| 21. |
- Maletius, Wolfgang
(författare)
-
Long term prognosis of intraarticular knee injuries
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Intraarticular knee injuries, still are a challenge for proper treatment in Sports Medicine today .The increasing life expectancy as well as the patient expectation to maintain a sufficiant physical activity up to high ages gives the topic an increasing publicity. Still, the long tenn prognosis of the most conunon intraarticular knee injuries including cartilage injuries remaines unclear. The general purpose of this work was to investigate the long- term prognosis after common intraarticular knee injuries in respect to lrnee function, sports performance, knee stability and development of radiographical osteoarthrosis.In this series, 221 patients were examined. The initial diagnosis in all cases was placed by manual examination under anesthesy and arthroscopy. The patients were reexamined at different long-term follow-up intervalls by an interview, including a subjective lmee score and an activity score, a thorough manual examination, and a radiographical examination including weight-bearing radiographs. In a part of the patients, a quality of life score was used.Patients with isolated chondral damage in one knee had a good long-term functional' prognosis but developed mild to moderate signs of radiographical osteoarthrosis in the majority of the cases.Complete ACL tears resulted in a permanent increase of sagittal knee translation no matter which initial treatment Injuries to knee joint cartilage or menisci or partial injuries to the ACL did not result in an increase of sagittal translation.Radiographical signs for osteoarthrosis were encountered in 55 to 87% after different knee injuries, and seemed to advance slowly during the years.Combined intraarticular knee injuries seemed to have a higher risk for development of radiographical osteoarthrosis than isolated injuries within the same time period.Older age at initial diagnosis and treatment of an intraarticular knee injury is associated with a higher risk to develop radiographlcal osteoarthrosis.After 12 to 20 years, patients with minor intraarticular knee injuries seem to have only a marginally better longterm prognosis for knee function and activity participation than patients with combined, major intraarticular knee injuries. However, the higher dissatisfaction with the results, the higher rate of symptoms and subsequent repeat surgery as well as the higher development of oeteoarthrosis during the years in the latter cases may point to that the risk for future lmee deterioration is greater after a combined than after a minor or/and isolated knee injury.Subjective satisfaction and quality of life was high after a partial rupture of the ACL with minor concomitant injuries, and stayed unchanged over the years. In contrast, a complete rupture of the ACL did adversely influence quality of life, and subjective satisfaction with knee performance declined with time.
|
|
| 22. |
- Nordström, Marie
(författare)
-
Epidemiological aspects on hairy cell leukaemia
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Non Hodgkin's lymphoma (NHL) has an increasing incidence in many Western countries. In Sweden, about 1800 new cases were reported to the Cancer Registry in 1996 including cases of chronic lymphatic leukaemia (CLL). Hairy cell leukaemia (HCL) is a rare subgroup of malignant lymphoma. About 25 new cases are diagnosed among males in Sweden yearly. The mean age at diagnosis is 55-60 years.To further evaluate the findings in a pilot-study conducted in Uppsala, where a large proportion of patients with HCL had worked in the areas of agriculture or gardening, a case-control study was initiated. The study included 121 male cases of HCL diagnosed between 1987 and 1992, and 484 controls matched for age, sex and county. The aim of the study was to investigate potential risk factors for HCL such as occupation, and different occupational exposures such as organic solvents, pesticides, exhausts and animals. Information was also obtained on previous medical history and medications.No significantly increased risk for HCL among farmers was found. An increased risk for HCL was seen for exposure to domestic animals and different subgroups of pesticides, as well as for exposure to organic solvents and exhausts. A decreased risk for hairy cell leukaemia was correlated with smoking. A previous history of certain diseases of the cardiovascular system was associated with a moderately reduced risk for HCL.Epstein-Barr virus (EBV) has been correlated with certain subtypes of malignant lymphomas. In a subgroup of the individuals in the study, levels of certain antibodies to EBV were analysed as risk factors for HCL. These levels were related to selfreported exposure to other potential risk factors. The results suggest the possibility of an interaction between EBV and self-reported occupational exposures.Organochlorines have been suggested as risk factors for NHL. Concentrations of 36 PCB-congeners, p,p' -ODE (a metabolite of DOT), hexachlorobenzene (HCB) and 4 congeners of chlordanes in blood were measured in a subgroup of included induviduals. These concentrations were analysed as risk factors for HCL, and were also related to the levels of certain antibodies to EBV. The possibility of an interaction between EBV and these exposures is suggested.
