| 31. |
- Blomstedt, Patric, 1972-
(författare)
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Analysis of deep brain stimulation and ablative lesions in surgical treatment of movement disorders : with emphasis on safety aspects
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background The last decade has witnessed a renaissance of functional stereotactic neurosurgery in the treatment of patients with movement disorders, especially advanced Parkinson’s disease (PD), essential tremor (ET) and dystonia. Ablative lesions such as thalamotomy and pallidotomy have been gradually replaced by the technique of chronic deep brain stimulation (DBS) applied to targets in the basal ganglia and thalamus, and assumed to be more lenient to the brain than stereotactic radiofrequency lesions. Since the aim of functional neurosurgery is to alleviate symptoms of these chronic, progressive, non-fatal diseases, and to improve life quality of the patients, it is imperative that the surgical procedures remain safe and do not result in complications mitigating any anticipated positive effect of the surgery on the symptoms of the disease.Aim The aim of this thesis is to evaluate, compare and analyse the safety of various surgical procedures used to treat patients with movement disorders, and to document side effects and complications both peri operatively and in a long term follow-up. Further to compare the effects of pallidotomy and pallidal DBS, and to evaluate the longterm efficacy of Vim-DBS.Method 256 consecutive surgical procedures, 129 DBS and 127 stereotactic lesions, were reviewed with respect to complications in 197 treated patients. In a series of 119 patients operated on with DBS during a 10 year period, the occurrence of hardware related complications (infection, breakage, erosion etc) was documented and analysed. Additionally, the interference of external magnetic field with the stimulation was documented. In one patient operated on with subthalamic nucleus DBS, a highly unusual and unexpected psychiatric side effect was carefully analysed. In 5 patients operated on with both methods (lesion and DBS) on each hemisphere, respectively, the effect and side effects of each method were compared. The long term effect and side effects of thalamic DBS was analysed in a series of patients with ET followed for 7 years.Results There were no deaths and few severe neurological complications in this material. Unilateral ablative lesions in the pallidum were well tolerated by patients with advanced PD, while for tremor, thalamic DBS was much safer than thalamotomy, even if its effect on certain aspects of tremor could show some decrease of efficacy over time. Some of the side effects of lesioning are transient while most but not all side effects of DBS are reversible. Hardware-related complications were not uncommon especially in the early “learning curve” period, and the DBS technique, being a life-long therapy, will necessitate a life long follow up of patients. Provided safety protocols are followed and provided patient’s and carer’s education and awareness, external electromagnetic interference should not constitute a risk for patients with DBS. PD patients undergoing STN DBS should be carefully selected to avoid psychiatric or cognitive side effects, due to this brain target´s proximity to, and involvment in, non-motor associative and limbic circuitry.Conclusions In terms of mortality and morbidity, modern stereotactic neurosurgery for movement disorders, both ablation and DBS, is a safe procedure even in advanced stages of disease. Symptoms of PD, ET and dystonia can be alleviated mainly with DBS and even unilaterally with pallidal lesions, at the expense of, in most cases, minor side-effects.
