Biomedical subjects

S Nilsson

Publications and source records attributed to S Nilsson.

At least 127 records · Page 7Linked to original sources

PubMed1998

Pregnancy outcome among non-participants in a trial on ultrasound screening.

Our objective was to characterize and evaluate pregnancy outcome in women who declined participation in a trial on ultrasound screening in the second trimester. Between 1985 and 1987, 8768 women were recruited for a trial on ultrasound screening. By randomization, 4997 women were assigned to either a screening or a non-screening group. Of the 1414 excluded women, data were retrieved from 1211 (86%). Participation was declined by 526 of these 1211 women, either because of anxiety regarding harmful effects of ultrasound or because they could see no benefits of ultrasound scanning. Non-participants and participants were compared. The non-participants were older, had a higher birth/pregnancy ratio, were less often smokers, and had fewer ultrasound examinations than the participants. There was a longer mean pregnancy length, an increased number of post-term deliveries, more suspicions of small-for-gestational-age fetuses and later detections of multiple pregnancies among non-participants as compared with the screening group. No differences in neonatal morbidity were found except for a greater number of mild respiratory disorders in the non-participant group. The non-participant women were more obstetrically experienced and showed indications of a healthier lifestyle in comparison with participants. The differences found in pregnancy outcome could be explained by the ultrasound screening procedure. There were no major differences in neonatal morbidity between the groups.

Adult↗

PubMed1998

Long-term outcome of chronic hepatitis C infection in a low-prevalence area.

BACKGROUND: Although hepatitis C virus (HCV) infection is recognized as an important causative factor in the development of liver cirrhosis and hepatocellular cancer (HCC), the strength of this correlation has been difficult to confirm in low-prevalence areas. METHODS: Stored serum samples from 987 consecutive (1978-88) patients with chronic liver disease were tested with an enzyme-linked immunosorbent assay for anti-HCV and further confirmed by immunoblot. To evaluate the long-term outcome, the cohort was followed up until 1995, for a median observation time of 10 years. RESULTS: Anti-HCV, confirmed by immunoblot, was found in 9.5% (94 of 987) of the patients, and at inclusion most patients were asymptomatic irrespective of anti-HCV status. Of the 445 patients who died during the study period, 44 were HCV-positive. A liver-related cause of death was far commoner and the age-adjusted survival shorter among HCV-positive patients than among HCV-negative ones. At death 68% (30 of 44) of the HCV-positive subgroup had developed cirrhosis, and 30% (13 of 44) had concurrent HCC, as compared with 36% (142 of 393) (P = 0.001) and 8% (31 of 393) (P = 0.001), respectively, of the HCV-negative subgroup. HCV infection (P < 0.001), alcohol abuse (P < 0.001), and immigrant status (P = 0.045) were independent factors with regard to the development of cirrhosis, whereas HCV infection (P = 0.040) and immigrant status (P = 0.012) were independent factors with regard to HCC. CONCLUSIONS: HCV infection is common among patients with chronic liver disease, even when clinical evidence of viral infection is sparse, and constitutes a significant cause of death even in a low-prevalence area.

Carcinoma, Hepatocellular↗

PubMed1998

Value of sextant biopsies in the assessment of local cure following external beam radiotherapy of prostatic adenocarcinoma.

Between 1982 and 1992, 73 patients received radical external beam radiotherapy (EBR) for prostatic adenocarcinoma at the Central Hospital, Västerås, with an average dose of 68.1 Gy (range 64.5-72.5 Gy) and an average cumulative radiation effect (CRE) of 18.2 (range 17.1-19.9) All patients had a negative bone scan prior to treatment and presented with clinical stage T1-T4,Nx,Mo. Twenty-four out of 36 surviving patients consented to participate in a follow-up study which included transrectal, ultrasonically guided prostate biopsies. The average follow-up from EBR to biopsy was 5.5 years (range 3.6-11.1 years). Sixteen (67%) of the patients had a positive biopsy. The average PSA level in the biopsy-positive group was 35.7 ng/mL (range 3.9-200 ng/mL). In the biopsy-negative group, the average PSA was 3.7 ng/mL (range 0.2-13.0 ng/mL). The conclusion is that the degree of local cure achieved in patients with prostatic cancer treated with external beam radiotherapy is low (33%), and that a higher radiation dose may be required to eradicate this malignancy.

