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  • 1. Asan, Noor Badariah
    et al.
    Velander, Jacob
    Redzwan, Syaiful
    Augustine, Robin
    Hassan, Emadeldeen
    Umeå University, Faculty of Science and Technology, Department of Computing Science. Department of Electronics and Electrical Communications, Menoufia University, Menouf, Egypt.
    Noreland, Daniel
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    Voigt, Thiemo
    Blokhuis, Taco J.
    Reliability of the Fat Tissue Channel for Intra-body Microwave Communication2017In: 2017 IEEE Conference on Antenna Measurements & Applications (CAMA), IEEE , 2017, p. 310-313Conference paper (Refereed)
    Abstract [en]

    Recently, the human fat tissue has been proposed as a microwave channel for intra-body sensor applications. In this work, we assess how disturbances can prevent reliable microwave propagation through the fat channel. Perturbants of different sizes are considered. The simulation and experimental results show that efficient communication through the fat channel is possible even in the presence of perturbants such as embedded muscle layers and blood vessels. We show that the communication channel is not affected by perturbants that are smaller than 15 mm cube.

  • 2.
    Bailey, Leslie
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Infection biology of Chlamydia pneumoniae2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    There are two main human pathogens in the family of Chlamydiaceae. Different serovars of Chlamydia trachomatis cause sexually-transmitted disease and eye infections whereas C. pneumoniae (TWAR) is a common cause of community-acquired respiratory infection. Chlamydia species are obligate, intracellular bacteria sharing a unique developmental cycle that occurs within a protected vacuole termed an inclusion. These microorganisms can be distinguished by two different forms: the infectious, metabolically inert elementary body (EB) and the reproducing non-infectious form, termed the reticulate body (RB). The cycle is terminated when re-differentiation of RBs back to infectious EBs occurs. Chlamydia possesses a type III secretion system (T3SS) essential for delivery of effector proteins into the host for host-cell interactions. This virulence system has been systematically characterized in several mammalian pathogens. Due to lack of a tractable genetic system for Chlamydia species, we have employed chemical genetics as a strategy to investigate molecular aspects of the T3SS. We have identified that the T3S-inhibitors INP0010 and INP0400 block the developmental cycle and interfere with secretion of T3S effector proteins in C. pneumoniae and C. trachomatis, without any cytotoxic effect. We have further shown that INP0010 decreases initiation of transcription in C. pneumoniae during the early mid-developmental cycle as demonstrated by a novel calculation, useful for measurement of transcription initiation in any intracellular pathogen. The mechanism regulating the signal(s) for primary as well as terminal differentiation of RBs has not been defined in Chlamydia. We show using T3S-inhibitors that INP0010 targets the T3SS and thereby arrests RB proliferation as well as RB to EB re-differentiation of C. pneumoniae as where INP0400 targets the T3SS and provokes a bacterial dissociation from the inclusion membrane presumed to mimic the natural occurrence of terminal differentiation. The effect of INP0010 on iron-responsive genes indicates a role for T3S in iron acquisition. Accordingly, our results suggest the possibility that C. pneumoniae acquires iron via the intracellular trafficking pathway of endocytosed transferrin. Moreover, we have for the first time presented data showing generalized bone loss from C. pneumoniae infection in mice. The infection was associated with increased levels of the bone resorptive cytokines IL-6 and IL-1beta. In addition, an increased sub-population of T-cells expressed RANKL during infection. Additionally, C. pneumoniae established an infection in a human osteoblast cell line in vitro with a similar cytokine profile as seen in vivo, supporting a causal linkage. Collectively, these data may indicate a previously unknown pathological role of C. pneumoniae in generalized bone loss.

  • 3.
    Eriksson, Marie
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
    Aspects on stroke outcome: survival, functional status, depression and sex differences in Riks-Stroke, the National Quality Register for Stroke Care2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Stroke is a major cause of death and disability worldwide. In Sweden, about 30 000 strokes occur each year. The aim of this thesis was to analyse survival, functional outcome and self-reported depression after stroke, and to explore possible differences between men and women in stroke care and outcome.

    These studies were based on Riks-Stroke, the Swedish national quality register for stroke care. Information on background variables and treatment were collected during the hospital stay. The patient’s situation and outcome after stroke were followed-up after 3 months. Long term survival was retrieved from the Swedish Population Register (Folkbokföringen).

    Possible sex-differences in stroke care and outcome 3 months after stroke were explored in 24 633 strokes, registered during 2006. In conscious patients, the proportions treated at stroke units were similar for men and women. Men and women had equal chance to receive thrombolytic therapy or secondary prevention with oral anticoagulants. Compared to men, women were less likely to develop pneumonia, but more likely to experience deep venous thromboses and fractures during hospital stay. Women had worse 3-month survival and functional outcome, differences that were explained by their higher age and impaired level of consciousness on admission. Women felt more depressed and perceived their health as worse than men did. Women were also less satisfied with the care they had received in the hospital.

    The agreement between self-reported functional outcome 3 months after stroke and the commonly used modified Rankin Scale (mRS) was explored in 555 stroke survivors from 4 hospitals during May-September 2005. Riks-Stroke’s self-reported questions classified 76% of the patients into correct mRS grade.

    The association between functional outcome 3 months after stroke and 3-year survival was assessed in 15 959 men and women who had had a stroke during 2001-2002. Patients with estimated mRS grades 3, 4 and 5 had hazard ratios for death of 1.7, 2.5 and 3.8, respectively, as compared with patients with lower grades, 0-2. Depressed mood, male sex, high age, diabetes, smoking, antihypertensive therapy at onset and atrial fibrillation were also identified as predictors of poor survival.

    Self-reported depression 3 months after stroke and use of antidepressants were analysed in 15 747 stroke survivors from 2002. Fourteen percent felt depressed 3 months after stroke. Female sex, age <65, previous stroke, living alone or in institution, or being dependent in activities of daily living (ADL) were factors associated with self-reported depression. At the follow-up, 22% of the men and 28% of the women were using antidepressant medication, which were approximately twice as many as in the general population. Still, 8% of all patients in Riks-Stroke reported depressive mood but no treatment with antidepressants.

    In conclusion, men and women with stroke in Sweden experience similar treatment and outcome in most aspects. Patient-reported functional outcome can be reliably transformed to a standard disability scale. Impaired functional outcome three months after stroke is an independent predictor of poor long-term survival. Depressive mood is common after stroke and is associated with poor survival and impaired functional outcome.

