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Bakgrund:Stroke är den vanligaste orsaken till neurologisk funktionsnedsättning i Sverige. Tiden efter insjuknandet i stroke delas in i tre återhämtningsfaser och patienter kan uppleva förbättringar under alla tre faser. Bålfunktion är grundläggande för gångförmåga och balans varför bålträning är en av flera fysioterapeutiska behandlingsmetoder vid rehabilitering av stroke. Viss tillförlitlighet finns avseende effekt av bålträning vid akut och subakut fas av stroke men den är oklar vid kronisk fas av stroke. Kunskapsläget behöver därför granskas och sammanställas.  Syfte: Att undersöka effekten av bålträning på gånghastighet och balans vid kronisk stroke.  Metod:Studiens design var en systematisk översikt där randomiserade kontrollerade studier inkluderades. Systematiska sökningar utfördes i databaserna PubMed, CINAHL och Web of Science samt kompletterande sökning i referenslista i Cochrane protokoll. Bedömning av artiklarnas kvalitet genomfördes enligt PEDro skalan och den sammanvägda tillförlitligheten granskades med modifierad förenklad GRADE. Resultat:Urvalsprocessen genererade tio artiklar, varav en artikel med låg kvalitet exkluderades från vidare granskning. En artikel bedömdes ha måttlig kvalitet och åtta artiklar bedömdes ha hög kvalitet enligt PEDro. Resultatet av granskningen visade på motstridiga resultat gällande effekter av bålträning på balans och gånghastighet samt en låg tillförlitlighet i den sammanvägda bedömningen. Konklusion:Utifrån denna systematiska översikt är det inte möjligt att fastställa bålträningens effekt på gånghastighet eller balans vid kronisk stroke. Översikten visar på motstridiga resultat samt låg tillförlitlighet i den sammanvägda bedömningen. Ytterligare forskning behövs för att fastställa bålträningens effekt på gånghastighet och balans vid kronisk stroke. / Background: Stroke is the most common cause of neurological disability in Sweden. Stroke is divided into different phases and improvements can occur several years after debut. Trunk function is fundamental for gait ability and balance, which is why trunk training is one of several physical therapy methods. Regarding the chronic phase of stroke, there is a need to compile state of evidence for trunk training. Purpose: To investigate the effect of trunk training on gait speed and balance in chronic stroke. Method: Literature review with randomized controlled trials included. Systematic searches were made in the databases PubMed, CINAHL and Web of Science and in the reference list of a Cochrane protocol. Quality assessment of the articles was done with PEDro and the combined reliability was examined with Modifierad förenklad GRADE. Results: The selection process generated ten articles, of which one low-quality article was excluded. one article were of moderate quality and eight of high quality. The results of the review showed conflicting results regarding the effects of trunk training on balance and walking speed, as well as a low reliability in the combined assessment.  Conclusion: Based on this systematic review, it is not possible to determine the effect of trunk training on walking speed or balance in chronic stroke. The overview shows conflicting results and low reliability in the combined assessment. Further research should determine the effect of trunk training on gait speed and balance in chronic stroke.