|
|
| 23. |
- Ohrt, Torbjörn
(författare)
-
Cognitive dysfunction : Assessed by Questionnaires in a Population Sample and in Patients with Affective or Anxiety Disorders Before, During and After Treatment
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of the present thesis was to study the Swedish versions of the Dysfunctional Attitude Scale (DAS) and the Automatic Thoughts Questionnaire (ATQ) regarding their psychometric properties and to investigate their place in the cognitive theory of psychopathology. For these purposes samples were collected of the general population and of different psychopathological groups in different stages of illness and the results were compared with clinical diagnoses according to the DSM-III-R and IV and selfand observer ratings of depression and anxiety.The assumed parallelism between DAS-A and DAS-B received strong support through the present study. The correlations between sum scores of the two forms A and B at two occasions indicates a rather high reliability of the Swedish version. The validity of the DAS-A as a measure of depressive cognitive content was supported. The present thesis incorporates, as far as known to the author, the first study which has investigated the DAS in a randomly selected normal sample with sex and age distributions similar to that of the normal population. The psychometric properties iu this sample were similar to the results of earlier normative studies of the scale. A cumulative percentage normative scale of the DAS-A scores is presented. Dysfunctional attitudes was shown to be a state dependent variable in depressive disorder. This is consistent with results from several earlier studies. Contradictory to earlier results a predictive value of the DAS and the ATQ for pharmacological treatment response was not supported. Patients with panic disorder without depression were shown to have scores on the DAS and ATQ in the normal range. The hypothesis of a specificity of dysfunctional attitudes and negative automatic thoughts for major depression contra panic disorder and a sensitivity of negative automatic thoughts to absolute and relative levels of mild depressive symptomatology in patients with panic disorder is supported. Patients with generalised anxiety disorder without major depression were shown to have DAS scores in the same range as patients with major depression and ATQ scores in the same range as patients with panic disorder and normal subjects. The high DAS score was not reduced by pharmacotherapy, in spite of normalised anxiety level, in contrast to the treatment effect on high DAS scores in major depression. The results indicate that the DAS score, apart from being related to depressive mood, reflects a trait quality in GAD, separating GAD from PD. The lack of effect of pharmacological treatment on the dysfunctional attitudes could implicate a need for psychotherapy.
|
|
| 24. |
- Olejnicka, Beata Teresa
(författare)
-
Insulin-Producing Cells, Iron, Oxidative Stress, and Lysosomal Pathology
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Accumulating evidence suggests that injnries caused by oxygen-derived radicals contribute to the destruction of pancreatic islet ß-cells in autoinnnune diabetes mellitus (diabetes type I, or IDDM). Oxidative stress may be caused by an enhanced production of oxygen-derived radicals, or by a decreased scavenging of such molecules. It was recently suggested that iron-mediated intralysosomal oxidative reactions result in the destabilization of lysosomal membranes, leakage of lysosomal contents to the cytosol, cellular destruction and, moreover, that such mechanisms may operate in IDDM.In the present study, we have investigated the mechanisms by which hydrogen peroxide induces cell damage, and its possible relationship to intralysosomal iron. The work was done on three insulin-producing insulinoma cell lines: HIT-TI5, NIT-1, and RINmF cells, on mouse pancreatic islets ß-cells, and the macrophage-like J-774 cells. In particular, we studied the influence of induced autophagocytosis (by glucose- and amino acid starvation) on the sensitivity to oxidative stress; the influence of high-glucose growth media on hydrogen peroxide cytotoxicity; the protective effects by starvation-stimulated intracellular fertitin synthesis against oxidative stress; the possible relationship between oxidative stress, lysosomal destabilization and apoptotic/necrotic cell death; and the impact of iron chelation on lysosomal stability, and insulinoma- and ß-cell survival.A higb susceptibility to oxidative stress was demonstrated for all the insulin-producing cells. Starvation-induced autophagocytosis increased the concentration of desfertioxarnine-available lowmolecular- weight iron in HIT-T15 cells, as assayed by HPLC. Tbe iron was mainly found in secondary lysosomes, as shown by the autometallography technique when applied at electron nticroscopical level. Starvation enhanced