Doctoral Theses from Sahlgrenska Academy

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Kinesiophobia : various aspects of moving with musculoskeletal pain
(2006) Lundberg, Mari
Aim: The overall aim of this thesis was to investigate various aspects of the phenomenon of kinesiophobia among patients with musculoskeletal pain. Study population: For the purpose of this thesis 1304 patients, with musculoskeletal pain, were asked to participate. Of the 1304 patients, 714 (55%) chose to participate. This study population constitutes eight subgroups. Methods and Results: In order to be able to assess kinesiophobia, a reliable and valid measure was needed. Study I evaluated the psychometric properties of the Swedish language version of the Tampa Scale for Kinesiophobia (TSK-SV) questionnaire. The reliability test included stability over time, internal consistency and homogeneity. The test of validity included face validity, content validity and construct validity. The TSK-SV was found to be reliable and evidence supported its validity, although the results indicated a lack of construct validity. An exploratory factor analysis was performed in Study II to explore the conceptual dimensions of the TSK-SV questionnaire based on a large Swedish sample. The findings showed that the TSK-SV measured five different dimensions of kinesiophobia. The aims of Study III were to describe the occurrence of kinesiophobia and to investigate the association between kinesiophobia and pain variables, physical exercise measures and psychological characteristics in patients with musculoskeletal pain. A multiple logistic regression model was preformed to identify associations. Kinesiophobia was a commonly (70%) identified phenomenon in patients with musculoskeletal pain. The results further indicated that kinesiophobia was associated with pain variables, physical exercise measures and psychological characteristics. Study IV explored how patients with persistent musculoskeletal pain experienced moving with pain. The interviews were analyzed according to a qualitative method called the Empirical Phenomenological Psychological (EPP) method. The results were described in three typologies called Failed adaptation, Identity restoration and Finding the way out. Conclusions: In conclusion, TSK-SV can be used prior to the start of a rehabilitation process in order to assess to what extent the patient fears physical movement. It is, however, important to stress that TSK-SV cannot be used as a single measure of diagnosis, but simply gives a rough indication of the level of pain-related fear. This thesis also shows that moving with pain has a deep existential impact on the individual, which needs to be taken into account when treating patients with persistent musculoskeletal pain. Keywords: fear of movement, kinesiophobia, persistent pain, physical therapy, phenomenology, psychometric properties, reliability, validity.
Medication adherence, side effects and patient-physician interaction in hypertension
(2006) Svensson, Staffan
Hypertension is an important risk factor for cardiovascular disease, the incidence of which it is possible to reduce by prophylactic treatment with antihypertensive drugs. In clinical practice, however, only a minority of patients reach target blood pressure levels. The resulting gap between actual and potential health gains has been attributed to the fact that many patients do not take prescribed treatment as recommended, i.e. ”medication non-adherence”. This phenomenon is, however, insufficiently understood. We investigated the topic of adherence by way of a randomised questionnaire material comprising 1013 patients, and audio-recordings of 51 patient-physician consultations and 33 interviews with the patients made after the consultations. All patients came for regular follow-up appointments with their physicians and were under treatment with antihypertensives. In the questionnaire material, we found that patients who reported side effects of their drugs tended to rate their future risk of cardiovascular complications as being higher. Analysis of the interview data showed that patients had various reasons for sticking to the treatment recommendations: trust in physicians and wanting to avoid sequelae of hypertension were common arguments for doing so, while having side effects and disliking pharmaceuticals in general were reasons against. In the follow-up appointments, we found that the determinants of treatment decisions, i.e. the measured blood pressure values and (suspected) side effects, were defined through negotiation between patients and physicians. On the whole, patients and physicians were more in agreement about the interpretation of blood pressure values than of side effects, and physicians had the last say in the decision-making. We concluded that the antecedents of decisions about using medication are surrounded by uncertainty, and that it is the patient’s interpretation of the ”facts” that, ultimately, determines if and how antihypertensive medications will be taken.
Achilles tendinopathy : evaluation and treatment
(2006) Grävare Silbernagel, Karin
Abstract. Background: Achilles tendinopathy is considered to be one of the most common overuse injuries in elite and recreational athletes. There are, however, only a few randomized studies of treatment and there is a need for standardized outcome measures for the patients’ symptoms and function. Purpose: The overall purpose of this thesis was to develop and evaluate outcome measures and treatment protocols for patients with Achilles tendinopathy. Material, Methods and Results: Initially, a method was developed to evaluate both symptoms and function in Studies I and II. The method was shown to have good reliability in 10 patients with acute Achilles tendon injuries and in 32 patients with chronic Achilles tendinopathy. We questioned, however, the validity of the methods since only small changes were detected while symptoms improved. At that time there was no standardized symptom questionnaire for the assessment of patients with Achilles tendinopathy. A questionnaire of this kind became available in 2001 in English. In Study III this questionnaire, the Victorian Institute of Sports Assessment – Achilles questionnaire (VISA-A), was cross-culturally adapted and evaluated for reliability, validity and structure on 15 healthy subjects and 51 patients. The Swedish version of the VISA-A questionnaire (VISA-A-S), which measured two factors, pain/symptoms and physical activity, was shown to have good reliability and to be a valid instrument, fully comparable to the original version. The VISA-A-S can be used in both research and clinical settings. A test battery for lower leg muscle/tendon function, including jump and strength tests, was developed and evaluated on 42 patients in Study IV. The purpose of the test battery was to evaluate, in more detail than had previously been possible, whether Achilles tendinopathy caused functional deficits on the injured side compared with the non-injured side. The test battery was found to be reliable and able to detect clinically relevant differences in lower leg function between the injured or “most symptomatic” and non-injured or “least symptomatic” sides in patients with Achilles tendinopathy. The test battery imposed more rigorous demands on patient function compared with each individual test. Treatment comprising iontophoresis using dexamethazone combined with exercise for patients with acute Achilles tendinopathy was evaluated on 25 patients in a randomized, double-blind design in Study II. Positive effects on symptoms were found from using iontophoresis with dexamethazone, compared with a control group in patients with acute Achilles tendon pain. Achilles tendon and calf muscle strengthening exercises (intensity modified with the use of a pain-monitoring model) as treatment for patients with chronic (symptoms for more than 2-3 months) Achilles tendinopathy was evaluated in 40 patients in Study I and in 38 patients in Study V. Furthermore, the effect of continued running and jumping on treatment outcome was evaluated in Study V. A treatment protocol which includes Achilles tendon and calf muscle exercises resulted in significant improvements in patients with chronic Achilles tendinopathy. When the pain-monitoring model was used, no negative effects could be demonstrated from continuing Achilles tendon loading activity (such as running and jumping) during treatment. Conclusion: The VISA-A-S questionnaire can be used to evaluate the clinical severity of patients with Achilles tendinopathy and it is useful in both research and clinical settings. Patients with Achilles tendinopathy reports not only pain, but also demonstrate deficits in lower leg function. In the acute phase, the use of iontophoresis with dexamethazone could potentially be beneficial. For patients with both acute and chronic Achilles tendinopathy, the performance of Achilles tendon and calf muscle strengthening exercises with the use of a pain-monitoring model for 6 months can be recommended. A training regimen of continued, pain monitored, Achilles tendon loading physical activity, such as running and jumping, might represent a valuable option for patients with Achilles tendinopathy.