<p>Some individuals remain at risk for adverse outcomes such as chronic wrist/hand pain, falls, and fall-related osteoporotic fractures after distal radius fracture (DRF) remain. This thesis includes five studies that were conducted to establish prediction rules for assessing the risk of these adverse outcomes following DRF.</p> <p>The first manuscript outlines a theoretical framework (RACE - <strong>R</strong>educing pain, <strong>A</strong>ctivating, <strong>C</strong>ognitive reshaping, <strong>E</strong>mpowering) for managing the risk of adverse outcomes, mainly chronic pain, in individuals with DRF. The RACE is one of the first frameworks to suggest a risk-based management approach for individuals with DRF.</p> <p>The Patient-Rated Wrist Evaluation (PRWE) is a condition-specific measure for DRF used in research as well as clinical practice to measure pain and functions in individuals with different wrist/hand injuries. The second manuscript contributes to the literature by providing the first systematic literature review that synthesizes the evidence regarding the psychometric properties of the PRWE. The review determined that the PRWE has excellent reliability, construct validity, and responsiveness in individuals with DRF.</p> <p>The third manuscript indicates that the baseline pain intensity is an independent predictor of chronic pain in individuals with DRF. The results also suggest that the individuals who score ≥35/50 on the pain scale of the PRWE at baseline have 8 times greater risk for developing chronic wrist/hand pain compared to those who score < 35/50.</p> <p>The fourth and fifth manuscripts describe results of a two step study. The fourth manuscript is a structured literature synthesis that identified suitable measures for predicting the risk of falls and fall-related osteoporotic fractures following DRF. The fifth manuscript summarizes the results of preliminary analysis of psychometric properties of selected fall risk measures identified in the fourth manuscript. The fifth manuscript also provides feasibility and sample size requirements for conducting a fall prevention trial in individuals with DRF.</p> / Doctor of Philosophy (PhD)

<p> Older adults with persistent pain experience reduced physical functioning, increased disability, and higher rates of depression. Previous research suggests that different types of positive and negative expectancies (e.g., optimism and hopelessness) may be associated with the severity of these pain-related outcomes. Moreover, different types of expectancies may interact with perceived control to predict these outcomes. However, it is unclear whether different types of expectancies are uniquely predictive of changes in pain-related outcomes over time in older adults and whether perceived control moderates these relationships. The primary aims of the current study were to 1) examine how the shared and unique aspects of optimism and hopelessness differentially predict changes in pain-related outcomes (i.e., pain severity, pain interference, disability, and depressive symptoms) in older adults experiencing persistent pain over a 10-year and 2-year timeframe and 2) examine whether perceptions of control over one’s health moderate these relationships. The present study sampled older adults with persistent pain who participated in a nationally representative, longitudinal study (i.e., The Health and Retirement Study) at three timepoints across a 10-year period. First, confirmatory factor analyses (CFA) were conducted to determine appropriate modeling of expectancy variables. Second, mixed latent and measured variable path analyses were created to examine the unique relationships between expectancy variables and changes in pain-related outcomes over both a 10- year and 2-year period. Finally, mixed latent and measured variable path analyses and PROCESS were used to test perceived control as moderator of the relationships between expectancy variables and changes in pain-related outcomes over time. CFA results suggested that measures of optimism and hopelessness were best understood in terms of their valence, as positive (i.e., optimism) or negative (i.e., pessimism and hopelessness) expectations. Results from path analyses suggested that only negative, not positive, expectancies were significantly associated with worsening pain severity, pain interference, disability, and depressive symptoms across both 10-year and 2-year periods. Moderation analyses demonstrated inconsistent results and difficulties with replication. However, post-hoc path analyses found that perceptions of control over one’s health independently predicted some changes in pain-related outcomes over time, even when controlling for expectancies. Altogether, the current findings expand our knowledge of the associations between expectancies and pain by suggesting that negative expectancies are 10 predictive of changes in mental and physical pain-related outcomes across years of time. The current study also suggests that positive and negative expectancies may be related, but distinct factors in older adults with persistent pain and that health-related perceived control may be predictive of changes in pain over time. The current discussion reviews these extensions of our current knowledge in greater detail, discusses the potential mechanisms driving these relationships through a theoretical lens, and identifies the implications of this work. </p>