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| 32. |
- Boldrup, Linda, 1978-
(författare)
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p63 and potential p63 targets in squamous cell carcinoma of the head and neck
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Squamous cell carcinoma of the head and neck (SCCHN), the 6th most common cancer worldwide, has a low 5-year survival. Disease as well as treatment often causes patients severe functional and aesthetic problems. In order to improve treatment and diagnosis at earlier stages of tumour development it is important to learn more about the molecular mechanisms behind the disease. p63, an important regulator of epithelial formation, has been suggested to play a role in the development of SCCHN. Six different isoforms of p63 have been found and shown to have various functions. The aim of the studies in this thesis was to learn more about the role of p63 and proteins connected to p63 in SCCHN. Expression of p63, Cox-2, EGFR, beta-catenin, PP2A and p53 isoforms was mapped in tumours and normal tumour adjacent tissue from patients with SCCHN using western blot or RT-PCR. Results showed no significant difference between tumours and normal tumour adjacent tissue concerning expression of EGFR and beta-catenin. Cox-2 and PP2A showed significantly higher expression in tumours while p63 was more expressed in normal tumour adjacent tissue. However, expression of all these proteins in normal tumour adjacent tissue differed from tissue from disease-free non-smoking individuals. Smoking in itself did not affect expression of these proteins. The p53 isoforms p53, p53beta, p53gamma, ∆133p53, ∆133p53beta and ∆133p53gamma were expressed at RNA level in samples both from tumours and normal tumour adjacent tissue, though most of them at fairly low levels. The functional properties of the different p63 isoforms have not been fully mapped. By establishing stable cell lines over-expressing the different p63 isoforms we investigated their specific effect on tumour cells from SCCHN. Only the ∆Np63 isoforms could be stably over-expressed, whereas no clones over-expressing TAp63 could be established. Using microarray technique, cell lines stably expressing the ∆Np63 isoforms were studied and CD44, Keratins 4, 6, 14, 19 and Cox-2 were found to be regulated by p63. In conclusion, the present project adds new data to the field of p63 and SCCHN. For example, we have shown that clinically normal tumour adjacent tissue is altered compared to normal oral mucosa in non tumour patients, and that smoking does not change expression of p63, Cox-2, EGFR, beta-catenin or PP2A in oral mucosa. Novel p53 isoforms are expressed in SCCHN, and even though levels are very low they should not be overlooked. Furthermore, CD44, keratins 4, 6, 14, 19 and Cox-2 were identified as p63 targets in SCCHN.
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| 33. |
- Boson, Jonas, 1976-
(författare)
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Improving accuracy of in situ gamma-ray spectrometry
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gamma-ray spectrometry measurements performed on site, or “in situ”, is a widely used and powerful method that can be employed both to identify and quantify ground deposited radionuclides. The purpose of this thesis is to improve the calibration of high purity germanium (HPGe) detectors for in situ measurements, and calculate the combined uncertainty and potential systematic effects. An improved semi-empirical calibration method is presented, based on a novel expression for the intrinsic detector efficiency that includes both the energy and angular response of the detector. A three-layer model for the description of the depth distribution of the radionuclide and the soil density is proposed. The combined uncertainty of intrinsic detector efficiency calibrations and in situ measurements according to the proposed method was estimated. The uncertainty in the intrinsic detector efficiency was found to be 5.1 and 8.1% (coverage factor k=1, i.e. for a confidence interval of about 68%), for the two detectors calibrated. These numbers were, however, at a later stage reduced to 3.7 and 4.2%, using a revised expression for the intrinsic detector efficiency. For in situ measurements, the combined standard uncertainty was found to be 15-20% (k=1), based on the original expression for the intrinsic detector efficiency. Monte Carlo models of the two detectors were created and Monte Carlo calculated values for intrinsic detector efficiency were compared with experimental data. As a discrepancy was found, a thorough investigation of the detector response was performed. Scanning of the detector surface with a collimated 59.5 keV photon beam revealed the detector response to be highly irregular over the detector surface. It was concluded that the efficiency deficit of the detector could most likely be attributed to an increase in dead layer thickness compared with manufacturer supplied data. The thickness of the dead layer was estimated to be 1.5-1.9 mm, whereas the nominal value was 0.7 mm. Radiographs of the detectors were produced that provided valuable information about the physical dimensions of the germanium crystal, as well as its actual location within the detector housing. The Monte Carlo models were employed to calculate in situ measurement efficiencies for measurements of 137Cs deposition from the Chernobyl fallout. Results from the Monte Carlo simulations were compared both with the semi-empirical method and with soil sample data, and satisfactory agreement was confirmed. It was then proceeded to employ the Monte Carlo model to calculate the effect on in situ measurement results by two influencing parameters: ground curvature and activity in trees. Neither of these parameters was found to influence the result by more than about 25%. This deviation is comparable with the measurement uncertainty, and should not deter from measurements in such terrain.