oxidative stress-induced damage of the IDT-T15, RINm5F and J-774 cells, as assayed by the trypan blue dye exclusion test and tests for lysosomal stability (the actidine orange relocation/uptake tests). In contrast, the pronounced starvationinduced autophagocytosis that was shown by the most vulnerable insulinoma cell line (NIT -1) was paralleled by enhanced resistance to oxidative stress, and by increased lysosomal stability as well. A rapid NIT -1 fertitin synthesis was demonstrated by inununocytochentistry under conditions of starvation. It is believed that autophagocytotic lysosomal uptake of non-iron-saturated fertitin will allow such fertitin to act as an iron chelator and stabilize lysosomes against oxidative stress. NIT -1 and B-cells which were subjected to a low level of oxidative stress (30 J.LM H20 2 for 15 min) were still largely intact at the light nticroscopical level ,but 10-20% of the cells exhibited nuclear chromatin condensation as an early sign of apoptosis when examined by the Ho334/PI staining technique, or by TEM, 0.5-1 h after the insult. At the same point of time, a decrease in the number of intact lysosomes was also observed. The rate of oxidative stress-induced lysosomal destabilization progressed with time, and a widespread apoptotic/necrotic-type degeneration/fragmentation ensued, as demonstrated by SEM, TEM, and the TUNEL-reaction. The ntitochondria revealed a mixture of lamelliform and swollen cristae, indicating altered properties of the mitochondrial membranes. Pre-treatment with the iron chelator desfenioxamine attenuated the lysosomal destabilization, and increased cell viability, following exposure to oxidative stress.At high-glucose conditions, the ~02-sensitivity of HIT-T15, NIT-I, and B-cells was reduced which, was consistent with a moderately enhanced stability of their lysosomes, as measured by the acridine orange-relocation test, and with reduced amounts of desfenioxamine-available iron.We conclude that the decisive role of free lysosomal iron in oxidative stress is strongly supported by the following lines of evidence, provided by the present study (a) glucose- and amino acid-starvation promotes autophagic/crinophagic activity of the cells, resulting in enrichment of intracellular (intralysosomal) desfenioxamine-available iron; (b) high-glucose conditions depress autophagic/crinophagic activity and, consequently, the occurrence of intralysosomal iron; (c) starvation-stimulated fenitin synthesis enhances lysosomal stability during oxidative stress by limiting lysosomal redox-active iron; (d) lysosomal destabilization and related apoptotic cell death are associated with the amounts of intralysosomal iron in redox -active form,
|
|
| 25. |
- Palfi, Miodrag, 1954-
(författare)
-
Antibodies during pregnancy : Aspects on complications during pregnancy and complications related to transfusion
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The fetus acquires half of its genetic infonnation from the father and represents a foreign graft in pregnancy. The overall mechanisms contributing to immunologic tolerance and successful pregancy still are an enigma. Accumulating results of immunologic research, however, offer an explanation for many events in pregnancy. The purpose of this study was to investigate immune responses in pregnancy, antibody production, fetomatemal transport of antibodies and their impact on complications during pregnancy and complications related to transfusion.The human immune system exerts its effects by cellular (T-cell mediated, Thl dominated) and humoral (antibody mediated, Th2-dominated) immunity. Cellular immunity provides protection against foreign and infected cells while humoral immunity protects against extracellular pathogens. According to the Thl/Th2 paradigm successful pregnancy is Th2 dominated. We found elevated numbers of cytokine secreting cells of both Th-1 and Th-2 type in normal pregnancy and recurrent spontaneous abortions. However, the overall immune response may functionally be Th2-dominated and possibly more pronounced locally, at the fetomaternal interface.The fetus, despite the fetomaternal barrier, represents a huge antigenic challenge for the mother. As a consequence, the mother produces a variety of antibodies, directed against fetal antigens of paternal origin. In pregnancy, only IgG antibodies are, by an active process, transported from the mother to the fetus. Normal fetal IgG concentrations during pregnancy were established, as reliable published data were rare. The calculated regression line for f/m IgG ratio can be considered an accurate description of the nonnal IgG distribution in the fetus in relation to the mother.It has been proposed that lgG transport may be decreased in Rh (D) immunizations. According to this hypothesis, the impaired transport of anti-D should represent a protective mechanism against hemolytic disease of the newborn. Our studies gave controversial results. We