| 1. |
- Nilsson, Bengt-Olof, et al.
(författare)
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Effects of polyamine synthesis inhibition on polyamines, growth and mechanical properties in hypertrophic rat urinary bladder
- 1998
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Ingår i: Pharmacology and Toxicology. - 1600-0773. ; 82:6, s. 287-294
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Tidskriftsartikel (refereegranskat)abstract
- The polyamines putrescine, spermidine and spermine, are ubiquitous intracellular metabolites associated with growth and protein synthesis. In this study effects of polyamine synthesis inhibition on bladder growth, polyamine levels and mechanical properties were investigated in rat urinary bladder subjected to partial outflow obstruction that causes bladder hypertrophy. The S-adenosyl methionine decarboxylase inhibitor CGP-48664 (5 and 20 mg kg-1) was administered alone or in combination with the ornithine decarboxylase inhibitor DFMO (500 mg kg-1), starting one day before creation of partial outflow obstruction and then daily for 7 days. The bladder muscle level of putrescine was increased 38 times and that of spermine reduced by 4 times while spermidine was unchanged after treatment with CGP-48664 (20 mg kg-1). The increase in putrescine was abolished in animals receiving CGP-48664 in combination with DFMO. Treatment with polyamine synthesis inhibitors could not prevent or reduce the hypertrophy of the bladder as judged by bladder wet weight and protein contents. The effects on polyamine quantities were not associated with changes in Ca(2+)-force relationship or in agonist and electrically stimulated force. In summary, treatment of rats with polyamine synthesis inhibitors resulted in changes in polyamine levels in the growing urinary bladder but did not affect growth or mechanical properties.
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| 2. |
- Ahlgren, Göran
(författare)
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Prognostic factors in prostate cancer with special reference to the effect of hormonal therapy
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- We have used image cell analysis to analyse nuclear DNA content on fine needle aspiration biopsies from 96 patients diagnosed to have prostate cancer 1980-81. By stratifying diploid and tetraploid tumours according to a cytometric proliferation index (PI), we suggest a new DNA-classification that is prognostic of death from prostate cancer in multivariate analysis including conventional prognostic factors. Patients with diploid tumours and a low PI, had almost no mortality from prostate cancer with mean 14.5 years follow-up. We used the same method on imprints of ultrasound guided tissue biopsies in a prospective study on 137 patients. The pognostic value of the new DNA-classification was confirmed although the follow-up is limited to 39 months. Prognostic factors of the risk of recurrence and of hormone dependence in prostate cancer were studied in a randomised prospective study comparing 3 months neoadjuvant GnRh-analouge treatment followed by radical prostatectomy (55 patients) and surgery alone (56 patients). We found tumour growth at the surgical margin of the specimen to be reduced by hormonal treatment prior to surgery (p<0.001) in large tumours (T2c-T3a). This finding did not correlate to an improved cure rate after more than 3 years follow up. Tumour cell proliferation in the primary tumour was found to be a highly significant prognostic factor of recurrence in multivariate analysis after combined hormonal and surgical treatment (p=0.0002). Neuroendocrine (NE) differentiation in the primary tumour increased after neoadjuvant hormonal treatment but was not associated with the extension of regressive changes or prognosis. Instead, NE-differentiation in the tumour correlated to tumour volume, wich was prognostic of treatment failure in both treatment arms.
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| 3. |
- Berggren, Tord
(författare)
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Effects of Denervation and Infravesical Obstruction in the Rat Urinary Bladder
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Median micturition volume decreased early after partial outlet obstruction, 24 hrs total obstruction and hemidenervation. Degeneration release of transmitter may explain this, assuming that bladder wall distension causes nerve degeneration. Micturition pressure decreased simultaneously in the partially denervated and 24 hrs obstructed groups, probably due to the reduced number of functionally intact nerve terminals. Atropine resistance, not present in man, except in pathological conditions, increased early in all groups, but returned to normal with time, except in the 24 hrs obstructed group where it finally reached subnormal levels. Persistingly increased micturition volumes were found from 7 and 10 days after hemidenervation and 24 hrs total obstruction. This may be attributed to a non-recovery of afferent, sensory nerves after initial damage. However, micturition pressure normalized with time for both groups, suggesting a recovery of motor function. A 50% increase was found in ganglion cell volume 7 weeks after contralateral ganglionectomy and an 80% increase 6 - 8 weeks after inducing partial obstruction. The latter process was found to be reversible after removing the obstruction. It seems that there exists a maximal size of the ganglion cells. Heavy staining of LDH was found in pelvic ganglion neurons of both control and obstructed animals. A high capacity for glycolysis in anoxia could be expected in the nerves of the bladder under normal conditions as well as under obstruction. AVP concentration was decreased, but total AVP content increased in the partially obstructed bladder. Also, maximal response to AVP in vitro was significantly decreased and cystometry showed decreased excitability by AVP. These phenomena are parallel to those of substance P. Both partial obstruction and total denervation caused an increase in total amounts of actin and myosin and a higher desmin/actin ratio after 10 days. Even a limited bladder lesion, unilateral ganglionectomy, induced g a net syntesis of contractile proteins. The extent of growth, rather than the functional status, seems to determine the degree of net synthesis of contractile and cytoskeletal proteins.
