The purpose of this investigation was to study sexual function in women with neurological disorders at fairly distinct and separate locations. The dissertation comprises descriptive, retrospective, quantitative studies on sexual functioning in women with hypothalamo-pituitary disorders (HPD) (n:48), multiple sclerosis (MS)(n:47), and insulin-dependent diabetes mellitus (IDDM) (n:42). The results werecompared with those in an age-matched control group (C) (n:42), and as reported by representative Swedish women (n:742) in the Swedish sex survey SiS). The studies were based on comprehensive interviews, neurological examinations, incl. Vibration Perception Thresholds (IDDM), concentrations of prolactin and testosterone in serum (HPD), and a checklist on life satisfaction (IDDM, C, and SiS). Sexual dysfunction was prevalent in almost all women with HPD and MS, and in 40% of the IDDM group. The problem of insufficient vaginal lubrication was more common in those with neurological disorders than among women in the SiS group. Sexual problems caused by reduced libido and orgasmic difficulties were more commonin the HPD and MS groups than in the SiS group. In the HPD group, women with intrasellar adenomas had better sexual function than women having expansively growing pituitary adenomas with both intra- and suprasellar extension. Normal serum testosterone values correlated to masturbation activity. Amenorrhea and older age werecorrelated with sexual problems in all groups. In the MS group, symptoms of a weak pelvic floor and of bladder and bowel dysfunction were correlated with reduced lubrication and orgasmic ability. In the IDDM group, signs of autonomic neuropathy were correlated with sexual dysfunction. Concerning life satisfaction generally,proportionately fewer women with IDDM were satisfied or very satisfied, though differing significantly from the other two groups in only two domains of life: contacts with friends, and physical health.

Long-term potentiation (LTP) and depression (LTD) are important forms of activity-dependent synaptic plasticity believed to play a role in memory at the cellular level. It has previously been described that synthesis of new proteins is needed to maintain LTP longer than a few hours. Other reports argue that sufficient proteins for stable LTP are already available. The present study aims to examine the role of protein synthesis in LTD, the presumed mirror mechanism of LTP. Experiments were carried out in hippocampal slices from young (12-45 days) and old (12-18 weeks) Sprague-Dawley rats. Extracellular techniques were used to study synaptic responses in the Schaffer-collateral-commissural pathway. Plasticity was induced electrically by low frequency stimulation (2-3 trains at 1 Hz for 15 min) or chemically by brief exposure to certain glutamate receptor agonists (NMDA at 20 µM for 3 min or DHPG at 100 µM for 10 min). Whole slice protein synthesis was quantified by assessing 3H-leucine incorporation. Stable LTD (> 8 h) was be obtained by either electrical or chemical activation. Protein synthesis inhibitors anisomycin (40 uM) and cycloheximide (100 uM) both failed to influence the magnitude of LTD. Moreover, no age difference was found, in terms of stable LTD in both young and old rats under inhibition of protein synthesis. The potency of the inhibitors was found to be high, depressing synthesis down to a few percent. It is concluded that sufficient proteins for generating stable LTD are normally present in the brain, implying a large safety-margin for cellular memory.

