| 41. |
- Bäckryd, Emmanuel, 1974-
(författare)
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The Cerebrospinal Fluid in Severe Pain Conditions : Clinical, Pharmacological and Proteomic Aspects
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The treatment of both cancer pain and non-cancer chronic pain is still suboptimal. The overall aim of this PhD thesis was to conduct translational pain research at the interface between clinical pain medicine and the field of human proteomics, using the practice of intrathecal analgesia at our institution as a starting point. Hence, the cerebrospinal fluid (CSF) is at the centre of the present dissertation, both as a target for infusing analgesics (Papers I and II – clinical and pharmacological aspects) and as an important biofluid for human biomarker studies (Papers III and IV – proteomic aspects). In Paper I, 28 cases of intrathecal analgesia in cancer patients were prospectively followed. Movement-evoked breakthrough pain remained a major clinical problem throughout the study month despite otherwise successful intrathecal analgesia (defined as good control of spontaneous resting pain paralleled by a marked decrease of concomitant systemic opioid doses). This study therefore illustrates the importance of considering not only spontaneous resting pain but also movement-evoked breakthrough pain.In Paper II, an expert-based algorithm for trialing the intrathecal analgesic ziconotide by bolus injections was evaluated in an open-label study of 23 patients with chronic neuropathic pain. We found few responders (13%) according to the strict criteria of the algorithm, but ziconotide bolus injection trialing seems feasible. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (with very slow tissue penetration due to high hydrophilicity) calls the rationale for ziconotide bolus trialing into question.In Paper III, we found low levels of beta-endorphin in the CSF of chronic neuropathic pain patients (n=15) compared to healthy controls (n=19). We speculate that this might indicate dysfunctional top-down control of nociception. Substance P levels in the CSF did not differ by univariate statistics. In Paper IV, the CSF proteome of 11 patients with chronic neuropathic pain and 11 healthy controls was exploratively studied, combining gel-based proteomics with multivariate data analysis. After eliminating four proteins associated with age, 32 proteins were found to highly discriminate between groups. Among these, the seven proteins having the highest discriminatory power between patients and controls were: one isoform of angiotensinogen, two isoforms of alpha-1-antitrypsin, three isoforms of haptoglobin, and one isoform of pigment epithelium-derived factor.In conclusion, this PhD thesis demonstrates the fruitfulness of studying the CSF, both as a target for infusing analgesics and as a potential mirror of the neurobiological processes involved in pathological pain conditions. The thesis points to the need for more research into the mechanisms of different pain conditions, in order to hopefully achieve the vision of mechanism-based pain diagnoses.
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| 42. |
- Bäckström, Denise, 1976-
(författare)
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Injury mortality in Sweden; changes over time and the effect of age and injury mechanism
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Injuries are one of the most common causes of death in the world. Varying types of injuries dominate in different parts of the world, which also have separate influences mortality. In Scandinavia blunt injuries dominates and the majority of those who die do so pre hospital. Over time different injury pattern may vary and by analyzing this we can assess when, where and how preventive work can be reinforced. The aim of this thesis was to study injury epidemiology in Sweden and assess the contribution of different injury patters on mortality. Method: We used the Swedish cause of death and the national patient registries which have a complete national coverage. ICISS was calculated (based on ICD-10) in the in hospital population. We have chosen to do this investigation with a broad perspective using the term injury, which includes trauma but also other diagnoses like suffocation and drowning. Results: During the study period (1999-2012) the number of deaths because of injury was 1213, 25 388, and 18 332 among children, working age and elderly, respectively. Mortality declined in the children and in the working age but inclined in the elderly. Mortality increased with each age group except between the ages of 15–25 and 26–35 years. One thousand two hundred sixty four (97%) of those who died because of penetrating trauma (sharp objects and firearms) were killed by intentional trauma (assault and intentional self-harm). One thousand and seventeen (83%) of the children died prehospital. In the working age 22 211 (80%) of 25 388 died pre hospital. Nine thousand six hundred and eighteen (53%) of 18 332 of the elderly died prehospital. During 2001- 2011 the risk adjusted in hospital mortality decreased in traffic and assault but not in fall related injuries. Discussion: Largely, the anticipated injury mortality picture was found, with blunt injuries (traffic accidents) dominating in the working age and falls in elderly. Further a significant portion of the deaths occurred pre hospital. The intentional injuries are dominated by intentional selfharm. The decrease in child injury mortality is notable as Sweden already has one of the lowest incidences in child injury mortality in the world. The decrease in injury mortality in the working age also implies that preventive work has had an effect. The incline in injury mortality in elderly on the other hand needs to be further studied. Areas of particular importance for future preventive work is the incline in injury mortality in elderly and intentional injuries among children.