  • 4.
    Fonseca Rodriguez, Osvaldo
    et al.
    National Centre for Animal and Plant Health (CENSA), OIE Collaborating Centre for Disaster Risk Reduction in Animal Health, San José de las Lajas, Mayabeque, Cuba.
    Coronado, Liani
    Centro Nacional de Sanidad Agropecuaria (CENSA), OIE Collaborating Centre for Diagnosis and Risk Analysis of the Caribbean Region, La Habana 32700, Cuba.
    Amarán, Laymara
    National Laboratory for Veterinary Diagnostic (NLVD), Avenida 51 No. 33 222, Arroyo Arenas, La Lisa, La Habana, Cuba.
    Perera, Carmen Laura
    Centro Nacional de Sanidad Agropecuaria (CENSA), OIE Collaborating Centre for Diagnosis and Risk Analysis of the Caribbean Region, La Habana 32700, Cuba.
    Centelles, Yosdany
    National Centre for Animal and Plant Health (CENSA), OIE Collaborating Centre for Disaster Risk Reduction in Animal Health, San José de las Lajas, Mayabeque, Cuba.
    Montano, Damarys N.
    National Centre for Animal and Plant Health (CENSA), OIE Collaborating Centre for Disaster Risk Reduction in Animal Health, San José de las Lajas, Mayabeque, Cuba.
    Alfonso, Pastor
    National Centre for Animal and Plant Health (CENSA), OIE Collaborating Centre for Disaster Risk Reduction in Animal Health, San José de las Lajas, Mayabeque, Cuba.
    Fernández, Octavio
    National Centre for Animal and Plant Health (CENSA), OIE Collaborating Centre for Disaster Risk Reduction in Animal Health, San José de las Lajas, Mayabeque, Cuba.
    Santoro, Kleber R.
    Postgraduate Program in Biometrics and Applied Statistics (PPGBEA), Federal Rural University of Pernambuco (UFRPE). Rua Dom Manuel de Medeiros s/n. Dois Irmãos, Recife, PE 52171-900.
    Frías-Lepoureau, María Teresa
    Centro Nacional de Sanidad Agropecuaria (CENSA), OIE Collaborating Centre for Diagnosis and Risk Analysis of the Caribbean Region, La Habana 32700, Cuba.
    Percedo, María Irian
    Centro Nacional de Sanidad Agropecuaria (CENSA), OIE Collaborating Centre for Diagnosis and Risk Analysis of the Caribbean Region, La Habana 32700, Cuba.
    Descriptive epidemiology of endemic Classical Swine Fever in Cuba2018In: Spanish Journal of Agricultural Research, ISSN 1695-971X, E-ISSN 2171-9292, Vol. 16, no 2, article id e0506Article in journal (Refereed)
    Abstract [en]

    In Cuba, Classical Swine Fever (CSF) has become an endemic disease since 1993 with several outbreaks each year despite the compulsory vaccination program implemented. To deepen the disease characterization is essential for improving the CSF control measures and to achieve its eradication. The aim of this study was to describe the epidemiological characteristics of CSF occurrences in Cuba during a seven-year period within the endemic situation. Data on CSF occurrence from January 2010 to December 2016 were analyzed. The seven-year period shows a tendency of the number of affected premises to increase (r=0.31, p=0.005) over time (month). Directional distribution (1SD ellipse) indicated a great dispersion of affected premises by year across the country with a trend to a higher occurrence to the west. It was demonstrated by the negative correlation (r=-0.893, p=0.007) between the longitude of the mean center of the ellipses over the years. The Kernel density indicated that the disease was spatially distributed across the whole country, but four hot spots were found in the western (Pinar del Río and Artemisa) and eastern (Guantánamo and Holguín) regions. The clinical sign most frequently reported in affected premises was fever, followed by loss of appetite, conjunctivitis, and diarrhea. The most frequent observed clinical signs were non-specific, which complicates the disease recognition in the field. The obtained results have a practical importance for improving the efficiency of the CSF control program implemented in the country and contribute to enhance epidemiological surveillance taking into account the risk based principles.

  • 5.
    Gisslén, Karl
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences.
    The patellar tendon in junior elite volleyball players and an Olympic elite weightlifter2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The principal aim of the present thesis was to prospectively follow (clinical status and ultrasound + Doppler findings) the patellar tendons in the young elite volleyball players at the Swedish National Centre for high school volleyball in Falköping. In an Olympic weightlifter with chronic painful jumper´s knee, the effects of treatment with sclerosing injections followed by early instituted very heavy weightlifting training, was also evaluated.

    First, in a prevalence study, we demonstrated that the clinical diagnosis patellar tendinopathy-jumper’s knee, together with structural tendon changes and vascularisation in the painful area of the tendon, was demonstrated in 12/114 tendons in Swedish junior elite volleyball players, but not in any tendons of individually matched (age, height and weight) not regularly sports active controls. Structural tendon changes alone was demonstrated among the volleyball players but also among the controls.

    In a 7 months prospective study of a total of 120 tendons, we demonstrated that the clinical diagnosis patellar tendinopathy-jumper’s knee was associated with neovessels/vascularity in the area with structural tendon changes in 17/19 tendons. Seventy tendons that at start were clinically normal, and had normal ultrasound + Doppler findings, remained clinically normal after 7 months with intensive training and playing volleyball.

    In a 3-year prospective study it was demonstrated that normal clinical tests and normal ultrasound + Doppler findings at school start, indicated a low risk (8%) for these players to sustain patellar tendinopathy-jumper’s knee during the 3 school years with intensive training and playing.

    In a case study, involving an Olympic elite weightlifter with chronic painful patellar tendinopathy-jumper’s knee, successful treatment with ultrasound and Doppler-guided injection of the sclerosing agent polidocanol, allowed for pain-free very heavy weight training two weeks after treatment. Further heavy weightlifting training on a daily basis, preparing for European Championships, was done without causing tendon rupture and/or pain.

