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1326401.
  • Mörk, Anna-Karin (författare)
  • Improved scientific basis for human health risk assessment factors by toxicokinetic population modeling
  • 2013
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Exposure limits or guidelines are derived to protect humans from adverse effects caused by exposure to chemical substances in the environment or at the workplace. The internal dose of a chemical is determined by toxicokinetic (TK) processes such as uptake, distribution and elimination, and is closely related to the risk of adversity. The internal dose varies among individuals due to differences in age, genetics, physical activity, health status and life-style. Thus, it is important to address population variability for the exposure limits to be protective. TK variability is typically accounted for by the use of a default assessment factor of 3.16. However, the scientific basis of the exposure limits may be improved by replacing the default value with a chemical specific adjustment factor (CSAFHK), derived from experimental data. By doing so, more appropriate exposure limits are achieved, and large costs for society associated with both too high and too low exposure limits may be avoided. Substitution of the default value is often obstructed by the lack of suitable experimental data. In this thesis, this limitation was addressed by the development of a probabilistic framework using physiologically based pharmacokinetic (PBPK) modeling. It was used to derive CSAFHK for four commonly used organic solvents; acetone, toluene, styrene and methyl chloride. PBPK models based on information on anatomical, physiological and biochemical parameters were used to calculate the internal doses following inhalation exposure to the four chemicals. A description of washin-washout in the respiratory tract was evolved for polar solvents such as acetone. Additional information on the model parameters contained in human experimental toxicokinetic data was taken advantage of by Bayesian analysis. Meanwhile, the methodology was explored with respect to prior assumptions. CSAFHK were derived from population distributions of internal dose obtained by Monte Carlo (MC) simulation from distributions of the model parameters. The influence of age and gender on the internal dose was slight. Thus, the factors obtained for all substances were below 2.5. However, the effects of fluctuations in exposure level and workload increased the CSAFHK up to 6.1, indicating that workplace exposure may need specific attention. Given the diverse properties of acetone, toluene, styrene and methyl chloride, the results can probably be generalized to most organic solvents and similar chemicals. The CSAFHK presented in this thesis are derived from extensive information on intraspecies toxicokinetic differences and cover the effects of common toxicokinetic modifiers. Thus, they are well suited to replace the default value. The population framework may be further extended to include other chemicals, as well as additional experimental data on population variability when such becomes available.
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1326402.
  • Mörlin, Birgitta (författare)
  • On the role of nitric oxide in uterine secretion
  • 2004
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Background: Uterine secretion is important in many different aspects of reproduction e.g. sperm transport and survival, fertilization, nourishment of the ovum and implantation. A cholinergic autonomic nervous secretory innervation has been established and modulation of the secretion by prostaglandins and NSAID drugs has been postulated. Nitric oxide has been suggested as a second messenger in neuronal modulated glandular secretion of the seminal vesicle and a similar pattern for nervous induced carbohydrate secretion of the endometrium and cervix was assumed. It has been suggested that an inhibitory nonadrenergic, non-cholinergic neurotransmission is dependent on endogenous formation of NO, and that the NO-effect is mediated via a soluble guanyl cyclase pathway. Nitric oxide has also been suggested to have a significant role in the process of implantation and early pregnancy. Methods: The uterus from guinea-pig was dissected out, everted and the uterine horn and cervix with or without the hypogastric nerve was placed in isolated organ baths. The secretion was measured as the amount of glucose released to the medium. The nitric oxide synthase (NOS) activity was estimated via formation of L-citrulline and histochemically with the nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) nitro blue technique. To identify the isoforms of NOS, a PCR was done. Cervical secretion in women, was measured by collecting cervical mucus before and after oral administration of nitroglycerine and in a control experimental series. Results and conclusions: The glandular cells of the uterine linings of the guinea-pig possess a sympathetic cholinergic secretomotor innervation with a muscarinic receptor. An increase of the secretion was seen after application of carbacholin and nitroglycerine, while a reduction was noted when the NOS-inhibitors were added. It is suggested that glandular nitric oxide production is a prerequisite for the autonomic cholinergic nervous modulation of cervical and endometrial secretion. Stimulation of the hypogastric nerve induced carbohydrate secretion, which was inhibited by the NOSinhibitor L-NAME. This further strengthens the notion that nitric oxide acts as a second messenger in the autonomic nervous modulation of cervical secretion. Administration of a guanyl cyclase inhibitor gave a reduction of secretion and after a guanyl cyclase stimulator an increase of the carbohydrate secretion was recorded. Three isoforms of NOS, eNOS, iNOS and nNOS were identified by PCR. In a cervical secretion study in women, a marked increase was noted after oral administration of nitroglycerine, while no changes were seen during the control experimental series. This is in line with the findings in the guinea-pig experimental model. The results suggest that glandular nitric oxide production is a prerequisite for the autonomic nervous modulation of the endometrial and cervical secretion in the guinea-pig and also in the human female. NO appears to play a role in the uterine secretory function and may be important in the regulation of fertility.