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| 43. |
- Cao, Ziquan, 1982-
(författare)
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VEGF-mediated vascular functions in health and disease
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Angiogenesis is essential for physiological processes including embryonic development, tissue regeneration, and reproduction. Under various pathological conditions the same angiogenic process contribute to the onset, development, and progression of many human diseases including cancer, diabetic complications, ocular disease, chronic inflammation and cardiovascular disease. Vascular endothelial growth factor (VEGF) is a key angiogenic factor for physiological and pathological angiogenesis. In addition to its strong angiogenic activity, VEGF also potently induces vascular permeability, often causing tissue edema in various pathological tissues. VEGF transduces its vascular signal through two tyrosine kinase receptors-VEGFR1 and VEGFR2, the latter being a functional receptor that mediates both angiogenic and vascular permeability effects. To study physiological and pathological functions of VEGF, we developed novel zebrafish disease models that permit us to study hypoxia-induced retinopathy and cancer metastasis processes. We have also administered anti-VEGF and anti-VEGFR specific antibodies to healthy mice to study the homeostatic role of VEGF in the maintenance of vascular integrity and its functions in various tissues and organs.Finally, using a zebrafish model, we evaluated if VEGF expression is regulated by circadian clock genes. In paper I, we developed protocols that create hypoxia-induced retinopathy in adult zebrafish. Adult fli1:EGFP zebrafish were placed in hypoxic water for 3-10 days with retinal neovascularization being analyzed using confocal microscopy. This model provides a unique opportunity to kinetically study the development of retinopathy in adult animals using non-invasive protocols and to assess the therapeutic efficacy of orally administered anti-angiogenic drugs. In paper II, we developed a zebrafish metastasis model to dissect the complex events of hypoxia-induced tumor cell invasion and metastasis in association with angiogenesis at the single-cell level. In this model, fluorescent DiI-labeled human or mouse tumor cells were implanted into the perivitelline cavity of 48-hour-old zebrafish embryos, which were subsequently placed in hypoxic water for 3 days. Tumor cell invasion, metastasis and pathological angiogenesis were analyzed using fluorescent microscopy in the living fish. The average experimental time for this model is 7 days. Our protocol offers an opportunity to study molecular mechanisms of hypoxia-induced cancer metastasis. In paper III, we show that systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody cause global vascular regression in mice. Among all examined tissues, the vasculature in endocrine glands, intestinal villi, and the uterus are most affected in response to VEGF or VEGFR-2 blockades. Pro-longed anti-VEGF treatment resulted in a significant decrease in the circulating levels of the predominant thyroid hormone, free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid function. These findings provide structural and functional bases of anti-VEGF-specific druginduced side effects in relation to vascular changes in healthy tissues. In paper IV, we show that disruption of the circadian clock by constant exposure to light coupled with genetic manipulation of key genes in the zebrafish led to impaired developmental angiogenesis. A bmal1-specific morpholino inhibited developmental angiogenesis in zebrafish embryos without causing obvious nonvascular phenotypes. Conversely, a period2 morpholino accelerated angiogenic vessel growth, suggesting that Bmal1 and Period2 display opposing angiogenic effects. These results offer mechanistic insights into the role of the circadian clock in regulation of developmental angiogenesis, and our findings may be reasonably extended to other types of physiological or pathological angiogenesis. Overall, the results in this thesis provide further insight to angiogenic mechanistic properties in tissues and suggest possible novel therapeutic targets for the treatment of various angiogenesis-dependent diseases.
