the magnetic vortex state and the collinear state, was found in square arrays of magnetic discs. In a more complicated interaction regime, square artificial spin ice, the dynamical range of the Ising-like mesospins in the lattice was probed, in terms of magnetization relaxation studies.          

      Utilizing the configurational freedom in mesoscopic spin systems, together with the possibility to alter the spin dimensionality of the elements, it is possible to create a lattice with no naturally occurring analogue. In such a lattice, where XY mesospins were added to square artificial spin ice, it was found that the degeneracy of the square ice model was restored. Furthermore, using a reciprocal space analysis tool, the magnetic spin structure factor, the system was shown to possess the characteristic features of a Coulomb spin liquid with strong local correlations and absence of long range order. Increasing the interaction between the elements, results in an emergent magnetic order on a large length-scale.

    Delarbeid
    1. Ising like behaviour of mesoscopic magnetic chains
    Åpne denne publikasjonen i ny fane eller vindu >>Ising like behaviour of mesoscopic magnetic chains
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-338704 (URN)
    Tilgjengelig fra: 2018-01-11 Laget: 2018-01-11 Sist oppdatert: 2018-01-12
    2. Hysteresis-free switching between vortex and collinear magnetic states
    Åpne denne publikasjonen i ny fane eller vindu >>Hysteresis-free switching between vortex and collinear magnetic states
    Vise andre…
    2014 (engelsk)Inngår i: New Journal of Physics, ISSN 1367-2630, E-ISSN 1367-2630, Vol. 16, s. 053002-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    We demonstrate a lossless switching between vortex and collinear magnetic states in circular FePd disks arranged in a square lattice. Above a bifurcation temperature (Te) we show that thermal fluctuations are enough to facilitate flipping between the two distinctly different magnetic states. We find that the temperature dependence of the vortex annihilation and nucleation fields can be described by a simple power law relating them to the saturation magnetization.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-224245 (URN)10.1088/1367-2630/16/5/053002 (DOI)000335383800002 ()
    Forskningsfinansiär
    Knut and Alice Wallenberg FoundationSwedish Research Council
    Tilgjengelig fra: 2014-05-07 Laget: 2014-05-07 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    3. Thermally induced magnetic relaxation in square artificial spin ice
    Åpne denne publikasjonen i ny fane eller vindu >>Thermally induced magnetic relaxation in square artificial spin ice
    Vise andre…
    2016 (engelsk)Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 37097Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The properties of natural and artificial assemblies of interacting elements, ranging from Quarks to Galaxies, are at the heart of Physics. The collective response and dynamics of such assemblies are dictated by the intrinsic dynamical properties of the building blocks, the nature of their interactions and topological constraints. Here we report on the relaxation dynamics of the magnetization of artificial assemblies of mesoscopic spins. In our model nano-magnetic system - square artificial spin ice - we are able to control the geometrical arrangement and interaction strength between the magnetically interacting building blocks by means of nano-lithography. Using time resolved magnetometry we show that the relaxation process can be described using the Kohlrausch law and that the extracted temperature dependent relaxation times of the assemblies follow the Vogel-Fulcher law. The results provide insight into the relaxation dynamics of mesoscopic nano-magnetic model systems, with adjustable energy and time scales, and demonstrates that these can serve as an ideal playground for the studies of collective dynamics and relaxations.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-315927 (URN)10.1038/srep37097 (DOI)000392061500001 ()27883013 (PubMedID)
    Forskningsfinansiär
    Knut and Alice Wallenberg FoundationSwedish Research CouncilGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologyThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
    Tilgjengelig fra: 2017-02-22 Laget: 2017-02-22 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    4. Interaction modiers in articial spin ices
    Åpne denne publikasjonen i ny fane eller vindu >>Interaction modiers in articial spin ices
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-328864 (URN)
    Tilgjengelig fra: 2017-10-10 Laget: 2017-10-10 Sist oppdatert: 2018-01-12
  • Disputas: 2018-03-02 10:00 ITC/2446, Uppsala
    Zafari, Afshin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för beräkningsvetenskap. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Tillämpad beräkningsvetenskap.
    Advances in Task-Based Parallel Programming for Distributed Memory Architectures2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    It has become common knowledge that parallel programming is needed for scientific applications, particularly for running large scale simulations. Different programming models are introduced for simplifying parallel programming, while enabling an application to use the full computational capacity of the hardware. In task-based programming, all the variables in the program are abstractly viewed as data. Parallelism is provided by partitioning the data. A task is a collection of operations performed on input data to generate output data. In distributed memory environments, the data is distributed over the computational nodes (or processes), and is communicated when a task needs remote data.

    This thesis discusses advanced techniques in distributed task-based parallel programming, implemented in the DuctTeip software library. DuctTeip uses MPI (Message Passing Interface) for asynchronous inter-process communication and Pthreads for shared memory parallelization within the processes. The data dependencies that determine which subsets of tasks can be executed in parallel are extracted from information about the data accesses (input or output) of the tasks. A versioning system is used internally to represent the task-data dependencies efficiently. A hierarchical partitioning of tasks and data allows for independent optimization of the size of computational tasks and the size of communicated data. A data listener technique is used to manage communication efficiently.

    DuctTeip provides an algorithm independent dynamic load balancing functionality. Redistributing tasks from busy processes to idle processes dynamically can provide an overall shorter execution time. A random search method with high probability of success is employed for locating idle/busy nodes.

    The advantage of the abstract view of tasks and data is exploited in a unified programming interface, which provides a standard for task-based frameworks to decouple framework development from application development. The interface can be used for collaboration between different frameworks in running an application program efficiently on different hardware.

    To evaluate the DuctTeip programming model, applications such as Cholesky factorization, a time-dependent PDE solver for the shallow water equations, and the fast multipole method have been implemented using DuctTeip. Experiments show that DuctTeip provides both scalability and performance. Comparisons with similar frameworks such as StarPU, OmpSs, and PaRSEC show competitive results.

    Delarbeid
    1. Programming models based on data versioning for dependency-aware task-based parallelisation
    Åpne denne publikasjonen i ny fane eller vindu >>Programming models based on data versioning for dependency-aware task-based parallelisation
    2012 (engelsk)Inngår i: Proc. 15th International Conference on Computational Science and Engineering, Los Alamitos, CA: IEEE Computer Society, 2012, s. 275-280Konferansepaper, Publicerat paper (Fagfellevurdert)
    sted, utgiver, år, opplag, sider
    Los Alamitos, CA: IEEE Computer Society, 2012
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-187446 (URN)10.1109/ICCSE.2012.45 (DOI)000317475000038 ()978-1-4673-5165-2 (ISBN)
    Konferanse
    CSE 2012
    Prosjekter
    eSSENCEUPMARC
    Tilgjengelig fra: 2013-01-24 Laget: 2012-12-06 Sist oppdatert: 2018-01-16bibliografisk kontrollert
    2. DuctTeip: An efficient programming model for distributed task based parallel computing
    Åpne denne publikasjonen i ny fane eller vindu >>DuctTeip: An efficient programming model for distributed task based parallel computing
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-338832 (URN)
    Prosjekter
    UPMARCeSSENCE
    Tilgjengelig fra: 2018-01-14 Laget: 2018-01-14 Sist oppdatert: 2018-01-24bibliografisk kontrollert
    3. TaskUniVerse: A Task-Based Unified Interface for Versatile Parallel Execution
    Åpne denne publikasjonen i ny fane eller vindu >>TaskUniVerse: A Task-Based Unified Interface for Versatile Parallel Execution
    2018 (engelsk)Inngår i: Parallel Processing and Applied Mathematics, Springer, 2018Konferansepaper, Publicerat paper (Fagfellevurdert)
    sted, utgiver, år, opplag, sider
    Springer, 2018
    Serie
    Lecture Notes in Computer Science
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-338836 (URN)
    Konferanse
    PPAM 2017
    Prosjekter
    eSSENCE
    Merknad

    to appear

    Tilgjengelig fra: 2018-01-14 Laget: 2018-01-14 Sist oppdatert: 2018-01-24bibliografisk kontrollert
    4. Task parallel implementation of a solver for electromagnetic scattering problems
    Åpne denne publikasjonen i ny fane eller vindu >>Task parallel implementation of a solver for electromagnetic scattering problems
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-338833 (URN)
    Prosjekter
    eSSENCE
    Tilgjengelig fra: 2018-01-14 Laget: 2018-01-14 Sist oppdatert: 2018-01-24bibliografisk kontrollert
    5. Distributed dynamic load balancing for task parallel programming
    Åpne denne publikasjonen i ny fane eller vindu >>Distributed dynamic load balancing for task parallel programming
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-338835 (URN)
    Prosjekter
    UPMARCeSSENCE
    Tilgjengelig fra: 2018-01-14 Laget: 2018-01-14 Sist oppdatert: 2018-01-24bibliografisk kontrollert
  • Disputas: 2018-03-02 13:00 Enghoffsalen, Uppsala
    Bagge, Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi-arrytmi.
    Surgical ablation for the treatment of atrial fibrillation in different patient populations: A study of clinical outcomes including rhythm, quality of life, atrial function and safety2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Patients with atrial fibrillation (AF) have markedly reduced quality of life (QoL) and catheter ablation has become a useful tool in the rhythm control therapy. However, because of the poor outcome for patients with persistent AF, new surgical ablation strategies for rhythm control are emerging.

    The aims of this thesis were to evaluate QoL, the main indication for rhythm control, after three different types of surgical ablation for AF, two stand-alone epicardial AF ablation procedures and one concomitant procedure during mitral valve surgery (MVS), and to perform a long-term follow-up of one of the techniques with regard to rhythm outcome, left atrial function, exercise capacity and safety.

    As the first center in the Nordic countries to adopt the video-assisted epicardial pulmonary vein isolation and ganglionated plexi ablation combined with left atrial appendage excision (LAA), the  freedom from AF at one year follow-up was found to be 71% and associated with improved exercise capacity, QoL and symptoms as well as preserved left atrial function and size. The most common complication was bleeding events (14%). After 10 years, the improved symptoms and QoL remained, reaching comparable levels of the general Swedish population, despite a marked decline in the rate of freedom from AF (36%). 4 strokes appeared during follow-up despite LAA excision in 3 of these patients.

    In order to improve the rhythm outcome for patients with longstanding persistent AF a box-lesion was added to the procedure. At one year follow-up, both symptoms and QoL improved and was indistinguishable from those in the Swedish general population.

    Finally, concomitant AF ablation during MVS did not improve QoL compared to MVS alone in a double blinded randomized controlled trial. Moreover, no difference was seen between patients in AF or sinus rhythm at one year follow-up, irrespective of the allocated therapy, indicating that their preoperative symptoms were mainly related to their valve disease.

    In conclusion, the stand-alone procedures using surgical ablation was found to be effective but at the expense of procedural complications. In contrast, the concomitant surgical AF ablation did not improve QoL, a finding that raises concerns regarding current recommendations for this procedure. 

