| 1. |
- Gunnarsson, David, 1975-
(författare)
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Reproductive toxicology of endocrine disruptors : effects of cadmium, phthalates and phytoestrogens on testicular steroidogenesis
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A number of investigations during the last two decades describe adverse trends in male reproductive health, which have been proposed to be caused by environmental factors with endocrine disrupting properties. In contrast to many other toxicants, endocrine disruptors often do not show linear dose-response relationships typical of those found in traditional toxicological studies. For many compounds, low-dose exposure causes effects opposite to the ones seen after high-dose exposure. In addition, the timing of exposure has been found to be critical. Hence, to correctly assess the impact of endocrine disruptors on reproductive health requires in-depth knowledge of their mechanisms of action. This thesis aimed at identifying the mechanisms underlying the effects of cadmium (Cd), phthalates and phytoestrogens on testicular steroidogenesis. For this purpose, in vitro as well as in vivo models were used. Cd was found to inhibit testosterone synthesis in vivo by down-regulating LH receptor gene expression and reducing the testicular levels of cAMP and StAR protein. In addition, Cd caused a pronounced increase in testicular prostaglandin F2ɑ (PGF2ɑ), suggesting that Cd exerts its suppressive effect on steroidogenesis also by inducing the inhibitory PKC pathway. Pre-treatment with zinc (Zn) protected completely against Cd-induced effects on testosterone and PGF2ɑ. Furthermore, we observed that Cd exposure increased glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA expression in the testis. GAPDH is a potent coactivator of androgen receptor-mediated transcription and the up-regulation found in our study is probably a compensatory response to reduced testosterone concentrations. This finding is interesting since GAPDH has been proposed to have an important role in the regulation of apoptosis as well as sperm motility. We discovered that mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of the frequently used phthalate di-(2-ethylhexyl) phthalate (DEHP), stimulates Leydig cell steroidogenesis in vitro, by a cAMP- and StAR-independent mechanism. MEHP exposure caused a similar effect in granulosa cells. Gene expression analysis revealed that MEHP is likely to stimulate steroidogenesis by increasing the amount of cholesterol available for steroid synthesis. In the last investigation, we examined the effects of low-dose phytoestrogen exposure on testosterone synthesis during puberty in male goats. Isoflavones present in clover increased plasma concentrations of testosterone and free as well as total triiodothyronine (T3). T3 has previously been shown to induce testosterone synthesis and it is possible that an elevated T3 secretion underlies the increased plasma testosterone levels. Reduced fertility and reproductive tract malformations affect both the individual and the society. Hence, a sound knowledge of reproductive toxicants is of crucial importance. The findings presented in this thesis provide new insights into the reproductive toxicology of endocrine disruptors and may be valuable for risk assessment purposes.
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| 2. |
- Nordberg, Per
(författare)
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Various aspects of treatment in cardiac arrest prior to hospital arrival
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Out-of-hospital cardiac arrest (OHCA) is a major public health issue, affecting almost 300,000 victims per year in Europe, who have an overall survival rate of about 10 per cent. In general, the current Emergency Medical Services (EMS) do not have the capacity to act quickly and effectively enough in regard to this vast group of patients. The objectives of the current work were: to study the importance of bystander cardiopulmonary resuscitation (CPR) from a national perspective; to determine the safety, feasibility and efficacy of trans-nasal evaporative cooling initiated during CPR; to investigate the effects of dual dispatch of fire-fighters and EMS on short- and long-term survival; to explore regional differences in response times and survival rates in relation to dual dispatch of fire-fighters and EMS in cases of OHCA. Methods and results: Study I. Observational study of 34,125 patients. From 1992 to 2005, bystander CPR significantly increased, especially when performed by laypersons, in witnessed (40% to 55%, p<0.0001) and unwitnessed (22% to 44%, p<0.0001) OHCA. Bystander CPR was associated with higher ventricular fibrillation (VF) rates (adjusted OR 1.73, 95% CI 1.62–1.86) and improved 30-day survival (adj. OR 2.20, 95% CI 1.68–2.90). Study II. Randomised trial concerning 200 cases of witnessed OHCA. Trans-nasal evaporative cooling was feasible in pre-hospital arrests. Eighteen device-related adverse events were reported, where one case of epistaxis was defined as serious. Time to target temperature of 34°C was shorter in the treatment group for both tympanic (102 vs. 282 minutes, p=0.03) and core (155 vs. 284 minutes, p=0.13) temperature. Study III. Intervention study (trained fire-fighters dispatched in cases of OHCA) using historical controls. When dispatched, fire-fighters were first on the scene and connected an automated external defibrillator (AED) in 41% of the cases. Thirty-day survival improved from 3.9% (control) to 7.6 % (intervention) (p=0.001, adjusted OR 2.8, 95% CI 1.6–4.9). Survival to 3 years increased from 2.4% to 6.5% respectively (p<0.001, adjusted OR 3.8, 95% CI 1.9–7.6). Study IV. Intervention study using historical controls, assessing the regional impact of Study III in areas with different population densities. Median response times shortened significantly in all subgroups, ranging from 0.8 (downtown) to 3.2 minutes (rural). The effect on 30-day survival rates varied depending on population density, with the lowest impact in rural areas. Conclusions: Bystander CPR, especially when performed by laypersons, increased in Sweden between 1992 and 2005 and is associated with increased VF and survival rates. Intra-arrest trans-nasal cooling in cases of OHCA is safe and feasible and it shortened the time interval required to cool patients. Implementation of a dual dispatch system (fire-fighters and EMS) in cases of OHCA was associated with increased 30-day- and 3-year survival. Shortened response times were seen in sparsely as well as in highly populated regions. The lowest impact of a dual dispatch system on survival was seen in rural areas.