In recent years vitamin D has gained popularity in the media, on the internet, and throughout alternative treatment practitioners as a cheap and effective option to treat many diseases. Research showing that vitamin D receptors are present in virtually all cells of the body, and the increasing data demonstrating a relationship of vitamin D metabolites to chronic diseases, have led to widespread treatment of medical conditions with vitamin D supplementation. Chronic pain and inflammatory conditions are increasingly linked to vitamin D deficiency. The question posed in this review is whether there is significant, quality research to recommend vitamin D supplementation for patients with chronic pain conditions. Utilizing publications from PubMed for the review, various search terms were entered for vitamin D (vitamin D; vitamin D2; vitamin D3; 1,25-dihydroxyvitamin D3; 1,25-dihydroxycholecalciferol; 25 hydroxycholecalciferol; 25-hydroxyvitamin D; alfacalcidol; calcidiol; calcitriol; calcifediol; calciferol; ergocalciferal; cholecalciferol); and "pain." The search was continued from the last day of the Straub et. al. review, September 8th, 2008. The last search was conducted on December 5, 2012. The search protocol from Straub et. al was followed as well. Also, added to this search protocol were the terms: vitamin D receptor; VDR and "pain." These terms enabled a search for genetic links between vitamin D and pain. The search criteria resulted in nine relevant articles (from the original 1,069 studies) with varying treatment protocols in each article making any statistical representation impossible. Results on the effectiveness of vitamin D correlation with chronic pain were extremely variable, with most papers drawing the conclusion that more quality research needs to be implemented on the subject. Due to the variability and lack of quality randomized controlled trials, the current literature can only suggest a possible link between vitamin D levels and pain. Also, recent research into Vitamin D Receptors (VDR) has opened up a possible connection between VDR polymorphisms and pain. So, after a comprehensive review of vitamin D, Vitamin D Receptors, and pain, there is still not enough evidence to recommend supplementation to treat chronic pain conditions. However, enough evidence is available to recommend future high quality, randomized controlled trials to help determine the influence vitamin D and VDRs have on pain issues. / Oral Biology

Vascular access dysfunction is a cause of morbidity and mortality in chronic kidney disease (CKD) patients that require hemodialysis. The major cause of vascular access failure is venous stenosis due to neointimal hyperplasia (NH). Vascular smooth muscle cells (VSMC) are critical for the development of NH lesions, as they have the ability to modulate their phenotype from a "contractile" to a "synthetic" phenotype in the presence of uremia, through the regulation of sensor genes for uremia danger signals and VSMC-specific differentiation genes. Recent research indicates that Caspase-1 (casp-1) activation plays an essential role in sensing metabolic danger signal-associated molecular patterns and initiating vascular inflammation. Carbamylated LDL, a uremic toxin that has been shown to be found in higher levels in patients with CKD and in CKD murine models when compared to controls, and could play a role in casp-1 activation. Therefore, the goal of this project is to examine the role of cLDL/CKD-driven casp-1 activation in VSMC and CKD-related NH. We have established a CKD mouse model and published on CKD-associated vascular remodeling. We exposed wild type and caspase-1 knockout mice to our CKD model, analyzed and quantified the NH lesion formed. We also examined in vitro and ex-vivo changes in VSMC-specific differentiation genes when exposed to uremic serum and cLDL, in the presence or absence of caspase-1 inhibitor. We found that CKD serum induces with casp-1 activation and phenotypic changes in VSMCs from a "contractile" to a "synthetic" phenotype, which are reversed with casp-1 inhibition. In an ex-vivo model using relative quantification we found that VSMC contractile markers &#945; -Actin, Calponin, SM-22, and Smoothelin gene expression of CKD mouse carotid VSMC were higher in casp-1 knockout mice when compared to wild-type (1.40, 