Adenocarcinoma↗

PubMed1998

Molecular and structural biology of thyroid hormone receptors.

1. Thyroid hormone receptors (TR) are expressed from two separate genes (alpha and beta) and belong to the nuclear receptor superfamily, which also contains receptors for steroids, vitamins and prostaglandins. 2. Unliganded TR are bound to DNA thyroid hormone response elements (TRE) predominantly as homodimers, or as heterodimers with retinoid X-receptors (RXR), and are associated with a complex of proteins containing corepressor proteins. Ligand binding promotes corepressor dissociation and binding of a coactivator. 3. Recent studies from our group have focused on the acquisition and use of X-ray crystallographic structures of ligand-binding domains (LBD) of both the rat (r) TR alpha and the human (h) TR beta bound to several different ligands. We have also developed ligands that bind selectively to the TR beta, which may provide ways to explore the differential functions of TR alpha compared with TR beta isoforms. 4. The LBD is comprised mostly of alpha-helices. The ligand is completely buried in the receptor and forms part of its hydrophobic core. Kinetic studies suggest that the limiting step in formation of high-affinity ligand-receptor complexes is the rate of folding of the receptor around the ligand. Ligands can be fitted tightly in the ligand-binding pocket and small differences in this fitting may explain many structure-activity relationships. Interestingly, analysis of the structures of antagonists suggests that they have chemical groups, 'extensions', that could impair receptor folding around them and, thus, prevent the agonist-induced conformation changes in the receptor. 5. The TR structures allowed us to see that the mutations that occur in the syndrome of generalized resistance to thyroid hormone are located in the vicinity of the ligand-binding pocket. 6. X-ray structure of the TR has also been used to guide construction of mutations in the TR surface that block binding of various proteins important for receptor function. Studies with these TR mutants reveal that the interfaces for homo- and heterodimerization map to similar residues in helix 10 and 11 and also allow the definition of the surface for binding of coactivators, which appears to be general for nuclear receptors. Formation of this surface, which involves packing of helix 12 of the TR into a scaffold formed by helices 3 and 5, appears to be the major change in the receptor structure induced by hormone occupancy.

Animals↗

PubMed1998

Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists.

The existence of two rather than one estrogen receptor, today characterized as estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta), indicates that the mechanism of action of 17beta-estradiol and related synthetic drugs is more complex than previously thought. Because the homology of amino acid residues in the ligand-binding domain (LBD) of ERbeta is high compared with those amino acid residues in ERalpha LBD, previously shown to line the ligand binding cavity or to make direct contacts with ligands, it is not surprising that many ligands have a similar affinity for both receptor subtypes. We report that 17alpha-ethynyl, 17beta-estradiol, for example, has an ERalpha-selective agonist potency and that 16beta,17alpha-epiestriol has an ERbeta-selective agonist potency. We also report that genistein has an ERbeta-selective affinity and potency but an ERalpha-selective efficacy. Furthermore, we show that tamoxifen, 4-OH-tamoxifen, raloxifene, and ICI 164,384 have an ERalpha-selective partial agonist/antagonist function but a pure antagonist effect through ERbeta. In addition, raloxifene displayed an ERalpha-selective antagonist potency, in agreement with its ERalpha-selective affinity. However, although ICI 164,384 showed an ERbeta-selective affinity, it had a similar potency to antagonize the effect of 17beta-estradiol in the ERalpha- and ERbeta-specific reporter cell lines, respectively. In conclusion, our data indicate that the ligand binding cavity of ERbeta is probably more different from that of ERalpha than can be anticipated from the primary sequences of the two ER subtypes and that it will be possible to develop receptor-specific ligands that may form the basis of novel pharmaceuticals with better in vivo efficacy and side effect profile than current available drugs.

Cells, Cultured↗

PubMed1998

Interactions between methylsulfonyl PCBs and the glucocorticoid receptor.