could partly confirm the hypotesis as measured by correlation of fetal IgG vs maternal anti-D concentrations and fetal/newborn hemoglobin concentrations. In contrast we did not find significantly lower fetal IgG concentrations in Rh (D) immunizations compared with normal pregnancy.The lgG subclass composition of anti-D in Rh (D) immunizations was studied by an established test performed in microtiter plates and our own novel gel-test. Comparison of these two test showed that the same IgG subclasses of anti-D were detected by both methods. However, the gel-test had two major advantages: it was much more rapid and most importantly, interpretation of results was easier than with the microtitre assay.Women immunized during pregnancy may later become blood donors. The concentration of antibodies produced during pregnancy may afterwards decrease. However, the antibodoes do not disappear, and may thereby cause post-transfusion reactions. It has been reported that granulocyte- and I-ILA antibodies may cause transfusion-related acute lung injury (TRALI). TRALI is a rare but life-threatening complication of blood transfusion. Data from our study suggest that multiparous donors(≥ 3 pregnancies) should donate only plasma for fractionation or, if cell concentrates must be used, they shouid be washed before transfusion.
|
|
| 26. |
- Rahman, Mahfuzar
(författare)
-
Nonmalignant health effects of arsenic exposure
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis comprises a series of studies concerning occupational and environmental exposure to arsenic and some novel chronic health effects of this element, namely diabetes mellitus and hypertension. Substantial prevalence of the well-known skin manifestations of arsenic ingestion was also found to occur as a result of environmental exposure through drinking water.Two case-control studies on diabetes mellitus and occupational exposure to arsenic included individuals employed at a copper smelting industry (Paper I) and in art glassworks (Paper 11) in Sweden. Although the number of smelter workers involved was small (12 cases and 31 controls), a significant exposure-response trend was obtaifted (p = 0.03). The assessment of arsenic exposure among 888 glass workers was lesS detailed, nonetheless it revealed an approximately doubled risk (MH-OR = 2.1; 95% confidence interval 1.2-3.7) for the workers with occupational titles that suggested exposure. Overall, the results of these studies provide evidence that occupational arsenic exposure may play a · role in the development of diabetes mellihls. Four cross~sectional studies were carried out in Bangladesh, where a fairly large part of the population is exposed to inorganic arsenic in drinking water. In the first study (Paper Ill), the prevalence of diabetes mellitus among subjects with keratosis (n = 163) was compared with unexposed subjects (n = 854); keratosis was considered to be a definite sign of exposure. A dose-response relationship was found between categories of time-weighted arsenic exposure (mg/L in drinking water) and the prevalence of diabetes mellitus (p < 0.001), and the crude overall prevalence ratio amounted to 4.4. Despite the lack of detailed individual exposure data and information on potential confounders other than age, sex, and ·body mass index (BMI), the association seems strong enough to support a causal relatiortship, because the adjusted overall prevalence ratio was 5.9 (95% confidence interval 2.9-11.6).One of the other studies performed in Bangladesh (Paper V; 1481 exposed individuals, 430 exhibiting keratosis) showed a somewhat higher prevalence rate of skin lesions in males (31%) than females (26%) due to chronic arsenic toxicity. The crude overall prevalence was 29% in the shldied villages, and there was a distinct dose~response relationship between arsenic concentrations in drinking water and skin lesions (p < 0.01). A clear dose-response relationship was also observed (Paper VI) between arsenic exposure and glucosuria for subjects both with and without skin lesions (p < 0.01). The possibility of using the skin lesions for initial screening for glucosuria was considered. However, the appearance of dermatological signs of chronic arsenic toxicity proved to be a poor marker in this respect, because glucosuria also occurred in the absence of skin lesions.A third Bangladeshi study (Paper IV) indicated a significantly increased risk of hypertension in connection with exposure to inorganic arsenic in drinking water (1481 exposed and 114 unexposed subjects). The overall crude prevalence ratio of hypertension amounted· to 1.7, and the adjusted (for age, sex, and BM!) ratio was 1.9 (95% confidence interval 1.0-3.6). A significant trend in risk (p << 0.001) was observed between an approximate time-weighted mean exposure to arsenic, considered in milligrams per liter or milligram-years per liter, which strengthens the possibility of a causal association.