Migraine is a disabling neurological disorder with high prevalence, the clinical manifestations of which are highly dependent on stress. The overall theme of the present thesis was to address aspects of stress in migraine. A multimodal behavioral treatment (MBT) program was developed specifically designed for migraine and focusing on stress as a trigger and an intervention was performed using this Internet-administered program. Migraine symptoms were followed via an Internet administered diary and questionnaires were answered at regular intervals during the 11-month study period. The thesis is based on four papers: In Paper I, life events and current stress, personality traits, and gender were studied cross-sectionally in 106 women and 44 men with migraine, who suffered at least two attacks a month at inclusion. Paper II describes a randomized controlled trial of the MBT program performed on 58 women and 25 men recruited from participants of the study described in Paper I. In the MBT study participants were randomized into one control group and two MBT groups, one of which received hand massage as part of the treatment. In Paper III, complete migraine drug use and changes in use and in drug efficacy during the MBT program were studied. In Paper IV, the salivary cortisol levels of MBT participants were evaluated as a biological stress marker. The MBT program proved effective in decreasing migraine headache; it was feasible and there was low attrition. Moreover, MBT resulted in decreased migraine drug use and increased drug efficacy, but had no discernible effects on salivary cortisol profiles. No effect of hand massage on migraine headache frequency was seen. Personality trait profiling revealed high scores for the neuroticism factor. Stress susceptibility was the single most aberrant personality trait and correlated highly with the reported level of current stress and with experienced negative life events. Gender differences included higher scores for women on trait anxiety, negative life events, depressive mood, anxiety, tension type headache, use of triptans, and efficacy of analgesics, whereas men displayed higher use of analgesics. In conclusion, the efficacy and low attrition associated with the present MBT program appears promising and timely with regard to the development of better and more accessible migraine treatment. Stress susceptibility, gender, negative life events and psychosomatic comorbidity are important factors to consider in relation to the care of persons with migraine.

Stroke är den vanligaste orsaken till förvärvat neurologiskt funktionshinder hos vuxna och den tredje vanligaste dödsorsaken i Sverige. Antal symtom samt svårighetsgrad varierar beroende på skadans områdesbegränsning. Riskutsatt hjärnvävnad kan återhämta sig vid tidig behandling och kan minimera permanenta skador på hjärnan. Initialt genomförs en datortomografi (DT) av hjärnan, för att möjliggöra trombektomi behandling rekommenderas det att förutom DT-angiografi även diagnostik av räddningsbar hjärnvävnad göras med DT-perfusion (DTP).   Syftet med denna litteraturstudie är att ur ett radiografiskt perspektiv beskriva DTPs roll vid utredning och behandling av akut ischemisk stroke vid ocklusion av större cerebrala artärer. Metoden är en litteraturstudie med systematisk metod där 108 studier genomgått en urvalsprocess samt en kvalitetsgranskning. Totalt inkluderades 20 studier.   Resultatet visar på att urval för trombektomi baserad på avancerad bildbehandling fördubblar sannolikheten för goda funktionella resultat jämfört med standard DT metod. Urval baserad på standard DT-protokoll kan inkludera patienter som skulle ha uteslutits av DTP på grund av stor variation i DTP-corevolym.  Slutsats: Vår studie visar att DTP tillför ökad diagnostisk säkerhet vid akut ischemisk stroke och kan påverka efterföljande behandling. / Stroke is the most common cause of acquired neurological disability in adults and the third most common cause of death in Sweden. Symptoms and severity vary depends on the area limitation of the injury. Risk-prone brain tissue can recover with early treatment and can minimize permanent damage to the brain. Initially, a CT (Computed Tomography) scan of the brain is performed, but to enable thrombectomy treatment, it is recommended that in addition to CT angiography, diagnostics of salvageable brain tissue be done with CT-perfusion (CTP).   The aim of this literature review based on 20 quality reviewed studies is to elucidate, from a radiographic perspective, the role of CTP of the brain in the diagnosis and treatment of acute ischemic stroke (AIS) in occlusion of major cerebral arteries.   The results show that selection for thrombectomy based on advanced image processing doubles the probability of good functional results compared to the standard CT. Selection based on the CT method may include patients who would have been excluded by CTP due to large variation in CTP core volume.  Conclusion: Our study shows that CTP provides increased diagnostic safety in AIS and may affect subsequent treatment.

