| 1. |
- Ludvigsen, Eva, 1974-
(författare)
-
Somatostatin Receptor Expression and Biological Functions in Endocrine Pancreatic Cells
- 2006
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes is resulting from the selective destruction of insulin-producing beta-cells within the pancreatic islets. Somatostatin acts as an inhibitor of hormone secretion through specific receptors (sst1-5).All ssts were expressed in normal rat and mouse pancreatic islets, although the expression intensity and the co-expression pattern varied between ssts as well as between species. This may reflect a difference in response to somatostatin in islet cells of the two species.The Non-Obese Diabetic (NOD) mouse model is an experimental model of type 1 diabetes, with insulitis accompanied by spontaneous hyperglycaemia. Pancreatic specimens from NOD mice at different age and stage of disease were stained for ssts. The islet cells of diabetic NOD mice showed increased islet expression of sst2-5 compared to normoglycemic NOD mice. The increase in sst2-5 expression in the islets cells may suggest either a contributing factor in the process leading to diabetes, or a defense response against ongoing beta-cell destruction.Somatostatin analogues were tested on a human endocrine pancreatic tumour cell line and cultured pancreatic islets. Somatostatin analogues had an effect on cAMP accumulation, chromogranin A secretion and MAP kinase activity in the cell line. Treatment of rat pancreatic islets with somatostatin analogues with selective receptor affinity was not sufficient to induce an inhibition of insulin and glucagon secretion. However, a combination of selective analogues or non-selective analogues via co-stimulation of receptors can cause inhibition of hormone production. For insulin and glucagon, combinations of sst2 + sst5 and sst1 + sst2, respectively, showed a biological effect.In summary, knowledge of islet cell ssts expression and the effect of somatostatin analogues with high affinity to ssts may be valuable in the future attempts to influence beta-cell function in type 1 diabetes mellitus, since down-regulation of beta-cell function may promote survival of these cells during the autoimmune attack.
|
|
| 2. |
- Cunningham, Janet Lynn, 1974-
(författare)
-
Tumour Biological Factors Characterizing Metastasizing Serotonin-producing Ileocaecal Carcinoids
- 2007
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this study, metastasizing serotonin-producing ileocaecal carcinoid tumours (MSPCs) were examined for biological characteristics that could be used to define clinically relevant subgroups within this patient population. Possible targets for new treatment options were also explored.It was found that MSPCs share several biological characteristics such as expression of serotonin, tachykinins (TKs), chromogranin A, islet autoantigen-2 and connective tissue growth factor (CTGF). TKs and serotonin were demonstrated in the same endocrine tumours in the gut and lung. IA-2 expression was shown to be up-regulated in MSPCs, possibly in connection with active hormone secretion. CTGF expression was high in tumour areas adjacent to extensive stroma expressing alpha-smooth muscle actin. This indicated myofibroblast differentiation, which may be associated with fibrosis-related complications prevalent in patients with MSPCs. When compared with other endocrine tumours, MSPCs behaved as a relatively homogeneous group, though within the MSPC population several subgroups could be defined. Patients with tumours displaying either a solid growth pattern and/or a Ki67 index ≥1% had a less favourable prognosis than those who did not. Another group of patients, who had increased plasma TK concentrations, were more likely to suffer from severe diarrhea. This information should be considered when discussing clinical treatment and when undertaking tumour biological studies. New treatment possibilities, such as drugs that specifically target TK receptors and antibodies to CTGF, are also discussed.In conclusion, MSPCs comprise a clinically relevant tumour group with similar biological features that are distinct from other endocrine tumours. Subgroups of patients within this patient category can be defined which may be relevant when establishing prognosis and when selecting future treatment modalities.