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| 44. |
- Carina, Stenman, 1964-
(författare)
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Standardized ultrasonography with cine-loop documentation : diagnostic variability in liver and kidney examinations
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Ultrasound examination of the abdomen is often a first choice at radiology departments due to the lack of ionizing radiation. For diagnostic accuracy and economic benefits there has been a need for new routines in this area that incorporate the benefits of an radiographer or sonographer performing a multitude of ultrasound examinations following strictly standardized examination protocols and documentation forms made by cine-loops that will give the radiologist access to all relevant information needed for an accurate postexamination diagnosis.Aim: The overall objective of this thesis was to evaluate the diagnostic variability in examinations of the kidneys and liver that use a standardized ultrasound method along with video documentation of the entire examination and off-line review by radiologists. More specifically, we wanted to compare the agreement between readers and between operators.Design and method: This thesis is based on four quantitative studies using standardized protocols for kidney, liver and gallbladder examinations. In paper I, including 64 patients, and paper IV, including 98 patients, the patients were prospectively enrolled and the examinations were retrospectively reviewed. The patients in papers I and IV were examined by one radiographer (sonographer) and one radiologist during the same session. In paper I, findings using the standardized ultrasound method were compared with traditional bedside assessments by a radiologist. In paper IV, the patients were examined using only the standardized method. In paper II, including 98 patients, and in paper III, including 115 patients, the patients were examined by one sonographer using the standardized method and the examinations were reviewed by two or three radiologists.Results: In paper I, no significant systematic differences were found between the findings using the standardized method and the traditional bedside assessment.Paper II showed good intra- and inter-observer agreement between three experienced radiologists when reviewing examinations conducted using the standardized method.In paper III we verified good inter-observer agreement between two radiologists reviewing ultrasound examinations using the standardized technique in patients who had undergone surgery for colorectal cancer. Intravenous contrast was used and the injection of contrast medium increased the visibility of liver lesions.In paper IV, we observed that using a standardized cine-loop technique, there was a slightly better inter-operator agreement than inter-reader agreement.Conclusion: The satisfactory agreement shown in all four studies suggests that the new workflow method using standardized ultrasound examinations and stored cine-loops, performed by a radiographer or sonographer and analyzed off-line by a radiologist, is a promising technique. The results are less affected when a radiologist examiner is replaced by a radiographer or sonographer than when the reviewer is replaced by a different radiologist.
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| 45. |
- Carlander, Johan, 1971-
(författare)
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Energy based surgical instruments : With particular focus on collateral thermal injury
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Iatrogenic post-operative nerve dysfunction is a significant problem in many areas of surgery and can be caused by collateral thermal injury from activation of energy based surgical devices (EBD).The aims of this thesis were to: create an animal model in order to compare mono- and bipolar electrosurgery (ES) and an ultrasonic dissection (UD) with regard to collateral thermal nerve injury, and with data of a national multicenter register to study the use of EBD and their potential effects on operation time and complication rates in thyroid surgery.urgical devices (EBD).Material and Methods: The biceps femoris muscle of 104 anesthetized rats was cut in a standard manner adjacent to the sciatic nerve using clinical relevant settings of mono- and bipolar ES and UD. The sciatic nerve was stimulated supramaximally and the electromyographic (EMG) potential recorded before and after each experiment. Nerve dysfunction was defined as > 10% reduction of the evoked EMG potential. In Paper II and III temperature was measured before, during and after instrument activation. The sciatic nerves were coded and examined blinded with light (LM) and electron microscopy (EM). Advanced temperature measurements were conducted in Paper II and III. In Paper IV, the use of EBD was specifically registered in the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery (SQRTPA) during one year and 1297 patients were included. Operation time, recurrent laryngeal nerve (RLN) injury, post-operative hypoparathyroidism and the use of topical haemostatic agents were compared between bipolar ES, electric vessel sealing (EVS) and UD. Clamp and Tie technique (C-A-T) being without thermal risk constituted the control group.Results: In Paper I the EMG potential was significantly more frequent reduced in the monopolar and bipolar ES group compared to the UD group and LM showed significantly less nerve damage in the UD group. In Paper II exact temperature measurements was possible with thermoelectric micros sensors and the thermal dose was significantly less and with less variation for the UD compared to the bipolar ES. Similar to the Paper I the EMG potential was significantly more frequent reduced in the ES group. Moderate and severe morphological damage was significantly less common in the UD group compared to monopolar ES. We found no statistical correlation between the highest temperatures/doses and the degree of morphological damage or functional loss. In Paper III the temperature increase was significantly less and with shorter duration in the UD group, compared to bipolar ES. LM and EM demonstrated loss of density in the myelin sheet only in a small number of nerves in all groups after instrument activation 1 mm from the nerve.In Paper IV, operation time was significantly shorter in the UD group and significantly longer in the EVS and bipolar ES group, compared to C-A-T. Postoperative hypoparathyroidism with need for Calcium treatment at discharge and at 6 weeks was significantly higher with ES instruments compared to UD. The incidence of reported RLN injury was 2.5% at 6 weeks postoperatively without statistical differences between the groups. Topical haemostatic agents were more frequently used in the EBD groups compared to C-A-T.Conclusion: The experimental Papers (I-III) demonstrated a lower risk of adverse collateral thermal nerve injury with activation of the mechanical UD technique compared to ES techniques. In the nationwide multicenter register Paper (IV), the use of UD shortened end EVS increased operation time compared to the low cost C-A-T. The UD instruments had a lower risk of hypoparathyroidism than electrosurgery.