Whiplash-associated disorders from a physical therapy and health-economic perspective. A study of an active physical therapy involvement and intervention for the treatment of acute whiplash-associated disorders and an analysis of its costs and consequences.
(2006-05-31T13:00:12Z) Rosenfeld, Mark
Whiplash-associated disorders (WAD) resulting from a biomechanical event in motor vehicle collisions is a major cause of suffering and high costs to society. The overall aim of this thesis was to evaluate the clinical and cost-effectiveness of an early, active physiotherapy involvement and intervention in patients exposed to neck trauma in motor vehicle crashes compared to a standard intervention which has been common practice in Sweden. The thesis consists of a review (I) and an interventions study (II-IV). The objective of Paper I was to review the literature systematically to analyse the evidence basis of many commonly used treatments for patients suffering from WAD both in the acute phase and for patients with persistent symptoms. The methodological quality of 26 randomised clinical trials was analyzed. The median quality scores for all three instruments were poor. Based on the degree of evidence and practical considerations, the following treatments can be recommended: Early physical activity in acute WAD, combination of cognitive behavioural therapy with physical therapy interventions, and coordination exercise therapy in chronic WAD. High-quality RCTs are not common in the field of WAD. More research is needed, particularly on the treatment of chronic WAD. The objective of Paper II was to evaluate an active physical therapy involvement and intervention versus a standard intervention and the importance of early versus delayed onset of treatment. Paper III aimed to compare long-term efficacy of active physical therapy involvement and intervention with standard intervention and the effect of early versus delayed initiation of intervention. The aim of Paper IV was to compare the costs of an active physical therapy involvement and intervention versus a standard intervention and to relate them to the clinical benefits in patients exposed to whiplash trauma in automobile crashes to facilitate decision making regarding intervention and resource allocation. The results of the inter-vention study showed that the active physical therapy involvement and intervention was significantly superior in reducing pain intensity and sick leave. Costs were significantly lower after 6 and 36 months with an active involvement and intervention as compared to the standard intervention. In conclusion, active involvement and intervention is a cost-saving alternative with positive consequences for health compared to a standard intervention in patients exposed to whiplash trauma, when costs related to physical therapy treatment and productivity were considered. It should thus be considered in the choice of treatment of these patients.
Orbital floor fractures - aspects of diagnostic methods, treatment and sequelae
(2006-06-08T09:00:44Z) Folkestad, Lena
Despite surgical intervention, orbital floor fractures are associated with risks of persisting sensibility disturbances, enophthalmos and diplopia. Cheek asymmetry and trismus may result when the zygoma is dislocated. In evaluating the surgical results patients’ experiences of the outcomes have to be investigated. To investigate sequelae a questionnaire was sent to 107 patients previously treated for an orbital floor fracture (Paper I). Visual analogue scales (VASs) were used in a prospective study (Papers II and III) to assess patients’ experiences of persisting signs and symptoms. The possibility of using electronystagmography (ENG) equipment, normally employed in vestibular testing in ENT practice, for measuring bilateral vertical eye motility was investigated in a methodological study (Paper IV). Fractures were mainly due to assaults and falls. Sequelae were common (83%). A high frequency of diplopia (36%) was associated with antral packing. When stable floor implants replaced this technique, the subsequent prospective study revealed absence of severe cases of diplopia as well as a lower occurrence of diplopia (9.5%). Patients and doctors agreed on the presence of ‘objective’ signs (affected physical appearance and diplopia). Sensibility disturbances and reduced mouth opening capacity were not sufficiently reflected by the diagnostic assessment methods used, and these symptoms were underestimated by the clinicians. Surgery of the internal orbit involves risks. For this reason, operations for purely diagnostic purposes must be avoided. However, 21% of the orbital floor operations in the present study were performed for purely diagnostic purposes. Surgeons did not apprehend the CT scans as being representative of the fracture. No test is at present available that can objectively establish entrapment of soft tissues as a cause of diplopia, although this is an absolute indication for surgery. However, vertical electro-oculography (vEOG) was shown to (i) objectively measure vertical eye motility; (ii) detect and verify mechanical restriction of vertical eye motility; and (iii) distinguish patients experiencing vertical diplopia from healthy test subjects with ‘normal’ eye motility. Both recognition of patients’ experiences and prolonged follow-ups in selected cases are important for treatment feedback, and are prerequisites for improvement of future surgical outcomes. Current diagnostic methods appear to be insufficient. Vertical electro-oculography is suggested as a simple, objective and noninvasive eye motility test with the potential of helping predict which patients will benefit or not benefit from orbital floor surgery.