    Delarbeid
    1. Epicardial off-pump pulmonary vein isolation and vagal denervation improve long-term outcome and quality of life in patients with atrial fibrillation
    Åpne denne publikasjonen i ny fane eller vindu >>Epicardial off-pump pulmonary vein isolation and vagal denervation improve long-term outcome and quality of life in patients with atrial fibrillation
    Vise andre…
    2009 (engelsk)Inngår i: Journal of Thoracic and Cardiovascular Surgery, ISSN 0022-5223, E-ISSN 1097-685X, Vol. 137, nr 5, s. 1265-1271Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVES: The limited information available on thoracoscopic pulmonary vein isolation combined with ganglionated plexi ablation and the lack of studies regarding its effect on quality of life and physical capacity urged us to study its acute and long-term results in patients with atrial fibrillation. METHODS: Forty-three patients (mean age 57.1 years) with symptomatic atrial fibrillation referred for thoracoscopic off-pump epicardial pulmonary vein isolation and ganglionated plexi ablation using radiofrequency energy were included. RESULTS: The physical capacity improved significantly at 6-month follow-up compared with baseline (mean +/- standard deviation, 165.2 +/- 65 Watt versus 155.9 +/- 57 Watt, P = .02). Quality of life (Short Form-36 health survey) significantly improved 12 months after surgery compared with baseline in all subscales except for bodily pain. The symptom severity questionnaire score decreased significantly from mean 15.2 +/- 4.0 points to 10.7 +/- 4.8 points (P = .02). Overall, 25 of 33 patients (76%) followed up for 12 months had no symptomatic atrial fibrillation recurrences or atrial fibrillation episodes on 24-hour Holter recordings. The corresponding figures were 79% (19/24) for patients with paroxysmal atrial fibrillation, 100% (2/2) for persistent atrial fibrillation, and 57% (4/7) for permanent atrial fibrillation. The most common complication was bleeding events (9%) during pulmonary vein dissection. CONCLUSIONS: Epicardial off-pump pulmonary vein isolation combined with ganglionated plexi ablation improved quality of life, symptoms, and exercise capacity and therefore may be considered for patients with atrial fibrillation who fail endocardial pulmonary vein ablation or as a first-line procedure if left atrial appendage exclusion is warranted.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-103119 (URN)10.1016/j.jtcvs.2008.12.017 (DOI)000265299000034 ()19380002 (PubMedID)
    Tilgjengelig fra: 2009-05-14 Laget: 2009-05-14 Sist oppdatert: 2018-01-14bibliografisk kontrollert
    2. Left atrial function after epicardial pulmonary vein isolation in patients with atrial fibrillation.
    Åpne denne publikasjonen i ny fane eller vindu >>Left atrial function after epicardial pulmonary vein isolation in patients with atrial fibrillation.
    Vise andre…
    2017 (engelsk)Inngår i: Journal of interventional cardiac electrophysiology (Print), ISSN 1383-875X, E-ISSN 1572-8595, Vol. 50, nr 2, s. 195-201Artikkel i tidsskrift (Fagfellevurdert) Published
    Emneord
    left atrial function; epicardial; atrial fibrillation; left atrial size; minimally invasive; pulmonary vein isolation; vagal denervation; ganglionated plexi
    HSV kategori
    Forskningsprogram
    Kardiologi
    Identifikatorer
    urn:nbn:se:uu:diva-338090 (URN)10.1007/s10840-017-0290-2 (DOI)000416448400007 ()29127542 (PubMedID)
    Tilgjengelig fra: 2018-01-07 Laget: 2018-01-07 Sist oppdatert: 2018-02-08bibliografisk kontrollert
    3. Quality of life is not improved after mitral valve surgery combined with epicardial left atrial cryoablation as compared with mitral valve surgery alone: a substudy of the double blind randomized SWEDish Multicentre Atrial Fibrillation study (SWEDMAF)
    Åpne denne publikasjonen i ny fane eller vindu >>Quality of life is not improved after mitral valve surgery combined with epicardial left atrial cryoablation as compared with mitral valve surgery alone: a substudy of the double blind randomized SWEDish Multicentre Atrial Fibrillation study (SWEDMAF)
    Vise andre…
    2017 (engelsk)Inngår i: Europace, ISSN 1099-5129, E-ISSN 1532-2092Artikkel i tidsskrift (Fagfellevurdert) Epub ahead of print
    Emneord
    concomitant surgical ablation; mitral valve surgery; atrial fibrillation; quality of life; ablation;
    HSV kategori
    Forskningsprogram
    Kardiologi
    Identifikatorer
    urn:nbn:se:uu:diva-338091 (URN)10.1093/europace/eux253 (DOI)
    Tilgjengelig fra: 2018-01-07 Laget: 2018-01-07 Sist oppdatert: 2018-02-14bibliografisk kontrollert
    4. 10 years follow-up of video-assisted epicardial pulmonary vein isolation and vagal denervation in patients with atrial fibrillation
    Åpne denne publikasjonen i ny fane eller vindu >>10 years follow-up of video-assisted epicardial pulmonary vein isolation and vagal denervation in patients with atrial fibrillation
    (engelsk)Inngår i: Artikkel i tidsskrift (Annet vitenskapelig) Submitted
    Emneord
    Atrial fibrillation; epicardial; pulmonary vein isolation; qualiy of life; minimally invasive; vagal denervation; ganglionated plexi
    HSV kategori
    Forskningsprogram
    Kardiologi
    Identifikatorer
    urn:nbn:se:uu:diva-338092 (URN)
    Tilgjengelig fra: 2018-01-07 Laget: 2018-01-07 Sist oppdatert: 2018-02-14
    5. A Prospective Study of the Effects of Thoracoscopic Epicardial Left Atrial Ablation on Symptoms and Quality of Life: A comparison with the normal Swedish population and other severe disease states
    Åpne denne publikasjonen i ny fane eller vindu >>A Prospective Study of the Effects of Thoracoscopic Epicardial Left Atrial Ablation on Symptoms and Quality of Life: A comparison with the normal Swedish population and other severe disease states
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    Atrial fibrillation; quality of life; thoracoscopic; epicardial; left atrial ablation;
    HSV kategori
    Forskningsprogram
    Kardiologi
    Identifikatorer
    urn:nbn:se:uu:diva-338093 (URN)
    Tilgjengelig fra: 2018-01-07 Laget: 2018-01-07 Sist oppdatert: 2018-01-15
  • Disputas: 2018-03-02 13:15 Humanistiska Teatern, Uppsala
    Sköld, Olle
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Historisk-filosofiska fakulteten, Institutionen för ABM.
    Documenting Videogame Communities: A Study of Community Production of Information in Social-Media Environments and its Implications for Videogame Preservation2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Drawing on the disciplines of library and information studies and archival studies, this study seeks to explore the production of information in online videogame communities and to elucidate how such insights can offer practical and conceptual support to the knotty issue of how to preserve those sociocultural aspects of videogames that exist 'beyond' the code and audiovisual data resources of the videogame itself. This is accomplished in two principal moves: (i) by delving into the current state of socioculturally-focused videogame preservation and; (ii) by inquiring into the production of information carried out by videogame communities in what arguably is one of their most important interfaces of interaction—discussion forums, wikis, and other social-media services. The study is based on four papers (I–IV). Paper I develops the theoretical framework of the study on the basis of practice theory and document theory. Papers II and III report on field-studies of videogame-community information production in the context of two processes of importance in community social life: memory-making (II) and knowledge production (III). Paper IV offers a qualitative systematic review of videogame-archiving literature, allowing Papers I–III to be situated in an archival context. The study employs multiple methods and encompasses several empirical sites of inquiry and was inspired by the framework of exploratory research and of 'bricolage' research strategies.

    The results of the study add to the present state of knowledge on how information in the social-media environments of the large and influential present-day videogaming domain emerges as a result of community practices of production, and how videogame-community social life is entangled with information production in such spaces. The study also furthers archival inquiry on the topic of videogame preservation by providing a description and analysis of what information objects videogame-related social media plausibly hold, and by what communal practices and processes they have been brought into existence. Furthermore, the study examines the consequences of collecting community-produced social media and framing it as documentation of the sociocultural aspects of videogames—a key issue in videogames preservation.

    Delarbeid
    1. Tracing Traces: A Document-Centred Approach to the Preservation of Virtual World Communities
    Åpne denne publikasjonen i ny fane eller vindu >>Tracing Traces: A Document-Centred Approach to the Preservation of Virtual World Communities
    2013 (engelsk)Inngår i: Information research, ISSN 1368-1613, E-ISSN 1368-1613, Vol. 18, nr 3Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Introduction. The aim of this paper is to form a framework capable of theorizing how virtual communities are entangled with their new media environments, thereby contributing to the understanding of present-day virtual communities and how to preserve them.

    Method. An extensive bibliography on virtual worlds, virtual world preservation, document- and practice theory, and virtual communities forms the conceptual basis of the paper.

    Analysis. The proposed framework was formed by the way of qualitative and synthetic conceptual analysis of the collected literature. Results. Virtual world communities can be fruitfully conceptualized as distinct domains with specialized documentary practices. In each domain of practice, the virtual world’s related new media ecology functions as a central hub where the configuration of shared routinized sayings, doings, and knowings specific to that virtual world are negotiated. 

    Conclusion. By theorizing the activities of virtual communities in new media environments as documentary practices, and blog posts, comments, and tweets as documents, the framework accentuates new media as infrastructures that do not solely carry informative traces of the activities of virtual communities, but in effect are an active and formative part of them. As such, they merit high preservational priority.

    Emneord
    Documents, Practices, New Media, Digital cultural heritage preservation, Virtual worlds
    HSV kategori
    Forskningsprogram
    Biblioteks- och informationsvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-213410 (URN)000329310400018 ()
    Konferanse
    Proceedings of the Eighth International Conference on Conceptions of Library and Information Science, Copenhagen, Denmark, 19-22 August, 2013
    Tilgjengelig fra: 2013-12-20 Laget: 2013-12-20 Sist oppdatert: 2018-01-14
    2. Documenting Virtual World Cultures: Memory-Making and Documentary Practices in the City of Heroes Community
    Åpne denne publikasjonen i ny fane eller vindu >>Documenting Virtual World Cultures: Memory-Making and Documentary Practices in the City of Heroes Community
    2015 (engelsk)Inngår i: Journal of Documentation, ISSN 0022-0418, E-ISSN 1758-7379, Vol. 71, nr 2, s. 294-316Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Purpose. The purpose of this paper is to explore how virtual world communities employ new media as a repository to record information about their past.

    Design/methodology/approach. Using the notions of documentary practice and memory-making as a framework, a case study of MMORPGCity of Heroes’ (CoH) virtual community on Reddit discussion board “/r/cityofheroes” was conducted. The study consists of an interpretative analysis of posts, comments, images, and other materials submitted to /r/cityofheroes during a period of approximately seven months.

    Findings. The principal finding of the study is that the CoH community, with varying levels of intentionality, documented a range of pasts on /r/cityofheroes, relating to CoH as a game world, a site of personal experience, a product, a nexus of narratives, and a game. The analysis also lays bare the community’s memory-making processes, in which the documented conceptions of CoH’s past were put to work in the present, informing community action and viewpoints.

    Originality/value. Games and gaming practices are increasingly prevalent in leisure and professional settings. This trend, which makes virtual environments and online media proxies for or augmentations of “real life”, makes it necessary for information scholars to understand how the full range of human information behaviours, including documenting, and memory-making, emerge or are replicated online. Additionally, few studies have examined the interplay between new media affordances, documentary practices, and memory-making in the context of virtual world communities.

    sted, utgiver, år, opplag, sider
    Emerald Group Publishing Limited, 2015
    HSV kategori
    Forskningsprogram
    Biblioteks- och informationsvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-247471 (URN)10.1108/JD-11-2013-0146 (DOI)000352716700007 ()
    Tilgjengelig fra: 2015-03-18 Laget: 2015-03-18 Sist oppdatert: 2018-01-14
    3. Getting-to-Know: Inquiries, Sources, Methods, and the Production of Knowledge on a Videogame Wiki
    Åpne denne publikasjonen i ny fane eller vindu >>Getting-to-Know: Inquiries, Sources, Methods, and the Production of Knowledge on a Videogame Wiki
    2017 (engelsk)Inngår i: Journal of Documentation, ISSN 0022-0418, E-ISSN 1758-7379, Vol. 73, nr 6, s. 1299-1321Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Purpose. The purpose of this paper is to investigate the sociocultural underpinnings of wiki-based knowledge production in the videogame domain, and to elucidate how these underpinnings relate to the formation of wikis as resources of videogame documentation.