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| 46. |
- Carlén, Anna, 1985-
(författare)
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Exercise Testing in Firefighters : Work Capacity and Cardiovascular Risk Assessment in a Low-Risk Population
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background. Firefighting is one of the most physically demanding occupations and it requires a high cardiorespiratory fitness level.Pre-duty medical evaluation of firefighters includes fitness testing and assessment of cardiac health to ensure that firefighters meet the minimum physical fitness standard and to ensure that they are not at increased risk of cardiac events. The medical evaluation methods for Swedish firefighters are regulated by the Swedish Work Environment Authority and include a 6 min constant workload treadmill (TM) test for fitness evaluation in which the firefighter wears full smoke diving equipment and a maximal effort exercise electrocardiography test (ExECG) at cycle ergometer (CE) for assessment of cardiac health. Previously, fitness was also evaluated by cycle ergometry.The standard parameter for evaluation of ischaemic heart disease (IHD) is exercise-induced ST depression. In general, exercise testing of asymptomatic low-risk individuals is discouraged due to low sensitivity and specificity for IHD, generating both false-positive and false-negative test results. Heart rate (HR) adjustment of the ST-segment response has been shown to be superior to simple ST depression to evaluate cardiac ischaemia in some populations, but has not been extensively evaluated in an occupational setting.Methods. We retrospectively analysed a cohort of 774 firefighters who were asymptomatic at the time of the testing.In paper I, test approval, HR response, and calculated oxygen uptake from TM tests and CE tests for 424 firefighters (44±10 years) were compared.Paper II methodologically described the process for data extraction, processing, and calculation of ExECG data from a clinical database. Procedures for noise assessment, error checking, and computerized calculation of ST/HR parameters were described.In paper III, ExECG and medical records of 521 male firefighters (44±10 years) were studied. During 8.4 ± 2.1 years of follow-up, IHD was verified angiographically in 12 subjects. The predictive value of HR-adjusted ST variables (ST/HR index, ST/HR slope, and ST/HR loop) for IHD was evaluated.In paper IV, subjects with objectively verified IHD were excluded and factors associated with exercise-induced nonischaemic ST depression were studied in the remaining 509 males (46±11 years). Results. The firefighters had an average maximal exercise capacity of 281 ± 36 W (range 186-467 W) achieved by incremental CE exercise. To enable comparison, the maximal workload was converted to the workload sustainable for 6 min. It was more common to pass the 6 min TM fitness test but to fail the supposedly equivalent CE test rather than vice versa.Twenty percent of the firefighters developed an ST depression of ≥o.1 mV in at least one lead during exercise and half of the firefighters had a horizontal or downsloping ST depression. While an abnormal ST response associated with an increased risk for IHD only in V4, both an abnormal ST/HR index and an abnormal ST/HR slope associated with IHD in three leads each. Clockwise rotation of the ST/HR loop was infrequent in all precordial leads (1%), but it associated with an increased risk for IHD.In the subgroup without evidence of coronary artery disease, age and the HR response associated with ST depression, whereas hypertension, hyperlipidaemia, diabetes, blood pressure response, and exercise capacity did not. Conclusions. Even though the calculated oxygen uptake was higher for the TM test than for the supposedly equivalent CE test, the higher treadmill approval rate may indicate that the fitness requirement for Swedish firefighters has been lowered by changing the test modality.Exercise-induced ST depression was common in asymptomatic physically active men, although there were only a few cases of IHD during follow-up. If performing ExECG in asymptomatic, low-risk populations, ST/HR analysis could be given more importance. However, the limited clinical value of ExECG in low-risk populations was emphasised and needs to be reconsidered.In asymptomatic, physically active men without coronary artery disease, false-positive ST depressions can be partially explained by HR variables rather than by common cardiovascular risk factors and blood pressure response to exercise.
