| 31. |
- Lundgren, Oskar, 1979-
(författare)
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Psychological Resources and Risk Factors in Coronary Heart Disease : Assessment, Impact and the Influence of Mindfulness Training
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There is strong evidence for the observation that psychological risk factors, such as depressive symptoms, hopelessness, and anxiety are associated with higher risk of developing coronary heart disease (CHD), and also contribute to a worse prognosis among CHD patients. Much less is known about psychological resources, such as Mastery, and their role in cardiovascular medicine. Although the current state of science about the importance of psychological factors has advanced during the last decades, the mental health status of patients is often neglected in clinical practice. The reason behind this gap is multifaceted, including unawareness of the current state of science among professionals and a lack of clear guideline, which in turn, results from a lack of evidence-based ways to address the issues. Furthermore, the measurement of psychological resources is complex and a debated topic in psychology. The aim of this thesis was to investigate: 1) If the use of inverted items in three questionnaires that measure psychological resources and risk factors represent a validity risk in the context of CHD. 2) If psychological resources and risk factors are independently associated with incidence in CHD. 3) If an eight-week course in Mindfulness-Based Stress Reduction (MBSR) is a feasible psychological intervention, as an addition to cardiac rehabilitation. 4) How CHD patients experience the practices of mindfulness and yoga in MBSR.In Study I and II, data from 1007 participants randomly selected from a Swedish community sample, aged 45-69 at baseline (50 % women), were analysed. To study the validity of the self-report instruments Mastery, Self-esteem and Centre for Epidemiological Studies Depression scale (CESD), subscales with only positive and negative items were created. The new subscales were evaluated against three criterion measures; cross-sectional against each other and the circulatory marker of inflammation interleukine-6 (IL-6) (concurrent construct validity); prospectively against 8-year incidence in CHD (predictive validity), and in addition, a factor analysis was used to investigate construct dimensionality. The instruments seemed to be valid measures of psychological resources and risk factors in the context of CHD risk. The new subscales showed the same associations as the original scales, except for the positive items in CES-D. However, this did not have a major influence on the full scale. In Study II a prospective analysis of the impact of psychological factors on 8-year incidence in CHD was performed. The psychological resources Mastery and Self-esteem were negatively associated with CHD, also after adjustment for nine traditional cardiovascular risk factors in Cox proportional hazard models. The protective effect of the two resources, and the increased risk of Hopelessness, remained after adjustment for depressive symptoms. In Study III and IV, a group of CHD patients with depressive symptoms (n=79) was invited to participate in MBSR as a complement to cardiac rehabilitation. Twenty-four patients started MBSR and 16 completed it. The results were compared with a reference group (n=108) of patients from the same clinic, which showed stability in psychological variables over 12 months. MBSR was appreciated by the patients and improvements in psychological risk factors (e.g., depressive symptoms), and an increase in Mastery were observed. Study IV made use of a qualitative content analysis of diary entries written by patients immediately after practice sessions throughout MBSR. Participants described difficulties, both physical and psychological, during the whole course, but as the weeks passed they more frequently described an enhanced ability to concentrate, relax and deal with distractions. From the combined findings in Study III and IV, we conclude that MBSR could be a promising complement to cardiac rehabilitation for a selection of patients.The overall picture, emerging from this thesis, strengthens the argument that psychological factors should be recognized and addressed in clinical practice. It also encourages further studies of how psychological resources could be built, which could inform the development of effective prevention and treatment strategies for CHD patients with psychological distress and also contribute to improved public health interventions.