    Design/methodology/approach. The paper is based on a three-month ethnographic investigation of knowledge practices on the Dark Souls Wiki (DSW). In focus of the analysis were the boundaries and knowledge aims of the DSW, together with how its contributors organized inquiries and used various sources, methods of investigation, and ways of warranting knowledge claims.

    Findings. The principal result of the paper is an empirical account of how the DSW functions as a culture of knowledge production, and how the content and structure of the wiki connects to the knowledge practices of its contributors. Four major factors that influenced knowledge practices on the wiki were identified: the structures and practices established by the community’s earlier wiki efforts; principles and priorities that informed wiki knowledge practices; the characteristics of the videogame in focus of the site’s knowledge-building work; the extent and types of relevant documentation provided by videogame industry, the videogaming press included.

    Originality/value. Previous research has shown interest in investigating the mechanisms by which community-created knowledge and online resources of documentation emerge, and how these are utilized in play. There is, however, little research seeking to elucidate the sociocultural structures and practices that determine and sustain collaborative online videogame knowledge production.

    Emneord
    Wikis, Knowledge production, Ethnography, Social media, Practices, Videogames
    HSV kategori
    Forskningsprogram
    Biblioteks- och informationsvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-336745 (URN)10.1108/JD-11-2016-0145 (DOI)
    Tilgjengelig fra: 2017-12-16 Laget: 2017-12-16 Sist oppdatert: 2018-01-14
    4. Understanding the “Expanded Notion” of Videogames as Archival Objects: A Review of Priorities, Methods, and Conceptions
    Åpne denne publikasjonen i ny fane eller vindu >>Understanding the “Expanded Notion” of Videogames as Archival Objects: A Review of Priorities, Methods, and Conceptions
    2018 (engelsk)Inngår i: Journal of the Association for Information Science and Technology, ISSN 2330-1635, E-ISSN 2330-1643, Vol. 69, nr 1, s. 134-145Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    This paper aims to show how videogames are construed as archival objects in the videogame-preservation literature by investigating drivers and motivations, selection of material, and methods of preservation. The review focuses on the expanded notion of videogames (“the EN”), a concept this paper introduces to collectively refer to the cultural and social aspects of videogames—for example, game culture, experiences, play, and community life and activity. The study's research aims are pursued on the basis of a critical systematic literature review of 42 publications originating from academic research and videogame-archiving projects. The study's main finding is that the archiving literature construes the EN of videogames in three principal ways: i) as an essential part of the videogame as an archival object; ii) as a useful resource in archiving videogames, able to provide documentation of game culture and social context; and iii) as a useful resource in inquiries focused on the current state and recent history of society and culture from a sociotechnical viewpoint. The study suggests videogame community dynamics, videogame ontology, the development of archival theory, and videogame-archive studies as rewarding directions for further research.

    HSV kategori
    Forskningsprogram
    Biblioteks- och informationsvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-336747 (URN)10.1002/asi.23875 (DOI)
    Tilgjengelig fra: 2017-12-16 Laget: 2017-12-16 Sist oppdatert: 2018-01-14
  • Disputas: 2018-03-08 13:00 Rosen, Uppsala
    Santos, Arnoldo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet.
    Hemodynamic Effects of Lung Function Optimization in Experimental Acute Respiratory Distress Syndrome2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Acute Respiratory Distress Syndrome (ARDS) is a severe pulmonary inflammation affecting thousands of patients every year in Sweden and has a mortality of 30-50%. Mechanical ventilation (MV) is usually necessary, but could per se augment the inflammation and contribute to mortality. MV strategies protective for the lung parenchyma have been developed but without considering the pulmonary circulation or the right heart ventricle (RV) that also are affected in ARDS. MV should ideally be optimized to protect both the lung parenchyma and the RV/pulmonary vasculature. My hypothesis was that MV that prevents alveolar collapse and overdistension, i.e., the “open lung approach (OLA)” would be optimal. The aims of this project were 1) to carefully describe the pulmonary vascular mechanics (PVM) in ARDS compared with healthy lungs, 2) to assess how different ventilatory methods influence PVM, and 3) to propose a ventilatory method that protects both lung parenchyma and circulation.

    In a porcine model, high fidelity pressure and flow sensors were applied directly on the main pulmonary artery to evaluate steady and oscillatory components of PVM.  In this way a complete PVM description was obtained for normal and injured lungs at different MV. In particular, the effects of OLA were compared with standard MV and, in addition, with MV methods where overdistension or collapse were present.

    Results: 1) Compared with collapse or overdistension, OLA provided better PVM. 2) The effects on PVM of OLA and the standard protective MV were similar. 3) Early ARDS augmented the effects of pulse wave reflection on PVM leading to a situation in which the RV had to increase its work to maintain adequate blood flow. Thus, a part of this work was wasted by the effect of wave reflections, making the RV/pulmonary vasculature inefficient. 4) Tidal breathing affected PVM cyclically and this effect was enhanced in ARDS compared with healthy lungs.

    In conclusion, ARDS and different ventilatory methods, as well as tidal ventilation per se, affected PVM. OLA improved PVM compared with other MV settings where significant collapse and overdistension were allowed. However, OLA was not superior to standard protective MV.

    Delarbeid
    1. The Open Lung Approach Improves Pulmonary Vascular Mechanics in an Experimental Model of Acute Respiratory Distress Syndrome
    Åpne denne publikasjonen i ny fane eller vindu >>The Open Lung Approach Improves Pulmonary Vascular Mechanics in an Experimental Model of Acute Respiratory Distress Syndrome
    Vise andre…
    2017 (engelsk)Inngår i: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 45, nr 3, s. e298-e305Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVE: To test whether positive end-expiratory pressure consistent with an open lung approach improves pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressures in experimental acute respiratory distress syndrome.

    DESIGN: Experimental study.

    SETTING: Animal research laboratory.

    SUBJECTS: Ten pigs, 35 ± 5.2 kg.

    INTERVENTIONS: Acute respiratory distress syndrome was induced combining saline lung lavages with injurious mechanical ventilation. The positive end-expiratory pressure level resulting in highest compliance during a decremental positive end-expiratory pressure trial after lung recruitment was determined. Thereafter, three positive end-expiratory pressure levels were applied in a random order: hyperinflation, 6 cm H2O above; open lung approach, 2 cm H2O above; and collapse, 6 cm H2O below the highest compliance level. High fidelity pressure and flow sensors were placed at the main pulmonary artery for measuring pulmonary artery resistance (Z0), effective arterial elastance, compliance, and reflected pressure waves.

    MEASUREMENTS AND MAIN RESULTS: After inducing acute respiratory distress syndrome, Z0 and effective arterial elastance increased (from 218 ± 94 to 444 ± 115 dyn.s.cm and from 0.27 ± 0.14 to 0.62 ± 0.22 mm Hg/mL, respectively; p < 0.001), vascular compliance decreased (from 2.76 ± 0.86 to 1.48 ± 0.32 mL/mm Hg; p = 0.003), and reflected waves arrived earlier (0.23 ± 0.07 vs 0.14 ± 0.05, arbitrary unit; p = 0.002) compared with baseline. Comparing the three positive end-expiratory pressure levels, open lung approach resulted in the lowest: 1) Z0 (297 ± 83 vs 378 ± 79 dyn.s.cm, p = 0.033, and vs 450 ± 119 dyn.s.cm, p = 0.002); 2) effective arterial elastance (0.37 ± 0.08 vs 0.50 ± 0.15 mm Hg/mL, p = 0.04, and vs 0.61 ± 0.12 mm Hg/mL, p < 0.001), and 3) reflection coefficient (0.35 ± 0.17 vs 0.48 ± 0.10, p = 0.024, and vs 0.53 ± 0.19, p = 0.005), comparisons with hyperinflation and collapse, respectively.

    CONCLUSIONS: In this experimental setting, positive end-expiratory pressure consistent with the open lung approach resulted in the best pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressure settings.

    Emneord
    Fluid responsiveness, Spontaneous breathing, Head-up tilt, Pulse pressure variation, Stroke volume variation, Systolic pressure variation
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-307915 (URN)10.1097/CCM.0000000000002082 (DOI)27763913 (PubMedID)
    Tilgjengelig fra: 2016-11-22 Laget: 2016-11-22 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    2. Effects on Pulmonary Vascular Mechanics of Two Different Lung-Protective Ventilation Strategies in an Experimental Model of Acute Respiratory Distress Syndrome.
    Åpne denne publikasjonen i ny fane eller vindu >>Effects on Pulmonary Vascular Mechanics of Two Different Lung-Protective Ventilation Strategies in an Experimental Model of Acute Respiratory Distress Syndrome.
    Vise andre…
    2017 (engelsk)Inngår i: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 45, nr 11, s. e1157-e1164Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVES: To compare the effects of two lung-protective ventilation strategies on pulmonary vascular mechanics in early acute respiratory distress syndrome.

    DESIGN: Experimental study.

    SETTING: University animal research laboratory.

    SUBJECTS: Twelve pigs (30.8 ± 2.5 kg).

    INTERVENTIONS: Acute respiratory distress syndrome was induced by repeated lung lavages and injurious mechanical ventilation. Thereafter, animals were randomized to 4 hours ventilation according to the Acute Respiratory Distress Syndrome Network protocol or to an open lung approach strategy. Pressure and flow sensors placed at the pulmonary artery trunk allowed continuous assessment of pulmonary artery resistance, effective elastance, compliance, and reflected pressure waves. Respiratory mechanics and gas exchange data were collected.

    MEASUREMENTS AND MAIN RESULTS: Acute respiratory distress syndrome led to pulmonary vascular mechanics deterioration. Four hours after randomization, pulmonary vascular mechanics was similar in Acute Respiratory Distress Syndrome Network and open lung approach: resistance (578 ± 252 vs 626 ± 153 dyn.s/cm; p = 0.714), effective elastance, (0.63 ± 0.22 vs 0.58 ± 0.17 mm Hg/mL; p = 0.710), compliance (1.19 ± 0.8 vs 1.50 ± 0.27 mL/mm Hg; p = 0.437), and reflection index (0.36 ± 0.04 vs 0.34 ± 0.09; p = 0.680). Open lung approach as compared to Acute Respiratory Distress Syndrome Network was associated with improved dynamic respiratory compliance (17.3 ± 2.6 vs 10.5 ± 1.3 mL/cm H2O; p < 0.001), driving pressure (9.6 ± 1.3 vs 19.3 ± 2.7 cm H2O; p < 0.001), and venous admixture (0.05 ± 0.01 vs 0.22 ± 0.03, p < 0.001) and lower mean pulmonary artery pressure (26 ± 3 vs 34 ± 7 mm Hg; p = 0.045) despite of using a higher positive end-expiratory pressure (17.4 ± 0.7 vs 9.5 ± 2.4 cm H2O; p < 0.001). Cardiac index, however, was lower in open lung approach (1.42 ± 0.16 vs 2.27 ± 0.48 L/min; p = 0.005).