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| 47. |
- Carlhäll, Sara, 1974-
(författare)
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Maternal obesity, duration of labor and the role of leptin
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The prevalence of obesity substantially increases in pregnant women. Maternal obesity is associated with adverse maternal and neonatal outcomes. The increased risk for cesarean section present in obese women has been related to potential impaired uterine contractility. The mechanism that underlies this theory is not clear. In vitro studies have shown that leptin, produced by adipose tissue and the placenta, exerts an inhibitory effect on myometrial contractility. The aim of this thesis was to evaluate the labor process in relation to maternal body mass index (BMI) and the clinical role of leptin in this process.Material and Methods: Studies I-IV are cohort studies. The first two studies analyze the association between labor duration and maternal BMI based on data from the Perinatal Revision South register and the Swedish Pregnancy Register. Study I included 63,829 nulliparous women with a spontaneous onset of labor between 1995 and 2009. Study II included 15,259 nulliparous women with induced labor between 2014 and 2017. In study III, the maternal leptin levels during and after pregnancy were analyzed in 343 obese women with respect to their obesity class (I-III) and degree of gestational weight gain (GWG). In study IV, the association between the maternal leptin levels measured in active labor and duration of the active phase of labor was analyzed in 914 women.Results: The duration of spontaneous labor significantly increased with an increasing maternal BMI; however, the duration of the pushing phase was inversely related to BMI. Time in induced labor increased with maternal BMI; however, the differences between the BMI categories were more pronounced in the latent phase than the active phase. Leptin levels were higher in women with obesity class III than women with class I during and after pregnancy. The degree of GWG in obese women was not associated with maternal leptin. No significant association between maternal leptin and the duration of the active phase of labor was identified in the adjusted analyses.Conclusions: Nulliparous obese women have a higher risk for a prolonged duration of spontaneous and induced labor. This is important to consider prior to diagnosing labor arrest that results in a cesarean delivery. As maternal leptin levels are increased with the degree of obesity during pregnancy, future research on the association of high maternal leptin levels and the duration of labor is warranted.
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| 48. |
- Chang, You, 1985-
(författare)
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A Finite Element Model of the Human Head for Simulation of Bone-conducted Sound
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bone conduction is usually understood as the hearing sensation based on the vibrations of the skull bone and surrounding tissues. The fact that vibration of the skull bones can result in a sound percept has been known for a long time. However, it is difficult to give a general definition of BC sound. Normally, BC sound is described as the sound energy transmitted through the body (comprising the solid and fluid parts) then the outer, middle and inner ear are involved and finally produce a perception of sound.Even if BC sound perception has been studied for more than a century, the whole pattern of BC sound transmission is still not complete. There are limitations for experimental investigation of BC sound, such as the complexity of experimental manipulations and individual differences between subjects resulting in difficult to interpret outcomes. One way to overcome some of those issues is the use of a simulation model for BC sound. However, until now, the published models are unable to provide a holistic response of BC sound in the human. Therefore, the primary aim of this thesis is to develop a finite element model that could simulate BC sound transmission in the human. Based on cryosectional images of a female, the LiUHead was developed as a FE model of the human head with the structure and material properties of real human. Most the structures and tissues which could contribute to the BC transmission were included in the LiUHead. The simulation results of the LiUHead agreed with experimental data obtained in both cadaver heads and live humans.After the development and validation of the LiUHead, the model was used to investigate BC sound. Since BC sound is transmitted in and between the tissues, the power transmission of BC sound was investigated in the LiUHead in the frequency domain. When the stimulation was applied on the surface of the skull at the mastoid position, the results of the simulations show that, as the name suggest, the skull bone dominants the BC sound transmission. The soft tissues and cartilages are as the second most important media of the BC sound while the skull interior is the least important for the BC transmission. Moreover, according to the power flux in the skull, the BC vibrations are mainly concentrated at the skull base. Other important transmission pathways are located at the occipital bone at the posterior side of the head, but the power transmitted over the face, forehead and vertex is minor. There is power interaction between the skull bone and skull interior near the stimulation position but the transmission of sound power through the brain seem to be minimal. Since the power or energy is difficult to measure in an experimental setting, this investigation gave