    Key words: Jumper’s knee, Patellar tendinopathy, Chronic pain, Ultrasonography, Doppler, Neovascularisation, Volleyball, Weightlifting

  • 6.
    Guez, Michel
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences.
    Chronic neck pain: An epidemiological, psychological and SPECT study with emphasis on whiplash-associated disorders2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Chronic neck pain, a common cause of disability, seems to be the result of several interacting mechanisms. In addition to degenerative and inflammatory changes and trauma, psychological and psychosocial factors are also involved. One common type of trauma associated with chronic neck pain is whiplash injury; this sometimes results in whiplash-associated disorder (WAD), a controversial condition with largely unknown pathogenetic mechanisms. We studied the prevalence of chronic neck pain of traumatic and non-traumatic origin and compared the prevalence of, sociodemographic data, self-perceived health, workload and chronic lowback pain in these groups. In a ready-made questionnaire (MONICA study), we added questions about cervical spine and low-back complaints. 6,000 (72%) completed a self-administered questionnaire. 43% reported neck pain: 48% of women and 38% of men. Women of working age had more neck pain than retired women, a phenomenon not seen in men. 19% of the studied population suffered from chronic neck pain and it was more frequent in women. A history of neck trauma was common in those with chronic neck pain. Those with a history of neck trauma perceived their health worse and were more often on sick-leave. About 50% of those with traumatic and non-traumatic chronic neck pain also had chronic low-back pain.

    We assessed the subjective and objective neuropsychological functioning in 42 patients with chronic neck pain, 21 with a whiplash trauma, and 21 without previous neck trauma. Despite cognitive complaints, the WAD patients had normal neuropsychological functioning, but the WAD group especially had deviant MMPI results—indicating impaired coping ability and somatization.WAD patients had no alterations in cerebral blood-flow pattern, as measured by rCBF-SPECT and SPM analysis, compared to healthy controls. This contrasts with the non-traumatic group with chronic neck pain, which showed marked blood-flow changes. The blood-flow changes in the non-traumatic group were similar to those described earlier in pain patients but— remarkably enough—were different from those in the WAD group. Chronic neck pain of whiplash and non-traumatic origin appears to be unique in some respects. A better understanding of the underlying pathological mechanisms is a prerequisite for prevention of the development of such chronic pain syndromes and for improvement of the treatment of patients with severe symptoms.

  • 7.
    Jiang, Wei
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
    Regeneration in the adult brain after focal cerebral ischemia: exploration of neurogenesis and angiogenesis2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Ischemic stroke ranks as the third major cause of clinical mortality and the leading cause of handicap in adults. Each year, stroke occurs in about 30,000 Swedes. The severity of an acute ischemic stroke depends mainly on the degree and duration of local cerebral blood flow (lCBF) reduction. Prompt reperfusion improves neurological deficits, spontaneous electrical activity, energy metabolism, cerebral protein synthesis (CPS), and tissue repair, among which cell proliferation (neurogenesis, gliosis) and revascularization (angiogenesis) may have important functional and therapeutic implications.

    Aims of the thesis: (1) To establish the photothrombotic ring stroke(PRS) model with late spontaneous reperfusion in adult mice; (2) To explore angiogenesis and neurogenesis in adult brain after focal cerebral ischemia.

    Materials and Methods: The PRS model in C57 BL adult mice and the middle cerebral artery suture occlusion (MCAO) model in adult Wistar rats were used. The 5-bromodeoxyuridine (BrdU) was delivered into animal after stroke induction to label DNA duplication. CBF, CPS and adenosine triphosphate (ATP) were measured by laser-Doppler flowmetry (LDF), [14C]–Iodoantipyrine and [3H]-Leucine double tracer autoradiography, and bioluminescence, respectively. Immunocytochemistry / immunofluoresence were performed to detect different proteins. The cell marker colocalization was analyzed by three-dimension (3-D) confocal. The cell counting was performed with a stereological counting system.

    Results: The PRS model was established in adult mice by irradiating the exposed skull with a 514.5 nm argon laser ring beam (3 mm diameter, 0.21 mm thick) at an intensity of 0.65 W/cm2 for 60s, with concurrent erythrosin B (4.25 mg/kg) intravenous infusion for 15s. The central cortical region within the ring locus was progressively encroached by an annular ring-shaped perfusion deficit, where lCBF LDF declined promptly to 43% of the baseline value at 30 min post irradiation. The lCBF-IAP amounted to 46-17-58 ml/100g/min, where CPS varied from 57-38-112% at 4h-48h-7days post ischemia. ATP declined at 4h, achieved its maximum level at 48h and was markedly reduced at 7 days postischemia. Morphologically, at 4h some neurons in the region at-risk appeared swollen, at 48h the majority were severely swollen, eosinophilic and pyknotic. Tissue morphology became partly restored at 7 days post stroke, when numerous cortical cells were immunolabeled by BrdU or the mitosis-specific marker phosphorylated histone H3 (Phos-H3). Some of these cells were even doubly immunopositive to the neuron-specific marker Neu N and the astrocyte marker GFAP, as analyzed by 3-D confocal. In adult rats exposed to MCAO, widespread BrdU-immunolabeled cells appeared in the cortex, ipsilateral striatum and dentate gyrus of the hippocampus. Some of which were doubleimmunolabeled by the neuron specific markers Map-2, β-tubulin III and Neu N as analyzed by 3-D confocal. As early as 24h postischemia, BrdU-immunopositive endothelial cells were aligned as microvessels, some of which exhibited distinguishable lumens in the ischemic boundary zone, where VEGF-A, B, C proteins and their receptors flt-1, fik-1, flt-4 were overexpressed at 72h after MCAO.

    Conclusion: PRS model in adult mice elicits a dynamic deterioration and then restoration of local CBF, CPS, ATP and tissue morphology in the spontaneously reperfused cerebral cortex at 7d after stroke, where cortical neurogenesis and gliosis occurred. In adult rats with MCAO, neurogenesis occurred at 30 and 60d in the penumbral cortex and striatum. Angiogenesis occurred as early as 24h, which contributed to the spontaneous reperfusion frequently observed in this setting of acute ischemic stroke.

  • 8.
    Lindström, Meta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Gynekologer och barnmorskor inom svensk abortvård: åsikter, erfarenheter och upplevelser2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Aim: To investigate gynecologists’ and midwives’ views and experiences regarding work in abortion care in Sweden.

    Methods: Questionnaire to gynecologists (n=269) and midwives (n=258 comprising 48 questions, response 85%. The quantitative studies (articles I-III) were supplemented by a qualitative study (article IV), consisting of focus-group interviews with gynecologists and midwives/nurses.

