| 41. |
- Brito, Ema C, 1961-
(författare)
-
Gene x lifestyle interactions in type 2 diabetes mellitus and related traits
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Type 2 diabetes is thought to result from interactions between genetic and lifestyle factors, but few robust examples exist. The overarching aim of this thesis was to discover such interactions by studying cohorts of white youth and adults from northern Europe in which physical activity, genotypes, and diabetes-related traits or diabetes incidence had been ascertained. Methods: The thesis includes four papers. In Paper I, we investigated associations and interactions between 35 common PPARGC1A polymorphisms and cardiovascular and metabolic disease traits in 2,101 Danish and Estonian children from the European Youth Heart Study (EYHS). Paper II used the same cohort to test associations and interactions on cardiometabolic traits for the diabetes-predisposing TCF7L2 polymorphism. In Paper III, we assessed associations for 17 type 2 diabetes gene polymorphisms on impaired glucose regulation (IGR) or incident type 2 diabetes, and tested whether these effects are modified by physical activity in a prospective cohort study of ~16,000 initially non-diabetic Swedish adults – the Malmö Preventive Project (MPP). Paper IV aimed to replicate main genetic effects and gene x physical activity interactions for an FTO polymorphism on obesity in 18,435 primarily non-diabetic Swedish (MPP) and Finnish (Prevalence, Prediction and Prevention of Diabetes in Botnia) adults. Results: In Paper I, nominally significant associations were observed for BMI (rs10018239, P=0.039), waist circumference (rs7656250, P=0.012; rs8192678 [Gly482Ser], P=0.015; rs3755863, P=0.02; rs10018239, P=0.043), systolic blood pressure (rs2970869, P=0.018) and fasting glucose concentrations (rs11724368, P=0.045). Stronger associations were observed for aerobic fitness (rs7656250, P=0.005; rs13117172, P=0.008) and fasting glucose concentrations (rs7657071, P=0.002). None remained significant after correcting for multiple statistical comparisons. We proceeded by testing for gene × physical activity interactions for the polymorphisms that showed statistical evidence of association (P<0.05) in the main effect models, but none was statistically significant. In Paper II, the minor T allele at the rs7903146 variant was associated with higher glucose levels in older (beta=–0.098 mmol/l per minor allele copy, P=0.029) but not in younger children (beta=–0.001 mmol/l per minor allele copy, P=0.972). A significant inverse association between the minor allele at rs7903146 and height was evident in boys (beta=–1.073 cm per minor allele copy, P=0.001), but not in girls. The test of interaction between the TCF7L2 rs7903146 variant and physical activity on HOMA-B was nominally statistically significant (beta=0.022, Pinteraction=0.015), whereby physical activity reduced the effect of the risk allele on estimated beta-cell function. In Paper III, tests of gene x physical activity interactions on IGR-risk for three polymorphisms were nominally statistically significant: CDKN2A/B rs10811661 (Pinteraction=0.015); HNF1B rs4430796 (Pinteraction=0.026); PPARG rs1801282 (Pinteraction=0.04). Consistent interactions were observed for the CDKN2A/B (Pinteraction=0.013) and HNF1B (Pinteraction=0.0009) variants on 2 hr glucose concentrations. Where type 2 diabetes was the outcome, only one statistically significant interaction effect was observed and this was for the HNF1B rs4430796 variant (Pinteraction=0.0004). The interaction effects for HNF1B on 2 hr glucose and incident diabetes remained significant after correction for multiple testing (Pinteraction=0.015 and 0.0068, respectively). In Paper IV, the minor A allele at rs9939609 was associated with higher BMI (P<0.0001). The tests of gene x physical activity interaction on BMI were not statistically significant in either cohort (Sweden: P=0.71, Finland: P=0.18). Conclusions: Variation at PPARGC1A is unlikely to have a major impact on cardiometabolic health in European children, but physical activity may modify the effect of the TFC7L2 variants on beta-cell function in this cohort. In Swedish adults, physical activity modifies the effects of common HNF1B and CDKN2A/B variants on risk of IGR and also modifies the effect of the HNF1B on type 2 diabetes risk. In Swedish and Finnish adults, we were unable to confirm previous reports of an interaction between FTO gene variation and physical activity on obesity predisposition.