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| 32. |
- Mukwaya, Anthony
(författare)
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Regulation of inflammation and angiogenesis in the cornea
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inflammation and angiogenesis, the growth of new blood vessels from pre-existing ones, are involved in tumor growth, ocular diseases and wound healing. In ocular angiogenesis, new pathological vessels grow into a specific eye tissue, leak fluid, and disrupt vision. The development of safe and effective therapies for ocular angiogenesis is of great importance for preventing blindness, given that current treatments have limited efficacy or are associated with undesirable side effects. The search for alternative treatment targets requires a deeper understanding of inflammation and how it can lead to angiogenesis in the eye in pathologic situations. This thesis provides new insights into the regulation of inflammation and angiogenesis, particularly at the gene expression and phenotypic levels, in different situations characterized by angiogenesis of the cornea, often called corneal neovascularization. For instance, specific genes and pathways are either endogenously activated or suppressed during active inflammation, wound healing, and during resolution of inflammation and angiogenesis, serving as potential targets to modulate the inflammatory and angiogenic response. In addition, as part of the healing response to restore corneal transparency, inflammation and angiogenesis subside with time in the cornea. In this context, LXR/RXR signaling was found to be activated in a time-dependent manner, to potentially regulate resolution of inflammation and angiogenesis. During regression of new angiogenic capillaries, ghost vessels and empty basement membrane sleeves are formed, which can persist in the cornea for a long time. Here, ghost vessels were found to facilitate subsequent revascularization of the cornea, while empty basement membrane sleeves did not revascularize. The revascularization response observed here was characterised by vasodilation, increased inflammatory cell infiltration and by sprouting at the front of the reperfused vessels. Importantly, reactive oxygen species and nitrous oxide signaling among other pro-inflammatory pathways were activated, and at the same time anti-inflammatory LXR/RXR signaling was inhibited. The interplay between activation and inhibition of these pathways highlights potential mechanisms that regulate corneal revascularization. When treating corneal neovascularization clinically, corticosteroids are in widespread use due to their effectiveness. To minimize the many undesirable side effects associated with corticosteroid use, however, identifying new and more selective agents is of great importance. Here, it was observed that corticosteroids not only suppressed pro-inflammatory chemokines and cytokines, but also activated the classical complement pathway. Classical complement may represent a candidate for further selective therapeutic manipulation to investigate its effect on treatment of corneal neovascularization.In summary, this thesis identifies genes, pathways, and phenotypic responses involved in sprouting and remodeling of corneal capillaries, highlights novel pathways and factors that may regulate inflammation and angiogenesis in the cornea, and provides insights into regulation of capillary regression and reactivation. Further investigation of these regulatory mechanisms may offer alternative and effective treatment targets for the treatment of corneal inflammation and angiogenesis.
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| 33. |
- Nestorson, Jens, 1969-
(författare)
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Arthroplasty in Elbow Fracture Treatment
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Open reduction and internal fixation is the treatment of choice for distal humeral fractures. Stable fixation is required to allow early mobilisation and to reduce the risk of poor functional results. In an elderly patient with osteoporotic bone and with a comminuted intra-articular fracture stable internal fixation can be difficult to achieve. In these cases elbow arthroplasty is an option.An irreparable radial head fracture can be treated by excision or replacement. The indications for the respective procedure are unclear since reports include an array of different associated soft-tissue and bony injuries.The aim of this thesis was to evaluate the use, complication rates and functional outcome of elbow arthroplasty as primary treatment for complex distal humeral fractures and assess the usefulness of radial head replacement in Mason IV fracture dislocations.50 patients, aged 56-89 years were treated for a distal humeral fracture with primary hemi-arthroplasty using the Kudo© humeral component or the Latitude® prosthesis. The functional outcome was assessed retrospectively. The majority of the 50 patients treated with a primary hemi-arthroplasty for a distal humeral fracture had a good or excellent functional result and regained a functional arc of movement of at least 100 degrees at medium term follow-up. There were six patients suffering secondary surgery and two with persistent ulnar nerve symptoms. Wear of the olecranon fossa was seen, mainly in the eight patients treated with a non-anatomical implant (Kudo®). Functional results were comparable to total elbow arthroplasty and open reduction and internal fixation (ORIF) for distal humeral fractures. The use of implants that are more anatomical seemed to reduce the degree of olecranon wear but long-term results are lacking.The nationwide use of primary arthroplasty for a distal humeral fracture between 1999 and 2014 was examined using three different registers. The survival rates in relation to prosthetic desing, age and sex were investigated using Cox regression analysis and number of adverse events recorded.In total 405 patients were treated with primary arthroplasty for a distal humeral fracture. The mean age at surgery was 75 years and the mean observation time was 67 months. Eighteen patients had undergone revision surgery and another 26 patients suffered an adverse event, 24 of which required secondary surgery.Increasing age reduced the risk for revision and there was no significant difference in survival between total- and hemi arthroplasty. The cumulative survival rate at 5 years was 99% (CI 98-100) and at 10 years 90% (CI 85-96). Elbow arthroplasty as primary treatment for distal humeral fractures produced reliable results with regards to revision surgery and adverse events.18 patients, age 19-79 years, treated with radial head replacement, and 14 patients, age 29-70 years, treated with radial head resection, for a Mason IV fracture dislocation were retrospectively reviewed.There were no significant differences in functional outcome in patients treated with replacement or excision for a Mason IV fracture dislocation. The rate of secondary surgery was higher in patients treated with replacement and ulno-humeral osteoarthritis was more pronounced in patients treated with radial head excision but follow-up was longer in these patients. Functional results were not improved by using radial head arthroplasty for Mason IV fracture dislocation. Secondary osteoarthritis is a concern in patients treated with excision but did not affect functional outcome after a mean follow-up time of 108 months.