Persistent polychlorinated biphenyl (PCB) metabolites were studied with respect to their interaction with the human glucocorticoid receptor (GR). 3-Methylsulphonyl-2,5,6,2',4',5'-hexachlorobiphenyl (3-MeSO2-CB149) was shown to compete with 3H-dexamethasone for binding to the GR, with an IC50 (concentration that inhibits 50%) of approximately 1 microM. Using GRAF cells expressing human GR, glucocorticoid responsive element, and a reporter enzyme, we demonstrated that 3-MeSO2-CB149 functionally acts as an antagonist at the GR (IC50 = 2.7 microM). In accordance with the receptor binding, the antagonism mainly appeared to be of a competitive nature. When studying the competitive binding of 24 methylsulfonyl PCBs (relative to dexamethasone) to GR from mouse liver cytosol, seven compounds had a higher affinity to GR than 3-MeSO2-CB149. Structure-activity relationship studies indicated that the presence of three chlorine atoms in the ortho-position and chlorine and methyl sulfone groups on either end of the molecule (4 and 4'-position) increased the affinity to GR. The relevance of this finding for human health is not known, but PCB methyl sulfones are ubiquitous pollutants present in mother's milk. The results stress the need for studying endocrine disruptors that affect hormonal systems other than sex and thyroidogenic hormones.

Animals↗

PubMed1998

The ability of non-invasive physiological tests to detect arterial occlusions in the lower extremity. An ROC study with particular regard to recruitment of patients for clinical trials.

In the prerandomization phase of a clinical trial it is essential to be able to exclude, in a non-invasive way, patients who cannot be randomized into the trial. The ability of routine non-invasive physiological examinations to detect arterial occlusion in the lower extremities was investigated in 182 patients with hypercholesterolaemia. Ankle blood pressure measurement, pulse oscillometry, digital pulse plethysmography and treadmill and cycle exercise tests were performed as part of the prerandomization phase of the Probucol Quantitative Regression Swedish Trial (PQRST). The PQRST was designed to compare the antiatherosclerotic effect of two different lipid-lowering regimens. Before randomization the patients also underwent aorto-femoral arteriography, which was used as 'gold standard'. The results were analysed with ROC methodology. Ankle blood pressure measurement (ABP) and inclination time (IT), measured with digital pulse plethysmography, without significant mutual difference, were the variables, best able to detect occlusions. For ABP, the AZ-values were 0.85, 0.82 and 0.94 in detection of right-sided, left-sided and bilateral occlusion, respectively. The corresponding figures for IT were AZ = 0.86, 0.91 and 0.93. If a bilateral occlusion was predicted in a patient with an ABP value of < = or 0.98, a specificity of 0.90 and a sensitivity of 0.87 were obtained, using arteriography as reference method. For IT, with a critical value of 320 ms, sensitivity and specificity were 0.83 and 0.90, respectively.

Adult↗

PubMed1998

Conjugate chemistry, iodination and cellular binding of mEGF-dextran-tyrosine: preclinical tests in preparation for clinical trials.

A conjugate with specific binding to the epidermal growth factor receptor, EGFR, and of interest for clinical tests was prepared using mouse epidermal growth factor, mEGF, and dextran. The mEGF was first coupled to dextran by reductive amination in which the free amino group on the N-terminal of mEGF was reacted with the aldehyde group on the reductive end of the dextran chain. The end-end coupled intermediate was further activated by the cyanopyridinium agent CDAP and tyrosines introduced to the dextran part of the conjugate. The mEGF-dextran-tyrosine conjugate was, with high efficiency, iodinated with the chloramine-T method. Approximately 25-35% of the radioactivity could be removed from the conjugate after exposure to protease K while 65-75% of the radioactivity could be removed after exposure to dextranase. Thus, the largest amount of the iodine was on the dextran part of the conjugate. The iodinated mEGF-dextran-tyrosine had EGFR specific binding since the binding to an EGFR rich human glioma cell line could be displaced by an excess of non-radioactive mEGF. The conjugate was to a large extent internalized in these cells and the administrated radioactivity was thereby retained inside the cells for at least up to 50 h.

Animals↗

PubMed1998

Chiaroscuro hematopoietic stem cell.