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| 34. |
- Bosson, Jenny, 1975-
(författare)
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Ozone and diesel exhaust : airway signaling, inflammation and pollutant interactions
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It is well established that air pollution has detrimental effects on both human health as well as the environment. Exposure to ozone and particulate matter pollution, is associated with an increase in cardiopulmonary mortality and morbidity. Asthmatics, elderly and children have been indicated as especially sensitive groups. With a global increase in use of vehicles and industry, ambient air pollution represents a crucial health concern as well as a political, economical and environmental dilemma. Both ozone (O3) and diesel exhaust (DE) trigger oxidative stress and inflammation in the airways, causing symptoms such as wheezing, coughing and reduced lung function. The aim of this thesis was to further examine which pro-inflammatory signaling pathways that are initiated in the airways by ozone, as compared to diesel exhaust. Furthermore, to study the effects of these two ambient air pollutants in a sequential exposure, thus mimicking an urban profile. In order to investigate this in healthy as well as asthmatic subjects, walk-in exposure chambers were utilized and various airway compartments were studied by obtaining induced sputum, endobronchial biopsies, or airway lavage fluids. In asthmatic subjects, exposure to 0.2 ppm of O3 induced an increase in the cytokines IL 5, GM-CSF and ENA-78 in the bronchial epithelium six hours post-exposure. The healthy subjects, however, displayed no elevations of bronchial epithelial cytokine expression in response to the ozone exposure. The heightened levels of neutrophil chemoattractants and Th2 cytokines in the asthmatic airway epithelium may contribute to symptom exacerbations following air pollution exposure. When examining an earlier time point post O3 exposure (1½ hours), healthy subjects exhibited a suppression of IL-8 as well as of the transcription factors NFκB and c-jun in the bronchial epithelium, as opposed to after filtered air exposure. This inhibition of early signal transduction in the bronchial epithelium after O3 differs from the response detected after exposure to DE. Since both O3 and DE are associated with generating airway neutrophilia as well as causing direct oxidative damage, it raises the query of whether daily exposure to these two air pollutants creates a synergistic or additive effect. Induced sputum attained from healthy subjects exposed in sequence to 0.2 ppm of O3 five hours following DE at a PM concentration of 300 µg/m3, demonstrated significantly increased neutrophils, and elevated MPO levels, as compared to the sequential DE and filtered air exposure. O3 and DE interactions were further investigated by analyses of bronchoalveolar lavage and bronchial wash. It was demonstrated that pre-exposure to DE, as compared to filtered air, enhances the O3-induced airway inflammation, in terms of an increase in neutrophil and macrophage numbers in BW and higher EPX expression in BAL. In conclusion, this thesis has aspired to expand the knowledge of O3-induced inflammatory pathways in humans, observing a divergence to the previously described DE initiated responses. Moreover, a potentially adverse airway inflammation augmentation has been revealed after exposure to a relevant ambient combination of these air pollutants. This provides a foundation towards an understanding of the cumulative airway effects when exposed to a combination of ambient air pollutants and may have implications regarding future regulations of exposure limits.