    CONCLUSIONS: In this experimental model, Acute Respiratory Distress Syndrome Network and open lung approach affected pulmonary vascular mechanics similarly. The use of higher positive end-expiratory pressures in the open lung approach strategy did not worsen pulmonary vascular mechanics, improved lung mechanics, and gas exchange but at the expense of a lower cardiac index.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-334177 (URN)10.1097/CCM.0000000000002701 (DOI)28872540 (PubMedID)
    Tilgjengelig fra: 2017-11-21 Laget: 2017-11-21 Sist oppdatert: 2018-01-12
    3. Acute Respiratory Distress Syndrome deteriorates pulmonary vascular efficiency and increases cardiac energy wasting in a porcine model.
    Åpne denne publikasjonen i ny fane eller vindu >>Acute Respiratory Distress Syndrome deteriorates pulmonary vascular efficiency and increases cardiac energy wasting in a porcine model.
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background: Right ventricle failure worsen outcomes in acute respiratory distress syndrome (ARDS). However, the pathophysiology of right ventricle failure and vascular dysfunction in ARDS is not completely understood. In this study we aim to evaluate the effects of early ARDS on pulmonary vascular efficiency for transmission of flow and pressure in an experimental animal model.  

    Methods: ARDS was induced in 10 pigs (32.5±4.3 kg) combining saline lung-lavages with injurious mechanical ventilation. Pressure and flow sensors were placed at the main pulmonary artery for pulmonary vascular function evaluation, including arterial load parameters, cardiac power and energy transmission ratio.

    Results: Compared to baseline healthy conditions, ARDS increased pulmonary vascular resistance (199±62 versus 524±154 dyn.s.cm-5, p <0.001), effective arterial elastance (0.65±0.26 versus 1.13±0.36 mmHg/ml, p <0.001) and total hydraulic power (195±60 to 266±87 mW, p =0.015), decreased pulmonary arterial compliance (from 2.34±0.86 to 1.00±0.25 ml/mmHg, p <0.001) and energy transmission ratio (68±15 versus 55±14%, p = 0.014), whereas oscillatory power did not change (17±6 versus 16±6%, p = 0.359).

    Conclusions: In this experimental ARDS model, an increase in pulmonary arterial load was associated with a higher cardiac power and a decrease in the energy transmission ratio. These results suggest that right ventricle energy consumption is increased and part of this energy is wasted in pulmonary circulation worsening pulmonary vascular efficiency in the early course of ARDS. These findings may help to explain primary mechanisms leading to right ventricle dysfunction in ARDS.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-337402 (URN)
    Tilgjengelig fra: 2017-12-25 Laget: 2017-12-25 Sist oppdatert: 2018-01-12
    4. Cyclic Changes of Pulmonary Vascular Mechanics During mechanical ventilation in acute respiratory distress syndrome. A porcine experimental model.
    Åpne denne publikasjonen i ny fane eller vindu >>Cyclic Changes of Pulmonary Vascular Mechanics During mechanical ventilation in acute respiratory distress syndrome. A porcine experimental model.
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Objective: To test the hypothesis that acute respiratory syndrome (ARDS) worsens pulmonary vascular mechanics during the respiratory cycle under mechanical ventilation in an animal model.  

    Design: Experimental study.

    Setting: Animal research laboratory.

    Subjects: 6 pigs, 31.7 ± 5.4 kg.

    Interventions: ARDS was induced by combining saline lung-lavages with injurious mechanical ventilation. Pressure and flow sensors were placed at the main pulmonary artery (PA) and signals were collected simultaneously with airway pressure and flow. Pulmonary vascular mechanics and cardiac function parameters were calculates beat by beat during 2-3 minutes. We designed a novel method to quantify how the calculated variables behave during the whole respiratory cycle, i.e., during expiration and during inspiration. Results are expressed as the mean value during the corresponding phase of the respiratory cycle.

    Measurements and Main Results: During the whole respiratory cycle and at expiration ARDS decreased SV and arterial compliance while increased mean and pulse PA pressure, effective arterial elastance and Dp/Dtmax when compared to baseline. At baseline and after ARDS, inspiration in positive pressure ventilation caused a decrease in stroke volume (-3±1ml, p<0.001 and -3±1ml, p<0.001), pulmonary mean (-0.5±0.3, p=0.007 and -0.7±0.3mmHg, p=0.002) and pulse pressure (-0.8±0.4, p=0.003 and -1,5±0.7mmHg, p=0.003) and compliance (-0.07±0.04 and -0.04±0.00ml/mmHg, p<0.001) and an increase in resistance (34±13, p=0.001 and 50±32dyn.s.cm-5, p=0.012) and in effective arterial elastance (0.04±0.01, p=0.001 and 0.08±0.04mmHg/ml, p=0.003). ARDS produced a more pronounced inspiratory increase in effective arterial elastance (p=0.041) when compared to baseline. Positive pressure ventilation caused a decrease in Dp/Dtmax at baseline (-15±9mmHg/s, p=0.010) but this was not significant during ARDS (-27±28mmHg/s, p=0.068).  

    Conclusions: We found in this experimental model that MV induced tidal increase in arterial load and that this effect was higher during ARDS. This finding if transferred to patients, might partly explain the high rate of right heart failure clinically in ARDS.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-337405 (URN)
    Tilgjengelig fra: 2017-12-25 Laget: 2017-12-25 Sist oppdatert: 2018-01-12
  • Disputas: 2018-03-09 09:15 Sal X, Uppsala
    Salih Joelsson, Lana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Lifestyle and Reproductive Health among Women prior to Conception2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Health and lifestyle is of great importance when women intend to become pregnant, as well as during pregnancy. It is crucial that people seeking for infertility are aware of which lifestyle changes they can undertake to enhance the likelihood of treatment success. The overall aim of this project was to investigate the extent to which women comply with recommendations for lifestyle changes during the time they try to conceive and during early pregnancy and the impact of lifestyle risk factors on treatment results in sub-fertile women. Lifestyle factors and mental health at baseline and lifestyle changes women made while they were trying to conceive were assessed by a study-specific questionnaire. Both pregnant women and non-pregnant sub-fertile women in the mid-Sweden region were included. The level of pregnancy planning was associated with planning behavior. Only one-third of all pregnant women took folic acid one month prior to conception, 17% used tobacco daily and 11% used alcohol weekly three months before conception. In the sub-fertile non-pregnant women cohort, 13.2% used tobacco daily, 13.6% drank more than three cups of coffee per day, and 11.6% consumed more than two glasses of alcohol weekly. Among sub-fertile women, one-third were overweight or obese. Pregnant women who conceived with Assisted Reproductive Technology (ART) reported lower rates of anxiety and depression symptoms compared to sub-fertile women. They also showed no difference in depression and anxiety symptoms compared to women who conceived naturally. Among sub-fertile women undergoing their first IVF treatment cycle, an independent as well as a cumulative effect of smoking and BMI on the number of aspirated oocytes and the proportion of mature oocytes was observed, especially among women with low ovarian reserve. In conclusion, approximately half of the women in our studies retained habits with negative effects on fertility. This is worrying because the harmful consequences of negative lifestyle factors are well established. These negative lifestyle factors are easy to detect and adjust at an early stage in the assessment process and might allow for optimization of fertility treatment and pregnancy outcomes.

    Delarbeid
    1. Is pregnancy planning associated with background characteristics and pregnancy planning behavior?
    Åpne denne publikasjonen i ny fane eller vindu >>Is pregnancy planning associated with background characteristics and pregnancy planning behavior?
    Vise andre…
    2016 (engelsk)Inngår i: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 95, nr 2, s. 182-189Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    INTRODUCTION: Prevalence of planned pregnancies varies between countries but is often measured in a dichotomous manner. The aim of this study was to investigate to what level pregnant women had planned their pregnancies and whether pregnancy planning was associated with background characteristics and pregnancy planning behavior.

    MATERIAL AND METHODS: A cross-sectional study that utilized the baseline measurements from the Swedish Pregnancy Planning (SWEPP) study. Pregnant women (n= 3390) recruited at antenatal clinics answered a questionnaire. Data were analyzed with multinomial logistic regression, Kruskal-Wallis H and χ(2) tests.

    RESULTS: Three out of four pregnancies were very or fairly planned and 12 % fairly or very unplanned. Of women with very unplanned pregnancies, 32 % had considered an induced abortion. Women with planned pregnancies were more likely to have a higher level of education, higher household income, to be currently working ≥50 %, and to have longer relationships than women with unplanned pregnancies. The level of pregnancy planning was associated with planning behavior, such as information seeking and intake of folic acid, but without a reduction in alcohol consumption. One third of all women took folic acid one month prior to conception, 17 % used tobacco daily and 11 % used alcohol weekly three months before conception.

    CONCLUSIONS: A majority rated their pregnancy as very or fairly planned, with socio-economic factors as explanatory variables. The level of pregnancy planning should be queried routinely to enable individualized counselling, especially for women with unplanned pregnancies. Preconception recommendations need to be established and communicated to the public to increase health promoting planning behavior.

    Emneord
    Planned pregnancy; unplanned pregnancy; preconception care; folic acid; health behavior
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-270500 (URN)10.1111/aogs.12816 (DOI)000368004300007 ()26566076 (PubMedID)
    Tilgjengelig fra: 2015-12-29 Laget: 2015-12-29 Sist oppdatert: 2018-01-19bibliografisk kontrollert
    2. Do subfertile women adjust their habits when trying to conceive?
    Åpne denne publikasjonen i ny fane eller vindu >>Do subfertile women adjust their habits when trying to conceive?
    Vise andre…
    2016 (engelsk)Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, nr 3, s. 184-191Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    AbstractAIM:

    The aim of this study was to investigate lifestyle habits and lifestyle adjustments among subfertile women trying to conceive.

    MATERIALS AND METHODS:

    Women (n = 747) were recruited consecutively at their first visit to fertility clinics in mid-Sweden. Participants completed a questionnaire. Data were analyzed using logistic regression, t tests, and chi-square tests.

    RESULTS:

    The response rate was 62% (n = 466). Mean duration of infertility was 1.9 years. During this time 13.2% used tobacco daily, 13.6% drank more than three cups of coffee per day, and 11.6% consumed more than two glasses of alcohol weekly. In this sample, 23.9% of the women were overweight (body mass index, BMI 25-29.9 kg/m(2)), and 12.5% were obese (BMI ≥30 kg/m(2)). Obese women exercised more and changed to healthy diets more frequently than normal-weight women (odds ratio 7.43; 95% confidence interval 3.7-14.9). Six out of ten women (n = 266) took folic acid when they started trying to conceive, but 11% stopped taking folic acid after some time. Taking folic acid was associated with a higher level of education (p < 0.001).

    CONCLUSIONS:

    Among subfertile women, one-third were overweight or obese, and some had other lifestyle factors with known adverse effects on fertility such as use of tobacco. Overweight and obese women adjusted their habits but did not reduce their body mass index. Women of fertile age would benefit from preconception counseling, and the treatment of infertility should routinely offer interventions for lifestyle changes.

    KEYWORDS:

    Alcohol consumption; assisted reproduction; diet; infertility; lifestyle; obesity; pregnancy; tobacco use

    Emneord
    Alcohol consumption; assisted reproduction; diet; infertility; lifestyle; obesity; pregnancy; tobacco use
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-301385 (URN)10.1080/03009734.2016.1176094 (DOI)000381958400006 ()
    Tilgjengelig fra: 2016-08-22 Laget: 2016-08-22 Sist oppdatert: 2018-01-18bibliografisk kontrollert
    3. Anxiety and depression symptoms among sub-fertile women, women pregnant after infertility treatment, and naturally pregnant women
    Åpne denne publikasjonen i ny fane eller vindu >>Anxiety and depression symptoms among sub-fertile women, women pregnant after infertility treatment, and naturally pregnant women
    Vise andre…
    2017 (engelsk)Inngår i: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 45, s. 212-219Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background

    Infertility has been associated with psychological distress, but whether these symptoms persist after achieving pregnancy via assisted reproductive technology (ART) remains unclear. We compared the prevalence of anxiety and depressive symptoms between women seeking for infertility treatment and women who conceived after ART or naturally.