unique knowledge about BC sound transmission in the head and the interaction between the tissues.As a common application for BC sound, bone-conduction devices are used to stimulate the hearing and is a method for hearing loss rehabilitation. Nowadays many different kinds of BCDs are available. However, most studies failed to compare the different types of BCDs in the same conditions as well as between several BCDs as it is not possible to compare several BCDs within the same subject due to the implantation required for several BCDs. The model gives a unique opportunity to evaluate various BCDs in the same head. Eight different BCDs, including four kinds of skin-drive BCDs, three kinds of direct-drive BCDs, and one in-the-mouth device, were applied to the LiUHead and the simulation results were evaluated. The results proved that the direct-drive BCDs and the in-the-mouth device gave similar vibration responses at the cochlea. At low frequencies, the skin-drive BCDs had similar or even better cochlear responses than the direct-drive BCDs. However, the direct-drive BCDs gave stable responses at mid-frequencies and gave higher responses than the skin-drive BCDs at high frequencies. These results are beneficial evaluating and for designing and improving current BCDs.The ultimate goal of this thesis is to provide a computational model for BC sound that can be used for evaluation of BC sound transmission. This was accomplished by the LiUHead that gave results comparable to experimental data and enabled investigations that cannot easily be conducted in experiments.
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| 49. |
- Charitakis, Emmanouil, 1982-
(författare)
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Neurohormonal activation, Symptoms and health-related quality of life in patients with atrial fibrillation eligible for radiofrequency ablation
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atrial fibrillation (AF) is the most common cardiac arrhythmia. In order to improve the management of patients with AF, a better understanding of patients’ arrhythmia-related symptoms and health-related quality of life (HRQoL), as well as a finer grasp of the effect of AF initiation and the revolutionary treatment of radiofrequency ablation (RFA) on neurohormonal balance are of great importance.The aim of this dissertation was to study the effects of RFA and AF initiation on four different neurohormonal systems represented by two cardiac biomarkers: the N-terminal fragment of the proB-type natriuretic peptide (NT-proBNP), the mid-regional fragment of the N-terminal of pro-atrial natriuretic peptide (MR-proANP); and two extra-cardiac biomarkers: the C-terminal fragment of the prodromal molecule of arginine vasopressin (copeptin) and the mid-regional portion of pro-adrenomedullin (MR-proADM). Furthermore, we aimed to correlate objective indicators with the variety of arrhythmiarelated symptoms and HRQoL in patients with AF.We studied 192 consecutive AF patients, eligible for RFA, referred to the University Hospital, Linköping, Sweden between January 2012 and April 2014. Forty-five patients, out of the initially selected sample, were included in the interventional part of the study. Biomarkers were collected from the femoral vein (fv), the coronary sinus (CS) and the left atrium (LA), and from fv immediately and the day after RFA. With regard to the interventional part of the study, 36 patients were randomized to AF initiation and 19 to control group. Biomarkers were retrieved from fv, CS and LA prior to AF initiation (baseline) and 30 minutes later. The Arrhythmia-Specific questionnaire in Tachycardia and Arrhythmia (ASTA) symptom scale was used in order to assess patients’ arrhythmiarelated symptoms. The ASTA HRQoL scale and the generic short-form 36 (SF-36) physical and mental component summaries were used in order to express patients’ disease-specific and overall HRQoL respectively.While analysing the effect of RFA on biomarkers, it was noticed that the level of NTproBNP decreased the day after RFA in participants in AF, compared with the participants in sinus rhythm who showed a slight increase. Regardless of the actual rhythm, the level of MR-proANP showed an increase immediately after RFA was carried out, followed by a decrease the day after. The copeptin level showed a six-fold increase, compared with baseline, immediately after the RFA procedure, while the MR-proADM level increased the day after. The levels of copeptin and MR-proADM were similar in the CS compared to peripheral blood.When it came to the effects of AF initiation on biomarkers, compared with the control group, MR-proANP and NT-proBNP concentrations were increased. Copeptin levels in patients without ischemic heart disease were decreased after the initiation of AF.We also found that signs of anxiety, low-grade inflammation (defined by high-sensitive C-reactive protein levels>3mg/l) and LA dilatation significantly predicted arrhythmiarelated symptoms. Probable depression was the most important predictor of arrhythmiaspecific HRQoL, and obesity and signs of anxiety were the most important predictors of the physical and mental component summaries respectively.AF is a complex arrhythmia that affects the cardiac and extra-cardiac neurohormonal balance directly after its initiation. RFA causes a neurohormonal imbalance not only due to secondary myocardial injury, but also due to other factors such as patient’s actual rhythm, volume overload and procedural stress. Treatable factors such as anxiety, depression and obesity, which can affect HRQoL and symptoms in patients with AF, should be addressed, and possibly a more intensive life style factor modification can be of value.