|
|
| 42. |
- Brohlin, Maria
(författare)
-
Mesenchymal stem cells for repair of the peripheral and central nervous system
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bone marrow-derived mesenchymal stem cells (MSC) have been shown to provide neuroprotection after transplantation into the injured nervous system. The present thesis investigates whether adult human and rat MSC differentiated along a Schwann cell lineage could increase their expression of neurotrophic factors and promote regeneration after transplantation into the injured peripheral nerve and spinal cord. Human and rat mesenchymal stem cells (hMSC and rMSC) expressed characteristic stem cell surface markers, mRNA transcripts for different neurotrophic factors and demonstrated multi-lineage differentiation potential. Following treatment with a cocktail of growth factors, the hMSC and rMSC expressed typical Schwann cells markers at both the transcriptional and translational level and significantly increased production of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). Age and time in culture are of relevance for clinical settings and growth-promoting effects of hMSC from young donors (16-18 years) and old donors (67-75 years) were compared. Undifferentiated hMSC from both young and old donors increased total neurite length of cultured dorsal root ganglion (DRG) neurons. Differentiation of hMSC from the young donors, but not the eldery donors, further enhanced the neurite outgrowth. Undifferentiated hMSC were cultured for eleven weeks in order to examine the effect of in vitro expansion time on neurite outgrowth. hMSC from the young donors maintained their proliferation rate and their ability to enhance neurite outgrowth from DRG neurons. Using a sciatic nerve injury model, a 10mm gap was bridged with either an empty tubular fibrin glue conduit, or conduits containing hMSC, with and without cyclosporine treatment. Cells were labeled with PKH26 prior to transplantation. At 3 weeks after injury the conduits with cells and immunosuppression increased regeneration compared with an empty conduit. PKH26 labeled human cells survived in the rat model and the inflammatory reaction could be suppressed by cyclosporine. After cervical C4 hemisection, BrdU/GFP-labeled rMSC were injected into the lateral funiculus rostral and caudal to the spinal cord lesion site. Spinal cords were analyzed 2-8 weeks after transplantation. Transplanted MSC remained at the injection sites and in the trauma zone for several weeks and were often associated with numerous neurofilament-positive axons. Transplanted rMSC induced up-regulation of vascular endothelial growth factor in spinal cord tissue rostral to the injury site, but did not affect expression of brain-derived neurotrophic factor. Although rMSC provided neuroprotection for rubrospinal neurons and significantly attenuated astroglial and microglial reaction, cell transplantation caused aberrant sprouting of calcitonin gene-related peptide immunostained sensory axons in the dorsal horn. In summary these results demonstrate that both rat and human MSC can be differentiated towards the glial cell lineage, and show functional characteristics similar to Schwann cells. hMSC from the young donors represent a more favorable source for neurotransplantation since they maintain proliferation rate and preserve their growth-promoting effects in long-term cultures. The data also suggest that differentiated MSC increase expression of neurotrophic factors and support regeneration after peripheral nerve and spinal cord injury.
|
|
| 43. |
- Brorsson, Camilla, 1967-
(författare)
-
Trauma - logistics and stress response
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Trauma is a major cause of death and disability. Adverse events, such as prolonged prehospital time, hypoxia, hypotension and/or hyperventilation have been reported to correlate to poor outcome.Adequate cortisol levels are essential for survival after major trauma. In hypotensive critically ill patients, lack of sufficient amount of cortisol can be suspected, and a concept of critical illness related corticosteroid insufficiency has been proposed. Corticosteroid therapy has many adverse effects in critically ill patients and should only be given if life-saving. Correct measurement of serum cortisol levels is important but difficult in critically ill patients with capillary leakage. Estimation of the free and biologically active cortisol is preferable. In serum less than 10% of cortisol is free and biologically active and not possible to measure with routine laboratory methods. Salivary cortisol can be used as a surrogate for free cortisol, but salivary production is reduced in critically ill patients. Liver resection could reduce cortisol levels due to substrate deficiency.Aims: 1. Evaluate the occurrence of early adverse events in patients with traumatic brain injury and relate them to outcome. 2. Assess cortisol levels over time after trauma and correlate to severity of trauma, sedative/analgesic drugs and cardiovascular function. 3. Evaluate if saliva stimulation could be performed without interfering with salivary cortisol levels. 4. Assess cortisol levels over time after liver resection in comparison to other major surgery.Results: There was no significant correlation between prehospital time ³60 minutes, hypoxia (saturation <95%), hypotension (systolic blood pressure <90 mmHg), or hyperventilation (ETCO2 <4.5 kPa) and a poor outcome (Glasgow Outcome Scale 1-3) in patients with traumatic brain injury. Cortisol levels decreased significantly over time after trauma, but there was no correlation between low (<200 nmol/L) serum cortisol levels and severity of trauma.Infusion of sedative/analgesic drugs was the strongest predictor for a low (<200 nmol/L) serum cortisol. The odds ratio for low serum cortisol levels (<200 nmol/L) was 8.0 for patients receiving continuous infusion of sedative/analgesic drugs. There was no significant difference between unstimulated and stimulated salivary cortisol levels (p=0.06) in healthy volunteers. Liver resection was not associated with significantly lower cortisol levels compared to other major surgery.Conclusion: There was no significant correlation between early adverse events and outcome in patients with traumatic brain injury. Cortisol levels decreased significantly over time in trauma patients. Low cortisol levels (<200 nmol/L) were significantly correlated to continuous infusion of sedative/analgesic drugs. Saliva stimulation could be performed without interfering with salivary cortisol levels. Liver resection was not associated with low cortisol levels compared to other major surgery.