    Methods

    Four hundred and sixty-eight sub-fertile non-pregnant women, 2972 naturally pregnant women and 143 women pregnant after ART completed a questionnaire in this cross-sectional study. The Anxiety subscale of the Hospital Anxiety and Depression Scale (HADS-A≥8) and Edinburgh Postnatal Depression Scale (EPDS≥12) were used for assessing anxiety and depressive symptoms, respectively. Multivariate Poisson regression models with robust variance were applied to explore associations with anxiety and depressive symptoms.

    Results

    The prevalence of anxiety and depressive symptoms among sub-fertile, non-pregnant women (57.6% and 15.7%, respectively) were significantly higher compared to women pregnant after ART (21.1% and 8.5%, respectively) and naturally pregnant women (18.8% and 10.3%, respectively). History of psychiatric diagnosis was identified as an independent risk factor for both anxiety and depressive symptoms. The presence of at least one unhealthy lifestyle behavior (daily tobacco smoking, weekly alcohol consumption, BMI≥25, and regular physical exercise < 2 h/week) was also associated with anxiety (Prevalence Ratio, PR: 1.24; 95%CI: 1.09–1.40) and depressive symptoms (PR: 1.25; 95%CI: 1.04–1.49).

    Conclusions

    Women pregnant after ART showed no difference in anxiety and depressive symptoms compared to naturally pregnant women. However, early psychological counseling and management of unhealthy lifestyle behaviors for sub-fertile women may be advisable, particularly for women with a previous history of psychiatric diagnosis.

    Emneord
    anxiety, depression, infertility, assisted reproductive technology, pregnancy
    HSV kategori
    Forskningsprogram
    Obstetrik och gynekologi
    Identifikatorer
    urn:nbn:se:uu:diva-338378 (URN)10.1016/j.eurpsy.2017.07.004 (DOI)000414461300029 ()28957789 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council
    Tilgjengelig fra: 2018-01-08 Laget: 2018-01-08 Sist oppdatert: 2018-02-12bibliografisk kontrollert
    4. Investigating the effect of lifestyle risk factors upon the number of aspirated and mature oocytes in in vitro fertilization cycles: interaction with antral follicle count
    Åpne denne publikasjonen i ny fane eller vindu >>Investigating the effect of lifestyle risk factors upon the number of aspirated and mature oocytes in in vitro fertilization cycles: interaction with antral follicle count
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    infertility, oocytes, lifestyle, obesity, alcohol, in vitro fertilization, nicotine use, smoking
    HSV kategori
    Forskningsprogram
    Obstetrik och gynekologi
    Identifikatorer
    urn:nbn:se:uu:diva-338379 (URN)
    Tilgjengelig fra: 2018-01-08 Laget: 2018-01-08 Sist oppdatert: 2018-01-18
  • Disputas: 2018-03-09 10:00 Hamberg, Uppsala
    den Boer, Wendy
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Geovetenskapliga sektionen, Institutionen för geovetenskaper, Paleobiologi.
    Evolutionary Progression of the Iconic Australasian Kangaroos, Rat-Kangaroos, and their Fossil Relatives (Marsupialia: Macropodiformes)2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The exceptionally diverse macropodiform’s (kangaroos, rat-kangaroos and their fossil allies) currently have a fossil record that spans from the late Oligocene to the Holocene with an Australasian widespread fossil occurence. The origins of the macropodiforms are believed to have been during the Eocene possibly having split from the Phalangeridae. This is largely based on molecular data as there is a complete lack of macropodiform fossil material prior to the late Oligocene leaving the origins of the macropodiforms to be largely speculative. Thus, late Oligocene rat-kangaroo dental fossil elements associated with Palaeopotorous priscus (which shares characteristics observed in both phalangerid and macropodiforms) were examined to get a better insight into the potential origins of the macropodiforms. The results obtained suggested that P. priscus is currently the most basal macropodiform known. Furthermore, due to the absence of adequate macropodiform post-cranial material, the functional eco-morphological interpretation of various macropodiform fossil taxa has been based largely on cranial and dental characteristics. Consequently, the examination of Miocene Balbaridae kangaroo’s (Balbaroo nalima and an untaxonomised balbarid) post-cranial elements was undertaken, suggesting an array of locomotion types (similar to living macropodiforms) and a likely persistent arboreal and quadrupedal lifestyle. In addition, the Pleistocene Protemnodon anak’s post-cranial material are examined, proposing a probable combination of quadrupedal bounding and a slow walking gait alternative to the eminent fast bipedal saltation seen in almost all extant macropodiforms.

    Delarbeid
    1. A New Species of the Basal "Kangaroo'' Balbaroo and a Re-Evaluation of Stem Macropodiform Interrelationships
    Åpne denne publikasjonen i ny fane eller vindu >>A New Species of the Basal "Kangaroo'' Balbaroo and a Re-Evaluation of Stem Macropodiform Interrelationships
    Vise andre…
    2014 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, s. e112705-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Exceptionally well-preserved skulls and postcranial elements of a new species of the plesiomorphic stem macropodiform Balbaroo have been recovered from middle Miocene freshwater limestone deposits in the Riversleigh World Heritage Area of northwestern Queensland, Australia. This constitutes the richest intraspecific sample for any currently known basal "kangaroo'', and, along with additional material referred to Balbaroo fangaroo, provides new insights into structural variability within the most prolific archaic macropodiform clade - Balbaridae. Qualitative and metric evaluations of taxonomic boundaries demonstrate that the previously distinct species Nambaroo bullockensis is a junior synonym of B. camfieldensis. Furthermore, coupled Maximum Parsimony and Bayesian phylogenetic analyses reveal that our new Balbaroo remains represent the most derived member of the Balbaroo lineage, and are closely related to the middle Miocene B. camfieldensis, which like most named balbarid species is identifiable only from isolated jaws. The postcranial elements of Balbaroo concur with earlier finds of the stratigraphically oldest balbarid skeleton, Nambaroo gillespieae, and suggest that quadrupedal progression was a primary gait mode as opposed to bipedal saltation. All Balbaroo spp. have low-crowned bilophodont molars, which are typical for browsing herbivores inhabiting the densely forested environments envisaged for middle Miocene northeastern Australia.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-240097 (URN)10.1371/journal.pone.0112705 (DOI)000345533200034 ()25409233 (PubMedID)
    Tilgjengelig fra: 2015-01-05 Laget: 2015-01-05 Sist oppdatert: 2018-01-22bibliografisk kontrollert
    2. Is the Fossil Rat-Kangaroo Palaeopotorous pricus the Most Basally Branching Macropodiform?
    Åpne denne publikasjonen i ny fane eller vindu >>Is the Fossil Rat-Kangaroo Palaeopotorous pricus the Most Basally Branching Macropodiform?
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Geovetenskap med inriktning mot historisk geologi och paleontologi
    Identifikatorer
    urn:nbn:se:uu:diva-339580 (URN)
    Tilgjengelig fra: 2018-01-21 Laget: 2018-01-21 Sist oppdatert: 2018-01-31bibliografisk kontrollert
    3. Autopodial Anatomy Elucidate Climbing Ability in Miocene Balbarid 'kangaroos' (Marsupialia, Macropodifromes)
    Åpne denne publikasjonen i ny fane eller vindu >>Autopodial Anatomy Elucidate Climbing Ability in Miocene Balbarid 'kangaroos' (Marsupialia, Macropodifromes)
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Geovetenskap med inriktning mot historisk geologi och paleontologi
    Identifikatorer
    urn:nbn:se:uu:diva-339581 (URN)
    Tilgjengelig fra: 2018-01-21 Laget: 2018-01-21 Sist oppdatert: 2018-01-31bibliografisk kontrollert
    4. Functional Eco-Morphology of the 'Giant Extinct Wallaby' Protemnodon anak from Morwell Local Fauna, Victoria, Australia
    Åpne denne publikasjonen i ny fane eller vindu >>Functional Eco-Morphology of the 'Giant Extinct Wallaby' Protemnodon anak from Morwell Local Fauna, Victoria, Australia
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Geovetenskap med inriktning mot historisk geologi och paleontologi
    Identifikatorer
    urn:nbn:se:uu:diva-339582 (URN)
    Tilgjengelig fra: 2018-01-21 Laget: 2018-01-21 Sist oppdatert: 2018-01-31bibliografisk kontrollert
    5. Systematic Review of the Fossil Macropodiformes (Kangaroo, Rat-Kangaroos, and their Allies)
    Åpne denne publikasjonen i ny fane eller vindu >>Systematic Review of the Fossil Macropodiformes (Kangaroo, Rat-Kangaroos, and their Allies)
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Geovetenskap med inriktning mot historisk geologi och paleontologi
    Identifikatorer
    urn:nbn:se:uu:diva-339583 (URN)
    Tilgjengelig fra: 2018-01-21 Laget: 2018-01-21 Sist oppdatert: 2018-01-31bibliografisk kontrollert
  • Disputas: 2018-03-09 13:00 Rudbecksalen, Rudbecklaboratoriet, Uppsala
    Georganaki, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Vascular targeting for enhanced cancer immunotherapy2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Induced angiogenesis and chronic inflammation are major components of tumor immunosuppression. The scope of this thesis is to understand the role of the vasculature in anti-tumor immunity and thereby to improve cancer immunotherapy.

    The anti-tumor effects of anti-angiogenic therapies range from vessel normalization to directly affecting immune responses. In Paper I, we demonstrate that VEGF, a major pro-angiogenic factor, inhibits TNFα-induced endothelial activation via interfering with the NF-κB pathway and suppressing T-cell chemoattractants. Sunitinib, an anti-angiogenic tyrosine kinase inhibitor targeting VEGFR2 signaling, enhanced T-cell recruitment and reverted endothelial cell anergy by upregulating pro-inflammatory cytokines in murine melanomas. Therefore, in Paper II, we study the anti-tumor potential of combining sunitinib treatment with CD40-stimulating immunotherapy. CD40 activation leads to increased anti-tumor T-cell responses. The combination therapy was superior in restricting tumor growth and enhancing survival, associated with decreased immunosuppression and increased endothelial activation leading to improved T-cell recruitment. In Paper III, RNA-sequencing reveals that tumor endothelial cells are capable of acquiring negative feedback mechanisms secondary to CD40 immunotherapy by upregulating immunosuppressive genes such as IDO1. Co-administration of agonistic CD40 antibody treatment with an IDO1 inhibitor delayed tumor growth, associated with increased intratumoral T-cell activation.

    In Paper IV, we investigate ELTD1, an orphan adhesion G protein-coupled receptor, which is upregulated in high-grade glioma vessels. ELTD1 deficiency did not affect developmental angiogenesis in mice but increased tumor growth. Interestingly, ELTD1 loss improved glioma vessel perfusion and reduced permeability and hypoxia. Thus, ELTD1 targeting may normalize tumor vessels, potentially enhancing drug delivery.

    In Paper V, we demonstrate that ectopic expression of specific cytokines in murine gliomas induces tertiary lymphoid organ- (TLO-) TLO-like structures in the brain. TLOs, mainly composed of T- and B-cell clusters and high endothelial venules, are onsite preservers of robust immune responses. In line with this, increased survival of mice with gliomas overexpressing either LT-αβ or LIGHT was associated with alleviated tumor immunosuppresion. This suggests that TLO-inducing agents may improve cancer immunotherapy for glioma treatment.

