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Biomedical subjects

U Johansson

Publications and source records attributed to U Johansson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Lysosomal release of cathepsin D precedes relocation of cytochrome c and loss of mitochondrial transmembrane potential during apoptosis induced by oxidative stress.

Apoptosis was induced in human foreskin fibroblasts by the redox-cycling quinone naphthazarin (5,8-dihydroxy-1,4-naphthoquinone). Most of the cells displayed ultrastructure typical of apoptosis after 8 h of exposure to naphthazarin. Apoptosis was inhibited in fibroblasts pretreated with the cathepsin D inhibitor pepstatin A. Immunofluorescence analysis of the intracellular distribution of cathepsin D revealed a distinct granular pattern in control cells, whereas cells treated with naphthazarin for 30 min exhibited more diffuse staining that corresponded to release of the enzyme from lysosomes to the cytosol. After 2 h, release of cytochrome c from mitochondria to the cytosol was indicated by immunofluorescence. The membrane-potential-sensitive probe JC-1 and flow cytometry did not detect a permanent decrease in mitochondrial transmembrane potential (delta psi(m)) until after 5 h of naphthazarin treatment. Our findings show that, during naphthazarin-induced apoptosis, lysosomal destabilization (measured as release of cathepsin D) precedes release of cytochrome c, loss of delta psi(m), and morphologic alterations. Moreover, apoptosis could be inhibited by pretreatment with pepstatin A.

Apoptosis↗
PubMed1998

A randomized trial of long term adjuvant tamoxifen plus postoperative radiation therapy versus radiation therapy alone for patients with early stage breast carcinoma treated with breast-conserving surgery. Stockholm Breast Cancer Study Group.

BACKGROUND: The use of adjuvant tamoxifen to treat postmenopausal breast carcinoma patients as an adjunct to primary surgery is well established. The current study reports the long term results for a low risk stratum in a randomized trial of adjuvant tamoxifen. The main focus of this analysis was to determine whether tamoxifen would result in a reduced local failure rate for lymph node negative, postmenopausal patients treated with breast-conserving surgery and postoperative radiotherapy. METHODS: The study population included 432 lymph node negative, postmenopausal patients with invasive breast carcinoma (classified as T1-T2) who underwent breast-conserving surgery followed by radiotherapy in Stockholm during the period 1976-1990. The patients constituted a separate stratum of the Stockholm Adjuvant Tamoxifen Trial, which included a total of 2729 patients. Of 432 patients, 213 received 40 mg of tamoxifen daily for either 2 or 5 years. The median follow-up time was 8 years (range, 5-19 years). RESULTS: At 10 years, the overall survival was 90% for the tamoxifen group and 88% for the control group. The event free survival at 10 years was 80% for the tamoxifen group and 70% for the control group (P=0.03). Tamoxifen reduced the overall rate of ipsilateral (hazard ratio=0.4, 95% confidence interval [CI]=0.2-0.9, P=0.02) and contralateral breast tumor recurrences (hazard ratio=0.4, 95% CI=0.1-1.1, P=0.06). Trends toward a reduced number of distant metastases (hazard ratio=0.6, 95% CI=0.3-1.2, P=0.1) and deaths due to breast carcinoma (hazard ratio=0.5, 95% CI=0.2-1.2, P=0.1) also were observed. CONCLUSIONS. The addition of tamoxifen to radiotherapy for postmenopausal, lymph node negative breast carcinoma patients treated with breast-conserving surgery resulted in a reduced rate of ipsilateral and contralateral breast tumor recurrences. The avoidance of salvage mastectomies, reexcisions, and new contralateral malignancies justifies the use of tamoxifen even in the treatment of patients with a 10-year survival rate of 90%.

Breast Neoplasms↗
PubMed1998

Antioxidative properties of organotellurium compounds in cell systems.