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| 35. |
- Brogårdh, Christina, 1968-
(författare)
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Constraint Induced Movement Therapy : influence of restraint and type of training on performance and on brain plasticity
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Partial paralysis of the hand is one of the main impairments after stroke. Constraint Induced Movement Therapy (CIT) is a new treatment technique that appears to improve upper extremity function after stroke. CIT consists of 6 hours of training/day for the affected arm (mainly with shaping exercises) and of restraint (mitt) of the non affected arm for two weeks. There are concerns about the practicality and resource issues in carrying out CIT according to the original model. In this thesis the benefit of modifications of CIT, of an assessment tool and of two common types of hand training have been evaluated. CIT (n=16) administered in groups for two weeks (paper I) seems to be a feasible alternative to improve upper limb motor function after chronic stroke. The arm/hand motor performance improved significantly on Motor Assessment Scale (MAS; p= 0.003) and on Sollerman hand function test (p= 0.037). The median self reported motor ability (MAL) also improved (p < 0.001). No additional effect was seen from wearing a mitt for an extended period of three months. The reliability of the Sollerman hand function test (paper II) was studied in patients with chronic stroke. Three examiners observed 24 patients at three experimental sessions. There was agreement (kappa ≥ 0.4) between the examiners for 15/20 subtests. Using total sum scores, the agreement within the examiners was higher than 0.96 (for Spearman’s rhos and ICCs) and agreement between the examiners was higher than 0.96 (Spearman’s rhos) and 0.92 (ICCs), respectively. In a cohort of 24 patients with subacute stroke (paper III) forced use therapy (FUT; mitt use and 3 hours of training/day for 2 weeks) improved arm/hand function, but not more than regular arm therapy given to the control group. Significant improvements in arm/hand motor performance were found in the FUT group (n=12) as well as in the control group (n=12) on the Sollerman hand function test (p= 0.001), on MAS (p< 0.05) and on MAL (p < 0.05). No significant differences were seen between the groups pre- or post training or at three months follow up, demonstrating that the mitt had limited importance. In a separate study on 30 healthy subjects (paper IV), employing transcranial magnetic brain stimulation (TMS), we found that shaping exercises but not general activity training increased dexterity (p<0.05; Purdue peg board test) of the trained non dominant hand. After shaping exercises the cortical motor map shifted forwardly into the premotor area but did not expand. After general activity training the cortical motor map expanded significantly (p=0.03) in the posterior (sensory) direction. Shift of location of active TMS positions rather than their numbers might therefore be a critical factor for the interpretation of cortical plasticity. In conclusion, the studies in this thesis have shown that less resource consuming modifications of CIT may be feasible to improve upper limb motor function after stroke. The type and amount of training for the more affected arm seems to be an important factor rather than the mitt use in itself. Shaping exercises, at least in healthy people, are effective in improving dexterity and the Sollerman hand function test reliable to evaluate arm/hand function after stroke.
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| 36. |
- Brunnegård, Karin, 1973-
(författare)
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Evaluation of nasal speech : a study of assessments by speech-language pathologists, untrained listeners and nasometry
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Excessive nasal resonance in speech (hypernasality) is a disorder which may have negative communicative and social consequences for the speaker. Excessive nasal resonance is often associated with cleft lip and palate, velopharyngeal impairment, dysarthria or hearing impairment. Evaluation of hypernasality has proved to be a challenge in the clinic and in research. There are questions regarding the accuracy and reliability of auditory perceptual evaluations of nasal speech, and whether instrumental measures can be used to improve the reliability of clinical evaluation. There is also the question of whether clinical evaluation reflects the impact of hypernasality in a speaker’s everyday life. The purpose of this thesis was to evaluate the extent of reliability problems connected with auditory perceptual assessment of nasality in speech, to explore whether they might interfere with treatment decisions or have an impact in the everyday life of patients, and whether they can be effectively diminished by the use of nasometry. Speakers with cleft lip and palate or velopharyngeal impairment formed the basis of the clinical population used in this study. Speech samples from 52 of these speakers, along with samples from a reference population of 21 speakers who did not have cleft palate, velopharyngeal impairment or speech disorders were used in perceptual evaluation tasks. Fourteen speakers from the clinical population and 11 from the reference population also underwent nasometric evaluation. A further reference population of 220 children from three Swedish cities, whose ages were consistent with those used for clinical checks of children born with cleft palate were assessed with nasometry to establish normative data for the Nasometer™. Perceptual speech assessments were conducted on hyper- and hyponasality, as well as audible nasal air emission and/or nasal turbulence, using 5-point ordinal scales. Listeners were SLPs experienced in the evaluation of cleft palate speech, non-expert SLPs and untrained listeners. Listening assessments were