|
|
| 27. |
- Serrander, Lena
(författare)
-
Neutrophil phagocytosis and secretion : The role of calcium and the cytoskeleton
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neutrophils assure rapid removal of bacteria by a variety of processes. They crawl out of the vessels, phagocytose the bacteria and kill them by secretion of bactericidal substances and production of oxidative metabolites. The aims of this study were to investigate the signalling pathways during these processes, in particular i) how complement receptors mediate phagocytosis and NADPH~oxidase activity ii) the role of Ca2+ in secretion and the role of a Ca2+-dependent, actin-binding protein, _gelsolin, in neutrophil phagocytosis and secretion. Conventional biochemical methods, capacitance measurements of secretion with the patchclamp technique and visualisation with fluorescence microscopy techniques were used. We found that phospholipase D (PLD) is an early Ca2+-independent signal in complementmediated phagocytosis, preceding cytoskeletal rearrangements. We also demonstrated'that the NADPH-oxidase could be activated in situ to generate oxidative metabolites intracellularly after particle stimulation of complement receptors in the absence of phagocytosis. This permits cells to use oxidative metabolites for signalling and not only to kill bacteria. This activation involved the cytoskeleton and PLD. Whereas signalling during pha~ocytosis can occur independently of Ca2+, other neutrophil functions are highly Ca +-dependent. Investigating the relative importance of Ca2+-release from intracellular stores versus Ca2+ influx over the plasma membrane, we found that secretion of primary granules induced by fMLP is dependent on Ca2+ -influx. ci+-influx alone is not sufficient to induce secretion in neutrophils. A second synergistic signal is required. This missing signal was not PLD, PLC or tyrosine kinases, but involved a pertussis-sensitive 0-protein and PI3-kinase. When further investigating the role of Ca2+ in secretion, we found that secretion of different granules is regulated by different [Ca2+:J. Primary granules are secreted at 100 ~ Ca2+ whereas the other granules are secreted at 1.5-5 ~ ci+, suggesting two mechanisms involving different Ca2+ activated systems/sensor proteins. One sensor protein could be the Ca2+-dependent, actinbinding protein, gelsolin, which has earlier been shown to stimulate secretion in different celltypes. Secretion from gelsolin-deficient mouse neutrophils was nevertheless nonnal. Gelsolin was however found to be essential for !gO-mediated-, but not complement-induced phagocytosis. Activation of the oxidase and phagolysosorne-fusion was unaffected in gelsolin-deficient neutrophils. This suggests gelsolin to be a Ca2+ -sensor specifically for !gOmediated phagocytosis. !gO-mediated phagocytosis often leads to more efficient killing than complement-mediated phagocytosis. Gelsolin seems to be part of the machinery that distinguishes the two pathways of phagocytosis. The present data show that receptor mediated activation of neutrophil functions involves several signalling pathways. This allows selective modulation of the inflammatory response.