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1326403.
  • Mörner, Andreas (författare)
  • Studies on HIV-2 antibody mediated neutralisation, coreceptor usage and in vivo tropism
  • 2001
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Human immunodeficiency virus type 2 (HIV-2) is the second virus that causes AIDS in humans. It has a genetic identity with HIV-1 of 40-60% and similar genetic organisation and biological properties, but the two viruses are distinguished certain features. HIV-2's geographical spread is mainly restricted to West Africa, the clinical latency period is significantly longer than for HIV-1, it has a reduced heterosexual and vertical transmission rate and lower levels plasma virus are found in infected individuals. The reasons for these differences are largely unknown. The aim of this thesis was to characterise different biological properties of HIV-2. Since induction of broadly neutralising antibodies is a desirable feature of a future HIV-2 vaccine, knowledge of neutralising epitopes in the HIV-2 envelope proteins is important. By peptide immunisation of guinea pigs, the central and C-terminal part of the V3 region of HIV2 gp125 was confirmed to be an important target for neutralising antibodies. However, subtle changes in the sequence and length of peptides resulted in major differences in the ability to elicit HIV-2 neutralising antibodies. The conserved F-315, H-316, W-329 and C-330 amino acid residues were suggested to participate in a conformational neutralising epitope. Production of recombinant human antibody Fab fragments by combinatorial library/phage display was shown to be a suitable method to obtain anti-HIV-2 antibodies with neutralising capacity. Six Fabs that neutralised the homologous strain SBL6669 were obtained, of which one also neutralised a heterologous virus isolate. The tropism of HIV is largely determined by the coreceptor usage of the virus. Primary HIV-2 isolates were shown to frequently use CCR5, but were often promiscuous in coreceptor usage. Broadening of coreceptor usage was not associated with disease progression. CXCR4 usage was observed for some isolates recovered from patients with advanced disease, and appeared to correlate with positively charged amino acid residues at positions 314 andlor 313 in the V3 loop. Low level BOB expression in MT-2 cells coupled with promiscuous coreceptor usage among HIV-2 isolates was suggested to account for difficulties in clearly distinguishing distinct phenotypic groups in MT-2 cells. CCR5 or CXCR4 were shown to be required for efficient infection of PBMC by primary HIV-2 isolates in vitro. However, inefficient CCR5 and CXCR4 independent infection of PBMC was observed for the majority of isolates tested. Productive HIV-2 infection in the brain was shown to be restricted to macrophages or microglia. Thus, the broad coreceptor usage and relative CD4 independence of HIV-2 in vitro appears to have little influence on the in vivo tropism, at least in the brain compartment. Other factors are therefore suggested to account for the higher frequency of encephalopathy observed in HIV-2 than in HIV-1 infection.
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1326404.