    Collectively, this thesis demonstrates that the tumor vasculature is crucial for anti-tumor immune responses and that vascular targeting can enhance cancer immunotherapy.

    Delarbeid
    1. VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation
    Åpne denne publikasjonen i ny fane eller vindu >>VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation
    Vise andre…
    2015 (engelsk)Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, nr 1, s. 227-238Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) signaling pathway is in clinical use, but its effect on vascular function and the tumor microenvironment is poorly understood. Here, we investigate cross-talk between VEGF and proinflammatory TNF-α signaling in endothelial cells and its impact on leukocyte recruitment. We found that cotreatment with VEGF decreased TNF-α-induced Jurkat cell adhesion to human microvascular endothelial cells by 40%. This was associated with inhibition of TNF-α-mediated regulation of 86 genes, including 2 T-lymphocyte-attracting chemokines, CXCL10 and CXCL11 [TNF-α concentration 1 ng/ml; 50% inhibition/inhibitory concentration (IC50) VEGF, 3 ng/ml]. Notably, VEGF directly suppressed TNF-α-induced gene expression through negative cross-talk with the NF-κB-signaling pathway, leading to an early decrease in IFN regulatory factor 1 (IRF-1) expression and reduced phosphorylation of signal transducer and activator of transcription 1 (p-Stat1) at later times. Inhibition of VEGF signaling in B16 melanoma tumor-bearing mice by sunitinib treatment resulted in up-regulation of CXCL10 and CXCL11 in tumor vessels, accompanied by up to 18-fold increased infiltration of CD3(+) T-lymphocytes in B16 tumors. Our results demonstrate a novel role of VEGF in negative regulation of NF-κB signaling and endothelial activation in the tumor microenvironment and provide evidence that pharmacological inhibition of VEGF signaling enhances T-lymphocyte recruitment through up-regulation of chemokines CXCL10 and CXCL11.-Huang, H., Langenkamp, E., Georganaki, M., Loskog, A., Fuchs, P. F., Dieterich, L. C., Kreuger, J., Dimberg, A. VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-239496 (URN)10.1096/fj.14-250985 (DOI)000347378600022 ()25361735 (PubMedID)
    Merknad

    Författare två och tre delar andraförfattarskapet.

    Tilgjengelig fra: 2014-12-29 Laget: 2014-12-29 Sist oppdatert: 2018-01-17bibliografisk kontrollert
    2. Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment
    Åpne denne publikasjonen i ny fane eller vindu >>Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment
    Vise andre…
    2016 (engelsk)Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 31, s. 50277-50289Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    CD40-activating immunotherapy has potent antitumor effects due to its ability to activate dendritic cells and induce cytotoxic T-cell responses. However, its efficacy is limited by immunosuppressive cells in the tumor and by endothelial anergy inhibiting recruitment of T-cells. Here, we show that combining agonistic CD40 monoclonal antibody (mAb) therapy with vascular targeting using the tyrosine kinase inhibitor sunitinib decreased tumor growth and improved survival in B16.F10 melanoma and T241 fibrosarcoma. Treatment of tumor-bearing mice with anti-CD40 mAb led to increased activation of CD11c(+) dendritic cells in the tumor draining lymph node, while sunitinib treatment reduced vessel density and decreased accumulation of CD11b(+)Gr1(+) myeloid derived suppressor cells. The expression of ICAM-1 and VCAM-1 adhesion molecules was up-regulated on tumor endothelial cells only when anti-CD40 mAb treatment was combined with sunitinib. This was associated with enhanced intratumoral infiltration of CD8(+) cytotoxic T-cells. Our results show that combining CD40-stimulating immunotherapy with sunitinib treatment exerts potent complementary antitumor effects mediated by dendritic cell activation, a reduction in myeloid derived suppressor cells and increased endothelial activation, resulting in enhanced recruitment of cytotoxic T-cells.

    Emneord
    CD40, sunitinib, MDSC, endothelial activation, T-cell
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-308035 (URN)10.18632/oncotarget.10364 (DOI)000385422000111 ()
    Forskningsfinansiär
    EU, FP7, Seventh Framework Programme, 317445Swedish Childhood Cancer FoundationGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology
    Tilgjengelig fra: 2016-11-24 Laget: 2016-11-23 Sist oppdatert: 2018-02-23bibliografisk kontrollert
    3. Tumor endothelial up-regulation of IDO1 is an immunosuppressive feedback mechanism that limits the response to CD40-stimulating immunotherapy
    Åpne denne publikasjonen i ny fane eller vindu >>Tumor endothelial up-regulation of IDO1 is an immunosuppressive feedback mechanism that limits the response to CD40-stimulating immunotherapy
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-339104 (URN)
    Tilgjengelig fra: 2018-01-16 Laget: 2018-01-16 Sist oppdatert: 2018-01-17
    4. Loss of tumor vessel marker ELTD1 (ADGRL4) reduces vascular abnormality and enhances tumor growth
    Åpne denne publikasjonen i ny fane eller vindu >>Loss of tumor vessel marker ELTD1 (ADGRL4) reduces vascular abnormality and enhances tumor growth
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-339107 (URN)
    Tilgjengelig fra: 2018-01-16 Laget: 2018-01-16 Sist oppdatert: 2018-01-17
    5. Induction of tertiary lymphoid organ-like structures in glioma promotes efficient anti-tumor immune responses
    Åpne denne publikasjonen i ny fane eller vindu >>Induction of tertiary lymphoid organ-like structures in glioma promotes efficient anti-tumor immune responses
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-339110 (URN)
    Tilgjengelig fra: 2018-01-16 Laget: 2018-01-16 Sist oppdatert: 2018-01-17
  • Disputas: 2018-03-09 13:15 Polhemssalen, Ångströmlaboratoriet, Uppsala
    Thörnblad, Erik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Matematiska institutionen.
    Degrees in Random Graphs and Tournament Limits2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis consists of an introduction and six papers on the topics of degree distributions in random graphs and tournaments and their limits.

    The first two papers deal with a dynamic random graph, evolving in time through duplication and deletion of vertices and edges. In Paper I we study the degree densities of this model. We show that these densities converge almost surely and determine their limiting values exactly as well as asymptotically for large degrees. In Paper II we study the evolution of the maximum degree and provide a precise growth rate thereof.

    Paper III deals with a dynamic random tree model known as the vertex-splitting tree model. We show that the degree densities converge almost surely and find an infinite linear system of equations which they must satisfy. Unfortunately we are not able to show that this system has a unique solution except in special cases.

    Paper IV is about self-converse generalised tournaments. A self-converse generalised tournament can be seen as a matrix whose entries take values in [0,1] and whose diagonally opposite elements sum to 1. We characterise completely the marginals of such a matrix, and show that such marginals can always be realised by a self-converse generalised tournament.

    In Paper V, we define and develop the theory of tournament limits and tournament kernels. We characterise transitive and irreducible tournament limits and kernels, and prove that any tournament limit and kernel has an essentially unique decomposition into irreducible tournament limits or kernels interlaced by a transitive part.

    In Paper VI, we study the degree distributions of tournament limits, or equivalently, the marginals of tournament kernels. We describe precisely which distributions on [0,1] which may appear as degree distributions of tournament limits and which functions from [0,1] to [0,1] may appear as the marginals of tournament kernels. Moreover, we show that any distribution or marginal on this form may be realised by a tournament limit or tournament kernel. We also study those distributions and marginals which can be realised by a unique tournament limit or kernel, and find that only the transitive tournament limit/kernel gives rise to a degree distribution or marginal with this property.

    Delarbeid
    1. Asymptotic Degree Distribution Of A Duplication-Deletion Random Graph Model
    Åpne denne publikasjonen i ny fane eller vindu >>Asymptotic Degree Distribution Of A Duplication-Deletion Random Graph Model
    2015 (engelsk)Inngår i: Internet Mathematics, ISSN 1542-7951, E-ISSN 1944-9488, Vol. 11, nr 3, s. 289-305Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    We study a discrete-time duplication-deletion random graph model and analyze its asymptotic degree distribution. The random graphs consist of disjoint cliques. In each time step, either a new vertex is brought in with probability 0 < p < 1 and attached to an existing clique, chosen with probability proportional to the clique size, or all the edges of a random vertex are deleted with probability 1 p. We prove almost sure convergence of the asymptotic degree distribution and find its exact values in terms of a hypergeometric integral, expressed in terms of the parameter p. In the regime 0 < p< 1/2 , we show that the degree sequence decays exponentially at rate p/1-p, whereas it satisfies a power law with exponent 2, if 1/2 < p< 1. At the threshold p = 1/2, the degree sequence lies between a power law and exponential decay.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-311631 (URN)10.1080/15427951.2015.1009523 (DOI)000388715000006 ()
    Tilgjengelig fra: 2016-12-30 Laget: 2016-12-30 Sist oppdatert: 2018-01-17bibliografisk kontrollert
    2. The dominating colour of an infinite Pólya urn model
    Åpne denne publikasjonen i ny fane eller vindu >>The dominating colour of an infinite Pólya urn model
    2016 (engelsk)Inngår i: Journal of Applied Probability, ISSN 0021-9002, E-ISSN 1475-6072, Vol. 53, nr 3, s. 914-924Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    We study a Pólya-type urn model defined as follows. Start at time 0 with a single ball of some colour. Then, at each time n≥1, choose a ball from the urn uniformly at random. With probability ½<p<1, return the ball to the urn along with another ball of the same colour. With probability 1−p, recolour the ball to a new colour and then return it to the urn. This is equivalent to the supercritical case of a random graph model studied by Backhausz and Móri (2015), (2016) and Thörnblad (2015). We prove that, with probability 1, there is a dominating colour, in the sense that, after some random but finite time, there is a colour that always has the most number of balls. A crucial part of the proof is the analysis of an urn model with two colours, in which the observed ball is returned to the urn along with another ball of the same colour with probability p, and removed with probability 1−p. Our results here generalise a classical result about the Pólya urn model (which corresponds to p=1).

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-274483 (URN)10.1017/jpr.2016.49 (DOI)000386349900019 ()
    Tilgjengelig fra: 2016-01-21 Laget: 2016-01-21 Sist oppdatert: 2018-01-17bibliografisk kontrollert
    3. Almost sure convergence of vertex degree densities in the vertex splitting model
    Åpne denne publikasjonen i ny fane eller vindu >>Almost sure convergence of vertex degree densities in the vertex splitting model
    2016 (engelsk)Inngår i: Communications in Statistics. Stochastic Models, ISSN 1532-6349, E-ISSN 1532-4214, Vol. 32, nr 4, s. 575-592Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    We study the limiting degree distribution of the vertex splitting model introduced in Ref.([3]). This is a model of randomly growing ordered trees, where in each time step the tree is separated into two components by splitting a vertex into two, and then inserting an edge between the two new vertices. Under some assumptions on the parameters, related to the growth of the maximal degree of the tree, we prove that the vertex degree densities converge almost surely to constants which satisfy a system of equations. Using this, we are also able to strengthen and prove some previously non-rigorous results mentioned in the literature.