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| 34. |
- Olsson, Anki
(författare)
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Hemostatic function and inflammatory activation after weaning from cardio pulmonary bypass
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cardiopulmonary bypass (CPB) contributes to perioperative platelet dysfunction, increased fibrinolysis and impaired coagulation, which can have an impact on postoperative bleeding. During CPB the blood is exposed to foreign surfaces leading to activation of the coagulation system and a systemic inflammatory response with complement and leukocyte activation. Anticoagulation with heparin is used to prevent immediate blood clotting within the circuit. The heparin effect is reversed with protamine sulfate after weaning from CPB. Protamine has been suggested to impair platelet function in high doses although the mechanism is incompletely understood. Platelet dysfunction can promote bleeding which can necessitate transfusion and sometimes surgical re-exploration.After weaning from CPB the residual blood in the heart lung machine is usually retransfused to the patient in order to reduce the need for blood transfusion. The most common technique to transfuse residual blood is to collect the blood from the CPB circuit in an infusion bag (IB). An alternative way to re-transfuse the residual blood is by chasing it through the heart lung machine with Ringers solution, the Ringer chase technique (RC).The aim of this thesis was to examine a possible inhibitory effect of protamine on platelet aggregation. A second aim was to evaluate different techniques for retransfusion after weaning from CPB.Study I and II in this thesis are focused on the protamine effect on platelet aggregation and study III and IV on the quality of the blood in relation to the two different retransfusion techniques.In Study I we found that platelet aggregation evaluated by impedance aggregometry was reduced by approximately 50% after in vivo protamine administration. Protamine added in vitro also reduced platelet aggregation, by itself or in combination with heparin. Study II showed that protamine induces a marked but transient decrease in platelet aggregation already at a protamine-heparin ratio of 0.7:1, which also was sufficient to reverse the heparin anticoagulation as measured by activated clotting time (ACT). No further decrease was observed when additional protamine was given within three minutes. Platelet aggregation had begun to recover 20 minutes after protamine administration.In study III and IV we evaluated possible differences in quality of the retransfused residual blood from the heart-lung machine depending on if it is returned to the patient by the RC-technique or by an IB. Study III focused on biochemical markers of hemostasis, coagulation and fibrinolysis. Study IV concerns biochemical markers of inflammatory activity characterizing the inflammatory response during cardiac surgery with CPB including heparin binding protein (HBP) a new marker of neutrophil activation. CPB is associated with a marked systemic inflammatory response and levels of HBP indicates a pronounced neutrophil activation as part of a systemic inflammatory process. HBP levels during CPB was much higher than previously found during severe inflammatory conditions. We also concluded that the handling of the blood after weaning from CPB reduces platelet function, activates coagulation and fibrinolysis, increases hemolysis and the inflammatory response. Retransfusion of pump blood with the RC-technique was associated with better preserved platelet function, less hemolysis, less signs of activation of coagulation and fibrinolysis and less pronounced inflammatory activity than the commonly used IB technique. In the event of cell salvage technique not being feasible, we suggest that the RC technique is preferable to the IB technique but acknowledge that the clinical importance of this finding in terms of outcomes warrants further investigation
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| 35. |
- Renhorn, Jakob, 1981-
(författare)
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Conformational Changes during Potassium-Channel Gating
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Voltage-gated ion channels have a paramount importance in many physiological processes such as cell-to-cell communication, action potential-propagation, and cell motility. Voltage-gated ion channels are characterized by their ability to sense membrane voltage and to greatly change channel activity in response to small changes in the voltage. The ability to sense voltage resides in the four voltage-sensor domains (VSDs) surrounding the central ion-conducting pore. Membrane depolarization causes the inside of the membrane to become positively charged, electrostatically repelling the positively charged fourth transmembrane segment (S4), or voltage sensor, in the VSD, causing the voltage sensor to move outwards. This motion provides necessary energy to open the pore and allow ion conductivity. Prolonged channel activation leads to alterations in the