These observations suggest several immediate clinical strategies. In gene therapy, approaches could be targeted to obtain cycling of hematopoietic stem cells and gene-carrying retrovirus vector integration followed by engraftment at an appropriate time interval which favors engraftment. The same type of approach can be utilized for stem cell expansion approaches. Alternatively marrow or peripheral stem cell engraftment can be obtained with minimal to no toxicity in allochimeric strategies in such diseases as sickle cell anemia or thalassemia. A similar approach could be useful in obtaining cell engraftment with minimal toxicity in therapies employing cellular immune (T-cell and NK-cell) attack against cancer. These areas of clinical application are outline in Table 3.

Animals↗

PubMed1998

A multicenter study comparing two endometrial sampling devices--Medscand Endorette and Pipelle de Cornier.

BACKGROUND: To compare two endometrial sampling devices Medscand Endorette and Pipelle de Cornier with respect to tissue collecting ability, diagnostic accuracy and side effects. METHODS: A prospective, multi-center, cross-over study in 152 women with a medical indication for endometrial biopsy. Samples were collected from each patient on the same occasion with both devices, the order of which was randomized. Statistical analysis was based on pairwise comparison in contingency tables with McNemars chi2 test. RESULTS: One hundred and forty-five of 152 (95%) women were successfully sampled. There was no difference between the devices concerning discomfort and bleeding. However, Medscand Endorette seemed to have a higher capacity than Pipelle for collecting an adequate sample. This difference was noted when the two devices were compared in the position as first instrument as well as when results were compared in the main target group for this type of examination, for women over 55 years. CONCLUSIONS: The new Medscand Endorette was preferred due to its higher capacity for collecting adequate samples.

Abdominal Pain↗

PubMed1998

Mechanisms of thyroid hormone action: insights from X-ray crystallographic and functional studies.

This review summarizes the studies conducted in our laboratory on the mechanisms of thyroid hormone action over the past two decades. We have attempted to place our studies on thyroid hormone receptors (TRs) in perspective with the work conducted by other investigators that established their nuclear localization, DNA-binding properties, DNA response elements, and the role of other proteins involved in TR-mediated regulation of gene transcription. Recently, our crystallographic studies of the TR ligand binding domain (LBD) revealed that the ligand has a structural role in the folding of the receptor's hydrophobic core. The analysis of the structure led to biochemical and genetic studies that have defined the surfaces on the TR LBD required for dimerization and binding of coactivator proteins. Placement of the mutations found in patients with the syndrome of generalized resistance to thyroid hormone on the TR LBD revealed that they were restricted to amino acids in the vicinity of the binding pocket for thyroid hormone. The insights gained from the elucidation of the TR LBD structure will provide the basis for the design of compounds with selective agonistic or antagonistic activities.

Animals↗

PubMed1997

The potential of radiolabeled EGF-dextran conjugates in the treatment of urinary bladder carcinoma.

BACKGROUND: Muscle-invasive urothelial carcinoma of the urinary bladder has a poor prognosis in spite of available therapies. These tumors frequently overexpress the epidermal growth factor receptor (EGFr), a possible target for therapeutic conjugates. The aim of this study was to construct an EGF-carbohydrate conjugate that would be potentially useful for both local (i.e., intravesical) and systemic radiotherapy. METHODS: EGF was coupled to periodate activated dextran by reductive amination. Receptor binding tests in vitro were conducted, using the human urothelial carcinoma cell line RT4 and the human malignant glioma cell line U-343-MG as a positive control. In the in vivo experiments, nude mice with subcutaneously grown xenografts of the RT4 tumor were injected intravenously with technetium-99m-labeled EGF conjugates. Samples of organs, blood, and tumors were collected after 24 hours. The radioactive uptake was calculated as a percentage of the dose per gram of tissue. RESULTS: The specific binding in the in vitro experiment was 90-95%. The binding was similar in both cell lines. There was a positive uptake in the tumors in the in vivo experiment, with tumor-to-blood ratios from 2:1 to 6:1. The uptake level in the kidneys was similar to that in the tumors (i.e., approximately 0.05% dose per gram of tissue). The other organs had a lower uptake compared with the tumor uptake. CONCLUSIONS: The results indicate that radiolabeled EGF-dextran has the potential to become a tool for local treatment of recurrent bladder carcinoma. With appropriate modifications, it should be possible to use this conjugate for systemic radiotherapy as well.