<p><p><strong>Bakgrund: </strong>Smärtor i ben är vanligt förekommande och neuropati (nervskada) är en orsak som troligen är underdiagnostiserad. Bimanuell (tvåhändig/tvåsidig) nervpalpation och känseltest med sporre har visat sig vara ganska tillförlitliga och enkla test för att hitta nervskada men har inte testats på friska individer.</p><p><strong>Syfte: </strong>Syftet var att undersöka om bimanuell nervpalpation i fossa poplitea framkallar smärta/obehag och om det finns skillnad mellan vänster och höger sida vid bimanuell undersökning med sporre på underben hos friska försökspersoner.</p><p><strong>Metod: </strong>Ett bimanuellt palpationstest av nervi tibialis och peroneus i fossa poplitea och även ett bimanuellt känseltest med sporre över dermatomen L4, L5 och S1 på underben genomfördes. Urvalet var ändamålsenligt och totalt deltog 37 försökspersoner. Åldersspannet var 20 till 57 och medianålder 23.</p><p><strong>Resultat: </strong>Vid palpationstestet hade intensiteten av smärta/obehag en median på 1 (variationsvidd 3) på den 11 gradiga skalan. En stor del skattade olika mellan sidorna i både palpationstestet (11 av 37) och känseltestet med sporre (25 av 37). Det var inte någon större skillnad mellan könen.</p><p><strong>Slutsats: </strong>När man utför dessa nervtester måste man ta hänsyn till att även friska individer ofta anger en liten sidoskillnad och inte alltid skattar noll vad gäller smärta/obehag. Det behövs dock fler studier för att bekräfta dessa resultat.</p></p> / <p><strong>Background: </strong>Leg pain is common and neuropathy (nerve disease) is one reason which probably is under diagnosed. Bimanual (bilateral) nerve palpation and sensory test with spurs has been shown to be quite reliable. Furthermore, the tests are straight forward detecting nerve disease but have not been tested on a healthy population.</p><p><strong>Purpose: </strong>The purpose was to investigate whether peripheral nerve palpation in fossa poplitea induces pain/discomfort, and if side difference exists in a sensibility test with spurs on the lower leg in healthy subjects.</p><p><strong>Method: </strong>A bimanual palpation test of the tibial and peroneal nerve in fossa poplitea and also a bimanual sensibility test with spurs of dermatome L4, L5 and S1 on the lower leg were carried out. In order to find healthy subjects a purposive sampling was made. A total of 37 subjects between 20 and 57 years with a median age of 23 participated in the study.</p><p><strong>Results: </strong>At the palpation test the intensity of pain/discomfort had a median of 1 (range 3) in the 11 degrees of pain scale. A large part estimated differences between the sides in both the palpation test (11 of 37) and the sensibility test with spur (25 of 37). There was no significant difference between the sexes.</p><p><strong>Conclusion: </strong>When performing these nerve tests it is important to keep in mind that even healthy individuals might perceive some pain/discomfort as well as side difference. However, we need more studies to confirm these results.</p>

<p>The developing nervous system depends largely on extracellular cues to shape its complex network of neurons. Classically, neurotrophins are known to be important mediators in this process. More recently, Bone Morphogenetic Proteins (BMPs), belonging to the Transforming Growth Factor beta (TGFβ) superfamily of secreted cytokines, have been shown to exert a wide range of effects, such as cellular growth, differentiation, survival and apoptosis, both in the developing and adult nervous system. They signal via serine/threonine kinase receptor essentially to the Smad pathway, which carries the signal to the nucleus where the transcription of target genes is regulated.</p><p>This thesis investigates the functions of BMPs in the nervous system, using a set of different models. Firstly, a targeted deletion of GDF10 (BMP3b) in the mouse was established to evaluate the role of this growth/differentiation factor in the hippocampal formation, a brain area known to be involved in memory processing. Other members of the TGFβ superfamily likely compensate for the lack of GDF10, since no detectable alterations in hippocampal function or gene transcription profile have been found. Secondly, a mouse model was set up, with the aim to study impaired BMP-signalling in dopaminergic neurons. The tyrosine hydroxylase (TH) locus was used to drive the expression of dominant negative BMP receptors by means of bicistronic mRNAs. TH is the rate-limiting enzyme in the biosynthesis of catecholamine and the mice described, show a graded decrease of TH-activity resulting in severe to mild dopamine deficiency. The contribution of the dominant negative BMP receptors to the phenotype is however secondary to the apparent TH hypomorphism. The final theme of this thesis is the potentiating effects of BMPs on neurotrophin-induced neurite outgrowth as studied in explanted ganglia from chick embryos and in the rat phaeochromocytoma cell line PC12. A number of pharmacological inhibitors of intracellular signalling kinases were applied to the cultures in order to reveal the contribution of different pathways to the enhanced neurite outgrowth. We made the unexpected finding that inhibition of MEK signalling mimicked the potentiating effects of BMP stimulation in the chick system. The underlying mechanisms for the synergistic effects, however, are still an enigma.</p>