The protective/antioxidative properties of diaryl tellurides were demonstrated in cellular systems of increasing complexity. In the presence of glutathione, bis(4-hydroxyphenyl) telluride (1a), bis(4-aminophenyl) telluride (1d) and bis(2-carboxyphenyl) telluride (1h) reduced by more than 50% t-butyl hydroperoxide-induced cell death in lung fibroblast cultures at concentrations below 2 microM. Bis(2,6-dimethyl-4-hydroxyphenyl) telluride (2b) reduced by more than 50% leukocyte-mediated and phorbol-12-myristate-13-acetate-stimulated damage to Caco-2 cells at 0.1 microM concentration. As judged by their abilities to reduce formation of thiobarbituric acid reactive substances at concentrations close to 1 microM, diaryl tellurides 1a, 1d and 2b protected rat kidney tissue against oxidative damage caused by anoxia and reoxygenation. The organotellurium compounds also offered protection after systemic administration. In the presence of diaryl telluride 2b (0.1-1 microM), the ischemia/reperfusion-induced vascular permeability increase in the hamster cheek pouch was significantly reduced as compared with the control. Some of the most active organotellurium cell protectants were evaluated for their ability to inhibit formation of the inflammatory mediators leukotriene B4 and interleukin-1beta. An inhibitory effect on the secretion of these species was seen for compounds 1a and 2b at or above 10 microM concentrations. The protective effects of diaryl tellurides against t-butyl hydroperoxide-induced cell injury can be ascribed mainly to the peroxide-decomposing, glutathione peroxidase-like capacity of the compounds. The chain-breaking, electron- or hydrogen atom-donating ability of diaryl tellurides seems to be the main reason for their protection against leukocyte-mediated cell damage in Caco-2 cells and in the oxidatively challenged rat kidney and hamster cheek pouch.

Aniline Compounds↗
PubMed1998

The genotype determines the B cell response in mercury-treated mice.

BACKGROUND: Mercury causes in mouse strains of the H-2s haplotype an autoimmune syndrome with antibodies to the nucleolar protein fibrillarin and systemic immune complex (IC) deposits. Other strains, like BALB/C (H-2d), develop only IC deposits, and most strains are resistant. However, mercury activates the murine immune system and causes lymphoproliferation in most strains: H-2s strains are high-responders also in this respect, while the relation between lymphoproliferation and autoimmune manifestations is unclear for other strains. We examined the B cell response to mercury in order to better understand the relation between lymphoproliferation and systemic autoimmunity, using the high-responder H-2s strains (A.SW and SJL), the intermediate responder strain BALB/C (H-2d), and the A. TL (H-2tl) and DBA/2 (H-2d) strains which are resistant to systemic autoimmunity. METHODS: During 4-7 weeks of subcutaneous mercuric chloride injections, the number of B cells and the expression of cell surface activation and proliferation markers was monitored by flow cytometry. The number of cytoplasmic Ig+ splenocytes was determined by direct immunofluorescence technique on slides, and serum Ig isotype levels as well anti-ssDNA and anti-DNP antibodies were determined by ELISA. Serum ANA were monitored weekly by indirect immunofluorescence technique. RESULTS: Mercury-treated A.SW and SJL mice (H-2s) developed an increased expression of the proliferation marker CD71 on B cells, an increased number of B cells in the spleen, and an early, strong, but transient increase in serum Ig concentrations of Th1- as well as Th2-regulated Ig isotypes. Mercury-treated H-2s mice rapidly developed a polyclonal B cell response including the IgM isotype, but also antinucleolar antibodies (ANoA) of the IgG isotype with a clumpy pattern, characteristic for antifibrillarin antibodies. The IgG ANoA response was of a long duration and high titer. The A.TL strain (H-2tl) showed only a slight, restricted B cell activation. The BALB/C strain developed a slight, transient B cell activation dominated by IgG1 and IgE, and antinuclear antibodies (ANA). The DBA/2 strain showed only a minimal B cell response without ANA. CONCLUSION: Mercury induces an early, transient, polyclonal B cell activation linked to the H-2A or H-2K locus in H-2s strains on the A background. This polyclonal response differs from the long-lasting, high-titered IgG autoantibody response to a nucleolar antigen with characteristics of fibrillarin in H-2s strains, which indicates that these responses arise from separate mechanisms. Another group of strains, exemplified by BALB/C (H-2d), responds to mercury with a slight, transient, Th2-dominated B cell response, a restricted antibody specificity targeting the cell nucleus, and systemic IC deposits. Another H-2d strain, DBA, is essentially resistant to mercury, illustrating the importance of non-H-2 genes for regulating the response to mercury.

Animals↗
PubMed1997

Interactions between the middle ear and the inner ear: bacterial products.

The round-window membrane (RWM) is extremely thin and is the only soft-tissue barrier between the middle ear and the inner ear. Under inflammatory conditions of the middle ear the various layers of the triple-layered RWM undergo characteristic changes parallel to the changes of the middle-ear mucosa. Several studies report that bacterial products, exo- and endotoxins, from bacteria invading the middle ear may result in profound inflammatory changes in the inner ear, followed by severe damage to the inner-ear function. The present review, in which we summarized experimental and clinical observations, on bacterial products in interactions between the middle and inner ear, focused on: 1. Bacteria and bacterial products in an inflamed middle ear that may influence inner-ear function. 2. RWM structure and RWM permeability under the influence of bacteria and bacterial products. 3. Morphological and functional inner-ear effects of bacterial infection of the middle ear, and the possible mechanisms involved. 4. Future studies to be directed in this field.