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| 50. |
- Chenna Narendra, Sudeep
(författare)
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Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, we have studied the immunological processes of joint inflammation that may be targets for future treatment of patients with arthritis. We focus on the immune-modulating properties of interferon-α (IFN-α) and uridine in experimental arthritis. The nucleoside uridine, which is regarded a safe treatment has anti-inflammatory properties notably by inhibiting tumor necrosis factor (TNF) release. Because the inflamed synovium in rheumatoid arthritis (RA) is characterised by pathogenic TNF-production, uridine could potentially be away to ameliorate arthritis. Systemic administration of uridine had no effect on antigeninduced arthritis (AIA), which is a T-cell dependent model where animals are immunized twice (sensitization) with bovine serum albumin (mBSA), before local triggering of arthritis by intra-articular antigen (mBSA) re-challenge. In contrast, intra-articular administration of uridine clearly down modulated development of AIA in a dose dependent manner and inhibited the expression of synovial adhesion molecules, influx of inflammatory leukocytes and synovial expression of TNF and interleukin 6, but did not affect systemic levels of proinflammatory cytokines or antigen-specific T-cell responses. Local administration of uridine may thus be a viable therapeutic option for treatment of arthritis in the future.Viral double-stranded deoxyribonucleic acid (dsRNA), a common nucleic acid found in most viruses, can be found in the joints of RA patients and local deposition of such viral dsRNA induces arthritis by activating IFN-α. Here we show that arthritis induced by dsRNA can be mediated by IFN-producing dendritic cells in the joint and this may thus explain why viral infections are sometimes associated with arthritis.Earlier, to study the effect of dsRNA and IFN-α in an arthritis model, that like RA, is dependent on adaptive immunity, dsRNA and IFN-α were administered individually during the development of AIA. Both molecules clearly protected against AIA in a type I IFN receptor-dependent manner but were only effective if administered in the sensitization phase of AIA. Here we show that the anti-inflammatory effect of IFN-α is critically dependent on signalling via transforming growth factor β (TGF-β) and the enzymatic activity of indoleamine 2,3 dioxygenase 1 (IDO). The IDO enzyme is produced by plasmacytoid DC and this cell type was critically required both during antigen sensitization and in the arthritis phase of AIA for the protective effect of IFN-α against AIA. In contrast, TGF-β and the enzymatic activity of IDO were only required during sensitization, which indicate that they are involved in initial steps of tolerogenic antigen sensitization. In this scenario, IFN- α first activates the enzymatic activity of IDO in pDC, which converts Tryptophan to Kynurenine, which thereafter activates TGF-β. Common for IDO-expressing pDC, Kyn and TGF-β is their ability to induce development of regulatory T cells (Tregs). We found that Tregs were crucial for IFN-α-mediated protection against AIA, but only in the arthritis phase. In line with this, adoptive transfer of Tregs isolated from IFN-α treated mice to recipient animals in the arthritis phase clearly protected against AIA. The numbers of Tregs were not significantly altered by IFN-α but IFN-α increased the suppressive capacity of Tregs against antigen-induced proliferation. This enhanced suppressive activity of Tregs in the arthritis phase was dependent on the earlier activated enzyme IDO1 during the sensitization phase of AIA. Thus, presence of IFN-α at the time of antigen sensitization activates the enzymatic activity of IDO, which generates Tregs with enhanced suppressive capacity that upon antigen re-challenge prevents inflammation. We have thus identified one example of how immune tolerance can be developed, that may be a future way to combat autoimmunity.
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