|
|
| 44. |
- Bruce, Elisabeth, 1973-
(författare)
-
Erfarenheter av stöd bland föräldrar till barn med medfödda hjärtfel
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bakgrund. Antalet överlevande barn som diagnostiserats med medfött hjärtfel (CHD) har ökat markant de senaste 15 åren, vilket har bidragit till en växande grupp av barn och familjer som behöver specialiserat stöd, eftersom familjelivet påverkas och begränsas av CHD. Studier har visat att föräldrar till barn med CHD har en ökad risk för psykosocial sjuklighet i jämförelse med föräldrar till barn med andra sjukdomar eller föräldrar till friska barn. Få studier har belyst föräldrars erfarenheter av stöd när de har barn med CHD. Därför fokuseras denna avhandling på föräldrarnas perspektiv av fenomenet stöd, för att öka förståelsen för vad stöd innebär för föräldrar till barn med CHD.Syfte. Avhandlingens syfte är att belysa innebörder i den levda erfarenheten av stöd, hos föräldrar till barn med CHD samt att till svensk kontext anpassa och validera ett familjecentrerat instrument för föräldrars skattning av stöd till hela familjen från sjuksköterskor.Metoder. Avhandling består av fyra delstudier. I tre av dessa (I, II, III) genomfördes datainsamlingen genom narrativa intervjuer, som tolkades genom fenomenologisk hermeneutisk tolkningsmetod. I den fjärde delstudien gjordes en översättning och psykometrisk testning av det isländska instrumentet ICE-FPSQ till svensk kontext. Dessutom beskrevs föräldrars skattning av uppfattat stöd från sjuksköterskor till familjer som har barn med CHD.Resultat. Fynden från delstudie I visade att innebörder i den levda erfarenheten av stöd hos föräldrar till tonåringar med CHD var stöd för att själva kunna vara stödjande för sin familj, men också för andra personer i tonåringens omgivning. Delstudie II visade att innebörder i den levda erfarenheten av stöd för mödrar till yngre barn med CHD var att få stöd så att de själva kunde hantera sin egen oro och sitt familjeliv. Delstudie III visade att innebörder i den levda erfarenheten av stöd för fäder till yngre barn med CHD var önskan att få stöd genom delande relationer med familjen och att bli involverad i vården av sitt barn. Den fjärde delstudien (IV) visade att den svenska versionen av instrumentet ICE-FPSQ var valid och reliabel i svensk kontext. Föräldrarnas skattningar av uppfattat familjecentrerat stöd till familjen från sjuksköterskor visade sig vara lågt.Slutsats. En övergripande slutsats från de tre första delstudierna pekar mot att innebörder i stöd för föräldrarna är stöd genom att ha goda, interaktiva relationer med vårdpersonalen, bli mött som en hel familj med unika och individuella behov samt inkluderade i vårdprocessen för att kunna stödja varandra inom familjen. Dessa fynd pekar mot familjecentrerad pediatrisk omvårdnad som sannolikt är lämplig för att, på ett mångfacetterat sätt, möta varje familjs behov av att bli bemött som en unik helhet. Det Isländska instrumentet ICE-FPSQ är designad utifrån teorin om familjecentrerad omvårdnad. I delstudie IV visade resultaten på acceptabla psykometriska egenskaper för den svenska versionen av instrumentet. Fynden visade även att föräldrarna inte skattade höga nivåer av familjecentrerat stöd från sjuksköterskor.