Animals↗
PubMed1997

Effects of the murine genotype on T cell activation and cytokine production in murine mercury-induced autoimmunity.

Mercury induces a systemic autoimmune condition characterized by auto-antibodies to the nucleolar protein fibrillarin (AFA) and systemic immune-complex (IC) deposits in genetically susceptible mouse strains. This study examines T cell activation and cytokine production following mercury exposure in genetically susceptible and resistant strains. Mercury injected s.c., according to the protocol for induction of autoimmunity, caused an early T cell activation, measured as an increase of IL-2-producing cells, and increased expression of the IL-2-receptor proteins CD25 and CD122 and of the proliferation marker CD71 on days 2-4 in the susceptible A.SW and A. TH strains. This was followed by a long-lasting increase in the number of T cells, dominated by CD4(+) cells. Mice of the susceptible A.SW strain showed a modest increase of TNF-alpha-, IFN-gamma-, and IL-4-producing cells after 4-6 days, and a very distinct increase of IL-4-producing cells on days 8-10. The susceptible SJL strain (H-2(s)), severely deficient in Th2-promoting CD4(+), NK1.1(+) T cells, showed no increase of IL-4(+) cells on days 8-10. Instead, the number of IFN-gamma-producing cells was increased. Susceptible mice developed an increase of Ig-producing cells, AFA, and systemic IC-deposits. Genetically mercury-resistant A.TL mice showed a minimal increase of T cells, but no increase in cytokine-producing cells. We conclude that autoimmunogenic doses of HgCl2 induce an activation and proliferation of T cells in genetically susceptible mouse strains, as well as a broad increase of cytokine-producing cells, followed by a late predominance of the Th2-associated IL-4. One strain, severely deficient in Th2-promoting CD4(+), NK1.1(+) T cells, lacked the increase in IL-4(+) cells, indicating that a predominantly Th2-response is not necessary for induction of autoimmunity by mercury. However, a Th2-dominated response led to a faster and stronger B cell activation.

Animals↗
PubMed1997

Breast conserving surgery for invasive breast cancer: risk factors for ipsilateral breast tumor recurrences.

To identify risk factors associated with an increased risk for ipsilateral breast tumor recurrence following breast-conserving surgery, a cohort of 759 women with T1-T2 tumors were studied. The majority of the patients (88%) had received postoperative radiation therapy to the breast. Median follow-up time was 10 (range: 6-17) years. There was a 1-1.5% yearly increase in ipsilateral breast tumor recurrences. For women < 50 ys the cumulative recurrence rate at 10 years was 18% and for women > or = 50 ys, 9%. Node positive women had a cumulative breast recurrence rate of 25% versus 10% for node negative women. Ten years postoperatively, irradiated patients had a cumulative recurrence rate of 11% versus 26% when no irradiation was given. The beneficial effect of radiotherapy was substantial during the first four postoperative years. The relative risk for an ipsilateral breast tumor recurrence during this period was 4.5 times higher than for non-irradiated patients. However, the protective effect of radiotherapy decreased with time. After ten years the relative risk of ipsilateral breast tumor recurrence was the same among irradiated and non-irradiated patients although the number of events during this period was low. Univariate analysis showed that seven factors were significantly associated with an increased risk of ipsilateral breast tumor recurrence, namely age < 50 ys, increasing tumor size, uncertain microscopic margins, axillary lymph node metastases, no postoperative tamoxifen treatment, premenopausal status, and no postoperative radiotherapy. Three factors remained independently significant after multivariate analysis: age < 50 ys, no postoperative radiation therapy, and positive lymph nodes. In conclusion, radiotherapy reduced the breast recurrence rate, but the effect decreased with time. Node-negative women > or = 50 were a low risk-group for ipsilateral breast tumor recurrence, with a cumulative risk at 10 years of 9% without radiation therapy and 5% with breast irradiation.

Adult↗
PubMed1997

Murine silver-induced autoimmunity: silver shares induction of antinucleolar antibodies with mercury, but causes less activation of the immune system.