selectivity filter which cease ion conductivity, in a process called slow inactivation. In this thesis, we investigated the movement of S4 during activation of the channel. We also studied the communication between the four subunits during activation as well as the communication between the pore domain and VSD during slow inactivation.We have shown that voltage sensors move approximately 12 Å outwards during activation. The positively charged amino acid residues in S4 create temporary salt bridges with negative counter-charges in the other segments of the VSD as it moves through a membrane. We have also shown that the movement of one of the four voltage sensors can affect the movement of the neighboring voltage sensors. When at least one voltage sensor has moved to an up-position, it stabilizes other voltage sensors in the up-position, increasing the energy required for the voltage sensor to return to the down position.We have also shown reciprocal communication between the pore domain and the VSDs. Alterations in the VSD or the interface between the pore and the VSD cause changes in the rate of slow inactivation. Likewise, modifications in the pore domain cause changes to the voltage-sensor movement. This indicates communication between the pore and the VSD during slow inactivation.The information from our work could be used to find new approaches when designing channel-modifying drugs for the treatment of diseases caused by increased neuronal excitability, such as chronic pain and epilepsy.
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| 36. |
- Sigurdardottir, Gunnthorunn, 1975-
(författare)
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Studies of the Systemic Inflammation in Psoriasis
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Psoriasis is a common immune-mediated disease, where an increased prevalence of extra cutaneous diseases and mortality is observed. Common inflammatory mechanisms are implicated. The general aim of this thesis was to investigate markers of inflammation and cardiovascular disease in psoriasis, now considered a systemic disease, assumed to reflect the systemic inflammation.In Study I, Th1-, Th2- and Th17-associated chemokines were elevated in the blood of psoriasis patients in comparison to controls and, in Study II, six markers of cardiovascular risk were demonstrated to be systemically elevated. After adjustment for body mass index and waist: hip ratio in Study II, only one marker, the total plasminogen activator inhibitor-1, showed sustained elevated levels. The levels of the chemokines and the cardiovascular markers were unaffected after treatment with narrowband UVB therapy (NB-UVB), despite a significant improvement in skin lesions, indicating more local than systemic effects of NBUVB. This was further strengthened by the fact that the response to in-vitro stimulation in the peripheral blood mononuclear cells (PBMCs) of psoriasis patients before and after NB-UVB treatment was unaffected. In Study I, CCL20 was shown to correlate to the psoriasis area severity index (PASI), but this correlation was lost after phototherapy, suggesting sources of CCL20 other than the skin. Conversely, systemic treatment with TNF-α inhibition in Study II alleviated the elevated systemic levels of the cardiovascular risk markers. In Study III, the levels of 17 potential biomarkers, with the emphasis on endothelial and adipocyte dysfunction, soluble receptors and the innate mechanisms were studied. Endocan-1, CXCL16, and sVEGFR1, were found to be systemically decreased in psoriasis patients at baseline. Endocan-1 showed a negative correlation to the PASI. In contrast to the results in Studies I and II, NB-UVB therapy affected the systemic levels of investigated markers; Endocan-1 and CXCL16 were restored to normal levels, while sVEGF1, FABP3, FABP4 and sIL-1R1 showed a significant reduction following NB-UVB. In Study IV, the focus was on the contribution of innate immune mechanisms and the effects of the cytokines IL-17 and TNF-α on systemic inflammation. In keratinocytes, the gene and protein expression of inflammasome components was increased upon exposure to IL-17 and TNF-α. Systemically, the constitutive expression of the inflammasome components NLRP1, NLRP3 and AIM2 was detected in neutrophils, classical monocytes, CD4+ lymphocytes and B-cell subsets from psoriasis patients. Upon exposure to IL-17 and TNF-α, increased systemic caspase-1 levels were detected, confirming systemic inflammasome activity.In conclusion, these studies support the hypothesis that there is a systemic inflammation in psoriasis to which both innate and adaptive immune mechanisms contribute. The systemic inflammation may be explained, to some extent, but not completely, by body weight and fat distribution. The different effects of NB-UVB therapy on the systemic levels of the investigated markers may reflect their different roles in psoriasis, but the ameliorating effects of the TNF-α inhibitor on the elevated cardiovascular markers suggests that systemic treatment should be evaluated in psoriasis patients with signs of a systemic inflammatory burden.