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| 4. |
- Björk, Thomas
(författare)
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Metabolism of free and complexed prostate - specific antigen and their utility for diagnosis and prognosis of prostate cancer
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate-specific antigen (PSA) is a glycoprotein produced by the prostate gland. It occurs in several molecular forms in the blood and assays have been developed to measure free PSA and PSA in complex with alpha-1-antichymotrypsin (PSA-ACT). Higher proportions of free PSA (PSA-F/T) in blood are found in subjects with benign prostatic hyperplasia (BPH) as compared to cancer patients. Utilizing immunocytochemistry and in situ hybridization we demonstrated production of PSA and ACT in normal and malignant prostatic tissue. In areas with BPH however, only PSA was detected, which may be linked to the differences in proportions of PSA-F/T found in blood from patients with cancer compared to subjects with BPH. Comparing selective measurements of the PSA forms and their ratios by receiver operating characteristics showed that PSA-F/T best discriminated cancer from BPH in patients with normal or slightly elevated PSA levels. After removal of the prostate the elimination of free PSA was bi-exponential with an initial, rapid re-distribution phase followed by a terminal phase with a half-life of 14 hours. PSA-ACT was eliminated slowly and non-exponentially with a mean rate of 0.8 ng/mL/day indicating a capacity-limited process. In hormonally deprived patients with high pre-treatment PSA concentrations, both free PSA and PSA-ACT were eliminated exponentially with mean half-lives of 10 and 13 days respectively. In 66 prostate cancer patients followed until death or for a minimum of nine years, univariate analysis showed that all PSA forms, but not their ratios, as well as tumour grade, local and distant stage gave prognostic information on cancer survival. In a multivariate analysis with step-wise entering of factors only grade, distant stage and the PSA-F/PSA-ACT ratio provided prognostic information.
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| 5. |
- Bratt, Ola
(författare)
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Familial and Hereditary Prostate Cancer
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is based on research concerning epidemiological, clinical, and psychological aspects of familial and hereditary prostate cancer. Epidemiology: Male first-degree relatives of prostate cancer patients had a three-fold increased prostate cancer risk. The risk was higher for relatives of younger patients than for relatives of older patients, most likely due to the effect of the higher prevalence of hereditary prostate cancer found among the former. For first-degree relatives of men with early onset prostate cancer, the risk of developing prostate cancer before the age of 70 years was increased 3.4 times, but their total cancer risk was not increased. Short CAG repeats in the androgen receptor gene correlated with early age at diagnosis of non-hereditary prostate cancer, but not with the risk of developing the disease per se. Clinical aspects: Patients with hereditary prostate cancer were diagnosed, on an average, 7 years earlier than those with sporadic prostate cancer. Family history of prostate cancer was not significantly associated with survival for patients with early onset disease. Psychological aspects: Most men with a family history of prostate cancer worried about the possibility of inheriting the disease. Almost all of them (90-94%) had positive attitudes towards genetic investigations, including genetic testing, and screening. Forty percent of unaffected men in families with hereditary prostate cancer substantially overestimated their lifetime risk of the disease. Perception of high risk was associated with symptoms of depression and cancer worries that affected daily living. High levels of cancerspecific stress may have counteracted participation in screening for some men.