Animals↗

PubMed1997

Radioimmunoscintigraphy with a novel monoclonal antiprostate antibody (E4): an experimental study in nude mice.

BACKGROUND: Prostate cancer is one of the leading causes of death among men, despite achievements in diagnosis and therapy. Radioimmunolocalization and radioimmunotherapy of malignant tumors have demonstrated increasing potential and may become useful tools in the management of prostate cancer. METHODS: Nude mice were inoculated subcutaneously with cells from the poorly differentiated human prostate cancer cell line DU-145. The intact monoclonal antibody (MoAb) E4 and an intact anticytokeratin-8 MoAb, TS1, used for comparison were labeled with 125I and injected intraperitoneally (i.p.) in the mice. Repetitive quantitative scintigraphic recordings were performed during 1 month. The mice were killed at Day 29 after injection of the radiolabeled MoAb. The tumors and the organs were dissected and weighed. The remaining activity was measured in a gamma well counter. One part of the tumor was immediately fixed in Bouin's solution for autoradiography and the other in formaldehyde for microscopy. RESULTS: The study demonstrated significant radioimmunolocalization of the MoAb E4 into the DU-145 prostate tumor tissue in the animal model, with an average radiation dose of 0.08 Gy/MBq in the tumor. TS1 localized preferentially in necrotic parts of the tumor, yielding a tumor dose of 0.02 Gy/MBq. CONCLUSIONS: The MoAb E4 is a promising radiotracer for prostate cancer and may be used in radioimmunotherapy. As in earlier studies, TS1 shows significant radioimmunolocalization into necrotic tumor tissue, which also exists in prostate cancer.

Animals↗

PubMed1997

Intraoperative gamma detection reveals abdominal endocrine tumors more efficiently than somatostatin receptor scintigraphy.

BACKGROUND: [(111)In]-diethylenetriamine pentaacetic acid (DTPA)-D-[Phe1]-octreotide (OctreoScan, Mallinckrodt Medical, Petten, The Netherlands), combined with single photon emission computed tomography (SPECT), has limited possibilities to detect small abdominal endocrine tumors. This study explores the efficacy of OctreoScan and a newly developed handheld gamma detector probe (H-probe2) for the localization of neuroendocrine abdominal tumors. METHODS: Twenty-one patients with endocrine pancreatic or midgut carcinoid tumors were given 100-200 megabecquerels (MBq) [(111)In]-DTPA-D-[Phe1]-octreotide and underwent preoperative SPECT examination, after which time surgery was undertaken within 24-48 hours. Intraoperatively the radioactivity of tumors and normal tissues was measured with the H-probe2 connected to a portable personal computer. Resected intestinal specimens of ten patients with carcinoid tumors were examined by gamma camera ex vivo. Biopsies of all tumors subsequently were investigated in a wellcounter and by routine histopathology. RESULTS: Disregarding liver metastases, a total of 34 of 60 abdominal tumors were detected by SPECT; however, SPECT failed to visualize any tumor < 9 mm. The shielding of the manual probe allowed intraoperative examination despite the substantial radiation energy of (111)In. The H-probe2 detected 91% of the tumors investigated, and these included all those > 5 mm. In the wellcounter the H-probe2-detected tumors exhibited 4.7-157.7 times higher radionuclide uptake than the surrounding normal tissues. The gamma camera analysis detected 68% of tumors in the resected specimens. CONCLUSIONS: The intraoperative H-probe2 examination provided substantial improvement in the detection of small endocrine lesions accumulating [(111)In]-DTPA-D-[Phe1]-octreotide and all lesions with a size > 5 mm in greatest dimension could be identified.

Adult↗

PubMed1997

A gamma detector probe with ex vivo detection of carcinoid tumors superior to intraoperative palpation.