performed from audio recorded speech samples assembled in random order. Nasometry measures were made on three speech passages each with specific phonetic content, using the Nasometer™, model II. Perceptual evaluation Results showed that for hypernasality assessment, 15% of hypernasality assessments had disagreements between expert SLPs that were potentially important for clinical decisions, as did 6% of assessments for audible nasal air emission and/or nasal turbulence. For nasality problems, a comparison of expert and untrained listeners showed that they generally agreed on which speakers were hypernasal and on the ranking of nasal speakers. All speakers that had been rated with moderate to severe hypernasality by expert listeners were considered by the untrained listeners as having a serious enough speech disorder to call for intervention. However, in the case of audible nasal air emission and/or nasal turbulence the expert listeners were more prone to notice this feature than the untrained listeners. Instrumental evaluation The development of normative values for the three Swedish passages for the NasometerTM (comparable to normative values in other languages) has provided a basis for use of instrumental measures in Swedish clinics, oral sentences mixed sentences nasal sentences. The measures showed no significant differences due to city, gender or age within an age range of 4-10 years. When nasometry measures were compared with perceptual evaluation of speech samples from the same speakers, all correlations were moderate to good for expert SLPs and non-expert SLPs. The difference between correlations was significantly higher for expert SLPs than for untrained listeners. Reliability figures for perceptual assessments for expert SLP listeners indicated that there were some cases where lack of reliability could affect clinical decision making. However, in the main, judgements of nasality problems made by clinicians had everyday validity. They reflected the impressions of the everyday listener, especially in regard to the need for intervention. The study also indicates that now that Swedish norms are available, the Nasometer™ might be useful as a complement to auditory perceptual clinical speech assessments in Swedish cleft palate clinics in order to improve reliability of clinical assessment.
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| 37. |
- Brännström, Kristoffer, 1974-
(författare)
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Molecular dissection of established and proposed members of the Op18/Stathmin family of tubulin binding proteins
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- My initial aim was a functional analysis of the conserved Op18/stathmin family of microtubule-regulators, which includes the ubiquitous cytosolic Op18 protein and the neural membrane-attached RB3 and SCG10 proteins. The solved X-ray structure has shown that these proteins form a complex with tubulin -heterodimers via two imperfect helical repeats, which result in two head-to-tail aligned heterodimers in a tandem-tubulin complex. We have analyzed GTP exchange and GTP hydrolysis at the two exchangeable GTP-binding sites (E-site) within the tandem-tubulin complex. A comparison of Op18, RB3 and SCG10 proteins indicates that Op18/Stathmin family proteins have evolved to maintain the two heterodimers in a configuration that restrains the otherwise potent GTPase productive interactions facilitated by the head-to-head alignment of heterodimers in protofilaments. We concluded from these studies that tubulin heterodimers in complex with Op18/stathmin family members are subject to allosteric effects that prevent futile cycles of GTP hydrolysis. To understand the significance of the large differences in tubulin affinity of Op18, RB3 and SCG10, we have fused each of the heterodimer-binding regions of these three proteins with the CD2 cell-surface protein to generate confined plasma membrane localization of the resulting CD2 chimeras. We showed that, in contrast to CD2-Op18, both the CD2-SCG10 and CD2-RB3 chimeras sequester tubulin at the plasma membrane, which results in >35% reduction of cytosolic tubulin heterodimer levels. However, all three CD2-chimeras, including the tubulin sequestration-incompetent CD2-Op18, destabilize interphase microtubules. Given that microtubules are in extensive contact with the plasma membrane during the interphase, these findings indicate that Op18-like proteins have the potential to destabilize microtubules by both sequestration and direct interaction with microtubules. Sm16/SmSLP (Stathmin-Like Protein) has been identified as a protein released during skin penetration of the Schistosoma mansoni parasite. This protein has been ascribed both anti-inflammatory activities and a functional similarity with the conserved cytosolic tubulin-binding protein stathmin/Op18. However, our studies refuted any functional similarity with stathmin/Op18 and we found instead that Sm16/SmSLP is a lipid bilayer binding protein that is taken up by cells through endocytosis. To study immuno-modulatory properties of Sm16/SmSLP, we designed an engineered version with decreased aggregation propensity, thus facilitating expression and purification of a soluble Sm16 /SmSLP protein from the eukaryotic organism Pichia pastoris. Determination of the hydrodynamic parameters revealed that both the recombinant and native Sm16/SmSLP is a ~9-subunits oligomer. The recombinant protein was found to have no effect on T lymphocyte activation, cell proliferation or the basal level of cytokine production of whole human blood or monocytic cells. Interestingly, however, recombinant Sm16 was found to potently inhibit the cytokine response to the Toll-like receptor (TLR) ligands lipopolysaccharide (LPS) and Poly(I:C). Since Sm16 specifically inhibits degradation of the IRAK1 signaling protein in LPS stimulated monocytes, it seems likely that inhibition is exerted proximal to the TLR-complex.