    Results: From the questionnaire studies it was apparent that all the gynecologists had worked in abortion care, whilst not all midwives had done so. The male gynecologists were older than both their female colleagues and the midwives; they had most years of experience but were now working least with abortion patients. Both groups considered it absolutely right, that Sweden have legal abortion and that the law was being followed. Most thought that women should be allowed to have an abortion even after they had felt fetal movements. The midwives were generally somewhat more restrictive than the gynecologists. Half of all thought that the work with abortion patients brought something positive with it. Those having worked longest and most extensively, especially during the previous year were most liberal. Both groups felt that there was a difference between working with surgical and late abortions compared with medical abortions. One in four had had misgivings when involved in surgical and medical abortions, and one in two with abortions after the 18th week. All were positive about the transition to medical abortions, and roughly two thirds of the midwives thought that the primary care sector should be able to take care of these, whereas less than half of the gynecologists thought this. The majority considered it important to receive further and continuing professional development and ongoing guidance. From the focus-group interviews it was clear that the experiences of the gynecologists were largely connected with the technical development of abortion methods and those of the midwives/nurses with improved pain relief. The work was sometimes described in paradoxical terms and was occasionally experienced as frustrating, especially in connection with repeat abortions. Neither of the two groups, however, had had any doubts about participating in abortion. The gynecologists described how women now expected to get an abortion, whereas previously they had asked for one. The midwife/nurse group maintained that the meetings with the women had become considerably more frequent. The interaction between the two professional groups was marked by great trust in each other’s professional competence.

    Conclusions: Gynecologists and midwives working in abortion care support Swedish abortion legislation and have no doubts about participating in abortions, despite the fact that they have frequently experienced complex and difficult work situations. The character of the work is experienced as contradictory and frustrating, but also as challenging and rewarding. The awareness that the two professional groups have of the importance of continuing professional development and ongoing guidance should be acted on. Furthermore, their collective views and experiences should be made use of, so that abortion care can be developed, not only in order to promote women’s health, but also to improve the work environment for the abortion staff.

  • 9.
    Lundgren, Magdalena
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
    Interplay between hormones, nutrients and adipose depots in the regulation of insulin sensitivity: an experimental study in rat and human adipocytes2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Obesity and specifically central obesity is related to insulin resistance, type 2 diabetes and other components of the so-called metabolic syndrome. The aim of this study was to elucidate the interplay between hormones, nutrients and adipose depots in normal and insulin-resistant fat cell metabolism.

    High levels of free fatty acids (FFAs) induce insulin resistance in muscle and liver in vivo. In the present study, rat adipocytes were treated with high physiological levels of oleic or palmitic acid in vitro for 4-24 h. This treatment had no effect on basal or insulin-stimulated glucose uptake capacity in these cells, neither did it affect the levels of the insulin signalling proteins; insulin receptor substrate (IRS)-1 or –2, phosphatidylinositol 3-kinase (PI3-K), protein kinase B (PKB) or glucose transporter (GLUT) 4, or the regulation of lipolysis rate.

    Visceral adiposity is considered to be more harmful than peripheral adiposity with respect to metabolic and cardiovascular complications. In adipose biopsies from subjects undergoing abdominal surgery, we found that glucose uptake capacity was elevated in omental as compared to subcutaneous adipocytes. The sensitivity (EC50) or maximum relative response to insulin, measured as % of basal, did however not differ between the depots. In women, subcutaneous adipocytes displayed a higher lipolysis rate following cAMP-stimulation than omental adipocytes, whereas there was a tendency towards the opposite in adipocytes from men. No differences were found between depots or sexes in the ability of insulin to inhibit lipolysis or in the levels of the lipolysis regulating proteins, i.e. protein kinase A (PKA), hormone sensitive lipase (HSL) and perilipin.

    Glucocorticoids, e.g. cortisol, exert pronounced insulin-antagonistic effects and are associated with redistribution of fat from peripheral to central fat depots in humans. Treatment of human subcutaneous and omental adipocytes in vitro, with the cortisol analogue dexamethasone, resulted in a dose dependent down-regulation of basal and insulin-stimulated glucose uptake capacity in omental, but not in subcutaneous cells. Concomitantly, the levels of IRS-1 and PKB were decreased only in omental adipocytes after dexamethasone treatment. The relative effect of insulin to stimulate glucose uptake was however not altered by dexamethasone treatment. The cAMP-stimulated lipolysis rate was elevated by dexamethasone treatment in cells from the subcutaneous depot in women and tended to be elevated in omental cells from men. No alterations however, were seen in the levels of the assessed lipolysis regulating proteins.

    Subcutaneous as well as omental fat cell size correlated negatively to insulin action in subcutaneous fat cells in vitro after adjusting for age, sex and body fat parameters in non-diabetic, but not in type 2 diabetic, subjects. Large subcutaneous fat cell size was strongly related to plasma leptin levels in non-diabetic and in type 2 diabetic subjects.

    We conclude that 1) adipocytes seem to be less vulnerable to elevated levels of fatty acids than muscle and liver cells, 2) the interactions between glucocorticoids and insulin in the regulation of glucose uptake differ between adipose depots, 3) depot specific hormonal lipolysis regulation differs between sexes and 4) fat cell size is related to insulin action in subcutaneous fat cells and to circulating levels of leptin.

  • 10.
    Löfgren, Magnus
    Umeå University, Faculty of Medicine, Clinical Sciences, Obstetrics and Gynaecology.
    Behavioral effects of female sex steroid hormones : models of PMS and PMDD in Wistar rats2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Animal models can be used to mimic human conditions of psychopathology, and also as pre-clinical models to evaluate candidate drugs. With hormonal treatment it is possible to produce behavior in the rat which corresponds to the mental symptoms of pre-menstrual syndrome (PMS), and pre-menstrual dysphoric disorder (PMDD). PMS affects 25-30 % of all women in fertile age and 3-8% are diagnosed with the more severe condition PMDD. The cardinal mental symptoms are; irritability, mood-swings, depression, anxiety, fatigue, insomnia, difficulties with concentration and memory and learning difficulties. The symptoms of PMS/PMDD occur in the luteal phase in conjunction with increasing concentrations of progesterone (P4) and P4-metabolites. In anovulatory cycles the symptoms are absent. The hormones which produce the monthly reoccurring negative symptoms on mood are foremost the neuroactive metabolites; allopregnanolone (ALLO) and tetrahydro-deoxycorticosterone (THDOC). ALLO is produced by the corpus luteum, but can also be synthesized in the brain, both ALLO and THDOC can also be released from the adrenal cortex during stress. These steroids are active on the inhibitory GABA neurotransmitter system through the GABAA receptor, and the effects are similar to that of alcohol and benzodiazepines. These steroids have strong sedative and hypnotic effects. A paradox is that some individuals seem to react with negative mood on sex steroids while all fertile women have the cyclical steroid changes during the menstrual cycle. Some individuals are more sensitive to neuroactive steroids with influences of personality, heritability and stress factors.