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| 3. |
- Ovrén, Hannes, 1984-
(författare)
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Continuous Models for Cameras and Inertial Sensors
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Using images to reconstruct the world in three dimensions is a classical computer vision task. Some examples of applications where this is useful are autonomous mapping and navigation, urban planning, and special effects in movies. One common approach to 3D reconstruction is ”structure from motion” where a scene is imaged multiple times from different positions, e.g. by moving the camera. However, in a twist of irony, many structure from motion methods work best when the camera is stationary while the image is captured. This is because the motion of the camera can cause distortions in the image that lead to worse image measurements, and thus a worse reconstruction. One such distortion common to all cameras is motion blur, while another is connected to the use of an electronic rolling shutter. Instead of capturing all pixels of the image at once, a camera with a rolling shutter captures the image row by row. If the camera is moving while the image is captured the rolling shutter causes non-rigid distortions in the image that, unless handled, can severely impact the reconstruction quality.This thesis studies methods to robustly perform 3D reconstruction in the case of a moving camera. To do so, the proposed methods make use of an inertial measurement unit (IMU). The IMU measures the angular velocities and linear accelerations of the camera, and these can be used to estimate the trajectory of the camera over time. Knowledge of the camera motion can then be used to correct for the distortions caused by the rolling shutter. Another benefit of an IMU is that it can provide measurements also in situations when a camera can not, e.g. because of excessive motion blur, or absence of scene structure.To use a camera together with an IMU, the camera-IMU system must be jointly calibrated. The relationship between their respective coordinate frames need to be established, and their timings need to be synchronized. This thesis shows how to automatically perform this calibration and synchronization, without requiring e.g. calibration objects or special motion patterns.In standard structure from motion, the camera trajectory is modeled as discrete poses, with one pose per image. Switching instead to a formulation with a continuous-time camera trajectory provides a natural way to handle rolling shutter distortions, and also to incorporate inertial measurements. To model the continuous-time trajectory, many authors have used splines. The ability for a spline-based trajectory to model the real motion depends on the density of its spline knots. Choosing a too smooth spline results in approximation errors. This thesis proposes a method to estimate the spline approximation error, and use it to better balance camera and IMU measurements, when used in a sensor fusion framework. Also proposed is a way to automatically decide how dense the spline needs to be to achieve a good reconstruction.Another approach to reconstruct a 3D scene is to use a camera that directly measures depth. Some depth cameras, like the well-known Microsoft Kinect, are susceptible to the same rolling shutter effects as normal cameras. This thesis quantifies the effect of the rolling shutter distortion on 3D reconstruction, depending on the amount of motion. It is also shown that a better 3D model is obtained if the depth images are corrected using inertial measurements.
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| 4. |
- Persson, Mikael, 1985-
(författare)
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Visual Odometryin Principle and Practice
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Vision is the primary means by which we know where we are, what is nearby, and how we are moving. The corresponding computer-vision task is the simultaneous mapping of the surroundings and the localization of the camera. This goes by many names of which this thesis uses Visual Odometry. This name implies the images are sequential and emphasizes the accuracy of the pose and the real time requirements. This field has seen substantial improvements over the past decade and visual odometry is used extensively in robotics for localization, navigation and obstacle detection. The main purpose of this thesis is the study and advancement of visual odometry systems, and makes several contributions. The first of which is a high performance stereo visual odometry system, which through geometrically supported tracking achieved top rank on the KITTI odometry benchmark. The second is the state-of-the-art perspective three point solver. Such solvers find the pose of a camera given the projections of three known 3d points and are a core part of many visual odometry systems. By reformulating the underlying problem we avoided a problematic quartic polynomial. As a result we achieved substantially higher computational performance and numerical accuracy. The third is a system which generalizes stereo visual odometry to the simultaneous estimation of multiple independently moving objects. The main contribution is a real time system which allows the identification of generic moving rigid objects and the prediction of their trajectories in real time, with applications to robotic navigation in in dynamic environments. The fourth is an improved spline type continuous pose trajectory estimation framework, which simplifies the integration of general dynamic models. The framework is used to show that visual odometry systems based on continuous pose trajectories are both practical and can operate in real time. The visual odometry pipeline is considered from both a theoretical and a practical perspective. The systems described have been tested both on benchmarks and real vehicles. This thesis places the published work into context, highlighting key insights and practical observations.