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| 38. |
- Brännström, Margareta, 1957-
(författare)
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Ett liv i berg och dalbana : innebörder av att leva med svår kronisk hjärtsvikt i palliativ avancerad hemsjukvård utifrån patienters, närståendes och sjuksköterskors berättelser
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall purpose of this thesis is to illuminate meanings of living with severe chronic heart failure (CHF) in palliative advanced home care (PAHC) as disclosed through patients’, close relatives’ and nurses’ narratives. This thesis comprises four papers that illuminate the phenomenon from various perspectives and with different focus. In paper I four patients with severe CHF in PAHC were interviewed. In paper II three of their close relatives were interviewed. In paper III one man and his wife in PAHC were interviewed at 3-5 month intervals over a 4.5-years period. In paper IV 11 nurses in PAHC were interviewed. In all papers narrative interviews were conducted and the text was interpreted using a phenomenological-hermeneutic method. The result shows that meanings of living with severe CHF in PAHC is to be ‘knocking on death’s door’ yet surviving. This means never knowing what to expect of tomorrow as one suffers from a complex array of unpredictable, interwoven symptoms. The course of the illness forces sufferer to ride a symbolical ‘roller coaster’, an ongoing oscillation between ‘ups and downs’. Being offered a safety belt in the ‘roller coaster’ by the PAHC team means feelings of safety (I). Meanings of being a close relative of a person with severe CHF in PAHC is to be following the life- threatening ups and downs that the ill person goes through. It is like being a fellow passenger on the ‘roller coaster’ ride that is their loved one’s disease, with burdensome responsibility for easing the ‘downs’ and supporting the ‘ups’. This means being on primary call, always on standby to mediate security and pleasure. In the deepest downs it is also to call for the back-up call i.e. the PAHC team (II). Meanings of living the ‘ups and downs’ over time is being captive in a roller-coaster ride, side by side, with the ‘ups and downs’ caused by the illness. Living close to death is inescapable when recurrent periods of deepest ‘downs’ force one to face that one’s life together is coming to an end. The relationship between the spouses is severely tested but seems to withstand the strain and meaning is found in togetherness in life. Sharing the safety belt on the ‘roller coaster’, offered by the PAHC team, evokes feelings of security. However, the safety belt is adjusted to the man with severe CHF leaving the wife partly without comfort and at times uncertain, especially in the deepest ‘downs’ (III). Meanings of being a palliative nurse for patients with severe CHF in PAHC is being firmly rooted and guided by the values of palliative culture. Being a facilitator for the patient with CHF to live his/her everydaylife in the best way possible is difficult, challenging but overall positive. The nurses get into a tight corner when palliative culture values clash and do not correspond to nurses’ interpretation of what is good for the patient with severe CHF. There is a limit to nurses’ pliability to patients’ and close relatives’ will, as they are strongly convinced that resuscitation is not an option. Nurses have already made up their mind about that they do not perform heart- lung resuscitation (IV). The comprehensive understanding is that meanings of living with severe CHF in PAHC is being captive in a ‘roller-coaster’ life with varying periods between unpredictable improvement and deterioration of the body, for the rest of life. Living with the unpredictable, deteriorated body means to oscillate between enduring the suffering in ‘downs’ and enjoying life in ‘ups’ (I-III). Living with death so close over and over again i.e. being in a limit situation evokes feelings of uncertainty (I-IV) and confidence (I-III). Being positive dependent on PAHC facilitates a life as normal as possible in togetherness at home (I-IV). The comprehensive understanding of the four papers (I-IV) are discussed in the light of a theoretical framework from the German psychiatrist and philosopher Karl Jaspers thoughts about limit situation, the Danish philosopher K.E Lögstrup thoughts about the ethical demand, palliative theories and relevant empirical studies.