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| 37. |
- Silverå Ejneby, Malin, 1987-
(författare)
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Site and Mechanism of Action of Resin Acids on Voltage-Gated Ion Channels
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Voltage-gated ion channels are pore-forming membrane proteins that open or close their gates when the voltage across the membrane is changed. They underlie the electrical activity that enables the heart to pump blood and the brain to receive and send signals. Changes in expression, distribution, and functional properties of voltage-gated ion channels can lead to diseases, such as epilepsy, cardiac arrhythmia, and pain-related disorders. Drugs that modulate the function of voltage-gated ion channels control these diseases in some patients, but the existing drugs do not adequately help all patients, and some also have severe side effects.Resin acids are common components of pine resins, with a hydrophobic three-ringed motif and a negatively charged carboxyl group. They open big-conductance Ca2+-activated K+ (BK) channels and voltage-gated potassium (KV) channels. We aimed to characterize the binding site and mechanism of action of resin acids on a KV channel and explore the effect of a resin acid by modifying the position and valence of charge of the carboxyl group. We tested the effect on several voltage-gated ion channels, including two KV channels expressed in Xenopus laevis oocytes and several voltage-gated ion channels expressed in cardiomyocytes. For this endeavour different electrophysiological techniques, ion channels, and cell types were used together with chemical synthesis of about 140 resin-acid derivatives, mathematical models, and computer simulations.We found that resin acids bind between the lipid bilayer and the Shaker KV channel, in the cleft between transmembrane segment S3 and S4, on the extracellular side of the voltage-sensor domain. This is a fundamentally new interaction site for small-molecule compounds that otherwise usually bind to ion channels in pockets surrounded by water. We also showed that the resin acids open the Shaker KV channel via an electrostatic mechanism, exerted on the positively charged voltage sensor S4. The effect of a resin acid increased when the negatively charged carboxyl group (the effector) and the hydrophobic three-ringed motif (anchor in lipid bilayer) were separated by three atoms: longer stalks decreased the effect. The length rule, in combination with modifications of the anchor, was used to design new resin-acid derivatives that open the human M-type (Kv7.2/7.3) channel. A naturally occurring resin acid also reduced the excitability of cardiomyocytes by affecting the voltage-dependence of several voltage-gated ion channels. The major finding was that the resin acid inactivated sodium and calcium channels, while it activated KV channels at more negative membrane voltages. Computer simulations confirmed that the combined effect on different ion channels reduced the excitability of a cardiomyocyte. Finally, the resin acid reversed induced arrhythmic firing of the cardiomyocytes.In conclusion, resin acids are potential drug candidates for diseases such as epilepsy and cardiac arrhythmia: knowing the binding site and mechanism of action can help to fine tune the resin acid to increase the effect, as well as the selectivity.