    Emneord
    Almost sure convergence, degree densities, random trees, vertex splitting, 05C80, 05C05
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-303159 (URN)10.1080/15326349.2016.1182029 (DOI)000380246200003 ()
    Tilgjengelig fra: 2016-09-15 Laget: 2016-09-15 Sist oppdatert: 2018-01-17bibliografisk kontrollert
    4. Eplett's theorem for self-converse generalised tournaments
    Åpne denne publikasjonen i ny fane eller vindu >>Eplett's theorem for self-converse generalised tournaments
    2018 (engelsk)Inngår i: The Australasian Journal of Combinatorics, ISSN 1034-4942, Vol. 70, nr 3Artikkel i tidsskrift (Fagfellevurdert) Accepted
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-335318 (URN)
    Tilgjengelig fra: 2017-12-04 Laget: 2017-12-04 Sist oppdatert: 2018-01-26
    5. Decomposition of tournament limits
    Åpne denne publikasjonen i ny fane eller vindu >>Decomposition of tournament limits
    2018 (engelsk)Inngår i: European journal of combinatorics (Print), ISSN 0195-6698, E-ISSN 1095-9971, Vol. 67, s. 96-125Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The theory of tournament limits and tournament kernels is developed by extending common notions for finite tournaments to this setting; in particular we study transitivity and irreducibility of limits and kernels. We prove that each tournament kernel and each tournament limit can be decomposed into a direct sum of irreducible components, with transitive components interlaced. We also show that this decomposition is essentially unique.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-335316 (URN)10.1016/j.ejc.2017.07.023 (DOI)000413385900007 ()
    Tilgjengelig fra: 2017-12-04 Laget: 2017-12-04 Sist oppdatert: 2018-02-05bibliografisk kontrollert
    6. Tournament limits: Degree distributions, score functions and self-converseness
    Åpne denne publikasjonen i ny fane eller vindu >>Tournament limits: Degree distributions, score functions and self-converseness
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-335319 (URN)
    Tilgjengelig fra: 2017-12-04 Laget: 2017-12-04 Sist oppdatert: 2018-01-17
  • Disputas: 2018-03-09 13:15 Häggsalen, Uppsala
    Bengtson, Charlotta
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Teoretisk kemi.
    Quantum Resources for Efficient Excitation Energy Transfer in Natural and Artificial Pigment-Protein Molecular Aggregates2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Recently, long-lasting quantum effects in a number of photosynthetic complexes, which are pigment-protein molecular aggregates (PPMAs), were experimentally verified. These findings created an interest in trying to connect the known highly efficient excitation energy transfer (EET) in these systems to the existence of quantum effects such as quantum coherence and quantum correlations. It also raised the question of how these sensitive quantum effects can survive in such a macroscopic system.

    This thesis explores the existence and possible role of quantum effects in the EET in PPMAs. These systems can be modeled as non-Markovian open quantum systems and quantum effects can be investigated and quantified by methods developed in quantum information theory.

    Firstly, it is found that quantum nonlocal correlations in the EET in the Fenna-Matthews-Olson complex - a PPMA found in nature - are unlikely to exist when the initial excitation occurs in a natural manner. When the initial excitation occurs in an artificial manner by localization of the excitation on one pigment, nonlocal correlations exist on a short time scale. It is further found that in order for nonlocal correlations to be preserved in such a system, the excitation must be trapped on two pigments at the time and these pigments must not interact strongly with other pigments in the complex.

    Secondly, it is shown that quantum coherence is not in general a resource for efficient EET in model systems consisting of a network of pigments; systems optimized with respect to the amount of coherence do not coincide with systems with optimal EET efficiency between two end-site pigments.

    Thirdly, it is found that environmental effects and system-environment interactions can be tuned to optimize the EET efficiency in model PPMAs. The features of optimal environments highly depends on the structure of the pigment system and in particular, the relationship between the pigments excitation energies. It is further shown that a non-Markovian dynamics cannot be connected to an increased EET efficiency in these systems.

    Delarbeid
    1. Quantum nonlocality in the excitation energy transfer in the Fenna-Matthews-Olson complex
    Åpne denne publikasjonen i ny fane eller vindu >>Quantum nonlocality in the excitation energy transfer in the Fenna-Matthews-Olson complex
    2016 (engelsk)Inngår i: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 116, s. 1763-1771Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The Fenna-Matthews-Olson (FMO) complex - a pigment protein complex involved in photosynthesis in green sulfur bacteria - is remarkably efficient in transferring excitation energy from light harvesting antenna molecules to a reaction center. Recent experimental and theoretical studies suggest that quantum coherence and entanglement may play a role in this excitation energy transfer (EET). We examine whether bipartite quantum nonlocality, a property that expresses a stronger-than-entanglement form of correlation, exists between different pairs of chromophores in the FMO complex when modeling the EET by the hierarchically coupled equations of motion method. We compare the results for nonlocality with the amount of bipartite entanglement in the system. In particular, we analyze in what way these correlation properties are affected by different initial conditions. It is found that bipartite nonlocality only exists when the initial conditions are chosen in an unphysiological manner and probably is absent when considering the EET in the FMO complex in its natural habitat. It is also seen that nonlocality and entanglement behave quite differently in this system. In particular, for localized initial states, nonlocality only exists on a very short time scale and then drops to zero in an abrupt manner. As already known from previous studies, quantum entanglement between chromophore pairs on the other hand is oscillating and exponentially decaying and follow thereby a pattern more similar to the chromophore population dynamics. The abrupt disappearance of nonlocality in the presence of nonvanishing entanglement is a phenomenon we call nonlocality sudden death; a striking manifestation of the difference between these two types of correlations in quantum systems. 

    Emneord
    Photosynthesis, quantum nonlocality, open quantum systems
    HSV kategori
    Forskningsprogram
    Fysik med inriktning mot kvantkemi; Biologi
    Identifikatorer
    urn:nbn:se:uu:diva-246119 (URN)10.1002/qua.25221 (DOI)000385587200001 ()
    Forskningsfinansiär
    Swedish Research Council, D0413201eSSENCE - An eScience CollaborationSwedish National Infrastructure for Computing (SNIC), snic2014-3-66
    Tilgjengelig fra: 2015-03-02 Laget: 2015-03-02 Sist oppdatert: 2018-01-19bibliografisk kontrollert
    2. Nonlocality in the Fenna-Matthews-Olson complex: Using Nature for learning about nonlocality preservation in a multi-qubit open system
    Åpne denne publikasjonen i ny fane eller vindu >>Nonlocality in the Fenna-Matthews-Olson complex: Using Nature for learning about nonlocality preservation in a multi-qubit open system
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    Quantum nonlocality, Quantum coherence, Open quantum systems
    HSV kategori
    Forskningsprogram
    Kemi med inriktning mot kvantkemi
    Identifikatorer
    urn:nbn:se:uu:diva-339463 (URN)
    Tilgjengelig fra: 2018-01-18 Laget: 2018-01-18 Sist oppdatert: 2018-01-19
    3. The role of quantum coherence in dimer and trimer excitation energy transfer
    Åpne denne publikasjonen i ny fane eller vindu >>The role of quantum coherence in dimer and trimer excitation energy transfer
    2017 (engelsk)Inngår i: New Journal of Physics, ISSN 1367-2630, E-ISSN 1367-2630, Vol. 19, artikkel-id 113015Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Recent progress in resource theory of quantum coherence has resulted in measures to quantify coherence in quantum systems. Especially, the l1-norm and relative entropy of coherence have been shown to be proper quantifiers of coherence and have been used to investigate coherence properties in different operational tasks. Since long-lasting quantum coherence has been experimentally confirmed in a number of photosynthetic complexes, it has been debated if and how coherence is connected to the known efficiency of population transfer in such systems. In this study, we investigate quantitatively the relationship between coherence, as quantified by l1 norm and relative entropy of coherence, and efficiency, as quantified by fidelity, for population transfer between end-sites in a network of two-level quantum systems. In particular, we use the coherence averaged over the duration of the population transfer in order to carry out a quantitative comparision between coherence and fidelity. Our results show that although coherence is a necessary requirement for population transfer, there is no unique relation between coherence and the efficiency of the transfer process.

    Emneord
    Quantum coherence, energy transport
    HSV kategori
    Forskningsprogram
    Fysik med inriktning mot atom- molekyl- och kondenserande materiens fysik
    Identifikatorer
    urn:nbn:se:uu:diva-327295 (URN)10.1088/1367-2630/aa916b (DOI)000415196900003 ()
    Forskningsfinansiär
    Swedish Research Council, D0413201Swedish National Infrastructure for Computing (SNIC), snic2017-7-17
    Tilgjengelig fra: 2017-08-08 Laget: 2017-08-08 Sist oppdatert: 2018-02-21bibliografisk kontrollert
    4. Environmental design principles for efficient excitation energy transfer in dimer and trimer pigment-protein molecular aggregates and the relation to non-Markovianity
    Åpne denne publikasjonen i ny fane eller vindu >>Environmental design principles for efficient excitation energy transfer in dimer and trimer pigment-protein molecular aggregates and the relation to non-Markovianity
    (engelsk)Inngår i: QuantumArtikkel i tidsskrift (Fagfellevurdert) Submitted
    Abstract [en]

    Lately there has been an interest in studying the effects and mechanisms of environment-assisted quantum transport, especially in the context of excitation energy transfer (EET) in pigment-protein molecular aggregates. Since these systems can be seen as open quantum systems where the dynamics is within the non-Markovian regime, the effect of non-Markovianity on efficient EET as well as its role in preserving quantum coherence and correlations has also been investigated in recent works. In this study, we explore optimal environments for efficient EET between end sites in a number of dimer and trimer model pigment-protein molecular aggregates when the EET dynamics is modeled by the HEOM-method. For these optimal environmental parameters, we further quantify the non-Markovianity by the BLP-measure to elucidate its possible connection to efficient EET. We also quantify coherence in the pigment systems by means of the measure l1−norm of coherence to analyze its interplay with environmental effects when EET efficiency is maximal. Our aim is to investigate possible environmental design principles for achieving efficient EET in model pigment-protein molecular aggregates and to determine whether non-Markovianity is a possible underlying resource in such systems. We find that the structure of the system Hamiltonian (i.e., the pigment Hamiltonian parameter space) and especially, the relationship between the site excitation energies, determines whether one of two specific environmental regimes is the most beneficial in promoting efficient EET in these model systems. In the first regime, optimal environmental conditions are such that the EET dynamics in the system is left as coherent as possible. In the second regime, the most advantageous role of the environment is to drive the system towards equilibrium as fast as possible. In reality, optimal environmental conditions may involve a combination of these two effects. We cannot establish a relation between efficient EET and non-Markovianity, i.e., non-Markovianity cannot be regarded as a resource in the systems investigated in this study. 

    Emneord
    Excitation energy transfer, Quantum coherence, non-Markovianity
    HSV kategori
    Forskningsprogram
    Kemi med inriktning mot kvantkemi
    Identifikatorer
    urn:nbn:se:uu:diva-339462 (URN)
    Tilgjengelig fra: 2018-01-18 Laget: 2018-01-18 Sist oppdatert: 2018-02-18
  • Disputas: 2018-03-10 10:00 Auditorium Minus, Uppsala
    Frisk, Pia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Surveys and services: The feasibility of conducting research in Swedish community pharmacies2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    For the past decades, there has been a shift in community pharmacy practice from dispensing and compounding towards provision of pharmacy services. Research is important to generate evidence for new services within pharmacy practice. Pharmacy practice research can be divided in two main themes: research related to pharmacy as a data source and to the pharmacy as the object of research, respectively.

    The purpose of this thesis is to increase the understanding of the conditions required for successful involvement of Swedish community pharmacy staff in pharmacy-based research, and to evaluate the data generated through a certain type of research: pharmacy-based patient surveys on drug utilization.