  • Mörner, Malin (författare)
  • Anaemia, blood loss and colorectal cancer
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Introduction: Colorectal cancer (CRC) is the fourth most common cancer worldwide and strikes both sexes. The age-adjusted 5-year survival in Sweden was 60% in the early 21 st century. Approximately 50% of patients are anaemic at the time of diagnosis. Many patients need blood transfusion due to anaemia or surgical blood-loss. Blood transfusions administered to patients with CRC have been associated with an increase in the risk for cancer recurrence, independent of tumour stage. One long-term complication to abdominal surgery is small bowel obstruction (SBO) necessitating further surgery. Hypotheses: • Anaemia prior to surgery and perioperative red blood cell transfusion increase overall mortality and risk of recurrence in patients after curative resections for CRC. • Blood-loss in surgery for colon cancer impairs overall survival. • The amount of blood lost at index surgery for colon cancer increases the risk of future surgery for SBO due to adhesions. • Major blood loss during surgery for rectal cancer increases the risk for SBO due to adhesions or tumour recurrence and reduces overall survival. Materials and methods: All studies are retrospective cohort studies of prospectively collected data. All patients who had abdominal resection for CRC stage I-III at Karolinska University hospital from 2007 to 2010 were included in the study considering the effects of anaemia and blood transfusion. Information was retrieved from the Swedish Colorectal Cancer Registry and linked to information on transfusion and laboratory data on haemoglobin. Patient records were validated for recurrent disease. The studies on blood loss are based on all patients with CRC in the Uppsala-Örebro region 1997 to 2003. Data from the Swedish Rectal and Regional Colon Cancer Registries were linked to information on hospital admissions for SBO and abdominal pain. Patient charts for those undergoing surgery for diagnoses congruent with SBO were validated for cause of SBO. Statistics were calculated using non-parametric methods, logistic regression, and Cox Proportional Hazards regression analyses. Results: Anaemia prior to surgery for CRC increased the risk of overall mortality (HR 2.2; 95% CI: 1.4-3.3). The analyses also revealed a trend towards an association between preoperative anaemia and recurrence (HR 1.6; 95% CI: 0.99-2.6). No association between perioperative blood transfusion and risk of recurrence or overall mortality was found. Blood loss ≥ median (250 ml) impaired overall survival (HR 1.1; 95% CI: 1.0-1.2) after surgery for colon cancer. There was no association between blood loss and survival for the rectal cancer patients. A blood loss ≥ median for patients with colon cancer (250 ml) increased the risk of future surgery for SBO caused by tumour recurrence (HR 2.2; 95% CI: 1.1-4.3). The same was found for patients with rectal cancers who had blood loss ≥ median 800 ml (HR 10.5; 95% CI: 1.4-81.5). There was no increased risk for surgery for SBO caused by adhesions for colon or rectal cancer patients. Conclusions: Anaemia prior to surgery for CRC is a predictive factor for mortality and a trend was seen towards an association with recurrence. Additional effort should be given to study this topic. No association was established between a perioperative blood transfusion and future risk of recurrence or mortality. Blood loss at surgery for CRC should be kept to a minimum to decrease mortality in patients with colon cancer and reduce future risk for SBO due to tumour recurrence.
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1326405.
  • Mörner-Svalling, Ann-Catherine (författare)
  • Digital intraoral radiography : determination of technical properties and application evaluations
  • 2002
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Digital registration of intraoral radiographs was introduced about 1990. One of the first systems on the market was the Sens-A-Ray (Regain Medical Systems AB, Sundsvall, Sweden). At the time of the introduction, it was deemed important to determine basic technical properties for this system. Methods to determine such properties for digital systems did not exist and were developed as the scientific investigations progressed. The technical properties first determined for the Sens-A-Ray were the Dose response function, the resolution defined as the Line Spread Function (LSF) and as the Modulation Transfer Function (MTF), the Dark current and the Signal-to-noise ratio (SNR). In a further study the noise characteristics were calculated as the Noise Power Spectrum (NPS) and as the Noise Equivalent Quanta (NEQ) From this last parameter the efficiency of the system to detect incident photons was calculated, the Detective Quantum Efficiency (DQE). Employing the methods developed for determining the LSF and MTF for the Sens-A-Ray system, these parameters were also determined for three other systems, the RVG (Throphy Radiologie, Paris, France), the VIXA/Visualix (Gendex, Des Plaines, Ill., USA) and the Flash Denta (Villa Sistemi Medicale srd, Buccinasco, Italy). At the introduction of digital intraoral systems, the display function was linear on computer monitors, which means that grey level values were directly converted to light intensity levels. Dentists used to viewing conventional film radiographs found the digital images not "film-like", which is due to the contrast properties of digital images. In order to investigate the subjective preference of the display of digital images a study was performed, which showed that a curved display function was preferred. An analysis of the function preferred by the viewers showed that this function de facto made the digital images more "film-like". In this connection, an important fact turned out to be that the curved display function approximately compensates for the exponential attenuation of x-rays, as radiographs are exposed. The consequence of this compensation is, that equal steps in object thickness are shown with approximately equal steps in light intensity on a computer monitor. When new image registration systems are introduced, it is important also to test applications in addition to technical parameters. In this dissertation, the Sens-A-Ray system was employed in a longitudinal study of bone inflammation in rats. The inflammation was introduced by intravenous injection of Staphylococcus aureus Periodical identical radiographs were exposed. The results show several advantages of digital radiographic techniques in animal studies. Implant therapy has become a standard method to replace lost teeth. A literature search could find no study comparing digital and conventional techniques in assessing implants, and thus such a study was deemed important. The study shows that the diagnostic yield using digital techniques was fully comparable to conventional film techniques, and showed a tendency to better results. The determination of technical parameters as well as the evaluations of applications show that digital techniques have such properties that conventional film techniques can suitably be replaced.