|
|
| 45. |
- Brändström, Helge, 1953-
(författare)
-
Accidental hypothermia and local cold injury : physiological and epidemiological studies on risk
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: (Papers I and II) The objectives were to first determine incidence and contributing factors to cold-related injuries in northern Sweden, both those that led to hospitalization and those that led to fatality. (Papers III and IV) A further aim was to assess post-cooling hand-rewarming responses and effects of training in a cold environment, both on fingertip rewarming and on function of the autonomic nervous system, to evaluate if there was adaptation related to prolonged occupational cold exposure.Methods: In a retrospective analysis, cases of accidental cold-related injury with hospital admission in northern Sweden during 2000-2007 were analyzed (Paper I). Cases of fatal hypothermia in the same region during 1992-2008 were analyzed (Paper II). A cohort of volunteers was studied before and after many months of occupational cold exposure. Subject hand rewarming response was measured after a cold hand immersion provocation and categorized as slow, moderate or normal in rewarming speed. This cold provocation and rewarming assessment was performed before and after their winter training. (Paper III). Heart rate variability (HRV) was analyzed from the same cold provocation/recovery sequences (Paper IV).Results: (Paper I) For the 379 cases of hospitalization for cold-related injury, annual incidences for hypothermia, frostbite, and drowning were 3.4/100,000, 1.5/100,000, and 1.0/100,000 inhabitants, respectively. Male gender was more frequent for all categories. Annual frequencies for hypothermia hospitalizations increased during the study period. Hypothermia degree and distribution of cases were 20 % mild (between 32 and 35ºC), 40% moderate (31.9 to 28ºC), and 24% severe (< 28ºC), while 12% had temperatures over 35.0ºC. (Paper II) The 207 cases of fatal hypothermia showed an annual incidence of 1.35 per 100,000 inhabitants, 72% in rural areas, 93% outdoors, 40% found within 100 meters of a building. Paradoxical undressing was documented in 30%. Ethanol was detected in femoral vein blood in 43%. Contributing co-morbidity was common including heart disease, previous stroke, dementia, psychiatric disease, alcoholism, and recent trauma. (Paper III) Post-training, baseline fingertip temperatures and cold recovery variables in terms of final rewarming fingertip temperature and vasodilation time increased significantly in moderate and slow rewarmers. Cold-related injury (frostbite) during winter training occured disproportionately more often in slow rewarmers (4 of the 5 injuries). (Paper IV) At ‘pre- winter-training’, normal rewarmers had higher power for low frequency and high frequency heart rate variability. After cold acclimatization (post-training), normal rewarmers showed lower resting power values for the low frequency and high frequency heart rate variability components. Conclusions: Hypothermia and cold injury continues to cause injury and hospitalization in the northern region of Sweden. Assessment and management is not standardized across hospitals. With the identification of groups at high risk for fatal hypothermia, it should be possible to reduce the incidence, particularly for highest risk subjects; rural, living alone, alcohol-imbibing, and psychiatric diagnosis-carrying citizens. Long-term cold-weather training may affect hand rewarming patters after a cold provocation, and a warmer baseline hand temperature with faster rewarming after a cold provocation may be associated with less general risk for frostbite. Heart rate variability results support the conclusion that cold adaptation in the autonomic nervous system occurred in both groups, though the biological significance of this is not yet clear.
|
|
| 46. |
- Brännström, Fredrik, 1975-
(författare)
-
The impact of structural factors in colon and rectal cancer surgery
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to investigate the importance and effect of some key-structural factors on outcome of colorectal cancer surgery.Considerable improvements in the treatment of colorectal cancer, i.e. radiotherapy, chemotherapy and operative technique, have taken place since the beginning of the 80s. Recent years have also seen the introduction of multidisciplinary team (MDT) meetings in routine care, although evidence that this has benefitted treatment selection and outcome is weak. A challenge still remaining, regarding colon cancer surgery, is to improve outcome for the large number of patients presenting as an emergency. Outcome in the emergency situation remains worse in both the short- and long-term perspective compared to elective cases. Although studied extensively, the impact of surgeon’s case-load and degree of specialisation on outcome of surgery remains unclear.The following specific factors were studied: the effect of surgeon’s case-load and degree of specialisation on long-term survival in a well-defined, population-based, and recent cohort; the impact of surgeon’s case-load or degree of specialisation on the number of lymph nodes harvested in routine colon cancer surgery; predictors of preoperative discussion of rectal cancer patients at a MDT conference in Sweden, and whether or not MDT assessment influences decision-making in the treatment of rectal cancer; factors associated with an increased risk for loco-regional recurrence in patients operated as an emergency for colon cancer, in a population-based cohort.Data from the Swedish Colorectal Cancer Register (SCRCR) and the local (Uppsala/Örebro) ROC-register were used to study the effect of surgeon’s caseload and surgeon’s degree of specialisation on long-term survival. Data from six hospitals in the Uppsala/Örebro health care region were extracted for the periods 1995-2006 for rectal cancer, and 1997-2006 for colon cancer. These data were updated with a surgeon-specific number and competence level as well as other missing data. Colon and rectal cancer were analysed separately and each cancer stage was analysed separately (Stages I and II grouped together). Data on patients who had undergone right-sided hemicolectomy were extracted from these data and used to investigate whether the surgeon’s case-load or degree of specialisation had an impact on the number of lymph nodes harvested. For the study on predictors of discussion at a preoperative MDT conference, data on all patients without known metastatic disease at diagnosis, who underwent elective surgery for rectal cancer 2007-2010 in Sweden, were extracted from the SCRCR. For the study on factors associated with preoperative radiotherapy, two groups were extracted from this cohort and analysed separately. The first group comprised patients who had undergone elective tumour resection with curative intent for pT3c, pT3d, pT4 tumours, and the second comprised patients