    Specific aims were to evaluate if there is a selection bias in drug utilization surveys conducted in Swedish community pharmacies, to explore the experiences of pharmacists either conducting the surveys or recruiting patients to research on adherence-promoting services, and to describe barriers and facilitators to conducting research in community pharmacies.

    Data were collected via pharmacy-based patient surveys, dispensing data, individual interviews, a cross-sectional staff survey and focus group interviews.

    In community pharmacy-based surveys or services research, with the dispensed drug as the trigger for inclusion, patients aged 75 years or older are underrepresented since they less often visit the pharmacy to redeem their prescriptions themselves. Due to their perceived workload, dispensing pharmacists sometimes avoid including patients perceived as complex due to age, polypharmacy or communication difficulties. These processes contribute to a healthy selection effect in both types of research and pharmacy services not reaching the patients in most need of support with their medication.

    The pharmacists were generally positive to conducting surveys and being involved in services research, but reported a perceived lack of sufficient communication and research skills, and a lack of time.

    Since competing commercial priorities hamper pharmacists’ research involvement, separate research funding is an important facilitator. For surveys to include all eligible patients, services to be relevant for both practice and patients and to target the patients in most need of support with their medication, research collaboration with healthcare, other professions and across pharmacies is also necessary.

    Delarbeid
    1. Selection bias in pharmacy-based patient surveys
    Åpne denne publikasjonen i ny fane eller vindu >>Selection bias in pharmacy-based patient surveys
    2014 (engelsk)Inngår i: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 23, nr 2, s. 128-139Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    PurposeTo evaluate if there is a selection bias in drug utilization surveys on prescription drugs regularly conducted in Swedish pharmacies, to describe the direction of this potential bias and discuss the implications for the results. MethodsAge and gender distributions within patient survey samples from drug utilization surveys conducted during 2006-2010 are compared to the age and gender distribution of all Swedish patients, receiving the same drug or drugs, as given by the Swedish Prescribed Drug Register. The differences between the proportions of patients within the age and gender segments of each pair of survey/register data were calculated. ResultsIn 25 (81%) out of 31 included surveys, patients aged 75 years or older are significantly underrepresented, as they are less likely to visit the pharmacy to collect their prescription drugs themselves and thus disqualify for the interviews. Data on women show similar results as overall survey data, whereas the underrepresentation of the oldest age group among men appears in a lower proportion of the surveys, 67%. The general consequence is a selection towards a healthier survey sample, but the consequences in the individual surveys vary, depending on what drug is being studied. ConclusionPharmacy-based patient surveys provide a convenient data collection method for patient self-reported data, but patients aged 75 years or older are consistently underrepresented. In surveys where this may influence the main research question, data should also be collected with other methods reaching the oldest patients.

    Emneord
    patient survey, pharmacy, selection bias, drug utilization, self-report, pharmacoepidemiology
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-219194 (URN)10.1002/pds.3488 (DOI)000329999100003 ()
    Tilgjengelig fra: 2014-02-25 Laget: 2014-02-24 Sist oppdatert: 2018-01-19bibliografisk kontrollert
    2. Exploring community pharmacists' experiences of surveying patients for drug utilization research purposes
    Åpne denne publikasjonen i ny fane eller vindu >>Exploring community pharmacists' experiences of surveying patients for drug utilization research purposes
    2015 (engelsk)Inngår i: International Journal of Clinical Pharmacy, ISSN 2210-7703, E-ISSN 2210-7711, Vol. 37, nr 3, s. 522-528Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background Patient self-reported data are important in drug utilization research, but often logistically difficult to collect. During 2006-2012, 72 Swedish community pharmacies regularly collected such data through structured survey interviews at the pharmacy counter, performed by the dispensing pharmacists. This study is part of a validation of that data acquisition method. Objectives (1) To explore the experiences of the pharmacists involved, (2) to explore a random or systematic exclusion of eligible patients by the pharmacists, and (3) to find areas of improvement to the applied method of surveying. Setting 72 Swedish community pharmacies, distributed all over the country. Method (a) A questionnaire was distributed to approximately 400 dispensing pharmacists at the pharmacies conducting the patient surveys; (b) semi-structured telephone interviews conducted with 19 pharmacists at 12 of the pharmacies. Main outcome measure Proportions of pharmacists reporting positive and negative experiences of structured survey interviews, the nature of their experiences, proportion of pharmacists reporting to avoid survey interviews and reasons for doing so, and suggested areas of improvement. Results A total of 126 pharmacists (32 %) completed the questionnaire. A majority (82 %) reported positive experiences of interviewing. In addition to the data generated as the primary goal of surveying, secondary benefits such as an improved patient-pharmacist dialogue and an increased detection and resolution of drug related problems were reported. However, a majority (63 %) of the pharmacists also reported negative experiences related to a perceived lack of time to fulfil one's professional obligations. Almost half of the pharmacists (44 %) in the survey admitted that they occasionally avoided interviewing eligible patients, due to the immediate increase in work load. The limited availability of staff resources was the most apparent area of improvement. Conclusion Under certain conditions, community pharmacies are feasible as a setting for conducting patient surveys in drug utilization research, and dispensing pharmacists suitable for conducting them. When regular dispensing staff perform the survey interviews as a part of the drug dispensing process, additional resources to manage the immediate increase in work load have to be considered. Otherwise, data quality may be compromised.

    Emneord
    Community pharmacy, Interview, Pharmacist, Survey, Sweden
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-252961 (URN)10.1007/s11096-015-0088-1 (DOI)000353472100016 ()25736386 (PubMedID)
    Tilgjengelig fra: 2015-05-20 Laget: 2015-05-18 Sist oppdatert: 2018-01-19bibliografisk kontrollert
    3. Utilisation of prescription and over-the-counter triptans: a cross-sectional study in Stockholm, Sweden
    Åpne denne publikasjonen i ny fane eller vindu >>Utilisation of prescription and over-the-counter triptans: a cross-sectional study in Stockholm, Sweden
    Vise andre…
    2016 (engelsk)Inngår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 72, nr 6, s. 747-754Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Triptans are widely used in acute migraine, and in some countries, they are also available over-the-counter (OTC). In Sweden, sales have increased for both prescription and OTC triptans. This study aimed to describe current prescribing and utilisation patterns of prescription and OTC triptans in Stockholm, Sweden. Register data from 4759 patients dispensed triptans in 2014 were used to study documented diagnosis of migraine, concomitant acute and preventive treatment for migraine, and contraindications. Survey data from 49 patients purchasing OTC triptans in three pharmacies were used to capture physician-diagnosed migraine, concomitant acute and preventive treatment for migraine, a behaviour of combining or alternating between prescription and OTC triptans, and pharmacy counselling rates. Among the prescription triptan users, 52 % had a recorded diagnosis of migraine, 48 % had no other acute treatment, preventive treatment was rare (12 %) and contraindications were found in 2 % of the patients. Among the OTC triptan users, the majority (63 %) had been diagnosed by a physician and had a history of prescription triptan use, but combining or alternating between OTC and prescription triptans was rare. Concomitant acute treatment was reported in 53 % and preventive treatment was rare (4 %), despite high self-reported migraine frequencies. Some off-label use was detected, despite moderate to high counselling rates. Triptans are prescribed with attention to safety but with poor recording of migraine diagnosis. OTC triptan users generally have a history of prescription triptan use. Preventive treatment rates are low in both groups. Strategies to discern patients who need other treatment options should be considered.

    Emneord
    Triptans, Over-the-counter, OTC, Drug utilisation, Prescription, Survey
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-298065 (URN)10.1007/s00228-016-2028-y (DOI)000376245600014 ()26922586 (PubMedID)
    Tilgjengelig fra: 2016-06-30 Laget: 2016-06-29 Sist oppdatert: 2018-01-19bibliografisk kontrollert
    4. Competence, competition and collaboration: Perceived challenges among Swedish community pharmacists engaging in pharmaceutical services research
    Åpne denne publikasjonen i ny fane eller vindu >>Competence, competition and collaboration: Perceived challenges among Swedish community pharmacists engaging in pharmaceutical services research
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    community pharmacy, Sweden, cognitive pharmaceutical services, research, patient-centered care
    HSV kategori
    Forskningsprogram
    Farmaceutisk vetenskap; Samhällsfarmaci
    Identifikatorer
    urn:nbn:se:uu:diva-338726 (URN)
    Tilgjengelig fra: 2018-01-12 Laget: 2018-01-12 Sist oppdatert: 2018-01-19
  • Disputas: 2018-03-12 09:00 B/A1:111a, Uppsala
    van der Schot, Gijs
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär biofysik.
    Imaging Living Cells with an X-ray Laser2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Imaging living cells at a resolution higher than the resolution of optical microscopy is a significant challenge. Fluorescence microscopy can achieve a degree of super-resolution via labeling cellular components with a fluorescent dye. Reaching nanometer or sub-nanometer resolution requires high-energy radiation with significantly shorter wavelength than that of optical light. X-rays and electrons have the requisite wavelengths and could be suitable for such studies; however, these probes also cause significant radiation damage. A dose in excess of 100,000,000 Gray (Gy, J/kg) would be required to reach nanometer resolution on a cell, and no cell can survive this amount of radiation. As a consequence, much of what we know about cells at high resolution today comes from dead material.

    Theory predicts that an ultra-short and extremely bright coherent X-ray pulse from an X-ray free-electron laser can outrun key damage processes to deliver a molecular-level snapshot of a cell that is alive at the time of image formation. The principle of ‘diffraction before destruction’ exploits the difference between the speed of light (the X-ray pulse) and the much slower speed of damage formation. The femtosecond pulse ‘freezes’ motion in the cell at physiological temperatures on the time scale of atomic vibrations, offering unprecedented time resolution and a plethora of new experimental possibilities.

    This thesis describes the first test experiments on imaging living cells with an X-ray laser. I present results in three essential areas of live cell imaging. (i) We have used an aerosol injector to introduce live cyanobacteria into the X-ray focus, and recorded diffraction patterns with extremely low background at very high hit rates. (ii) We demonstrated scattered signal beyond 4 nm resolution in some of these experiments. (iii) The thesis also describes image reconstruction, using a new fully automated pipeline that I developed during my studies. The reconstruction of diffraction patterns was successful for all patterns that did not have saturated pixels. The new software suite, called RedFlamingo, selects exposures with desired properties, can sort them according to sample size, shape, orientation, exposure, the number and type of objects in the beam during the exposure, their distance from each other, and so forth. The software includes validation tools to assess the quality of the reconstructions.

    Delarbeid
    1. Imaging single cells in a beam of live cyanobacteria with an X-ray laser
    Åpne denne publikasjonen i ny fane eller vindu >>Imaging single cells in a beam of live cyanobacteria with an X-ray laser
    Vise andre…
    2015 (engelsk)Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikkel-id 5704Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    There exists a conspicuous gap of knowledge about the organization of life at mesoscopic levels. Ultra-fast coherent diffractive imaging with X-ray free-electron lasers can probe structures at the relevant length scales and may reach sub-nanometer resolution on micron-sized living cells. Here we show that we can introduce a beam of aerosolised cyanobacteria into the focus of the Linac Coherent Light Source and record diffraction patterns from individual living cells at very low noise levels and at high hit ratios. We obtain two-dimensional projection images directly from the diffraction patterns, and present the results as synthetic X-ray Nomarski images calculated from the complex-valued reconstructions. We further demonstrate that it is possible to record diffraction data to nanometer resolution on live cells with X-ray lasers. Extension to sub-nanometer resolution is within reach, although improvements in pulse parameters and X-ray area detectors will be necessary to unlock this potential.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-245040 (URN)10.1038/ncomms6704 (DOI)000350034400002 ()25669616 (PubMedID)