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1326406.
  • Mörtberg, Anders, 1986, et al. (författare)
  • A Refinement-Based Approach to Computational Algebra in Coq
  • 2012
  • Ingår i: Lennart Beringer, Amy P. Felty (Eds.): Interactive Theorem Proving - Third International Conference, ITP 2012, Princeton, NJ, USA, August 13-15, 2012. Proceedings. Lecture Notes in Computer Science. - 9783642323461 ; 2012:7406, s. 83-98
  • Konferensbidrag (refereegranskat)abstract
    • We describe a step-by-step approach to the implementation and formal verification of efficient algebraic algorithms. Formal specifications are expressed on rich data types which are suitable for deriving essential theoretical properties. These specifications are then refined to concrete implementations on more efficient data structures and linked to their abstract counterparts. We illustrate this methodology on key applications: matrix rank computation, Winograd’s fast matrix product, Karatsuba’s polynomial multiplication, and the gcd of multivariate polynomials.
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1326407.
  • Mörtberg, Anders, 1986 (författare)
  • Constructive Algebra in Type Theory
  • 2012
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • This thesis contains four papers aiming at bridging the gap between algorithms implemented in computer algebra systems and interactive proof assistants. This is done by implementing and verifying efficient algorithms using the Coq proof assistant together with the SSReflect extension. First there is a methodology, based on refinements, for linking implementations of algorithms using rich dependent types to implementations on low-level data types. The first implementation is suitable for deriving theoretical properties while the second one is suited for computation. This methodology is illustrated on four key applications: matrix rank computation, Winograd’s fast matrix product, Karatsuba’s polynomial multiplication and the computation of the greatest common divisor of multivariate polynomials. The method has also been applied for verifying an implementation of the Sasaki-Murao algorithm for computing the determinant of a square matrix over a commutative ring in polynomial time. This algorithm can be written as a short and simple functional program, but its correctness involves nontrivial mathematics. The correctness proof, which is new, has been formalized in Coq. Next the formalization of the notion of (strongly discrete) coherent rings is described. This is a fundamental structure in constructive algebra which represents rings in which it is possible to solve (in)homogeneous systems of equations. Instances of this structure are Bézout domains (for instance Z and k[x] where k is a field) and Prüfer domains (a generalization of Dedekind domains). We obtain formally verified algorithms for solving systems of equations that are applicable on these structures. Finally the approach of the first paper is applied to develop algorithms for computing homology groups of simplicial complexes obtained from digital images. This give a formally verified program for counting the number of connected components and holes in digital images. We apply this to count the number of neurons in pictures obtained from synaptical structures.
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1326408.