Medical problems associated with spinal cord lesions - impact on functioning
(2006-09-01T12:04:06Z) Valtonen, Kirsi
Aims: The overall aim of this thesis was to study the effects of medical problems associated with spinal cord lesions on functioning - with special interest in work participation and sexual functioning. A special aim was to explore bone mineral density and associated factors in persons with meningomyelocele. Methods: The target population comprised persons with traumatic spinal cord injury or meningomyelocele living in the county of Western Götaland in Sweden. The subject characteristics, prevalence of medical problems and other disorders, as well as primary outcomes, were assessed with a structured questionnaire. In the osteoporosis study a physician and a physical therapist examined all subjects and assessed ambulatory status and the neurological level of the lesion. Bone mineral density in the lumbar spine, hip and forearm was measured with dual-energy x-ray absorptiometry. In the workplace intervention study each participant was visited by an ergonomist at the workplace where the working conditions were documented by means of video recordings, questionnaires and the ergonomist's evaluation of the workplace. Results: Work participation rate in Swedish spinal cord lesion population is about two thirds of that in the healthy population (50% against 75%). Among the men with traumatic spinal cord injury, neuropathic pain and the presence of other somatic or mental disorders were associated with work participation, whereas most of these associations were not observed in the women with traumatic spinal cord injury or in the persons with meningomyelocele. The results of the workplace intervention study showed that the working conditions of persons with spinal cord lesion can be improved by ergonomic measures. Satisfaction with sexual life was rather low in all subgroups except in the women with meningomyelocele. Medical problems associated with spinal cord lesion, such as incontinence and neuropathic pain, affected satisfaction with sexual life in persons with traumatic spinal cord injury. In persons with meningomyelocele, none of the studied medical problems was associated with satisfaction with sexual life. The results also indicated that osteopenia and osteoporosis are more common among young adults with meningomyelocele than in the normative population. The effect of medical risk factors of osteoporosis on bone mineral density was modified by ambulatory status in this patient group. Conclusions: Medical problems affect functioning in persons with spinal cord lesion. There are, however, some gender differences, as well as differences between persons with congenital and acquired spinal cord lesion. Osteoporosis is a medical problem, which must be considered when treating and rehabilitating persons with meningomyelocele. Key-words: spinal cord injuries, meningomyelocele, rehabilitation, osteoporosis, bone density, employment, sexuality
Sterile water injections and acupuncture as treatment for labour pain
(2006-09-28T14:11:33Z) Mårtensson, Lena
Most women experience pain during labour. Complementary pain relief methods such as sterile water injections and acupuncture are two alternatives for the child birthing women. The lack of knowledge about the use of these methods in clinical practice creates the need to develop and evaluate them. Aims and methods: To elucidate whether the new subcutaneous method of administering sterile water, as well as the previously described intracutaneous injection method, were effective for the relief of labour pain. Ninety-nine women in labour were randomized to either intracutaneous- , subcutaneous injections of sterile water or to placebo (Paper I). To investigate if there was any difference in perceived pain between the intracutaneous and subcutaneous techniques during injection of sterile water. One hundred female volunteers were given injections with both techniques in a cross-over trial (Paper II). To elucidate the clinical use of acupuncture and sterile water injections as pain relief and relaxation during childbirth in Swedish delivery wards. Five hundred and sixty-five midwives answered a questionnaire about their use of these methods (Paper III). To elucidate if there were any differences between acupuncture and sterile water injections in terms of pain relief and relaxation during labour. One hundred and twenty-eight pregnant women in childbirth were randomized to either sterile water injections or acupuncture (Paper IV). Results: Paper I: VAS pain scores were significantly lower in both treatment groups 10 minutes (p=0.001) and 45 minutes (p=0.005) after treatment, compared with the placebo group. Paper II: subcutaneous injections were still perceived as less painful than intracutaneous injections after trial, day and injection location were taken into consideration (p<0.001). Paper III: the midwives’ estimated frequency of administration of acupuncture was much higher than that of sterile water injections, 25 % versus 2 %. The intracutaneous injection technique was more common in clinical practice than the subcutaneous technique. Sterile water injections were used exclusively for pain relief during labour while acupuncture was used for both pain relief and relaxation during labour. Paper IV: women given sterile water injections experience significantly less labour pain and a higher degree of relaxation in labour, compared to women given acupuncture (p<0.001). Conclusions: The results indicate that the subcutaneous injection technique is preferable when using sterile water injections for low back pain during labour. Sterile water injections seem to provide more pain relief and a higher degree of relaxation, compared to acupuncture. However, acupuncture is a more common pain relief method in clinical practice. Key words: Labour pain, pain relief, sterile water injections, acupuncture, survey Correspond with: Lena Mårtensson, RNM, Med. Lic. Fac, School of Life Sciences, University of Skövde, Box 408, SE-541 28 Skövde, Sweden. ISBN-13: 978-91-628-6904-5 ISBN-10: 91-628-6904-3 Göteborg 2006
Genetic and molecular regulation of epithelial tube morphogenesis
(2006-09-29T08:39:27Z) Tonning, Anna
Networks of epithelial tubes, such as the vertebrate lung, kidney and vascular system, enable transport of gases and nutrients to all tissues in the body. These tubes are built up by a single layer of polarized epithelial cells, with the apical membrane facing the lumen. For optimal organ function it is critical that each tube in the network attains correct size and shape, as constricted or dilated tubes will affect the flow rate and impede organ function. When tubes form during organ development, they often have a narrow lumen that must expand to attain the typical mature length and diameter. Both apical (luminal) membrane growth and rearrangements of the subapical cytoskeleton are central to tube growth, but the mechanisms that coordinate these events across the tubular epithelium to ensure uniform tubes with functional dimensions have remained unknown. We have used the respiratory organ (trachea) of the fruit fly Drosophila melanogaster as a model system to gain insights into the molecular mechanisms that control tube size and shape. This thesis includes the analyses of five new tracheal tube size genes, which mutational analyses have revealed a new biological principle to ensure uniform functional tubes: newly formed tracheal tubes deposit a broad luminal chitin filament around which the tubular epithelium can rearrange. After tube expansion and before the tubes become functional in transport, the luminal filament is cleared. Four of the genes (krotzkopf verkehrt, knickkopf, retroactive and mummy) are required to build the luminal chitin filament, and their loss of function result in severe diameter constrictions and dilations in the expanding tubes. A fifth gene, which we have called humongous, encodes a novel protein required for formation of the septate junctions (SJs), which are analogous to vertebrate tight junctions. Many previously identified tracheal tube size genes encode SJ components, but their role in tube expansion has been unclear. We find that intact SJs are essential for correct assembly of the chitin filament, thus reinforcing the central role of the luminal chitin filament in tube size regulation.