who had undergone elective tumour resection with curative intent for lymph node-positive tumours. For the study on colon cancer patients operated as an emergency, the local colon cancer registry for the Stockholm-Gotland health care region was used to identify all colon cancer patients subjected to emergency resection with curative intent in this region 1997-2007. Patient records with missing information were updated. The impact of reason for emergency resection, time from admission to surgery, daytime versus night-time operation, ASA score, blood loss, and T- and N-stages on the risk for locoregional recurrence was assessed.When the highest degree of specialisation of surgeons participating in the operation was a non-colorectal surgeon, there was a slightly lower long-term survival for rectal cancer Stages I-II (HR 2.03; 95%CI 1.05-3.92). Apart from this, neither the degree of specialisation nor case-load was associated with better survival. Surgeons with colorectal accreditation were associated with a signifcantly higher proportion of patients having 12 or more lymph nodes harvested from surgical specimens after right-sided hemicolectomy in both non-adjusted and multivariate analyses, as was also university pathology department. Emergency surgery did not affect the lymph node yield. The number of rectal cancer procedures performed per year at each hospital (hospital volume) was the main predictor of MDT evaluation. Patients treated at hospitals with <29 procedures per year had an odds ratio (OR) for MDT evaluation of 0.15. Tumour stage and age also influenced the chance of MDT evaluation. MDT evaluation significantly predicted the likelihood of being treated with preoperative radiotherapy in patients with pT3c-pT4 tumours (OR 5.06) and lymph node-positive tumours (OR 3.55), even when corrected for co-morbidity and age. The only factor tested, apart from stage, influencing the risk for local recurrence after emergency colon cancer surgery was the indication for emergency surgery; perforations of the colon being a higher risk with a HR of 1.96 (95%CI 1.12-3.43).Case-load and degree of specialisation of the surgeon were found not to be important predictors of outcome in colorectal cancer surgery in this cohort. This suggests that there are other structural-related factors that are more important for outcome in colon and rectal cancer. The degree of specialisation of the surgeon did, however, influence the number of lymph nodes harvested from specimens obtained during routine right-sided colon cancer surgery, which might indicate that a higher degree of specialisation is associated with more extensive surgery. Patients with rectal cancer treated at high-volume hospitals were more likely to be discussed at a MDT conference. This in turn was identified as an independent predictor of treatment with adjuvant radiotherapy. MDT evaluation is thus a structural factor with a potentially greater impact on treatment and outcome than surgeon’s caseload and degree of specialisation, at least for patients with rectal cancer. Structural-related risk factors that were expected to predict outcome in emergency colon cancer surgery had no significant influence on the risk for locoregional recurrence.
|
|
| 47. |
- Bunikis, Ignas, 1981-
(författare)
-
Borrelia channel-forming proteins : structure and function
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Borrelia is a Gram-negative, corkscrew-shaped bacterium transmitted by infected ticks or lice. Borreliae are subdivided into pathogens of two diseases: Lyme disease, caused mainly by B. burgdorferi, B. afzelii and B. garinii; and relapsing fever caused primarily by B. duttonii, B. hermsii, B. recurrentis or B. crocidurae. Both diseases differ in their manifestations, duration times and dissemination patterns. Antibiotics are the major therapeutics, although unfortunately antibiotic treatment is not always beneficial. To date, drug resistance mechanisms in B. burgdorferi are unknown. Transporters of the resistance-nodulation-division (RND) family appear to be involved in drug resistance, especially in Gram-negative bacteria. They consist of three components: a cytoplasmic membrane export system, a membrane fusion protein (MFP), and an outer membrane factor (OMP). The major antibiotic efflux activity of this type in Escherichia coli is mediated by the tripartite multidrug resistance pump AcrAB-TolC. Based on the sequence homology we conclude that the besA (bb0140), besB (bb0141) and besC (bb0142) genes code for a similar efflux system in B. burgdorferi. We created a deletion mutant of besC. The minimal inhibitory concentration (MIC) values of B. burgdorferi carrying an inactive besC gene were 4- to 8-fold lower than in the wild type strain. Animal experiments showed that the besC mutant was unable to infect mice. Black lipid bilayer experiments were carried out to determine the biophysical properties of purified BesC. This study showed the importance of BesC protein for B. burgdorferi pathogenicity and resistance to antibiotics, although its importance in clinical isolates is not known. Due to its small genome, Borrelia is metabolically and biosynthetically deficient, thereby making it highly dependent on nutrients provided by their hosts. The uptake of nutrients by Borrelia is not yet completely understood. We describe the purification and characterization of a 36-kDa protein that functions as a putative dicarboxylate-specific porin in the outer membrane of Borrelia. The protein was designated as DipA, for dicarboxylate-specific porin A. DipA was biophysically characterized using the black lipid bilayer assay. The permeation of KCl through the channel could be partly blocked by titrating the DipA-mediated membrane conductance with increasing concentrations of different organic dicarboxylic anions. The obtained results imply that DipA does not form a general diffusion pore, but a porin with a binding site specific for dicarboxylates which play important key roles in the deficient metabolic and biosynthetic pathways of Borrelia species. The presence of porin P66 has been shown in both Lyme disease and relapsing fever spirochetes. In our study, purified P66 homologues from Lyme disease species B. burgdorferi, B. afzelii and B. garinii and relapsing fever species B. duttonii, B. recurrentis and B. hermsii were compared and their biophysical properties were further characterized in black lipid bilayer assay. Subsequently, the channel diameter of B. burgdorferi P66 was investigated in more detail. For this study, different nonelectrolytes with known hydrodynamic radii were used. This allowed us to determine the effective diameter of the P66 channel lumen. Furthermore, the blockage of the channel after addition of nonelectrolytes revealed seven subconducting states and indicated a heptameric structure of the P66 channel. These results may give more insight into the functional properties of this important porin.