  • Mörtberg, Anders, 1986 (författare)
  • Formalizing Refinements and Constructive Algebra in Type Theory
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The extensive use of computers in mathematics and engineering has led to an increased demand for reliability in the implementation of algorithms in computer algebra systems. One way to increase the reliability is to formally verify that the implementations satisfy the mathematical theorems stating their specification. By implementing and specifying algorithms from computer algebra inside a proof assistant both the reliability of the implementation and the computational capabilities of the proof assistant can be increased. This first part of the thesis presents a framework, developed in the interactive theorem prover Coq, for conveniently implementing and reasoning about program and data refinements. In this framework programs defined on rich dependent types suitable for proofs are linked to optimized implementations on simple types suitable for computation. The correctness of the optimized algorithms is established on the proof-oriented types and then automatically transported to the computation-oriented types. This method has been applied to develop a library containing multiple algorithms from computational algebra, including: Karatsuba's polynomial multiplication, Strassen's matrix multiplication and the Sasaki-Murao algorithm for computing the characteristic polynomial of matrices over commutative rings. The second part of the thesis presents the formalization of notions from constructive algebra. Focus is on the theory of coherent and strongly discrete rings, which provides a general setting for developing linear algebra over rings instead of fields. Examples of such rings include Bézout domains, Prüfer domains and elementary divisor rings. Finitely presented modules over these rings are implemented using an abstraction layer on top of matrices. This enables us to constructively prove that the category of these modules form a suitable setting for developing homological algebra. We further show that any finitely presented module over an elementary divisor ring can be decomposed to a direct sum of a free module and cyclic modules in a unique way. This decomposition gives a decision procedure for testing if two finitely presented modules are isomorphic.
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1326409.
  • Mörtberg, Anders, 1986, et al. (författare)
  • Towards a Certified Computation of Homology Groups for Digital Images
  • 2012
  • Ingår i: Massimo Ferri, Patrizio Frosini, Claudia Landi, Andrea Cerri, Barbara Di Fabio (Eds.): Computational Topology in Image Context - 4th International Workshop, CTIC 2012, Bertinoro, Italy, May 28-30, 2012. Proceedings. Lecture Notes in Computer Science. - 9783642302374 ; 2012:7309, s. 49-57
  • Konferensbidrag (refereegranskat)abstract
    • In this paper we report on a project to obtain a verified computation of homology groups of digital images. The methodology is based on programming and executing inside the Coq proof assistant. Though more research is needed to integrate and make efficient more processing tools, we present some examples partially computed in Coq from real biomedical images.
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1326410.
  • Mörtberg, Ewa (författare)
  • Treatment of social phobia : development of a method and comparison of treatments
  • 2006
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Social phobia is a common (13 %) and disabling anxiety disorder associated with considerable social and occupational handicap. It is not likely to remit without treatment. Although the efficacy of cognitive behavioural and pharmacological interventions are relatively well established there is a need for further development, as many patients remain disabled at the end of treatment. There is still a lack of understanding of the factors involved in incomplete treatment responses. In addition, it is important to examine how treatments actually work in clinical practice. The aims of the present thesis were to examine the effectiveness of an intensive (3 weeks) cognitive behavioural group treatment (CBGT) in a pilot study and in a waiting list controlled study. Taking into account some recent developments in psychological treatment the intensive CBGT was modified (and renamed intensive group cognitive treatment /IGCT/) and compared to individual cognitive therapy (ICT) and treatment as usual (TAU), involving medication, in a randomized controlled study of 100 patients. Finally, a trait-based study of personality patterns before and after treatment was conducted aiming to outline personality characteristics in patients with social phobia, and patterns of change following treatment. The result of the pilot study as well of the waiting list controlled study showed that patients improved significantly after three weeks of treatment, with reduced levels of social phobia related symptoms. The treatment effects were maintained at one year post-treatment. The efficacy of the intensive treatment was further confirmed in the randomized, controlled trial of IGCT, ICT and TAU. ICT was, however, more effective than IGCT and TAU, which showed equal efficacy. The personality patterns of patients were characterised by pronounced levels of harm avoidance and character traits associated with personality disorders. Dysfunctional traits were changed following treatments: however, non-responders still exhibited high levels of harm avoidance. To conclude, brief intensive group treatment is a feasible and effective option in the treatment of social phobia in routine psychiatric practice. It works fast and shows maintained or improved effects at one year post-treatment. IGCT, ICT and TAU are all effective and enduring treatments for social phobia. However, ICT is superior to IGCT and TAU. The 3-week IGCT seems to be more accepted and is as effective as the 12-month medication focused TAU. Pronounced harm avoidance is a general vulnerability trait in patients with social phobia and may be a general predictor of poor treatment response. Further studies are needed for additional understanding of factors contributing to incomplete treatments responses.
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