Membrane Proteins in Human Neutrophils - Identification and Characterization of Lipid Rafts in Subcellular Organelles
(2006-09-29T10:51:50Z) Feuk-Lagerstedt, Elisabeth
The human neutrophil is an important effector cell in acute inflammation and in the innate immune response against bacteria and fungi. When immune reactions occur in the tissue in response to antigen challenge, neutrophils are the first cells to enter the site of inflammation. The neutrophil is equipped with a vast amount of receptors that both interact with inflammatory mediators and host tissue as well as with the prey. These receptors are found on the cell surface but are also stored in different types of granules and vesicles in the cell. By mobilizing the granules and vesicles to various extents and thereby upregulate receptors to the plasma membrane, the mature neutrophil can modulate its communication with the environment. One granule type, the azurophil granules, primarily delivers a killing machinery to intracellular organelles containing a prey that has been engulfed. These granules have traditionally been regarded as classical lysosomes, but their membrane is so far largely uncharacterized. The aim of this thesis was to elucidate details regarding azurophil granule membrane composition in order to further understand their role in neutrophil function. The studies led to identification of so-called lipid rafts in the azurophil and other granule membranes, and a detailed characterization of the azurophil granule lipid rafts with regard to protein composition was thus performed. One of the proteins identified in azurophil granule membranes was stomatin. This protein was present also in other granule/vesicle membranes and the plasma membrane. Furthermore, the protein was localized to lipid rafts. Apart from stomatin, the azurophil granule membrane rafts contained a vast number of proteins, of possible importance for membrane structure/integrity and fusion. The fact that several cytoskeletal proteins also were identified, suggests that the granule membrane is organized in much the same way as the plasma membrane. The thesis also includes studies on the neutrophil receptors for galectin-3, a potent activator of extravasated human neutrophils. Since granule mobilization is a prerequisite for galectin-3-induced activation of the cells, the receptors have been suggested to be granule localized. Here, galectin-3-binding proteins from specific/gelatinase granules were isolated, and among these, CD66a and CD66b were identified as the most plausible receptor candidates. The CD66b is a glycophosphatidyl inositol (GPI)-linked protein that was found to be localized to lipid rafts, suggesting that raft-associated signaling may be of importance for the galectin-3-induced neutrophil responses.
Inguinal Hernia after Urologic Surgery in Males with Special Reference to Radical Retropubic Prostatectomy. A Clinical, Epidemiological and Methodological Study
(2006-10-02T07:23:39Z) Stranne, Johan
Background and aims: In 1996 the first report indicating that inguinal hernia (IH) was a complication to radical retropubic prostatectomy (RRP) was published. The main aims of this thesis were to further establish this relation, to establish the background incidence of IH in men not subjected to surgery, to identify risk factors for postoperative IH occurrence and to investigate whether postoperative IH is a complication also after other types of surgery performed through a lower midline incision. A further aim was to form a hypothesis regarding the etiology of this complication and explore which methodological considerations have to be addressed when postoperative IH incidence is investigated. Materials and methods: A retrospective patient file survey (PFS) was used on 1039 patients subjected to RRP (n=375 [I] + 664 [III]) and pelvic lymph node dissection for staging of prostate cancer before radiotherapy (PLND) (n=184 [I]). The factors studied in the PFS were post-RRP IH incidence, age at RRP, preoperative IH morbidity, postoperative anastomotic stricture, influence of concurrent PLND at RRP and duration of surgery. From the ongoing Scandinavian Prostate Cancer Group (SPCG) 6 study a database search was used where the annual IH incidence for patients not subjected to surgery (n=953) and patients subjected to RRP (n=152) was investigated (II). Two patient administered questionnaires (PAQ) were also used. One prospective PAQ was sent to patients subjected to RRP (n=207) in whom the postoperative IH incidence was studied and preoperative IH morbidity (III). One retrospective PAQ was sent to patients subjected to PLND (n=88), open prostatectomy for benign prostatic hyperplasia (n=95) and cystectomy (n=76) where the postoperative IH incidence was explored (IV). Results and conclusions: The results show that the incidence of IH within 2 years after RRP is increased at least fifteen-fold as compared to a non-surgical group of patients. The background incidence of clinically overt IHs in men with prostate cancer and a mean age of 69 years is less than 0.5% per year. Increased age and preoperative IH morbidity are risk factors, but postoperative anastomotic stricture, concurrent PLND at the time of RRP and duration of surgery do not seem to increase the risk of post-RRP IH development. The risk of postoperative IH development after other urological procedures in males performed through a lower midline incision seems to be of a similar magnitude as following RRP. The incision per se seems to be the cause of the lesion, probably resulting in a direct disruption of the “shutter mechanism” of the inguinal anulus internus. Constitutional factors predisposing for IH may add to the risk. In the methodological analysis PAQ was found to be superior to PFS to detect previous IH morbidity as well as postoperative IHs.