|
|
| 3. |
- Grönberg, Malin, 1980-
(författare)
-
Expression of Neuroendocrine Markers in Normal and Neoplastic Tissue with an Emphasis on Ghrelin and Obestatin
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to characterize the expression of the peptides ghrelin and obestatin, as well as other neuroendocrine markers in human normal tissues, in invasive breast cancer and a wide panel of neuroendocrine tumors (NETs). In normal tissues the expression of ghrelin and obestatin was mainly localized to the gastric mucosa, and in lesser extent in the remaining gastrointestinal tract, endocrine pancreas and mammary glands. Double immunofluorescence studies demonstrated that ghrelin and obestatin were co-localized in the same cells displaying the same cytoplasmic distribution. In normal breast tissue, ghrelin, obestatin, adrenomedullin, apelin and vesicular monoamine transporter 2 were specifically demonstrated in the luminal epithelial cells. Consecutive sections indicated that mammary epithelial cells could express several of these peptides. Secretogranin II and III were also detected in breast tissue, but their presence was restricted to the outer layer of myoepithelial cells, whereas chromogranin B immunoreactivity was found in both the epithelial and myoepithelial cells. Ghrelin and obestatin immunoreactivity was seen in invasive breast cancer, where the expression could be correlated to factors associated with prognosis. Furthermore, multivariate analysis indicated that ghrelin expression was a possible independent prognostic factor for prolonged recurrence-free and breast cancer-specific survival. In a panel of NETs and endocrine-related disorders it was revealed that ghrelin and obestatin immunoreactivity was primarily found in tumors originating from the respective normal tissues. The two proteins were detected in only a few cases and only occasional tumor cells were immunoreactive. In conclusion, ghrelin and obestatin are localized in the gastrointestinal tract, endocrine pancreas and mammary glands. This thesis has contributed to our understanding of the distribution of ghrelin and obestatin in both normal tissue and tumor cells. A potential role of ghrelin as a prognostic factor in invasive breast cancer has been identified and should be further explored.
|
|
| 4. |
- Stenberg, Jenny, 1976-
(författare)
-
Fluid Management in Haemodialysis : Studies on current practices and new methods
- 2020
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic fluid overload has been identified as an independent predictor of mortality in haemodialysis patients, and 30% remain fluid overloaded at dry weight. The use of bioimpedance spectroscopy (BIS) in fluid management may improve blood pressure control and cardiovascular status. However, the importance of regular and careful clinical assessment of fluid balance is repeatedly emphasised.This thesis is based on five papers and the overall aim was to investigate current practices and new methods for fluid management in haemodialysis, and to develop a management tool for dry weight determination, based on multiple complementary methods. The purpose was to contribute to reduced prevalence of fluid overload and intradialytic symptoms in haemodialysis patients, by providing the healthcare team and the patient with a tool, that facilitates communication and enables informed decision-making in dry weight determination.In the initial, cross-sectional study, clinical praxis for dry weight assessment in Sweden and Denmark was investigated. A wide variation in routines was found. Despite high access, BIS was sparsely used. Instead, nurses’ authorisation to adjust haemodialysis patients’ dry weight was associated with improved fluid status. The second study had a qualitative approach. Focus group interviews, with healthcare professionals, were carried out to achieve a deeper understanding of the factors preventing or facilitating the use of BIS. In the third study, the usefulness of a biomarker, brain natriuretic peptide (BNP), for assessing fluid status in haemodialysis patients, was investigated. An association between BNP and fluid overload was established. The between-individual variation in BNP levels was greater than the within-individual variation over time. Therefore, if BNP is to be used as a marker for fluid overload, repeated measurements are required. In the fourth study, we developed and validated a multifactorial decision aid, Recova®, that incorporates BIS in dry weight determination. Recova® is based on physiological parameters routinely measured in haemodialysis and provides guidance on when and how to respond to recognised fluid alterations. In the fifth study, the decision aid’s effect on volume status was tested in a cohort of haemodialysis patients. Implementation of Recova® had effect on fluid status symptoms, BIS-measured hydration status and NT-proBNP levels.
|
|
| 5. |
|
|