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| 5. |
- Wode, Kathrin, 1968-
(författare)
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Complementary and alternative medicine in cancer : from utilization to a randomized controlled trial
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Complementary and alternative medicine (CAM) are non-conventional health care approaches used in parallel with or instead of conventional medicine. Little is known about Swedish patients’ patterns of complementary CAM use in the context of cancer. Patient-provider communication concerning CAM is crucial and research about communication in situations when patients decline recommended cancer treatment and consider CAM as an alternative is scarce. One commonly used CAM approach is an herbal medicinal product from mistletoe. An open-label trial on mistletoe extract for patients with advanced pancreatic cancer reported promising results on overall survival and quality of life. Due to limited treatment options for this group of patients, this approach needs to be investigated further. Aim: The overall aim of this thesis is to explore CAM use from patients’ and physicians’ perspectives and to design a placebo-controlled randomized clinical trial to assess mistletoe extract as a complement to standard treatment in patients with advanced pancreatic cancer. Methods: A cross-sectional design with quantitative and qualitative mixed methods was used in Study I including 755 patients with solid tumors. In Study II a qualitative design with face-to-face interviews with seven patients with cancer and ten physicians from cancer care was used. In Study III, a study protocol for a multicenter, parallel group, double-blind, randomized, placebo-controlled clinical trial (RCT) was developed. Mixed methods were used by two nested ancillary studies on sub-sets of participants with a translational and a qualitative design respectively. Patients with advanced pancreatic cancer (n=290) were included; mistletoe extract/placebo was added to treatment of choice for the duration of nine months. The trial is currently being conducted. Results: One of four patients with solid tumors used CAM parallel with conventional treatment. Main reasons motivations were the hope for improvement of physical, general, and emotional wellbeing and the body’s ability to fight cancer. Satisfaction with CAM usage was generally high; reported adverse effects few and mild. One third had discussed their CAM use with cancer care providers. More than half of the patients thought that cancer care providers should be able to discuss and/or consider use of CAM modalities in cancer care. Patients declining conventional cancer treatment while using CAM had a variety of reasons for their choices: many of them valued CAM for a broader perspective on health and illness in the context of mind, body and spirit. The wish to take an active stance in relation to treatment decisions and previous negative experiences from conventional care were also cited as motives. Some patients felt a lack of respect for their choices and indicated lack of knowledge and interest on their physicians’ part. Some physicians felt a need for better expertise in CAM while others did not. Patients’ choice to decline cancer treatment was an ethical dilemma to most of the interviewed physicians. Even though communication in these situations tended to push some patients and physicians to take an extreme position, both parties wished for an open dialogue with mutual trust and understanding.The study protocol of Study III was designed and published according to the Standard Protocol Items for Clinical Trials (SPIRIT) guidelines. The trial started inclusion in 2016 and has been running at nine participating oncological departments. Inclusion was completed in December 2021 and expected end-of-study is September 2022. Thirty-one interviews have been conducted within the ancillary qualitative study and 100 patients were included in the biomarker study.Conclusions: Many patients with cancer use CAM, mainly as a complement to conventional treatment to improve wellbeing. Most have realistic expectations, express high satisfaction and awareness of side effects. In rare cases, patients decline conventional cancer treatment and use CAM as an alternative for complex reasons that are worthwhile to explore in concrete situations. Patients generally wish to stay in contact with cancer care but demand interest in and respect for their choices. The majority of CAM-using patients perceive a lack of knowledge about CAM among cancer care providers and do often not reveal their CAM use; however, patients want providers to be knowledgeable and able to give advice. Shared decision-making appears extra difficult in the clinically demanding situations when patients’ and physicians’ views on treatment choices profoundly diverge. Knowledge about CAM and competency in giving nuanced advice to interested patients seem crucial for an initiated patient-provider dialogue for safety reasons, patient satisfaction and mutual trust. Both design and conduct of the RCT are an example of research filling an identified gap of knowledge and will provide cancer care with much-needed information. The design and conduct of this trial as well as its future results may serve as a model for CAM knowledge capacity building. Evidence-based medicine is the practice of integrating individual clinical expertise and patient values with the best available external clinical evidence from systematic research. This thesis pays attention to patients’ values, builds professional competency and experience within CAM and acknowledges and contributes to systematic research.
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