1.28, 1.22, 1.41 respectively). Also using an in-vivo model, relative quantification of &#945;-actin decreased from 1.0 to 0.329 when VSMCs were exposed to uremic serum and but increased back to 0.588 when Caspase-1 inhibitor is added. The relative quantification of Calponin also decreased from 1.0 to 0.394 when exposed to uremic serum and increased back to 0.601 with caspase-1 inhibitor. We also found that caspase-1 deficiency significantly reversed CKD-related vascular remodeling in casp-1 knockout mice and reduced NH volume by 50% from 1,440,023in wild-type mice to 71,069 µm2 in casp-1 knockouts (p-value 0.002). This evidence provides evidence that casp-1 plays a critical role in NH formation. Furthermore our results provide a novel insight over the therapeutic potential of casp-1 inhibitors for CKD induced NH and other inflammation induced vascular remodeling. / Public Health

BCR-ABL is known as the most common translocation in the myeloproliferative (MPD) disorder chronic myelogenous leukemia (CML); it is the first leukemia to be described and associated with a consistent cytogenetic abnormality, termed the Philadelphia chromosome (Ph1). Ph1 is a shortened chromosome 22 that is the consequence of a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11). BCR-ABL is known to display constitutively active tyrosine kinase activity that leads to the recruitment of downstream effectors of cell proliferation and survival, via several adapter proteins (e.g., GRB2, GAB2, CRKL.) and signaling pathways (e.g., RAS, PI3K, JAK STAT, PDk2-NFkB), all thought to contribute to the pathogenesis of CML. CML, essentially consists of 3 different phases based on disease severity; namely Chronic Phase (CP-AML), Accelerated Phase (AP-CML) and blast crisis (BC-CML). Imatinib, a small molecule ABL kinase inhibitor has been highly effective in treating chronic phase (CP) CML patients. However, a substantial number of patients undergo relapse due to development of resistance to imatinib therapy that leads to BC-CML, which is invariably fatal within weeks to months. Additional genetic aberrations assist in progression and identification of key players that are responsible for transformation is of utmost importance from a therapeutic point of view. Growth arrest DNA damage 45a (Gadd45a) gene, a member in the gadd45 family of genes including Gadd45b & Gadd45g, was identified as a myeloid differentiation primary response gene. There is evidence consistent with it's involvement in G2/M cell cycle arrest and apoptosis in response to multiple stressors, including genotoxic and oncogenic stress. Gadd45a has been shown to participate in cell cycle arrest, DNA repair, cell survival and apoptosis in response to environmental and physiological stress, via protein-protein interactions with key regulators such as PCNA, histones, cdk1, p21, MEKK4, MKK7 and p38. To investigate the effect of Gadd45a in the development of CML, we performed adaptive bone marrow transplantation experiments with either wild type or Gadd45a null myeloid progenitors expressing 210-kD BCR-ABL fusion oncoprotein. We showed that that loss of Gadd45a accelerated BCR-ABL driven CML and correlated with enlarged liver and spleen pointing to more aggressive leukemia. Additionally, we demonstrated that Gadd45a expression in presence of BCR-ABL was independent/distinct from well-known tumor suppressor p53, which suggests that Gadd45a could be considered as a prime and novel candidate for intervention in CML therapy. We also showed that transformed Gadd45a deficient progenitors in the presence of BCR-ABL, exhibited increased proliferation, increased survival and decreased apoptosis when compared to WT/BCR-ABL counterparts. Additionally, we demonstrate that recipients transplanted with Gadd45ako/BCR-ABL bone marrow exhibit increased number of Leukemic stem cells (LSC) harboring BCR-ABL which correlated with accelerated disease development in Gadd45a deficient background. Furthermore, we show that Gadd45ako/BCR-ABL progenitors exhibit increased self-renewal capabilities compared to WT/BCR-ABL progenitors through serial replating assays. Remarkably, we demonstrate that Gadd45ako/BCR-ABL bone marrow cells could be established as a factor independent cell-line and that this cell- line exhibited progenitor like properties; thereby confirming the status of Gadd45a as potent tumor suppressor factor. To shed more light into the mechanism of disease development, we demonstrate that the Gadd45ako/BCR-ABL bone marrow cells exhibit enhanced PI3K-AKT-4E-BP1 signaling and upregulated oncogenic p30C/EBPα expression along with hyperactivation of p38 and Stat5. Finally, to validate our observations in human CML population, we demonstrate that Gadd45a expression correlated with disease progression. We show that Gadd45a expression is upregulated in more indolent CP-CML samples and downregulated in