|
|
| 48. |
- Calcutteea, Avin, 1978-
(författare)
-
New insights in the assessment of right ventricular function : an echocardiographic study
- 2013
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The right ventricle (RV) is multi-compartmental in orientation with a complex structural geometry. However, assessment of this part of the heart has remained an elusive clinical challenge. As a matter of fact, its importance has been underestimated in the past, especially its role as a determinant of cardiac symptoms, exercise capacity in chronic heart failure and survival in patients with valvular disease of the left heart. Evidence also exists that pulmonary hypertension (PH) affects primarily the right ventricular function. On the other hand, previous literature suggested that severe aortic stenosis (AS) affects left ventricular (LV) structure and function which partially recover after aortic valve replacement (AVR). However, the impact of that on RV global and segmental function remains undetermined. Objectives: We sought to gain more insight into the RV physiology using 3D technology, Speckle tracking as well as already applicable echocardiographic measures. Our first aim was to assess the normal differential function of the RV inflow tract (IT), apical and outflow tract (OT) compartments, also their interrelations and the response to pulmonary hypertension. We also investigated the extent of RV dysfunction in severe AS and its response to AVR. Lastly, we studied the extent of global and regional right ventricular dysfunction in patients with pulmonary hypertension of different aetiologies and normal LV function.Methods: The studies were performed on three different groups; (1) left sided heart failure with (Group 1) and without (Group 2) secondary pulmonary hypertension, (2) severe aortic stenosis and six months post AVR and (3) pulmonary hypertension of different aetiologies and normal left ventricular function. We used 3D, speckle tracking echocardiography and conventionally available Doppler echocardiographic transthoracic techniques including M-mode, 2D and myocardial tissue Doppler. All patients’ measurements were compared with healthy subjects (controls). Statistics were performed using a commercially available SPSS software.Results:1- Our RV 3D tripartite model was validated with 2D measures and eventually showed strong correlations between RV inflow diameter (2D) and end diastolic volume (3D) (r=0.69, p<0.001) and between tricuspid annular systolic excursion (TAPSE) and RV ejection fraction (3D) (r=0.71, p<0.001). In patients (group 1 & 2) we found that the apical ejection fraction (EF) was less than the inflow and outflow (controls: p<0.01 & p<0.01, Group 1: p<0.05 & p<0.01 and Group 2: p<0.05 & p<0.01, respectively). Ejection fraction (EF) was reduced in both patient groups (p<0.05 for all compartments). Whilst in controls, the inflow compartment reached the minimum volume 20 ms before the outflow and apex, in Group 2 it was virtually simultaneous. Both patient groups showed prolonged isovolumic contraction (IVC) and relaxation (IVR) times (p<0.05 for all). Also, in controls, the outflow tract was the only compartment where the rate of volume fall correlated with the time to peak RV ejection (r = 0.62, p = 0.03). In Group 1, this relationship was lost and became with the inflow compartment (r = 0.61, p = 0.01). In Group 2, the highest correlation was with the apex (r=0.60, p<0.05), but not with the outflow tract.2- In patients with severe aortic stenosis, time to peak RV ejection correlated with the basal cavity segment (r = 0.72, p<0.001) but not with the RVOT. The same pattern of disturbance remained after 6 months of AVR (r = 0.71, p<0.001). In contrast to the pre-operative and post-operative patients, time to RV peak ejection correlated with the time to peak outflow tract strain rate (r = 0.7, p<0.001), but not with basal cavity function. Finally in patients, RVOT strain rate (SR) did not change after AVR but basal cavity SR fell (p=0.04).3- In patients with pulmonary hypertension of different aetiologies and normal LV function, RV inflow and outflow tracts were dilated (p<0.001 for both). Furthermore, TAPSE (p<0.001), inflow velocities (p<0.001), basal and mid-cavity strain rate (SR) and longitudinal displacement (p<0.001 for all) were all reduced. The time to peak systolic SR at basal, mid-cavity (p<0.001 for both) and RVOT (p=0.007) was short as was that to peak displacement (p<0.001 for all). The time to peak pulmonary ejection correlated with time to peak SR at RVOT (r=0.7, p<0.001) in controls, but with that of the mid cavity in patients (r=0.71, p<0.001). Finally, pulmonary ejection acceleration (PAc) was faster (p=0.001) and RV filling time shorter in patients (p=0.03) with respect to controls.Conclusion: RV has distinct features for the inflow, apical and outflow tract compartments, with different extent of contribution to the overall systolic function. In PH, RV becomes one dyssynchronous compartment which itself may have perpetual effect on overall cardiac dysfunction. In addition, critical aortic stenosis results in RV configuration changes with the inflow tract, rather than outflow tract, determining peak ejection. This pattern of disturbance remains six month after valve replacement, which confirms that once RV physiology is disturbed it does not fully recover. The findings of this study suggest an organised RV remodelling which might explain the known limited exercise capacity in such patients. Furthermore, in patients with PH of different aetiologies and normal LV function, there is a similar pattern of RV disturbance. Therefore, we can conclude that early identification of such changes might help in identifying patients who need more aggressive therapy early on in the disease process.