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| 38. |
- Stensson, Niclas, 1974-
(författare)
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Endocannabinoids and Related Lipids in Chronic Pain : Analytical and Clinical Aspects
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In Europe, approximately one in five adults experience chronic pain, pain that lasts more than three months. Chronic pain is a significant problem not only for those people suffering from chronic pain but also for society. The prevalence of chronic pain is higher in women and lower socioeconomic groups. Although chronic pain often originates in a specific site, it may eventually spread to several sites, transforming into chronic widespread pain (CWP), a condition evident in about 10% of the adult population. Approximately 1.2-5.4% are classified with fibromyalgia (FM). In addition to CWP, common symptoms of FM include, stiffness, fatigue, sleep disturbances, and cognitive dysfunction and common co-morbidities include depression and anxiety. Although FM/CWP has been reported to alter both central and peripheral nociceptive mechanisms, no objective biomarkers have been found that correlate with CWP/FM and no standard examinations such as blood test, X-ray or computed tomography can provide support for a diagnosis. Because there are no objective biomarkers that correlate with the pathophysiological processes associated with CWP/FM, this debilitating disease is difficult to diagnose and ultimately treat. However, there are some promising therapeutic targets for chronic pain with inter alia analgesic, anti-inflammatory, and stress modulating properties: the endocannabinoids (ECs) arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) and their related lipids oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA).This thesis investigates whether ECs and the related N-acylethanolamines (NAEs) can be used as potential biomarkers for CWP/FM. Specifically, the studies compared the peripheral and systemic levels of ECs and NAEs in 121 women with CWP/FM and in 137 healthy controls in two different cohorts. In addition, the correlation between lipid levels and common pain characteristics such as intensity, sensitivity, and duration were investigated. The EC and related lipid levels were measured using liquid chromatography in combination with tandem mass spectrometry. Multivariate data analysis was used for biomarker evaluation.Compared to the healthy controls, the CWP/FM patients had significantly higher concentrations of OEA, PEA, and SEA in muscle and plasma (p ≤ 0.05) and significantly higher 2-AG in plasma (p ≤ 0.01). These results may indicate that NAEs, are mobilized differently in painful muscles compared with pain free muscles. Moreover, increased systemic levels of NAEs and 2-AG in patients might be signs of ongoing low-grade inflammation inCWP/FM. These findings contribute to a better understanding of how peripheral and systemic factors maintain and activate chronic pain. Although the investigated lipids have statistically significant effects but biologically uncertain role in the clinical manifestations of CWP/FM. Thus plasma lipids are not a good biomarker for CWP/FM. Nevertheless, increased lipid levels indicate a metabolic asymmetry in CWP/FM, a finding that could serve as a basis for more research on pain management.
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| 39. |
- Sundberg, Sofie, 1984-
(författare)
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Neuromodulation, Short-Term and Long-Term Plasticity in Corticothalamic and Hippocampal Neuronal Networks
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Research in neuroscience relies to a large extent on the use of genetically modified animals. Extensive validation of new and existing models is a requirement for the acquisition of trustworthy data and to enable generalization to human physiology and disease. This thesis includes, as one part (project I and II), validation of a transgenic mouse model with the expression of the enzyme Cre-recombinase restricted to neurons in a band in the deepest layer of the cerebral cortex. Secondly, in project III we use this mouse model to study the process of short-term plasticity in neuronal cultures. Lastly, we investigate synaptic plasticity by studying the effect that the developmental signaling factor Hedgehog (Hh) has on mature hippocampal cultures (project IV). In project I and II, we identified the transgenic mouse Neurotensin receptor 1-Cre GN220 (Ntsr1-Cre) to have Cre expression targeted to the corticothalamic (CT) pyramidal neuron population in neocortical layer 6. Further, we identified a small group of Ntsr1-Cre positive neurons present in the white matter that is distinct from the CT population. We also identified that the transcription factor Forkhead box protein 2 (FoxP2) was specifically expressed by CT neurons in neocortex. In project I, we further explored the sensitivity of CT neurons to cholinergic modulation and found that they are sensitive to even low concentrations of acetylcholine. Both nicotinic and muscarinic acetylcholine receptors depolarize the neurons. Presenting CT neurons as a potential target for cholinergic modulation in wakefulness and arousal. In project III we studied Ntsr1-Cre neurons in cortical cultures and found that cultured neurons have similar properties to CT neurons in the intact nervous system. Ntsr1-Cre neurons in culture often formed synapses with itself, i. e. autapses, with short-term synaptic plasticity that was different to ordinary synapses. By expressing the light-controlled ion channel channelrhodopsin-2 (ChR2) in Ntsr1-Cre neurons we could compare paired pulse ratios with either electrical or light stimulation. Electrical stimulation typically produced paired-pulse facilitation while light stimulation produced paired pulse depression, presumably due to unphysiological Ca2+ influx in presynaptic terminals. Thus, cultured Ntsr1- Cre neurons can be used to study facilitation, and ChR2 could be used as a practical tool to further study the dependence of Ca2+ for short-term plasticity. In project IV we investigated the role of Hedgehog (Hh) for hippocampal neuron plasticity. Non-canonical Hh-signaling negatively regulated NMDA- receptor function through an unknown mechanism resulting in changes in NMDA-receptor mediated currents and subsequent changes in AMPA- receptors in an LTP/LTD manner in mature neurons. Proposing Hh as a slow-acting factor with ability to scale down excitation for instances of excessive activity, e.g. during an epileptic seizure, as a mechanism to make the activity in the neuronal networks stable.