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| 6. |
- Hellmark, Thomas
(författare)
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Molecular dissection of the Goodpasture epitope
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Goodpasture disease is a prototype autoimmune disease that is characterized by a rapidly progressive glomerulonephritis, with or without lung haemorrhage, associated with autoantibodies against the glomerular basement membrane. The major antigen has previously been shown to be the non-collagenous domain of the a3 chain of type IV collagen, one of the six known a chains of type IV collagen. On average, one percent of the total IgG fraction from the patients is comprised of anti-type IV collagen autoantibodies. Ninety percent of these antibodies are a3(IV)-specific and the remaining ten percent are low-affinity antibodies, showing cross-reactivity with the other a(IV) chains. Furthermore, the epitope specificity seems to be limited, as shown by monoclonal antibody inhibition. To test the hypothesis that only antibodies against certain epitopes are nephrotoxic, clinical and serological data from 77 anti-GBM positive patients were retrieved. The results showed that the anti-a3(IV) titre, and especially the antibodies that can be blocked using a monoclonal antibody, correlated with the outcome, in terms of kidney survival. Thus, the study strongly indicates the pathogenic role of the circulating autoantibodies. Epitope mapping of the anti-GBM antibodies has been done using overlapping synthetic peptides. The epitope specificity of the autoantibodies from one patient with anti-a1(IV) antibodies was revealed, and reactivity in ELISA was successfully blocked using a four-amino-acid-long peptide from the a1(IV) sequence. The same approach did not show any reactivity with the anti-a3(IV) autoantibodies. By using recombinant antigens expressed in a human cell line as chimeric proteins, where the a3(IV) sequence was exchanged for the corresponding sequence from the a1(IV) chain, we could show that only autoantibodies against the N-terminal third of the a3(IV) chain correlated with disease. The reactive sequence was further narrowed down to nine discontinuous amino acid residues. A chimeric protein comprised of a1(IV), but with these nine positions expressed as a3(IV), bound the toxic autoantibodies with approximately the same affinity as native a3(IV). These studies provide evidence that only autoantibodies against a very limited region of the a3(IV) chain carry a toxic potential. Furthermore, epitope spreading is relatively limited, thus indicating a possibility for new forms of therapy, including epitope immunomodulatory treatment. In the future, therapy might be adjusted for each individual patient, on the basis of diagnostic tests, e.g., regarding the fine specificity and titre of the autoantibodies, thereby minimising unnecessary discomfort caused by the side effects of immunosuppressive treatment.
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| 7. |
- Månsson, Åsa G E
(författare)
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The patient with bladder cancer. From symptoms, through treatment, with special reference to psychosocial consequences of radical cystectomy
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Factors determining patient`s and doctor`s delay in diagnosis of bladder cancer were type of initial symptoms, level of health service first consulted and number of steps in the referral system. No correlation was found between psychosocial factors and patient`s delay. In retrospective studies after cystectomy for bladder cancer, patients with continent cutaneous diversion of urine had fewer stoma-related problems than those with conduit diversion, but sexual dysfunction, disturbed partner relationships and emotional problems, which were common, did not differ between these groups. Psychological support was seldom provided by medical personnel. Despite the patients` high acceptance level of the malignancy, inability to accept their present condition was common. Prospective studies were performed to assess the influence of psychological defence mechanisms as evaluated with MCT-test and of mood, general philosophical outlook and type of urinary tract reconstruction on risk of psychosocial complications after cystectomy, and also the importance of early psychosocial intervention. Preoperative MCT-test had low value for predicting risk of such complications in patients studied 3 and 12 months postoperatively, but at 5 years "risk" patients expressed lower self-esteem and greater difficulties in interpersonal contact-seeking. Patients who postoperatively ascribed their life`s course to non-personal factors and who believed in a deity or a supernatural power tended to do poorly after surgery. With regard to method of reconstruction, patients with orthotopic bladder replacement adjusted less well. Psychosocial intervention did not influence emotional adaptation a 3-month follow-up, but was helpful in patients with continent cutaneous diversion. Defensive strategies and philosophical outlook did not by and large influence the outcome of intervention.
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| 8. |
- Sriplakich, S., et al.
(författare)
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Epidermal growth factor receptor expression : predictive value for the outcome after cystectomy for bladder cancer?
- 1999
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Ingår i: BJU International. - Oxon, United Kingdom : Blackwell Publishing. - 1464-4096 .- 1464-410X. ; 83:4, s. 498-503
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To determine whether epidermal growth factor receptor (EGFR) immunostaining of tumour cells is associated with cancer-specific death after cystectomy for locally advanced bladder cancer.Patients and Methods: The hospital records of all patients treated with cystectomy for urothelial cancer of the urinary bladder between 1967 and 1992 were reviewed retrospectively. The paraffin-embedded specimens obtained before treatment from 173 patients were processed for immunohistochemical staining, using the monoclonal antibody NCL-EGFR (Novocastra, UK). EGFR immunostaining was considered positive if membrane staining was found in at > or = 20% of tumour cells in one or more fields at > or = 200 (area 0.59 mm2).Results: Most patients (149) received preoperative irradiation and one had neoadjuvant chemotherapy. The mean observation time was 81.3 months; 63 patients (36%) had tumour recurrence within 1-80 months (mean 18.3). Positive EGFR immunostaining was found in 100 patients (58%). The proportion of T2-4 tumours was higher in those EGFR-positive than in those EGFR-negative. Proportional-hazards analysis revealed that clinical stage was significantly associated with cancer-specific death, but EGFR expression was not.Conclusion: Although positive immunostaining for EGFR was more frequent in higher stages of locally advanced bladder cancer, this variable was not an independent predictor of outcome after cystectomy.