|
|
| 49. |
- Carlsen, Hanne Krage, 1981-
(författare)
-
Health effects of air pollution in Iceland : respiratory health in volcanic environments
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Air pollution has adverse effects on human health. The respiratory system is the most exposed and short-term changes in air pollution levels have been associated with worsening of asthma symptoms and increased rates of heart attacks and stroke. Air pollution in cities due to traffic is the major concern, as many people are exposed. However, natural sources of air pollution such as natural dust storms and ash from volcanic eruptions can also compromise human health. Exposure to volcanic eruptions and other natural hazards can also threaten mental health. Air pollution has not been extensively studied in Iceland, in spite of the presence of several natural pollution sources and a sizeable car fleet in the capital area.The aim of this thesis was to determine if there was a measurable effect on health which could be attributed to air pollution in Iceland. This aim was pursued along two paths; time series studies using register data aimed to determine the short-term association between daily variation in air pollution and on one hand daily dispensing of anti-asthma medication or the daily number of emergency room visits and emergency admissions for cardiopulmonary causes and stroke. The other method was to investigate if exposure to the Eyjafjallajökull volcanic eruption was associated with adverse health outcomes, either at the end of the eruption, or 6 months later.In paper I time series regression was used to investigate the association between the daily number of individuals who were dispensed anti-asthma medication and levels of the air pollutants particle matter with an aerodynamic diameter less than 10 μm (PM10), nitrogen dioxide (NO2), ozone (O3), and hydrogen sulfide (H2S) during the preceding days. For the study period 2006-9, there were significant associations between the daily mean of PM10 and H2S and the sales of anti-asthma medication 3 to 5 days later. Giving the exposure as the highest daily one-hour mean gave more significant results. Air pollution negatively affected the respiratory health of asthma medication users, prompting them to refill their prescriptions before they had originally intended to.In paper II the main outcome was the number of individuals seeking help at Landspitali University Hospital emergency room for cardiopulmonary disease or stroke. Time series regression was used to identify the lag that gave the best predictive power, and models were run for data for 2003-9 pollutants PM10, NO2, and O3. O3 was significantly associated with the number of emergency hospital visits the same day and two days later in all models, and both for men, women and the elderly. Only emergency hospital visits of the elderly were associated with NO2, and there were no associations with PM10.In paper III the aim was to investigate if the health effects of PM10 were affected by the addition of volcanic ash from the 2010 eruption of Eyjafjallajökull and 2011 eruption of Grímsvötn to PM10 in the capital area. Time series regression of emergency hospital visits and PM10 before and after the Eyjafjallajökull eruption showed that the effect tended to be higher after the eruption, but the results were not significant. Analysis with a binary indicator for high levels of PM10 from volcanic ash and other sources showed that volcanic ash was associated with increased emergency hospital visits. There were no associations with high levels of PM10 from other sources.In paper IV, the health of the population exposed to the ongoing eruption of Eyjafjallajökull in 2010 was investigated thoroughly. Lung function in adults was better than in a reference group from the capital area, though many reported sensory organ irritation symptoms and symptoms of stress and mental unhealth, especially those with underlying diseases.Paper V report the results from a questionnaire study which was carried out six months after the Eyjafjallajökull eruption. The study population comprised a cohort of south Icelanders exposed to the eruption to varying degrees and a reference group from north Iceland. Respiratory and eye symptoms were much more common in south Icelanders than in the reference group, after adjusting for demographic characteristics. Mental unhealth rates had declined considerably.In the studies, we found that urban air pollution and natural particles have short-term effects on anti-asthma medication dispensing and emergency room visits and hospital admissions. Exposure to natural particles in the form of volcanic dust was associated with increased respiratory symptoms in a very exposed population. There were indications that volcanic ash particles were associated with increased emergency hospital visits in the following days.