    Aims The thesis aims were to develop pre-clinical animal models of PMS/PMDD and to investigate induction of ALLO tolerance, individual sensitivity to neurosteroids and the interactions between chronic social stress and neurosteroids.

    Methods In these studies male and female Wistar rats were used to test steroid hormone effects on learning and memory and behaviors analogous to negative mood symptoms. This was accomplished through hormonal treatment and a subsequent withdrawal period from P4 (P4) + estradiol (E2) (PEWD), or ALLO. To assess tolerance, memory and learning in the Morris water maze (MWM) was studied. Anxiety-like behaviors were tested with the elevated plus maze (EPM), open field test (OFT), and the intruder test (IT). The EPM or OFT was used to classify the rats as high or low responders on risk-taking and explorative behavior (HR/LR). For social ranking order assessment the tube test (TT) and food competition test (FCT) were used. Chronic social stress was accomplished through co-habituation with two older rats (chronic subordination stress). In female rats the estrous cycle followed using staining of vaginal smears. Concentration of corticosterone (CORT) was measured by radio-immuno-assay (RIA).

    Results In the MWM ALLO pre-treatment produced tolerance to the acute negative ALLO effects. Both male and female rats showed behavioral correlations between the EPM and OFT tests, and correlations were also seen in CORT levels. Individuals with the stable trait of high risk-taking and explorative behavior (HR) were more sensitive to PEWD induction of anxiety-like behavior. These animals also showed decreased CORT levels during withdrawal. Chronic subordination stress enhanced the response to PEWD on measures of locomotor activity and social anxiety-like behavior.

    Conclusions It is possible to induce tolerance to the negative ALLO effects on learning and memory. The animal models of anxiety-like behavior show an individual PEWD response profile where HR rats are more sensitive. Exposure to chronic social stress enhanced the PEWD response. Hence there are both inherent and environmental factors behind the behavioral response to steroid hormones in rats.

  • 11.
    Löfgren, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Strömberg, Jessica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Meyerson, Bengt
    Department of Neuroscience, Division of Pharmacology, Box 593, BMC, SE-751 24 Uppsala, Sweden..
    Bäcktröm, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Chronic subordination stress augments combined progesterone and estradiol withdrawal behaviorManuscript (Other academic)
    Abstract [en]

    Exposure to stress is a risk factor for developing pre-menstrual syndrome (PMS) and pre-menstrual dysphoric disorder (PMDD), and stress enhances the anxiogenic effect of female sex steroids in animals. This study examines the interaction between chronic subordination stress and withdrawal from progesterone (P4) and estradiol (E2) (PEWD) in producing behaviors analogous to anxiety and irritability in rats. At the start of the experiment, male Wistar rats were housed in triads consisting of one younger rat (~35 days) and two older rats (~50 days). The housing condition was aimed at producing chronic subordination stress in the younger animals. Chronic subordination stress was assessed by the elevated plus maze (EPM) and by corticosterone (CORT) analysis. A triad of three 35-day-old rats was used as age control. Social rank within the triads was determined using a food competition test (FCT) and the tube test (TT). The younger rats (subordinate) and the dominant rats were assigned to 10 days of treatment with 5 mg/kg progesterone combined with 10 µg/kg 17β estradiol. Twenty-four hours after the last injection, the subordinate and dominant animals were tested in the open-field test (OFT) and in the intruder test (IT). The IT consists of a 10-minute exposure to 3 unfamiliar rats. Chronic subordination stress reduced EPM open-arm time and altered the CORT response. It also made the subordinate animals more vulnerable to PEWD. The effects were increased locomotion in the OFT, increased defensive burying, and increased social anxiety in the intruder test (IT). Dominant animals did not react to PEWD. Thus, chronic subordination stress augments PEWD.

  • 12.
    Moore, Jason W.
    Umeå University, Faculty of Arts, Department of historical, philosophical and religious studies.
    Environmental crises and the metabolic rift in world-historical perspective2000In: Organization & environment, ISSN 1086-0266, E-ISSN 1552-7417, Vol. 13, no 2, p. 123-157Article in journal (Refereed)
    Abstract [en]

    This article proposes a new theoretical framework to study the dialectic of capital and nature over the longue durée of world capitalism. The author proposes that today’s global ecological crisis has its roots in the transition to capitalism during the long sixteenth century. The emergence of capitalism marked not only a decisive shift in the arenas of politics, economy, and society, but a fundamental reorganization of world ecology, characterized by a “metabolic rift,” a progressively deepening rupture in the nutrient cycling between the country and the city. Building upon the historical political economy of Marx, Foster, Arrighi, and Wallerstein, the author proposes a new research agenda organized around the concept of systemic cycles of agro-ecological transformation. This agenda aims at discerning the ways in which capitalism’s relationship to nature developed discontinuously over time as recurrent ecological crises have formed a decisive moment of world capitalist crisis, forcing successive waves of restructuring over long historical time.

  • 13.
    Rahman, Mozibur
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Effects of neuroactive steroids on the recombinant GABAA receptor in Xenopus oocyte2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Introduction: Neuroactive steroids represent a class of both synthetic and naturally occurring steroids that have an effect on neural function. In addition to classical genomic mechanism by the hormones progesterone, deoxycorticosterone and testosterone 3α-OH metabolites of these hormones enhance GABAA receptor through rapid non-genomic mechanism. The site(s) of action of these neuroactive steroids namely 3α-OH-5α-pregnan-20 one, (3α,5α)-3,21-deoxycorticosterone(3α5α-THDOC) and 5α androstane-3α,17β-diol on GABAA receptor are distinct from that of benzodiazepines and barbiturate binding sites. The modulation site(s) has a well-defined structure activity relationship with a 3α-hydroxy and a 20-ketone configuration in the pregnane molecule required for agonistic action. Pregnenolone sulfate is a noncompetitive GABAA receptor antagonist and inhibit GABA activated Cl- current in an activation dependant manner. 3β-hydroxy A-ring reduced pregnane steroids are also GABAA receptor antagonist and inhibit GABAA receptor function and its potentiation induced by their 3α-diesteromers in a noncompetitive manner.