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| 9. |
- Tencer, Jan
(författare)
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Endogenous proteins as markers of glomerular function and dysfunction
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Plasma and urine concentrations of endogenous proteins are frequently used in the diagnosis of kidney diseases and in studies of glomerular filter function. The main issues addressed in these studies were: storage of urine samples for subsequent protein analysis, use of protein concentrations in urine and in plasma in health and as markers of glomerular diseases, and the application of renal plasma-to-urine clearance of endogenous proteins in estimating the size-selectivity properties of the glomerular capillary wall. Studies of the stability of endogenous proteins in urine stored under different conditions showed certain proteins (immunoglobulin G, protein HC, and a1-antitrypsin) to deteriorate in native urine stored at -20°C, and a1-antitrypsin to be also unstable in native urine kept at room temperature or at 4°C. The addition of the preservative solution employed in these studies was shown to allow reliable measurements to be made of all the proteins investigated, and under all conditions tested, with the exception of a1-antitrypsin in frozen urine. Measurements of urine concentrations of endogenous proteins in healthy adults, using rapid, generally available methods, showed that the same upper reference limits for urinary protein excretion may be used for both genders and regardless of age or the type of urine collection. Moreover, the protein content in normal urine does not correlate to the presence of haematuria or granular casts in urinary sediment. Increased plasma concentrations of acute phase proteins, a1-antitrypsin, haptoglobin and orosomucoid, but not C-reactive protein, were detected in patients with primary chronic glomerulonephritides. The findings imply that, despite the indolent clinical picture, persistent inflammatory processes occur in chronic glomerulonephritides and that, the three first-mentioned acute phase proteins may be used as markers of these diseases. Moreover, the C-reactive protein level may be used to diagnose infections or other inflammatory conditions affecting patients with chronic glomerulonephritides. Urine excretion of glycosaminoglycans was decreased in patients with primary glomerulonephritis or renal amyloidosis. Significant differences in this variable were also observed between various kinds of glomerular diseases, urine concentrations being lower in acute glomerulonephritis compared to the chronic forms of the disease, and in amyloidosis compared to other glomerular diseases. These findings indicate that urinary glycosaminoglycans excretion can not only be used as a marker of glomerulonephritis or renal amyloidosis, but it can also be used in the differential diagnosis of the acute and chronic forms of the former disease, and in screening for amyloidosis in patients with glomerular diseases or with chronic inflammatory diseases, with or without clinical signs of renal involvement. Finally, based on findings in the study of fractional protein clearance in rats with inhibited tubular protein reabsorption, the large pore radius of the glomerular basement mem-brane could be estimated to be 110-115 Å. Thus, the existence of ‘shunt pathways’ in the glomerular basal membrane is open to question.
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| 10. |
- Torffvit, Ole, et al.
(författare)
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Lack of association between cystopathy and progression of diabetic nephropathy in insulin-dependent diabetes mellitus
- 1997
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Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 31:4, s. 365-369
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Tidskriftsartikel (refereegranskat)abstract
- Whether an association exists between cystopathy and progression of diabetic nephropathy has never been clarified. The aim of the present study was to measure the degree of cystopathy in relation to the rate of progression of diabetic nephropathy. To that end, 17 insulin-dependent diabetic patients with diabetic nephropathy but without voiding symptoms were investigated urodynamically. The median age of the patients was 45 years (range 27-67 years), diabetes duration 23 years (range 14-44 years) and the serum creatinine level was 162 mumol/L (median, range 65-449 mumol/L) at the time of the study. The progression rate of diabetic nephropathy was analysed retrospectively by measuring changes in yearly mean values of Log10 serum creatinine for a period of 13 years (3-15 years) before the investigation. The progression rate was 0.028 mumol/L/year (median). Patients with a progression rate above and below the median rate were considered to be rapid (n = 8) and slow (n = 9) progressors, respectively. More women than men had a rapid progression rate of nephropathy. Rapid progressors were found to have smaller volume or residual urine (90 vs 165 ml; p < 0.05), larger volume voided (440 vs 270 ml; p < 0.05), lower opening pressure (18 vs 48 cm H2O; p < 0.05) and lower pressure at maximum flow (37 vs 64 cm H2O; p < 0.05) compared to slow progressors. However, these variables were not related to the progression rate of nephropathy (MANOVA). Furthermore, these results should be interpreted with caution because of the natural gender differences in pressure conditions. In conclusion, rapid progression of diabetic nephropathy does not seem to be associated with dysfunction of the urinary bladder measured with cystometry and pressure flow.
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