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| 40. |
- Sundström, Simon, 1985-
(författare)
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Prosodic and Phonological Ability in Children with Developmental Language Disorder and Children with Hearing Impairment : In the Context of Word and Nonword Repetition
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Many children with developmental language disorder (DLD) exhibit difficulties with phonology, i.e. the sounds of language. Children with any degree of hearing impairment (HI) are at an increased risk of problems with spoken language, including phonology. The cause of these difficulties is unknown in children with DLD, and is often assumed to result from reduced hearing acuity in children with HI. Variability in terms of language outcomes is large in both groups, and determining if a child’s language ability is within normal limits or not is problematic. A task that has proven useful in differentiating typical from atypical language development is nonword repetition, in which the child listens to a word form without meaning and repeats it back immediately. Performance in nonword repetition tasks is a potential indicator of language ability in both children with DLD and children with HI. However, it has not been established exactly what the task measures.In the present thesis, the ability to repeat prosodic and segmental features of real words and nonwords was investigated in Swedish-speaking four- to six-year-old children with DLD and HI, as well as in children with normal hearing and typical language development (TLD) (papers I, II and III). Further, relations of word and nonword repetition ability to language and hearing were explored (papers II and III), along with comparisons of phonological and grammatical production between the groups (paper IV).The findings indicated that the prosodic features stress and tonal word accent affect repetition performance in children with DLD, HI, and TLD. In general, the children with DLD and HI achieved lower results than the children with TLD on repetition of segments (consonants and vowels) and prosodic features, but tonal word accent was repeated with relatively high accuracy. Tonal word accent 1 was more accurately repeated than tonal word accent 2 by the DLD and HI children. The children with TLD repeated tonal word accent with few errors, but segments in nonwords with tonal word accent 2 were easier to repeat than segments in nonwords with tonal word accent 1.The results further revealed that the ability of children with DLD to repeat stress in real words is related to expressive grammar, but repetition of prosodic features does not reflect general language knowledge. In contrast, repetition of both segmental and prosodic nonword features may be indicative of receptive vocabulary, phonological production during naming of familiar words, and expressive grammar in children with HI. Repetition performance might be related to the degree of HI before cochlear implantation or fitting of hearing aids.Children with DLD and children with HI demonstrate similar strengths and weaknesses in phonological and grammatical production, despite the fact that they develop language under different conditions—with and without normal hearing. Tonal word accent use and syntax are relatively unimpaired in DLD and HI children.This thesis highlights prosodic and phonological strengths and weaknesses in children who have, or are at risk of, deficits in language and communication abilities. It also supports word and nonword repetition as potential predictors of some aspects of language ability in children with DLD and HI. Further, it emphasizes the importance of taking prosody into account when constructing, or interpreting results from, repetition tasks. Future research aiming to investigate the relationship between prosody in repetition and language, cognition and hearing, should use longitudinal study designs, and include younger children. Studies comparing prosodic and phonological ability in children with DLD and children with HI should employ both quantitative and qualitative analyses.
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