    Aim: The aim was to investigate if the effect of GABA, pentobarbital antagonism by bicuculline and if the effect of GABA-agonist and antagonist neuroactive steroids including pregnenolone sulfate is dependant on the α-subunits of GABAA receptor. Furthermore, the studies aimed at investigating the binding site of pregnenolone sulfate and if its effect is dependent on γ-subunit. In addition, the inhibitory effect of pregnenolone sulfate and 3β-hydroxy steroids has been characterized. We also wanted to investigate if the neuroactive steroids effect vary between the human and rat recombinant α1β2γ2L receptors and between the long (L) and short (S) variants of γ2-subunit.

    Method: Experiments were performed by the two electrodes voltage-clamp technique using oocytes of Xenopus laevis expressed with recombinant GABAA receptors containing α1, α4 or α5, β2, γ2L and γ2S-subunits.

    Results: There was no difference between the α1, α4 and α5-containing subunits regarding GABA and pentobarbital inhibition by bicuculline. GABA-activated current in the binary αβ was potent than that of ternary αβγ receptor. Unlike Zn2+ effect, inhibition by pregnenolone sulfate on the GABAA receptor is not dependant on the γ-subunit. It is likely that the 2’ residue closest to the N-terminus of the protein at M2 helix on both α1 and β2 subunit are critical to the inhibitory actions of PS and the function of Cl- channels. Point mutation at M2 helix of the β2-subunit (b2A252S) can dramatically reduce the inhibitory effect of PS on the GABAA receptors without affecting the inhibitory properties of 3β-hydroxysteroids. Agonist and antagonist steroids also varied in their efficacy between the human and rat α1β2γ2L receptor. Neuroactive steroids also showed difference between human γ2L and γ2S-containing receptor.

    Conclusions: GABA and pentobarbital antagonism by bicuculline is not dependant on α-subunit. Pregnenolone sulfate binding site is different from that of Zn2+. 3β-hydroxysteroids and pregnenolone sulfate inhibit GABAA receptor through different mechanisms. Neuroactive steroids also differ between species and between the long and short variant of γ- subunit.

  • 14.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Fat cell insulin resistance: an experimental study focusing on molecular mechanisms in type 2 diabetes2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of the present thesis was to further increase our understanding of mechanisms contributing to and maintaining cellular insulin resistance in type 2 diabetes (T2D). For this reason, the effects of high glucose and insulin levels on glucose transport capacity and insulin signaling, with emphasis on insulin receptor substrate 1 (IRS-1) were assessed in fat cells. Altered levels of IRS-1 have previously been observed in adipose tissue from insulin-resistant and T2D subjects.

    A high glucose level (≥15 mM) for 24 h exerted only a minor impairment on glucose transport capacity in human adipocytes, as opposed to rat adipocytes. However, when combined with a high insulin level (104 µU/ml), basal and insulin-stimulated glucose transport was significantly impaired in both human and rat adipocytes. This was associated with a depletion of IRS-1 and IRS-2 protein levels in rat adipocytes, as a result of post-translational changes and altered gene transcription, respectively. In human adipocytes was only IRS-1 protein levels reduced. The high glucose/high insulin setting achieved maximal impairment of glucose transport within 6 h. Subsequent incubations of rat adipocytes under physiological conditions could partially restore insulin sensitivity. Interestingly, in both human and rat fat cells, decreased levels of IRSs occurred after the establishment of impaired glucose transport, suggesting that the observed depletion of IRSs is a consequence rather than a cause of insulin resistance. Nonetheless, IRS depletion is likely to further aggravate insulin resistance.

    Tyrosine phosphorylation of IRS-1 upon insulin stimulation activates the signaling pathway that mediates glucose transport. Pre-treatment of human adipocytes with high glucose and insulin levels was not associated with any alterations in the total IRS-1 Tyr612 phosphorylation following 10 min insulin stimulation. However, a significant increase in basal Tyr612 phosphorylation was observed. Furthermore, a rise in basal IRS-1 Ser312 phosphorylation was found. This is associated with reduced IRS-1 function and is considered to target IRS-1 to degradation pathways, and thus could potentially explain the observed decrease in IRS-1 protein levels. Our results imply an enhanced activation of insulin’s negative-feedback control mechanism that inhibit IRS-1 function. This could potentially have contributed to the observed impairment of insulin action on glucose transport in these cells. Accordingly, we have also shown that the downstream activation of protein kinase B upon insulin-stimulation is significantly impaired in human adipocytes exposed to the high glucose/high insulin setting, indicating a defect in the signaling pathway mediating glucose transport.

    We also investigated whether there are humoral factors in the circulation of T2D patients that contribute to peripheral insulin resistance. Human adipocytes cultured for 24 h in medium supplemented with 25% serum from T2D subjects, as compared to serum from non-diabetic subjects, displayed significantly reduced insulin-stimulated glucose uptake capacity. The effect could neither be attributed to glucose, insulin, FFA, TNF-α or IL-6 levels in the serum, but other circulating factor(s) seem to be of importance.

    In conclusion, chronic conditions of elevated glucose and/or insulin levels all impair insulin action on glucose turnover, but to different extents. A clear distinction between rat and human fat cells in the response to these different milieus was also observed. Alterations in the function of the key insulin signaling protein IRS-1 might be involved in the mechanisms underlying the impaired glucose uptake capacity. IRS-1 reduction however, occurs after but probably aggravates the existing insulin resistance. The effects of high glucose and/or insulin levels may be of importance in T2D, but additional novel factors present in the circulation of T2D patients seem to contribute to cellular insulin resistance.

  • 15.
    Strand, Magnus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Estrogen signaling in stroke: genetic and experimental studies2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Stroke is a common and multifactorial disease influenced by genetic and environmental risk factors. It is a highly heterogeneous entity consisting of two main types, ischemic (80%) and hemorrhagic (20%) stroke. The most common form of hemorrhagic stroke is intracerebral hemorrhage (ICH). Ischemic stroke mainly results from thrombotic or embolic events, while ICH is caused by the rupture of an artery in the brain.