On Minor Salivary Gland Secretion
(2006-10-03T05:06:50Z) Eliasson, Lars
The overall aim of this series of studies has been to examine palatal, buccal and labial minor salivary gland secretions in relation to age and gender and other factors and conditions that could have effects on the saliva. Further aims were to analyze minor salivary gland secretions in relation to feelings of oral dryness and dental plaque pH. The studies are based on the Periotron method, which measures minor fluid volumes collected in absorbent filter papers. The concentrations of proteins in the saliva samples, recovered from the filter papers, were also examined using ELISA techniques. The accuracy and variability of the Periotron measurements were evaluated (Paper I). Mucosal gland secretion rates were analyzed in relation to age and gender, common diseases and medications (Papers I and V), during oestrogen treatment (Paper II) and hyposalivation due to Sjögren’s syndrome or head and neck radiation (Paper III). The secretion rates were also related to denture wearing (Papers I and V), pregnancy (Paper V) and tobacco use (Papers I and V). The salivary concentration of IgA was examined in relation to various factors in Paper V, while albumin and lactoferrin were examined together with IgA in relation to hyposalivation (Paper III). Acidogenic microorganisms and pH in dental plaque after a sugar challenge were determined in hyposalivation subjects and matched controls (Paper IV). The results showed high accuracy for the Periotron measurements but large inter- and intra-individual variations in minor gland secretions. The secretion rate per mucosal surface area was highest at buccal sites and lowest at palatal sites. In the palatal mucosa, the secretion rate was higher at medial sites than at lateral sites. Age was not correlated to the minor gland secretion rates but was positively correlated to the IgA concentration. Women displayed lower minor gland flow rates and lower buccal saliva IgA concentrations than men. The buccal mucosal secretion rate was reduced during the use of diuretics and anti-hypertensive medication, while elderly women had an increased labial salivary secretion rate during oestrogen treatment. Subjective feelings of oral dryness were reduced with increased labial salivary flow. Individuals with removable dentures had a significantly higher secretion rate in palatal glands compared with those without dentures. Lower secretion rates and higher protein concentrations were seen in minor gland saliva during hyposalivation and this applied especially to irradiated subjects. Compared with their respective matched controls, irradiated patients had a more acidic plaque after a sugar challenge than the Sjögren’s syndrome patients. A low buccal gland secretion rate was correlated to increased plaque acidity in hyposalivation subjects. The number of acidogenic microorganisms had a more important effect on this acidity in the healthy controls. The present studies also showed that buccal gland secretion rates and IgA concentrations were positively correlated to whole saliva secretion rates and IgA.
Counselling Patients with Hypertension at Health Centres - a Nursing Perspective
(2006-10-03T12:33:45Z) Drevenhorn, Eva
Counselling in hypertension care relating to lifestyle changes, i.e. non-pharmaco-logical treatment regarding smoking, alcohol, weight, diet, physical activity and stress, aims to reduce complications such as stroke and myocardial infarction. Many patients have several risk factors to deal with. There are few studies of nursing in hypertension care in Sweden and this issue therefore needs to be investigated in greater detail. The aims of this thesis were to analyse the communication between patients and nurses about lifestyle changes in hypertension care at health centres and to evaluate the effects of nursing interventions. In the first study, the Nurse Practitioner Rating Form was used to explore what 21 randomised public-health nurses discussed with hypertensive patients and their communication. In the second study, variables from 100 patients were collected to explore the effectiveness of using a hypertension nursing programme at a nurse-led clinic. The third study comprised consultation training for 19 randomised nurses, at nurse-led clinics in southern Sweden, with audio-recorded consultations with 36 patients before the training and 35 after the training. The recordings were analysed using content analysis. The results reveal that non-pharmacological treatment was not provided to any great extent during visits for blood pressure measurement with public-health nurses at open hours, but a great deal of information and advice was provided. One significant correlation was, however, found. The more years the nurses had been working, the more likely it was that their health promotion was psychosocially oriented in the consultations. The patients and nurses generally met at an equal communication level in their conversations. Starting a nurse-led hypertension clinic following a hypertension nursing programme resulted in many medication adjustments when assessing the patients’ treatment and blood pressure levels. The most positive changes were seen in blood pressure, blood lipids and exercise. Consultation training on the stages of change model and patient centredness resulted in the nurses acquiring a more distinct structure for their consultations and relevant information was supplied in a more individually adapted way. The number of words and turns increased in the consultations. The nurses paid attention to support more frequently, irrespective of the stage of behavioural change the patient had reached. Negotiations about reasons for and where to begin behavioural change increased in the consultations. A model for nurses counselling patients in hypertension care was suggested, applying Orem’s self-care deficit theory of nursing. It is concluded that public-health nurses in normal practice at health centres did not perform counselling on non-pharmacological treatment to any great extent. Applying a hypertension nursing programme resulted in positive changes in patients’ blood pressure, blood lipids and exercise. After consultation training, the nurses acquired a more distinct structure for their counselling, with more words and turns, and negotiations about reasons for and where to begin behavioural change increased. The results of this thesis could be of help when planning and starting nurse-led clinics in hypertension care and when developing a national hypertension nursing program. To improve the care for hypertensive patients it is suggested that nurses at nurse-led clinics should have the opportunity for recurrent counselling training and education in the cardiovascular area.
Role of GPIbαlpha Clustering and N-linked Carbohydrates in the Clearance of Refrigerated Platelets
(2006-10-06T08:47:13Z) Josefsson, Emma
The thesis focuses on understanding the mechanisms by which: 1) the macrophage alphaM-subunit recognizes betaN-acetylglucosamine (betaGlcNAc) residues on the von Willebrand factor receptor complex ((GPIbalpha,beta/IX)2V or vWfR) on refrigerated platelets and 2) refrigeration changes vWfR to elicit recognition through alphaMbeta2. Until recently, the only well-established mechanisms affecting platelet survival were antibody-mediated platelet clearance, consumption of platelets by coagulation reactions, and loss due to massive bleeding. An effort to address a practical problem, how to refrigerate platelets for transfusion, led us to define a previously unsuspected platelet clearance mechanism. We found that (1) macrophages recognize betaGlcNAc residues of N-linked glycans on clustered GPIbalpha subunits following short-term refrigeration (2 h) of platelets in the absence of plasma and (2) phagocytosis and clearance are mediated by the alphaMbeta2 integrin receptor of macrophages. Galactosylation of GPIbalpha blocks ingestion by the macrophage alphaMbeta2 and allows short-term refrigerated murine platelets to circulate but does not prevent the removal of platelets stored long-term in plasma. Work detailed in this thesis demonstrates that the ingestion of short-term refrigerated platelets is dependent on the alphaM lectin-domain, not the I-domain which is involved in the recognition of most alphaMbeta2 ligands. To address this question, CHO cells were directed to express different alphaM/alphaX receptor subunit chimeras and the relative contribution of alphaM-subdomains to platelet ingestion evaluated in these cells. Critically, the recognition and ingestion of refrigerated platelets by CHO cells occurs only when the alphaM-subunits contain the alphaM lectin-subdomain. The I- or cation binding subdomains of the alphaM-subunit are not required. Soluble recombinant alphaM lectin-domain, but not a soluble alphaM I-domain, also inhibited the phagocytosis of refrigerated platelets by differentiated macrophages and Sf9 cells expressing solely recombinant alphaM lectin-domain constructs bound refrigerated platelets. We conclude, therefore, that refrigeration exposes N-glycan betaGlcNAc residues on vWfR which are recognized by the lectin-domain of alphaMbeta2 to initiate platelet clearance. Next, the relationship between vWfR clustering/conformational changes and refrigeration was investigated. Clustering of vWfR is detectable by fluorescent resonance energy transfer (FRET) measured by flow cytometry. Refrigeration of platelets for 24 h markedly increases the FRET efficiency between GPIbalpha and GPV subunits, whereas the FRET between GPIbalpha and alphaIIb is unaltered. We conclude that vWfR aggregation begins immediately following refrigeration but becomes maximal only after extended refrigeration. A panel of monoclonal antibodies (mAbs) that recognize different vWfR subunits was employed to further probe for structural changes. We found that certain epitopes on GPIbalpha become cryptic as platelets are refrigerated, possibly due to clustering of the vWfR complex, and that the rate of epitope sequestration due to clustering is slowed in the presence of plasma. Changes in binding efficacy of the mAbs are not caused by the loss of GPIbalpha from the platelet surface as determined by immunoblotting of total GPIbalpha. Some vWf binding in cold plasma was detected that may influence the binding of mAbs which bind to GPIbalpha near its vWf binding site. These further changes in vWfR in platelets refrigerated long-term in plasma may be related to the additional phagocytic mechanisms involved in their removal.