|
|
| 28. |
- Stenmark-Askmalm, Askmalm Marie, 1966-
(författare)
-
p53 Alterations in Breast Cancer Related to Prognosis and Results of Therapy
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is the most common malignant tumour disease and also the main cause of cancer-related deaths among women. The lifetime risk in western countries is 10%. The basic treatment for a patient with a localised tumour is surgery. In addition, different pathobiological variables are considered and an estimation of the risk of recurrence is made before deciding whether adjuvant therapy should be recommended. This therapy can be chemotherapy, which mainly prevents distant recurrence, or radiotherapy, which is effective against local recurrence. The treatment can be combined with anti-oestrogen, which prevents distant recurrence among patients exhibiting an oestrogen-receptor-positive tumour. However, breast cancer remains the chief cause of cancerrelated deaths and there is a need· for further pathobiologica! variables that, at an early stage, both can be prognostic and predict the outcome of adjuvant therapy.The p53 gene and its product p53 have been shown to play a central role in tumour suppression by regulating the cell cycle or initiating apoptosis. Certain mutations are associated with a stabilisation of the protein, leading to an accumulation that is detectable by immunohistochemistry.The main purposes of this study were to analyse p53 protein accumulation and gene mutation in exons 5-8 and to investigate the prognostic and predictive role of p53.p53 protein accumulation was investigated with immunohistochemistry in frozen tumour samples from 776 patients; 164 patients with stage U, 205 patients with stage I and 407 patients with either lymph node metastases and/or a tumour diameter exceeding 30mm. Of the latter, 139 were premenopausal and 268 were postmenopausal. These 407 patients had been randomiscd to adjuvant CMF chemotherapy or postoperative radiotherapy. Gene analyses with PCR-SSCP followed by direct sequencing were performed in the 268 postmenopausal patients. The predictive value of p53 was only analysed in the randomised patient material.The results showed that nuclear p53 accumulation ranged between 9% and 25%. p53 accumulation was significantly associated with several pathobiological variables, "indicating an aggressive tumour, which was more likely to be oestrogen receptor negative, DNA aneuploid, and have a high S-phase fraction. p53 accumulation was also significantly correlated with an increased rate of distant recurrence, whereas mutations that were found in 16% of the 268 cases investigated were not significantly correlated with an increased risk of distant recurrence. However, the investigation of both protein accumulation and gene mutation in exons 5-8 contributed further information than was achieved with one of the methods alone. The protein accumulation reflected to a certain extent mutations of the gene, mainly missense mutations. A majority of the severe mutations that included alteration of the reading frame did not lead to any protein accumulation. Sixty-one per cent of the tumours exhibiting protein accumulation did not show any mutation in exons 5-8. Subgroups of different p53 alteration patterns seemed to be related to different prognoses.The patients with p53 altered tumours, either showing protein accumulation, gene mutation or both, benefited significantly from CMF chemotherapy compared with the radiotherapy group. This benefit could not be seen among the patients without p53 alterations. The test for interaction between p53 status and relative rate was significant. This response was most pronounced among premenopausal patients. Postmenopausal patients seemed to benefit although not significantly.In conclusion, the present study suggests that p53 accumulation is a prognostic factor associated with an increased risk of distant recurrence. p53 alteration defined as protein accumulation, gene mutation in exons 5-8, or both, was a predictor of good response to CMF chemotherapy as compared to postoperative radiotherapy. This benefit could not be seen among patients without p53-altered tumours.
|
|
| 29. |
- Terman, Alexei, 1957-
(författare)
-
Mechanisms of lipofuscin/ceroid accumulation and its impact on the function of the lysosomal system
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The accumulation of lipofuscin - an electron-dense, autofluorescent, polymeric, intralysosomal substance - is a recognized hallmark of aging postmitotic cells. Ceroid- a substance very close, or perhaps even identical, to lipofuscin - is a characteristic of various pathological processes, such as lysosomal storage diseases, malnutrition, atherosclerosis, oxidative stress, ionizing radiation, etc. Although the mechanisms of lipofuscin formation are now rather well understood (Brunk et al., 1992), what causes it to accumulate within aging postmitotic cells (namely, the role of its possibly impaired degradation/exocytosis) is still disputed. Moreover, little is known about whether lipofuscin accumulation interferes with normal cellular functions, perhaps it even promotes cell death and age-associated pathologies. The role, if any, of ceroid accumulation in the pathogenesis of many diseases also is not clear.To gain a better insight into the mechanisms of lipofuscin/ceroid accumulation, and to test whether this accumulation has any negative impact on cellular functions, especially on the autophagocytotic