<p>Traumatic brain injury (TBI) is a leading cause of death and disability TBI survivors often suffer from severe disturbances of cognition, memory and emotions. Improving the treatment is of great importance, but as of yet no specific neuroprotective treatment has been found. After TBI there are changes in ion homeostasis and protein regulation, causing generation of reactive oxygen species (ROS). Overproduction of ROS can lead to damage cellmembranes, proteins and DNA and secondary cell death. In the present thesis experimental TBI in rats were used to study the effects of the ROS scavengers α-phenyl-N-tert-butyl-nitrone (PBN) and 2-sulfophenyl-N-tert-butyl-nitrone (S-PBN) on morphology, function, intracellular signalling and apoptosis. </p><p>Posttreatment with PBN and S-PBN resulted in attenuation of tissue loss after TBI and S-PBN improved cognitive function evaluated in the Morris water maze (MWM). Pretreatment with PBN protected hippocampal morphology, which correlated to better MWM-performance after TBI.</p><p>To detect ROS-generation in vivo, a method using 4-hydroxybenzoic acid (4-HBA) microdialysis in the injured cortex was refined. 4-HBA reacts with ROS to form 3,4-DHBA, which can be quantified using HPLC, revealing that ROS-formation was increased for 90 minutes after TBI. It was possible to attenuate the formation significantly with PBN and S-PBN treatment. </p><p>The activation of extracellular signal-regulated kinase (ERK) is generally considered beneficial for cell survival. However, persistent ERK activation was found in the injured cortex after TBI, coinciding with apoptosis-like cell death 24 h after injury. Pretreatment with the MEK-inhibitor U0126 and S-PBN significantly decreased ERK activation and reduced apoptosis-like cell death. Posttreatment with U0126 or S-PBN showed robust protection of cortical tissue.</p><p>To conclude: ROS-mediated mechanisms play an important role in secondary cell death following TBI. The observed effects of ROS in intracellular signalling may be important for defining new targets for neuroprotective intervention.</p>

<p>Amyotrophic lateral sclerosis is a fatal, progressive neurodegenerative disease with unknown ethiology. The aim of this study was to increase understanding of the pathophysiological mechanisms of dying motor neurons and wasting muscle tissue in this particular disorder.</p><p>Quantitative receptor autoradiographic methodology was applied on cervical spinal cord sections from patients with ALS to evaluate the specific binding of the acetylcholine transporter ³H-vesamicol in motor neurons. Despite a significant reduction of the number of ventral motor neurons in ALS, the ³H-vesamicol binding was not reduced in ALS compared to control cases, which suggests an increased metabolic activity in remaining motor neurons.</p><p>Motor neurons dying in ALS might go through apoptosis (programmed cell death), so immunohistochemical and TUNEL techniques were applied on thoracic spinal cord from ALS patients to evaluate the possibility of an apoptotic process. The increased Bax expression indicates an apoptotic process and further, motor neurons were TUNEL-positive, indicating DNA degradation caused by programmed cell death.</p><p>Muscle biopsies were obtained from ALS patients, and mRNA levels for the neurotrophic factors GDNF and BDNF were measured and compared to control subjects. GDNF levels were increased in muscle tissue in ALS whereas BDNF levels were unaltered.</p><p>Levels of GDNF and BDNF were also measured in cerebrospinal fluid from ALS patients and controls using ELISA methodology. Levels of BDNF were unaltered in ALS cornpared to controls. GDNF however was not detectable in controls whereas 12 out of 15 ALS patients had measurab1e levels of GDNW. A marked upregulation of endogenous GDNF and GDNF mRNA in ALS CSF and muscle respectively is of special interest in relation to clinical trials where GDNF is administered to this group of patients.</p>