    The mean age of first-ever stroke is 75 years (73 vs. 78 years, for men and women, respectively) and the age-specific stroke incidence is higher for men as compared to women, suggesting that hormonal factors confer protection. A large body of experimental and observational studies shows that estrogens exert beneficial effects in the cardiovascular system. However, large, recent, clinical randomized trials have failed to demonstrate a lower risk of stroke with hormone replacement therapy (HRT) in elderly postmenopausal women. It is possible that HRT may only protect a subgroup of women. Here, genetic predisposition might be involved. Stroke incidence is 50% higher in northern compared to southern Sweden, suggesting a genetic predisposition in this population. This relatively homogeneous population displays founder effects, making it well suited for genetic studies. Since 1985, the MONICA and VIP projects have conducted large-scale cardiovascular health surveys in this population. Information about conventional stroke risk determinants and also DNA have been collected, and two prospective, nested case-referent cohorts (113 cases and 226 controls; 275 cases and 549 controls) have been sampled.

    To investigate whether genes of the estrogen signaling system may be important in stroke development, we performed genetic association studies, including specific functional single nucleotide polymorphisms in the genes for estrogen receptor alpha (ERα, ESR1), and its target genes osteoprotegerin (OPG, TNFRS11B) and interleukin-6 (IL-6, IL6). We found a significant association between the common c.454-397T/T genotype in ESR1 and ICH, remaining after adjustments for conventional stroke risk factors. The c.454-397T/T genotype also associated with increased systolic (SBP) and diastolic blood pressure (DBP). The combination of c.454- 397T/T and either hypertension, increased SBP, or increased DBP boosted this association substantially and significant synergistic effects on ICH risk between this genotype and increased blood pressure were demonstrated. In a second study, we found a similar association between the common OPG-1181C/C genotype and ICH.

    Cognitive impairments, including spatial memory and learning deficiencies, are common after stroke. Estrogens improve cognitive functions, including memory and learning processes, in postmenopausal women and ovariectomized rodents. Post-ischemic housing of rats in an enriched environment (EE) improves recovery of spatial memory and learning impairments. Both estrogen and EE induce neuroplasticity in the hippocampus. We hypothesized that 17β- estradiol combined with EE would accelerate recovery after experimental focal brain ischemia in ovariectomized rats and that such improvements could be related to expression of nerve growth factor-induced gene A (NGFI-A) in the hippocampus. Five to six weeks after middle cerebral artery occlusion, 17β-estradiol–treated rats housed in an EE showed significant improvements in cognitive function (i.e., shorter latency and path in the Morris water maze task) and significantly higher NGFI-A mRNA expression in bilateral cornu ammonis 1 (CA1) and ipsilateral dentate gyrus (DG) compared to placebo-treated animals in EE.

    In conclusion, we present evidence for the association between polymorphic variants in the ESR1 and TNFRS11B genes and ICH and show that 17β-estradiol in combination with EE accelerates cognitive functions in a rat stroke model, putatively through upregulation of NGFI-A in hippocampal subregions. These findings may contribute to an increased understanding of the underlying genetic etiology of ICH and may be informative for the primary prevention of this disease. They also provide hope for 17β-estradiol combined with early environmental enrichment as a novel therapeutic option following ischemic stroke.

  • 16.
    Strömberg, Jessica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sex and stress steroid modulation of GABA mediated chloride ion flux in rat CNS2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Sex and stress steroids are metabolized to 3a-hydroxy-pregnane-steroid metabolites such as allopregnanolone (Allo) and tetrahydrodeoxycorticosterone (THDOC). Allo and THDOC are neuroactive steroids that are metabolized in the brain and act in brain as potent positive GABAA receptor function modulators. Allo as well as THDOC levels increase during stress. Allo has been associated with a number of symptoms and malfunctions such as impaired memory function and negative mood symptoms in a subgroup of individuals both for animals and humans. Pregnane steroids with 3b-hydroxy-configuration (3b-steroids) have been shown to reduce the Allo enhanced GABA effect.

    Aims: The aims for the present thesis were to investigate the effect of 3b-steroids on the GABA mediated GABAA receptor function in presence of positive GABAA receptor modulators. Further, the regional variances between the 3b-steroids as well as the mechanism of the effect were studied. Finally, the effect of stress steroid metabolites on the GABAA receptor function was investigated.

    Results: 3b-OH-5a-pregnane-20-one reduced the Allo enhanced GABA mediated chloride ion uptake into cortical microsacs. The 3b-isomer reduced the efficacy of Allo without shift the concentration response curve. It is therefore suggested that the 3b-isomer has a non-competitive effect. Further, it was shown that the 3b-isomer reduced the Allo effect in a selective way since the 3b-isomer did not interact with other positive modulators or with GABA itself. Five tested 3b-steroids reduced the Allo enhanced GABA mediated chloride ion uptake in cerebral cortex and hippocampus as well as the Allo prolongation on spontaneous inhibitory postsynaptic currents (sIPSCs) in preoptic nucleus. In cerebellum on the other hand the 3b-steroids showed to have weaker or no effect compared to the other tested regions. Interestingly, in absence of Allo, two of the 3b-steroids positively modulated the GABA stimulated GABAA receptor function. In absence of Allo, 5b-pregnane-3b,20(R)-diol increased the desensitization rate of current response. In contrast to the reducing effect on the Allo induced prolongation on sIPSCs, the effect of the 3b-steroid on GABA application, was not altered in presence of Allo. The mechanism of the 3b-steroid is therefore suggested being desensitization dependent in contrast to Allo, which has been suggested to decrease the GABA unbinding rate. In contrast to the enhanced effect of Allo, glucocorticoid metabolites reduced the GABA mediated chloride ion uptake in a concentration dependent way. The results in present thesis indicate that both sex and stress steroid metabolites interact with the GABAA receptor function. The knowledge that diversity of endogenous steroids interact with the GABAA receptor function is of importance for further understanding of different sex and stress steroid related symptoms and syndromes.

  • 17.
    Sundström, Gunnel
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
    Hyaluronan in normal and malignant bone marrow: a clinical and morphological study with emphasis on myelofibrosis2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fibrosis in the bone marrow is usually denominated myelofibrosis and may contribute to impaired hematopoiesis. Myelofibrosis is seen both in malignant and non-malignant diseases.

    The normal microenvironment in the bone marrow consists of a heterogenous population of hematopoietic and non-hematopoietic stromal cells, their extracellular products and hematopoietic cytokines. The stromal cells produce a complex array of molecules, among others collagens and glycosaminoglycans (GAGs) of which hyaluronan (HYA) is the most abundant. Marrow fibrosis results from an increased deposition of collagens, which are polypeptides. Staining for reticulin, mostly composed of collagen type III, is the common way of visualizing myelofibrosis. HYA, like the collagens, is widely distributed in connective tissues. Little is known about the distribution of HYA in bone marrow.