Patients with acute hip fractures; motivation, effectiveness and costs in two different care systems
(2006-10-06T09:56:09Z) Olsson, Lars-Eric
Abstract The care of patients with a hip fracture in Sweden varies a lot in terms of length of hospital stay and these patients are often subjected to multiple transferrals for other than medical reasons. How this affects the rehabilitation result is largely unknown but it is probably not in the best interest of the patients. The overall aim was to investigate the hospital care for patients with acute hip fractures - their own perceptions of their situation and comparison of effectiveness and costs using two different care systems. A qualitative method was used to describe the patients’ perceptions of their situation after hip fracture surgery. A quasi-experimental design was used to compare the Integrated Care Pathway (ICP) intervention group to a comparison group and a cost-effectiveness method was used for the economic evaluation. The patients in the qualitative study varied greatly in their engagement in the rehabilitation process but common traits among all the patients were: the need for more information, strong worry for future physical ability and a very strong zest for life. The ICP included a patient-motivated accelerated training programme based on the individual patients’ own perceptions and motivation for rehabilitation. The ICP intervention group had a significantly shorter length of hospital stay (12.2 vs. 26.3 days; p<0.000) the rehabilitation was more successful (36 patients vs. 27 were discharged as low dependent) (p=0.003). Moreover, there was a 40% reduction of the average total cost in the intervention group (p=0.000). The results suggest that differences in patients’ perspectives on the rehabilitation process need to be taken into account to enhance outcomes. It was found to be important to obtain good knowledge about patients´ prerequisites and subject them to an accelerated rehabilitation in accordance with their personal ability. The transition theory was intertwined within the ICP providing help for caregivers when assisting the patients to develop new knowledge and skills. The use of an ICP was cost-effective and the cost for developing the ICP was accrued already after three patients.
N-acetylaspartate in brain - studies on efflux and function
(2006-10-16T05:05:08Z) Tranberg, Mattias
N-acetylaspartate (NAA) is an amino acid derivative present in high concentration in the brain. The function of NAA is still unsettled in spite of 50 years of research. The mainly neuronal synthesis and glial breakdown of NAA requires a well regulated neuronal efflux and glial uptake. In the present work hippocampal slices were used to study how NAA efflux from neurons is regulated and to further investigate possible functions of NAA. For the determination of NAA a reversed phase HPLC method with UV detection was developed. The method allowed for the simultaneous determination of NAA and creatine and was comparable or better in sensitivity than previous methods based on UV detection. A newly developed efflux protocol that allowed the determination of efflux and delayed cell death was used to study NAA efflux in cultured hippocampal slices. Activation of the NMDA receptor, a glutamate-receptor subtype that is involved in learning and memory but also in nerve cell death following stroke, evoked a prolonged Ca2+-dependent NAA efflux from cultured slices. The efflux of NAA was not due to unselective membrane rupture but at high NMDA concentrations the efflux of NAA correlated with the NMDA-mediated delayed (24 hours after efflux) excitotoxicity. However, no causal relationship between delayed excitotoxicity and extracellular NAA could be demonstrated as culturing with high concentrations of NAA was non-toxic. Extracellular osmolarity was decreased moderately for 10-48 hours to address the proposed function of NAA as an osmoregulator but no change in the tissue content of NAA was observed from either cultured or acutely prepared hippocampal slices. However, depolarisation resulted in efflux of NAA from acutely prepared slices that could be reduced both by a NMDA-receptor blocker and hyperosmotic solution. Culturing of hippocampal slices with the monomethyl ester of NAA increased intracellular NAA levels. This was followed by reduced levels of the anion phosphoethanolamine and a tendency towards decreased Cl- concentration in the slices. NMDA-mediated delayed excitotoxicity was unaffected by increased intracellular NAA concentration. Overall, the results suggest that the NMDA receptor is involved in the regulation of NAA efflux from neurons. Increased extracellular as well as intracellular NAA is non-toxic and NAA does not seem to function as an important Ca2+ chelator or as an osmoregulator under physiological decreases in osmolarity.