Amyotrophic lateral sclerosis is a fatal, progressive neurodegenerative disease with unknown ethiology. The aim of this study was to increase understanding of the pathophysiological mechanisms of dying motor neurons and wasting muscle tissue in this particular disorder. Quantitative receptor autoradiographic methodology was applied on cervical spinal cord sections from patients with ALS to evaluate the specific binding of the acetylcholine transporter 3H-vesamicol in motor neurons. Despite a significant reduction of the number of ventral motor neurons in ALS, the 3H-vesamicol binding was not reduced in ALS compared to control cases, which suggests an increased metabolic activity in remaining motor neurons. Motor neurons dying in ALS might go through apoptosis (programmed cell death), so immunohistochemical and TUNEL techniques were applied on thoracic spinal cord from ALS patients to evaluate the possibility of an apoptotic process. The increased Bax expression indicates an apoptotic process and further, motor neurons were TUNEL-positive, indicating DNA degradation caused by programmed cell death. Muscle biopsies were obtained from ALS patients, and mRNA levels for the neurotrophic factors GDNF and BDNF were measured and compared to control subjects. GDNF levels were increased in muscle tissue in ALS whereas BDNF levels were unaltered. Levels of GDNF and BDNF were also measured in cerebrospinal fluid from ALS patients and controls using ELISA methodology. Levels of BDNF were unaltered in ALS cornpared to controls. GDNF however was not detectable in controls whereas 12 out of 15 ALS patients had measurab1e levels of GDNW. A marked upregulation of endogenous GDNF and GDNF mRNA in ALS CSF and muscle respectively is of special interest in relation to clinical trials where GDNF is administered to this group of patients.

Traumatic brain injury (TBI) is a leading cause of death and disability TBI survivors often suffer from severe disturbances of cognition, memory and emotions. Improving the treatment is of great importance, but as of yet no specific neuroprotective treatment has been found. After TBI there are changes in ion homeostasis and protein regulation, causing generation of reactive oxygen species (ROS). Overproduction of ROS can lead to damage cellmembranes, proteins and DNA and secondary cell death. In the present thesis experimental TBI in rats were used to study the effects of the ROS scavengers α-phenyl-N-tert-butyl-nitrone (PBN) and 2-sulfophenyl-N-tert-butyl-nitrone (S-PBN) on morphology, function, intracellular signalling and apoptosis. Posttreatment with PBN and S-PBN resulted in attenuation of tissue loss after TBI and S-PBN improved cognitive function evaluated in the Morris water maze (MWM). Pretreatment with PBN protected hippocampal morphology, which correlated to better MWM-performance after TBI. To detect ROS-generation in vivo, a method using 4-hydroxybenzoic acid (4-HBA) microdialysis in the injured cortex was refined. 4-HBA reacts with ROS to form 3,4-DHBA, which can be quantified using HPLC, revealing that ROS-formation was increased for 90 minutes after TBI. It was possible to attenuate the formation significantly with PBN and S-PBN treatment. The activation of extracellular signal-regulated kinase (ERK) is generally considered beneficial for cell survival. However, persistent ERK activation was found in the injured cortex after TBI, coinciding with apoptosis-like cell death 24 h after injury. Pretreatment with the MEK-inhibitor U0126 and S-PBN significantly decreased ERK activation and reduced apoptosis-like cell death. Posttreatment with U0126 or S-PBN showed robust protection of cortical tissue. To conclude: ROS-mediated mechanisms play an important role in secondary cell death following TBI. The observed effects of ROS in intracellular signalling may be important for defining new targets for neuroprotective intervention.