    The aims of this thesis have been to determine how HYA is distributed in normal and malignant bone marrow, compared to reticulin staining, and to follow patients with chronic myeloproliferative diseases (CMPD) during two years treatment with anagrelide considering development of cellularity and fibrosis.

    In bone marrow biopsies from healthy volunteers, the controls, HYA was found in a pattern that was concordant with the reticulin staining.

    Comparing patients with different malignant diseases with and without bone marrow involvemen, HYA staining was found to be significantly stronger in both groups compared to the controls.

    The HYA scores were also significantly higher in the bone marrow of patients with de novo acute myeloid leukemia (AML), compared to the controls.

    There was a correlation between HYA and reticulin in the patients with de novo AML, and in the patients with different malignant diseases with and without bone marrow involvement as in the controls.

    Increase of HYA, reticulin and cellularity in the bone marrow of patients with CMPD after two years of treatment with anagrelide indicated progression of fibrosis. Anagrelide is a valuable drug for reduction of platelets but seems unable to stop progression of fibrosis and hypercellularity.

    HYA is an interesting molecule with properties not only contributing to the structure of extracellular matrix but also to cell signaling and behaviour, although the understanding of the detailed mechanisms is still incomplete.

  • 18.
    Türkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Löfgren, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Birzniece, Vita
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Tolerance development to Morris water maze test impairments induced by acute allopregnanolone2006In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 139, no 2, p. 651-659Article in journal (Refereed)
    Abstract [en]

    The progesterone metabolite allopregnanolone, like benzodiazepines, reduces learning and impairs memory in rats. Both substances act as GABA agonists at the GABA-A receptor and impair the performance in the Morris water maze test. Women are during the menstrual cycle, pregnancy, and during hormone replacement therapy exposed to allopregnanolone or allopregnanolone-like substances for extended periods. Long-term benzodiazepine treatment can cause tolerance against benzodiazepine-induced learning impairments. In this study we evaluated whether a corresponding allopregnanolone tolerance develops in rats. Adult male Wistar rats were pretreated for 3 days with i.v. allopregnanolone injections (2 mg/kg) one or two times a day, or for 7 days with allopregnanolone injections 20 mg/kg intraperitoneally, twice a day. Thereafter the rats were tested in the Morris water maze for 5 days and compared with relevant controls. Rats pretreated with allopregnanolone twice a day had decreased escape latency, path length and thigmotaxis compared with the acute allopregnanolone group that was pretreated with vehicle. Pretreatment for 7 days resulted in learning of the platform position. However, the memory of the platform position was in these tolerant rats not as strong as in controls only given vehicle. Allopregnanolone treatment was therefore seen to induce a partial tolerance against acute allopregnanolone effects in the Morris water maze.

  • 19.
    Winberg, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Nordström, Lisbeth
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Strinnholm, Åsa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Nylander, Annica
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Jonsäll, Anette
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Rönnmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    West, Christina E.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    New validated recipes for double-blind placebo-controlled low-dose food challenges2013In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 24, no 3, p. 282-287Article in journal (Refereed)
    Abstract [en]

    Double-blind placebo-controlled food challenges are considered the most reliable method to diagnose or rule out food allergy. Despite this, there are few validated challenge recipes available. The present study aimed to validate new recipes for low-dose double-blind placebo-controlled food challenges in school children, by investigating whether there were any sensory differences between the active materials containing cow's milk, hen's egg, soy, wheat or cod, and the placebo materials. The challenge materials contained the same hypoallergenic amino acidbased product, with or without added food allergens. The test panels consisted of 275 school children, aged 810 and 1415yr, respectively, from five Swedish schools. Each participant tested at least one recipe. Standardized blinded triangle tests were performed to investigate whether any sensory differences could be detected between the active and placebo materials. In our final recipes, no significant differences could be detected between the active and placebo materials for any challenge food (p>0.05). These results remained after stratification for age and gender. The taste of challenge materials was acceptable, and no unfavourable side effects related to test materials were observed. In summary, these new validated recipes for low-dose double-blinded food challenges contain common allergenic foods in childhood; cow's milk, hen's egg, soy, wheat and cod. All test materials contain the same liquid vehicle, which facilitates preparation and dosing. Our validated recipes increase the range of available recipes, and as they are easily prepared and dosed, they may facilitate the use of double-blind placebo-controlled food challenges in daily clinical practice.

  • 20.
    Zeisig, Eva
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine.
    Tennis elbow: sonographic findings and intratendinous injection treatment2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tennis elbow (TE) is a relatively common painful condition affecting the upper extremity. The aetiology is not known, but TE is most often seen in middle aged individuals using repetitive and forceful gripping at work or recreational activities, and is referred to overuse injuries. The pathogenesis is not known, but there are so-called degenerative changes in the wrist- and finger-extensor muscle origin (common extensor origin - CEO). The pain mechanisms involved have not been scientifically clarified.

    The studies in the present thesis aimed to 1) evaluate the structure and blood flow using ultrasound (US) and colour Doppler (CD) examinations of the CEO in patients with TE, and in pain-free elbows, 2) evaluate the clinical effects of US- and CD-guided intratendinous injection treatment with the sclerosing substance polidocanol, 3) evaluate the long term (2 years) effects of injection treatment on the tendon structure and blood flow, and 4) investigate if there is a local production of sympathetic and parasympathetic signal substances in non-neural cells in the CEO.

    Structural tendon changes and high blood flow was found in the CEO in patients with TE, but not in pain-free controls. Remaining structural changes and additional bone spur formation at the lateral epicondyle, but not high blood flow, were seen 2 years after successful injection treatment. In a randomised double-blind study, US- and CD-guided intratendinous injection treatment with sclerosing polidocanol or the local anaesthetic lidocaine combined with epinephrine, targeting the region with high blood flow, was found to reduce pain and increase grip strength in patients with TE. There were no differences in the outcome between the two treatment groups. A local production of catecholamines, but not acetylcholine, was found in fibroblasts in the CEO, in patients with TE.

    This thesis presents results showing US and CD examinations to be useful methods to diagnose TE, and to evaluate structure and blood flow in the CEO after treatment. US- and CD-guided injection treatment targeting high blood flow in the region with structural changes can reduce pain symptoms in patients with TE. The localised high blood flow, and local production of catecholamines in the tendon cells in the CEO, might be involved in the pain mechanisms.

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