Interpretation of diagnostic information given patient characteristics
(2006-10-20T05:17:22Z) Gellerstedt, Martin
The aim with this thesis was to describe, exemplify and develop theory for reference values and diagnostic tests, especially focusing on the variability between individuals. To facilitate interpretation of medical information it is common to establish some kind of limit. There are several different rationales for the choice of such a limit. Reference values are intended to be solely descriptive, while medical decision limits are used for identification of a present or future disorder. The frequently used bimodal model can be used not only for discrimination between healthy vs diseased but for separation of other conditions as well. Reference values for amplitude of accommodation among school children were suggested based on a bimodal model discriminating between children with vs without symptoms occurring at near work. If the variability between individuals is high compared to the variability found within an individual or if the diagnostic information is subjective, it may be favorable to use the individual as its own reference. The diagnosis of food-hypersensitivity for patients with subjective symptoms was used as an illustration. A pre-defined approach for interpretation of case records gave high inter-observer reliability, and gave different diagnoses than a previously used approach. To harmonize the sensitivity and specificity of reference values across subpopulations, partitioning of reference values is one possibility. Existing criteria are limited to the consideration of only two subpopulations. A computer assisted procedure for considering partitioning of several subpopulations was developed. The potential relationship between diagnostic accuracy of a test and other factors are highlighted in diagnostic theory. However, there is no advice regarding how to adjust for this relationship. Two possibilities have been presented; to use a multivariate model including interactions or to use different thresholds for different subpopulations. Diagnostic information could be individually adjusted by using a prevalence function which estimate probability of target disorder, given patient characteristics. A computer based decision support system including such a prevalence function was shown to have potential benefits for assisting medical decisions.
Studies of Sunscreens: Percutaneous Absorption of Benzophenone-3 and Photostability
(2006-10-20T05:19:47Z) Gonzalez, Helena
Studies of Sunscreens: Percutaneous Absorption of Benzophenone-3 and Photostability Helena Gonzalez Department of Dermatology and Venereology Institute of Clinical Sciences The Sahlgrenska Academy at Göteborg University Göteborg, Sweden Abstract Aim: To learn more about percutaneous absorption of the photoactive compound benzophenone-3 (BZ-3) and to study the excretion pattern of BZ-3 and its metabolite dihydroxy benzophenone (DHB). We also got the opportunity to develop a reverse-phase HPLC method to analyze BZ-3 and DHB. The photostability of seven commercial sunscreens was also studied. Material and methods: Paper I: 11 participants applied a sunscreen, 2 mg/cm2, containing 4% BZ-3. They collected urine for 48 hours after the application. Paper II: 26 participants applied a sunscreen, 2 mg/cm2, containing 4% BZ-3 morning and night for five days. Half of the participants were exposed to UV radiation (UVR). They collected urine for the five days the sunscreen was applied and an additional five days after the last application. Paper III: The assay uses: solid-phase extraction with C8 columns; a Genesis C18 column (4.6 mm x 150 mm ); a gradient acetonitrile-water mobile phase; a UV-detector set at 287 nm. Paper IV: Seven commercial sunscreens were studied with absorption spectrophotometry. Sunscreen product, 0.5 mg/cm2, was placed between plates of silica. The area under the curve (AUC) in the spectrum was calculated for the different UV regions. AUC before (AUCbefore) and after (AUCafter) artificial UV exposure and before and after natural UV exposure were calculated. If the AUC Index (AUCI), defined as AUCI=AUCafter/AUCbefore, was > 0.80, the sunscreen was considered photostable. Results: Paper I: The average total amount excreted was 11 mg, median 9.8 mg, which is approximately 0.4% of the applied amount BZ-3. Paper II: The volunteers excreted 1.2-8.7% BZ-3 of the total applied amount. The mean value found was 3.7%. There was no significant difference between the two groups; p<0.99. Paper III: The assay was linear r2 >0.99, with detection limits for BZ-3 and DHB of 0.01 µmol/l and 0.16 µmol/l respectively. Relative standard deviation was less than 10% for BZ-3 and less than 13% for DHB. The excretion pattern varied among the human volunteers, different patterns were discerned among the individuals. Paper IV: Three sunscreens were unstable after 90 min of natural UV, in the UVA range the AUCI was between 0.41 and 0.76. In the UVB range, one of these sunscreens was unstable with an AUCI of 0.75 after 90 min. Three sunscreens were photostable after 120 min of natural UV, in the UVA range the AUCI was between 0.85 and 0.99 and in the UVB range between 0.92 and 1.0. Conclusions: Paper I: BZ-3 is absorbed by the skin and excreted in the urine after one topical application of a sunscreen containing 4% BZ-3. There are individual differences in the amount excreted and in the excretion pattern. Paper II: Repeated topical applications of a sunscreen containing 4% BZ-3 lead to a higher excretion of BZ-3. There was no statistical difference after exposure to UVR. Paper III: The developed reverse-phase HPLC-method was reliable and suitable to handle a large number of samples. BZ-3 and DHB were excreted in a similar pattern. Paper IV: Three of the seven investigated sunscreens were photounstable in the UVA region. The combination ethylhexyl methoxycinnamate and butyl methoxydibenzoylmethane was unstable regardless of which other photoactive compound that was included in the sunscreen. Key words: benzophenone-3, dihydroxy benzophenone, sunscreens, UV radiation, reverse-phase HPLC, photostability
Swedish Pharmaceutical Benefit Reforms - Analyses of implementation, pharmaceutical sales patterns and expenditures
(2006-10-24T11:48:40Z) Andersson, Karolina
Background: Over the last few decades, the sales of prescription drugs have increased dramatically in many western countries; however, this increase requires individuals and society to bear larger economic consequences. To improve cost control for pharmaceuticals, several reforms attempt to reconcile the economic responsibility of the patients, prescribers and third party payers. Aims: The overall purpose was to investigate effects of policy changes concerning reimbursed pharmaceuticals in Sweden with focus on the latest reform comprising mandatory generic substitution. Specifically this thesis analyses effects of policy changes on development of expenditure and volume of pharmaceuticals, prescribers’ opinions on the latest reform and how prescribers, patients and pharmacy personnel acted during the implementation of generic substitution. Methods: One study analysed pharmacy invoice data comprising expenditure and volume between 1986 and 2002 for five selected drug groups and all pharmaceuticals in total. A questionnaire was distributed to 1388 physicians working in Region Västra Götaland. Associations between opinions and background characteristics were analysed with logistic regression. Three studies comprised data on reimbursed dispensed prescription medicines. One study examined data on the dispensing procedure for Region Västra Götaland between October 2002 and September 2003. Another study analysed expenditure data for each county council and the whole country between January 2000 and December 2004. One study examined data on volumes sold for the whole country between January 2000 and June 2005. In two studies, interrupted time series analysis was used to analyse the effects of policy changes. Results: Increased patient co-payment was not associated with any significant effects on expenditure and volume. Introduction of co-payments for pharmaceuticals that previously were free and co-payment based on the price of the products were associated with a temporary decline in cost increase. Reference-based pricing was associated with decreased cost per volume. Generic substitution was implemented rapidly after introduction and the key actors acted in accordance with the reform. A large percentage of the prescribers were positive to the reform. Sales of prescribed substitutable pharmaceuticals increased proportionally more than sales of non-substitutable pharmaceuticals in the same therapeutic group after introduction of generic substitution. The patients were price sensitive and chose substitution to cheaper alternatives when the price differences were high. Generic substitution was associated with decreased average patient co-payment, subsidised cost and total cost. Conclusions: Mandatory generic substitution effectively reduced overall expenditure. Policies that increase competition limited growth in pharmaceutical expenditures more effectively than co-payment reforms.