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| 39. |
- Bylesjö, Ingemar, 1948-
(författare)
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Epidemiological, clinical anf pathogenetic studies of acute intermittent porphyria
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Porphyrias are inherited metabolic disorders characterised by an impairment of heme biosynthesis. Acute intermittent porphyria (AIP) is the most common of the acute porphyrias in Sweden. Acute attacks of AIP are characterised by neuro-psychiatric symptoms, including epileptic seizures. Environmental and acquired factors are related to the induction of symptoms. Acute attacks of AIP are treated with high doses of glucose and/or hematin infusions. The pathogenesis of the neuro-psychiatric symptoms is not known. Reversible white-matter lesions, probably due to vasospasm, have been seen on brain MRI. Similarities between multiple sclerosis (MS) and AIP have previously been described, but to our knowledge no study has investigated whether AIP-gene carriers have white-matter lesions seen on brain MRI or oligoclonal bands (OB) in cerebrospinal fluid (CSF). The percentage of AIP-gene carriers who have experienced epileptic seizures has been calculated at 10-20%, but previous investigations are derived from highly selected clinic-based studies. Studies were therefore undertaken to investigate the prevalence of epileptic seizures, the relationship of seizures to AIP, the type of seizures and the relationship of seizures to other factors such as melatonin. A case report described the disappearance of porphyric attacks after the onset of diabetes mellitus (DM). In our study, we investigated the rate of attacks after the onset of DM. For many years, clinical issues relating to AIP have not been a focal area. We therefore carried out a study to update our knowledge of the clinical course of AIP in order to improve prevention, control and treatment. In our studies of AIP-gene carriers and epileptic seizures, we found that epileptic seizures are less common than has previously been described (3.7%) and they are not very different from what is expected in the general population, but the prevalence of 5.1% of seizures with manifest AIP is higher than in the general population. The seizures may be generalised or partial and the seizure frequency was generally low. The AIP-gene carriers who had had epileptic seizures had a lower melatonin excretion level in their urine compared with gender- and aged-matched AIP-gene carriers’ relatives without epileptic seizures, which may indicate that melatonin plays a possible anti-convulsive role. In our study of AIP and DM, no subject had an attack of AIP after the onset of DM. White-matter lesions on brain MRI were seen in 25% of the AIP-gene carriers examined outside attacks. One carrier had elevated protein levels in the CSF, but no carrier had cells or OB in the CSF. In our population-based study, 356 DNA-confirmed AIP-gene carriers from northern Sweden participated. Manifest AIP (MAIP) was identified in 42%, 65% of whom were women. Eight mutations were found. Women were more severely stricken by AIP attacks in terms of number and duration, hospital admission and early onset. Men (30%) reported most attacks > 40 years of age. The most commonly reported symptoms during attacks were severe abdominal pain (86%), fatigue (42%), constipation (41%), vomiting (36%), muscle pain (30%), psychiatric symptoms (29%), pareses (20%) and sensory impairment (10%). Chronic AIP symptoms were reported by 18%. Precipitating factors were often reported: menstruation (31%), psychological strain (30%), certain drugs and fasting (20%), infection and alcohol (14%), physical strain (12%) and pregnancy (5%). Smoking was more frequent in MAIP and was associated with the number of AIP attacks. Some 30% of MAIP carriers used drugs that were not considered safe (in 1999), mainly diuretics, calcium antagonists and ACE inhibitors. Twenty per cent of MAIP carriers reported that they were receiving a disability pension due to AIP. Elevated levels of ASAT, bile acids, creatinine, creatinine