|
|
| 50. |
- Carlsson, Maine, 1955-
(författare)
-
Nutritional status, body composition and physical activity among older people living in residential care facilities
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The main purpose of this thesis was to study, whether drinkable yoghurt enriched with probiotic bacteria could have any effect on constipation and body weight (BW) among older people with dementia. Further, it concerns poor nutritional status among older people with physical and cognitive impairments and its relationship with factors commonly occur in older people living in residential care facilities. It also discusses how body composition changes with ageing and the associations between changes in muscle mass and functional balance after a high-intensity weight-bearing exercise program (the HIFE program) and the ingestion of an additional milk-based protein-enriched energy supplement. A six-month feasibility study that included a probiotic drink was performed among 15 old people who were living in special units for people with dementia and who all had constipation. The effects of the probiotic drink on stool habits, and BW were studied. The outcome measures were followed daily for bowel movements and at three and six months for BW. The staff found the study easy to carry out and that the drink was well accepted by the participants. No convincing beneficial effects on stool habits were observed. In addition, a mean BW loss of 0.65 kg/month was registered. A poor nutritional intake, low physical activity level, and an over-night fast of almost 15 hours, 4 hours longer than recommended were also observed. As a part of the FOPANU Study (Frail Older People-Activity and Nutrition Study), a randomized controlled trial was carried out in Umeå - the associations between nutritional status and factors common among old people with physical and cognitive impairments living in residential care facilities was studied. Assessments were made of nutritional status using the Mini Nutritional Assessment (MNA) scale, fat-free mass (FFM) and fat mass (FM) using both bioelectrical impedance spectroscopy (BIS) and skinfold thickness measurements. The effects of a high- intensity functional exercise program with an additional protein-enriched milk drink on ability to build muscle mass were evaluated. Analyses were made to investigate whether nutritional status, assessed using the MNA scale, was associated with medical conditions, drugs, activities of daily living (Barthel ADL index), cognitive impairment (Mini Mental State Examination (MMSE)), and depressive symptoms (Geriatric Depression Scale (GDS)) at baseline. The associations were assessed with multiple linear regression analyses with additional interaction analyses. An independent association was found between poor nutritional status and having had a urinary tract infection (UTI) during the preceding year and being dependent in feeding for both women and men, and having lower MMSE scores for women. A large proportion of the participants, were at risk of malnutrition or were already malnourished. Women, but not men, had significantly lower Fat-Free Mass Index (FFMI) and Fat Mass Index (FMI) with age. Bioelectrical impedance spectroscopy results correlated with skinfold thickness measurements, but on different levels on value for FM%. Despite the high-intensity exercise had long-term effects (at six months, three months after the exercise) on functional balance, walking ability and leg strength. No effects on muscle mass and no additional effects from the protein-enriched drink could be observed after the three months of high intensity exercise. A negative, long-term effect on the amount of muscle mass and BW was revealed at six months (three months after the intervention had ended). The effects from the exercise did not differ for participants who were malnourished. No statistical interactions were observed between sex, depression, dementia disorder, and nutritional status, and the level of functional balance capacity on the outcome at three or six months. In summary, the majority of the included older people with dementia had a low dietary intake, low physical activity level, and lost BW despite receiving a probiotic drink supplement every day for six months. The supplementation had no detectable effect on constipation. Among the participants in the FOPANU Study, UTI during the preceding year was independently associated with poor nutritional status. Being dependent in feeding was associated with poor nutritional status as were lower MMSE scores for women but not for men. Despite the high-intensity exercise program had long-term effects on the fysical function was no effect on the amount of muscle mass at three months observed. The FFM and FM expressed as indexes of body height were inversely related to age for women, but not for men. A high-intensity exercise program did not have any effect on the amount of muscle mass. The ingestion of a protein-enriched drink immediately after exercise produced no additional effect on the outcome and the results did not differ for participants who were malnourished. The negative long-term effect on amount of muscle mass, and BW, indicate that it is necessary to compensate for increased energy demands during a high-intensity exercise program. High age, female sex, depression, mild to moderate dementia syndrome, malnutrition, and severe physical impairment do not seem to have a negative impact on the effect of a high-intensity functional weight-bearing exercise program. Consequently, people with these characteristics in residential care facilities should not be excluded from training and rehabilitation including nutrition. More research is needed in large randomized controlled trials to further explore the association between energy balance and malnutrition among frail old people, with a special focus on UTI and constipation, but also to study how physical exercise affects older people’s nutritional status.
|
|