BACKGROUND: Despite the generally successful scintigraphic detection of endocrine tumors with [(111)In]-DTPA-D-[Phe1]-octreotide (OctreoScan, Mallinckrodt Medical, Petten, The Netherlands), its intraoperative application awaits the development of suitable gamma detectors. This study describes a novel probe (H-probe2) and its ex vivo efficacy for the detection of midgut carcinoid tumors. METHODS: The probe measures 180 mm x 24 mm, and contains a bismuth germinate crystal connected to a photomultiplicator tube, a lead shield, and a tantalum collimator with an angled, 3-mm wide opening. It was characterized in a test bench utilizing solublilized (111)In and 99mTc, and 8 fresh operative specimens containing 26 histologically verified midgut carcinoid tumors (2-40 mm) from patients exposed to OctreoScan. Measurements were made at 2.5-mm intervals over the entire specimens and presented three dimensionally. RESULTS: The test bench analysis supported efficient shielding, and a total collimation of 27 degrees for (111)In and 20 degrees for 99mTc. In addition to 18 palpable tumors, 4 of 6 surgically occult tumors (2-3 mm in dimension) could be discovered with H-probe2. Small tumors in close apposition to a large tumor could not be separated. Wellcounter examination showed that tumors detected with the H-probe2 exhibited 1.7-84.1 times higher radionuclide uptake than the surrounding normal tissue. CONCLUSION: Ex vivo analysis of H-probe2 supported detection of tumors inaccessible to surgical palpation, but its clinical efficiency awaits intraoperative evaluation.

Carcinoid Tumor↗

PubMed1997

Objective responses after fractionated infusional brachytherapy of unresectable pancreatic adenocarcinomas.

BACKGROUND: The prognosis of unresectable pancreatic adenocarcinoma is poor. Therefore, the treatment potential of an intratumoral infusional brachytherapy using macroaggregated human albumin in combination with radioactive chromic phosphate [32P] was investigated in this group of patients. METHODS: Seventeen patients with unresectable tumors received intratumoral infusional brachytherapy. Treatment and assessment of response was performed with the aid of ultrasonography. RESULTS: Four patients had complete response with a duration ranging from 2-57 weeks and 5 patients had partial response with a duration ranging from 4-21 weeks, corresponding to an objective response of 53% (9 of 17 patients). Six of these patients were alive 33-57 weeks after treatment. Radiation necrosis was observed in 1 patient after a 19,000-gray cumulative radiation dose and a slight decrease in blood counts was observed in 2 patients. CONCLUSIONS: Intratumoral infusional brachytherapy using radioactive colloidal chromic phosphate has the potential to reduce inoperable pancreatic tumors with few side effects.

Adenocarcinoma↗

PubMed1997

Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites.

The transactivation properties of the two estrogen receptors, ERalpha and ERbeta, were examined with different ligands in the context of an estrogen response element and an AP1 element. ERalpha and ERbeta were shown to signal in opposite ways when complexed with the natural hormone estradiol from an AP1 site: with ERalpha, 17beta-estradiol activated transcription, whereas with ERbeta, 17beta-estradiol inhibited transcription. Moreover, the antiestrogens tamoxifen, raloxifene, and Imperial Chemical Industries 164384 were potent transcriptional activators with ERbeta at an AP1 site. Thus, the two ERs signal in different ways depending on ligand and response element. This suggests that ERalpha and ERbeta may play different roles in gene regulation.

Animals↗

PubMed1997

Expression of p21 and mutant p53 gene products in residual prostatic tumor cells after radical radiotherapy.

BACKGROUND: In a previous study, sextant core biopsies revealed residual tumor in the prostate in 37/55 investigated patients, with an average of 6.8 years after external beam radiation therapy (RRT). More than half of the biopsies exhibited Ki-67 and PCNA proliferation activity. METHODS: The present study aims at further characterizing residual tumor cells post-RRT by investigating whether the tumor cells exhibit immunohistochemical expression of p21 and mutant p53 gene products, which reflect the state of cell cycle regulatory mechanisms. RESULTS: Positive p53 staining was observed in 11% and p21 positivity in 47% of biopsies. The proportion of positively stained cells was low for both antigens. The staining patterns point to the existence of wild-type p53-dependent, as well as alternative pathways for p21 protein induction. CONCLUSIONS: A low proportion of tumor cells exhibited p53 protein accumulation post-RRT. G1 arrest, as assessed by p21 immunoexpression, was demonstrated in a low percentage of tumor cells in < 50% of post-RRT biopsies, indicating that the vast majority of residual tumor cells following RRT escape the G1/S checkpoint control and propagate into S-phase, presumably with a maintained malignant potential.

Adenocarcinoma↗