clearance, U-ALA and U-PBG were often found in MAIP-gene carriers. Hypertension, renal impairment and pain in the legs were associated with MAIP. Hepatoma was strikingly over-represented.To summarise; epileptic seizures are less common than has previously been described, melatonin may have an anti-convulsive effect and DM may have a beneficial effect on MAIP-gene carriers. White-matter lesions are seen on brain MRI. The lesions are unspecific but may relate to the patients’ porphyria. AIP is not a harmless disease. A large percentage of the AIP-gene carriers had frequent attacks, severe symptoms, long-lasting fatigue and chronic AIP and women were more severely stricken. Effects on the kidneys, blood pressure and the liver, including HCC, were evident. Measures should be taken to improve the quality of life and prognosis for AIP-gene carriers.
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| 40. |
- Bylund, Annika, 1954-
(författare)
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Phytoestrogens and prostate cancer : experimental, clinical, and epidemiological studies
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dietary factors may affect development and progression of prostate cancer. Experimental and epidemiological studies have suggested an effect of phytoestrogens on prostate cancer. Lignans are the predominant phytoestrogen in a Western diet. The effects of a diet rich in phytoestrogens and in particular lignans, as compared to a control diet, were assessed in several prostate cancer models. In paper I, 70 athymic nude mice with transplanted subcutaneous LNCaP tumours, an androgen sensitive human prostate cancer cell line, were fed one out of six phytoestrogen rich diets or a control diet after tumour injection. The rye diet, with high lignan content, decreased tumour take and growth, decreased secretion of prostate specific antigen and increased apoptosis. Addition of fat to the rye diet decreased the beneficial effects. In paper II, transgenic mice designed to develop prostate cancer (TRAMP) were fed rye bran or a control diet from the age of four weeks. Rye bran decreased prostate epithelial cell volume by 20%, and increased cell apoptosis by 31% as compared to the control diet. In paper III, we examined the effects of 7-hydroxymatairesinol (HMR), a purified lignan, in nude mice with subcutaneous LNCaP tumours in two different concentrations as compared to a control diet. Mice on the HMR diets had a reduced tumour take rate, lower total tumour volume, increased proportion of non-growing tumours, and increased apoptosis as compared to the control diet. Paper IV was a three week intervention study exploring the effects of rye bran bread vs. a control diet in men with prostate cancer. The men in the rye group had increased levels of plasma enterolactone and in biopsies from the prostate after the intervention an increase in apoptosis was observed in comparison with biopsies obtained before the intervention. In paper V, we examined the association between plasma levels of enterolactone, and risk of prostate cancer in a nested case control study. In the Northern Sweden Health and Disease Cohort, enterolactone concentrations were measured in plasma obtained at a mean time of 5 years before diagnosis from 265 cases of prostate cancer, and from 525 matched controls. We found no significant association between plasma enterolactone and risk of prostate cancer. Men with very low enterolactone levels (bottom decile) however, had significantly higher risk of prostate cancer. Phytoestrogen rich diet including soy, rye bran, substances purified from rye, and a purified lignan (HMR) all inhibited prostate tumour growth. However, it cannot be concluded that the effects observed were due solely to lignans as other components in rye grain such as tannins, phytic acid, ferulic acid, vitamins and minerals may have contributed to the beneficial effects. Thus, additional studies are needed to further elucidate the effects of phytoestrogens on prostate cancer development and progression.
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