aggressive AP-CML and BC-CML patient samples. Future studies to identify expression of downstream partners of Gadd45a in CML patients, gain of function experiments along with inhibitor studies to highlight mechanistic insights would shed more light into the tumor suppressor function of Gadd45a. Additionally, questions such as; do elevated levels of Gadd45a impede disease progression, does higher expression of Gadd45a indicate better response to Imatinib, still need to be answered in order to understand if Gadd45a agnostic and or combinatorial therapy in CML can be considered as a valid treatment option. The most common mutations of Ras are found in N-RAS (~30%), less frequently in K-RAS (~15%), and most rare in H-RAS in leukemia. Given the role of Gadd45a in modulating the response of hematopoietic cells to stress as well as its function in mediating oncogenic H-Ras carcinogenesis, we wanted to assess if and how Gadd45a loss modulates Nras driven leukemogenesis. By utilizing adaptive bone marrow strategy we show that loss of Gadd45a impeded activated Nras driven leukemia. This correlated with higher incidence of extramedullary hematopoiesis in the liver and spleen sections of WT/NrasD12 recipient mice compared to Gadd45ako/NrasD12 counterparts. Future studies to investigate the biological effects and shed more light on mechanistic insights in recipient mice is still underway. Taken together my work implies that also in the context of hematopoietic malignancies Gadd45a may function as suppressor or promoter of the leukemic phenotype dependent on the oncogenic stress. / Biochemistry

Pain is a leading cause of disability and the most common reason for clinical care. The field of pain research has focused on sex differences in the recent years with an expansive body of literature demonstrating sex-related differences in pain behavior and responsiveness to pharmacological interventions. Prescription opioids are potent analgesics and the mainstay for the clinical management of moderate-to-severe acute and chronic pain conditions. However, the long-term clinical use of prescription opioids for chronic pain remains controversial due to concerns about severe adverse effects, including tolerance, dependence, and addiction associated with opioid use. The non-medical use and abuse of prescription opioids has become a public health crisis, the problem even arising in a subset of chronic pain patients receiving opioid therapy. The vulnerability factors, specifically the role of pain in the propensity to prescription opioid abuse, are poorly understood. The present research project sought to investigate the propensity to opioid reward as a function of pain in male and female mice by incorporating acute (acetic acid-induced) visceral nociceptive and chronic chemotherapy (paclitaxel)-induced peripheral neuropathic pain models. Sexually dimorphic variations in the sensitivities of mice to nociceptive and allodynic behaviors were initially assessed using the two putative pain models. Following that, the two prescription opioids, morphine and oxycodone were examined under both pain contexts and the capacity of the two prescription opioids to produce reward-related behavioral effects were measured using drug discrimination, conditioned place preference, and intravenous drug self-administration procedures. The presence of acute noxious state but not chronic pain selectively attenuated the discriminative stimulus effects of the prescription opioid, morphine in male mice. The magnitude of modulation of the stimulus effects of opioids by the acute noxious state were further observed to be inversely related to the relative intrinsic antinociceptive effectiveness of the two opioids in reversing the acute noxious state and sex-specific sensitivities of mice to opioid-induced antinociception. In contrast, while no change was observed in opioid-reward as a function of the acute noxious state in both sexes, the presence of paclitaxel-induced chronic pain opioid-selectively and dose-selectively enhanced the conditioned rewarding effect of morphine (0.3 mg/kg dose), and the effect was more pronounced in male relative to female mice. These data were further supported by the self-administration results, in that the reinforcing efficacy (breakpoints under progressive ratio (PR) responding) and the incentive-motivational salience of morphine significantly increased in the presence of chronic pain in male mice, while non-selectively increasing regardless of the presence/absence of pain in female mice. Overall, the converging empirical evidence presented here suggest that these models provide preclinical tools to further understand the overlapping neurobiology of pain and opioid abuse, the behavioral effects of prescription opioids, and advance the development of novel sex-specific pain therapeutics with low addiction liability. / Pharmaceutical Sciences