process, we decided to study: (l) the role of oxidative stress (normobaric hyperoxia) and/or lysosomal protease inhibition (leupeptin treatment) in lipofuscin/ceroid accumulation in cultured AG-1518 human fibroblasts and neonatal rat cardiac myocytes; (2) the fate of formed lipofuscin/ceroid after the cessation of oxidative stress and/or protease inhibition; (3) the possible reversal of lipofuscin/ceroid accumulation in vitro with an anti-aging drug centrophenoxine; (4) the survival of lipofuscin/ceroid-loaded fibroblasts under amino acid starvation; (5) the effect of lipofuscin/ceroid accumulation on autophagocytosis and intralysosomal degradation; and (6) the sensitivity of lipofuscin/ceroid-loaded fibroblasts to oxidative stress.We have shown that: (1) both oxidative stress and lysosomal protease inhibition accelerated lipofuscin/ceroid formation, however the effects of these two factors increased dramatically when they acted concurrently; (2) protease-inhibition by itself does not lead to lipofuscin/ceroid formation, but rather allows the prolonged time needed for oxidative modification of autophagocytosed material; (3) lipofuscin/ceroid inclusions formed due to oxidative stress and protease inhibition do not disappear either after returning the cultured cells to normal conditions, during amino acid starvation, or under the influence of centrophenoxine; (4) lipofuscin/ceroid-loaded cells exposed to amino acid starvation show decreased survival time and diminished autophagocytosis; (5) exposure of fibroblasts with various amounts of lipofuscin/ceroid to naphthazarin (a redox cycling quinone producing 0 2 ·-and H20 2) results in selective survival of cells with lower quantities of the pigment; and (6) lipofuscin/ceroid-rich cells have an expanded lysosomal compartment with increased amounts of cathepsin D.The results suggest that: (i) lipofuscin/ceroid forms within secondary lysosomes due to oxidative damage of autophagocytosed material resulting in cross-linking of protein residues by aldehydes formed from decomposed peroxidized unsaturated lipids; (ii) lipofuscin/ceroid is not substantially eliminated from non-dividing cells by degradation or exocytosis, which explains the progressive accumulation of lipofuscin in postmitotic cells with age; and (iii) a heavy lipofuscin/ceroid loading of cells interferes with normal lysosomal functions by making them less able to autophagocytose and more sensitive to oxidative stress, conceivably due to increased amounts of lysosomal enzymes (potential mediators of oxidative damage) and/or due to a possible catalyzing role of lipofuscin/ceroid-associated iron.
|
|
| 30. |
- Valdimarsson, Trausti
(författare)
-
Bone in coeliac disease
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with untreated and treated coeliac disease were examined regarding bone mineral density (BMD) and biochemical factors of importance for bone metabolism. The occurrence of disturbances and their correction during treatment with a gluten-free diet were studied. BMD was measured in the forearm using single photon absorptiometry and in the hip and spine using dual-energy X-ray absorptiometry.Among the 288 adult patients with known coeliac disease in our catchment area, 13 patients with persistent villous atrophy of the proximal small bowel mucosa despite dietary recommendation were identified and compared with matched control-patients whose intestinal mucosa had normalised at least 4 years earlier. BMD was reduced in patients with persistent villous atrophy but within normal limits in patients responsive to the diet.In 105 adult patients with untreated coeliac disease, HN.ID was reduced compared to a local healthy control group. During the first year on a gluten-free diet the BMD increased rapidly (by a median of 3 %in the spine) even in patients with minor symptoms and in older patients. Secondary hyperparathyroidism was found in 27% of untreated patients and these patients had more severely reduced BMD compared to those with normal initial parathyroid hormone. Twenty-three % of the untreated patients also had low serum calcidiol (25-hydroxyvitarnin D) levels. BMD continued to increase in the second and third follow-up years, but only became normal within three years in the group of patients without initial secondary hyperparathyroidism.In 29 consecutive adult patients with untreated coeliac disease, serum insulin-like growth factor I and BMD were lower than in matched controls. In 14 untreated patients with normal parathyroid hormone values the increase in insulin-like growth factor I correlated positively to the increase in BMD during the first year after starting a gluten-free diet.In 46 adult patients with coeliac disease trt;atedfor 8-12 years in routine care, median BMD was normal but five patients who did not follow strict gluten-free diet had a lower BMD in the femoral neck than the group of 41 patients who claimed strict adherence.TI1ese studies show that untreated coeliac disease is associated with a low B:MD. BMD inereases rapidly when a gluten-free diet is followed, even in older patients. Circulating insulin-like growth factor I may reflect some changes in hone metabolism but its pathogenetic role behind the low BMD seen in adults with coeliac disease is unclear. Secondary hyperparathyroidism is common and vitamin D deficiency also seems to be an important underlying mechanism. These findings underline the importance of a gluten-free diet for all patients with coeliac disease.
|
|