Endogenous t-PA release and pharmacological thrombolysis - Experimental animal studies of the coronary circulation
(2006-10-25T11:55:54Z) Björkman, Jan-Arne
Abstract The physiologically most important activator of intravascular fibrinolysis is tissue-type plasminogen activator (t-PA) released from endothelial cells. In man, sympathomimetic drugs increase the systemic concentration of t-PA. It is therefore of interest to investigate whether cardiac sympathetic activation can induce a local t-PA release, which could counteract intra-coronary clot formation. Thrombolytic therapy with recombinant t-PA (rt-PA) is effective in acute myocardial infarction, but the treatment is limited by a fairly slow reperfusion rate and frequent early reocclusions. A potential mechanism behind early reocclusions might be that active thrombin is released from the thrombus during thrombolytic therapy. Thrombin has recently been shown to activate pro-carboxypeptidase U, which in its active form (CPU) down-regulates endogenous fibrinolysis. Therefore, one way of improving thrombolytic efficacy may be to combine rt-PA with a low-molecular weight direct thrombin inhibitor, which theoretically could have a pro-fibrinolytic effect, either by inhibition of fibrin-bound thrombin and/or by inhibition of CPU activation. An alternative way may be direct inhibition of CPU. In a porcine model, experimental activation of cardiac sympathetic nerves by electrical stimulation at 1 and 8 Hz induced 5- and 20-fold increase in the release of both total and active t-PA together with frequency-dependent increases in heart rate, blood pressure, and coronary blood flow. The t PA release was independent of the heart rate and coronary flow response, but local infusion of isoprenaline suggested that part of the t-PA response was mediated by stimulation of β-adrenergic receptors. Next, we studied the combined effect of rt-PA and thrombin inhibitors (melagatran, hirudin and heparin) in a canine model of copper coil-induced coronary thrombosis. The pro-fibrinolytic effect of rt-PA, either measured as patency rate or time-to-patency, was significantly enhanced with the low-molecular weight direct thrombin inhibitor melagatran, but to a lesser degree by hirudin and heparin. In the same model it was shown that active CPU is produced locally in the coronary vascular bed during both thrombus formation and clot lysis. Inhibition of thrombin attenuated CPU formation and improved patency. A similar effect was obtained with a direct inhibitor of CPU. In conclusion, the coronary t-PA response to sympathetic stimulation may constitute a thrombo-protective defence mechanism to counteract its prothrombotic effects on the systemic level. Furthermore, direct thrombin and/or CPU inhibition may be potential targets for prevention of thrombus formation via facilitation of the endogenous fibrinolytic system.
Transfemoral amputation, Quality of Life and Prosthetic Function. Studies focusing on individuals with amputation due to reasons other than peripheral vascular disease, with socket or osseointegrated prostheses.
(2006-10-27T07:29:04Z) Hagberg, Kerstin
Background: Individuals who have undergone a transfemoral amputation (TFA) due to causes other than peripheral vascular disease (PVD) constitute a sub-group of all amputees. This group is usually of young age at the amputation. Conventionally, prosthetic suspension is achieved with a socket. Using the osseointegration method, prostheses can be attached directly to the bone (OI prostheses) without a socket. Aim: The overall aim was to investigate the health-related quality of life (HRQL) and prosthetic function in persons with a unilateral TFA, due to causes other than PVD, with socket prostheses and OI prostheses. Material, methods and results: General HRQL was assessed using the SF-36. For condition-specific HRQL, a new self-report questionnaire was constructed: the Questionnaire for Individuals with a Transfemoral Amputation (Q-TFA). It provides results for four scores (prosthetic use, prosthetic mobility, problems and global health) and adequate levels of validity and reliability were demonstrated (Paper II). Physical assessments included measurement of the energy cost using the Physiological Cost Index and hip range of motion (ROM). The HRQL and prosthetic function are described for 97 persons (62% male, 38% female, mean age 48 years, mean time since amputation 22 years, cause: 55% trauma, 35% tumour, 10% other) (Paper I). The energy cost was investigated for 41 individuals with socket prostheses (Paper III), while hip ROM was investigated for 43 persons with socket prostheses and 20 with OI prostheses (Paper IV). Finally, prospective results at the two-year follow-up for the first 18 consecutive patients treated with an OI prosthesis within a clinical investigation are reported (Paper V). For the study group (Paper I), the general HRQL was reduced compared with healthy norms. Daily use of the socket prosthesis was reported by 82%. A large number of subjective complaints reducing the HRQL were reported. The most common were heat/perspiration (72%) and sores/skin irritation (62%) with the socket. Further, 48% reported phantom limb pain, 47% back pain and 44% uncomfortable sitting with the prosthesis. The energy cost was increased by 77% compared with controls. The hip ROM was reduced with the socket prosthesis, while individuals with an OI prosthesis had no restriction in hip ROM. Prospective results for the treatment with OI prostheses revealed that 17/18 used the prosthesis and reported an increase in general physical HRQL and more prosthetic use, better prosthetic mobility, fewer problems and better global health at the two-year follow-up compared with the preoperative situation. Conclusions: For persons with an established TFA, for reasons other than PVD, the general HRQL is lower than that of healthy norms and a considerable number of specific problems are perceived. The Q-TFA is a valid and reliable tool for assessments of this population. Treatment with OI prostheses represents a promising development in the rehabilitation of individuals with TFA who report improved general and condition-specific HRQL at the two-year follow-up.

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