BACKGROUND: Mercury and silver induce antinucleolar autoantibodies (ANoA) targeting the 34-kDa nucleolar protein fibrillarin in susceptible mouse strains. Mercury has the ability to cause a general activation of the immune system, but antigen-specific mechanisms following direct or indirect interaction between mercury and fibrillarin are now believed to play a crucial role in the autoimmune pathogenesis. Our previous studies showed that silver neither induced the systemic immune complex deposits nor the increase of serum immunoglobulins seen after mercury treatment. The main objective of this study was to examine the relation between activation of the immune system and the induction of ANoA. METHODS: During 4 weeks of subcutaneous silver nitrate injections into mice of the susceptible A.SW and SJL strains and the resistant A.TL strain, the number of T and B cells as well as the expression of cell surface activation and proliferation markers were monitored by flow cytometry. The number of cytoplasmic Ig+ splenocytes was determined by direct immunofluorescence technique on slides, and serum Ig levels as well as anti-ssDNA anti anti-DNP antibodies were determined by ELISA. Serum ANoA were monitored by the indirect immunofluorescence technique. RESULTS: Silver caused in the susceptible strains a weaker and later activation and proliferation of T and B cells than mercury, and no significant polyclonal B cell activation. In contrast, the ANoA titer was not different from that seen in mercury-treated mice of the same strains. Silver-treated mice of the A.TL strain showed neither activation of the immune system nor ANoA. CONCLUSIONS: Despite being as effective as mercury inducing ANoA, silver caused only a slight activation of the immune system. This demonstrates that the massive activation of the immune system in mercury treatment is not necessary for the induction of ANoA, and indicates that (auto)antigen-specific mechanisms are likely to play a key role in mercury- and silver-induced murine autoimmunity.

Animals↗
PubMed1997

Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer.

Previous studies of high-risk breast cancer families have proposed that two major breast cancer-susceptibility genes, BRCA1 and BRCA2, may account for at least two-thirds of all hereditary breast cancer. We have screened index cases from 106 Scandinavian (mainly southern Swedish) breast cancer and breast-ovarian cancer families for germ-line mutations in all coding exons of the BRCA1 and BRCA2 genes, using the protein-truncation test, SSCP analysis, or direct sequencing. A total of 24 families exhibited 11 different BRCA1 mutations, whereas 11 different BRCA2 mutations were detected in 12 families, of which 3 contained cases of male breast cancer. One BRCA2 mutation, 4486delG, was found in two families of the present study and, in a separate study, also in breast tumors from three unrelated males with unknown family history, suggesting that at least one BRCA2 founder mutation exists in the Scandinavian population. We report 1 novel BRCA1 mutation, eight additional cases of 4 BRCA1 mutations described elsewhere, and 11 novel BRCA2 mutations (9 frameshift deletions and 2 nonsense mutations), of which all are predicted to cause premature truncation of the translated products. The relatively low frequency of BRCA1 and BRCA2 mutations in the present study could be explained by insufficient screening sensitivity to the location of mutations in uncharacterized regulatory regions, the analysis of phenocopies, or, most likely, within predisposed families, additional uncharacterized BRCA genes.

Adult↗
PubMed1997

A bone-anchored percutaneous connector system for neural prosthetic applications.

A percutaneous connector system has been developed for use in neural prosthetic applications. It is based on a skin-penetrating, bone-anchored titanium pedestal, housing an II-channel electrode array. Initial applications for the system are in audiology and as such, the proposed fixture site is in the temporal bone. The titanium pedestal is based on existing design features of the EPI Bioglass implant, developed by University College London (UCL), and the Brånemark System, employed by Nobel Biocare AB. The electrode array, consisting of platinum wires in a silicone carrier, can be custom designed to suit the application. The design features of the connector system are reviewed. Animal studies have been used to assess soft tissue reactions and the osseointegration of the pedestal. The histological data are presented. The pedestal, electrode array and the mating external connector are currently undergoing mechanical and electrical testing. The percutaneous connector system will undergo clinical trials, initially in the study of tinnitus (employing stimulation via an extracochlear electrode), and as part of a cochlear implant system (using a multichannel intracochlear electrode array and digital signal processing techniques.

Animals↗
PubMed1996

Usage and users of natural remedies in a middle-aged population: demographic and psychosocial characteristics. Results from the Malmö Diet and Cancer Study.

BACKGROUND: In Sweden, large amounts of money are spent annually on natural remedies (NRs), in spite of the fact that most products in this category lack scientific documentation of their efficacy and side-effects. The usage and users of natural remedies are not well defined. This paper describes NR use and NR users in a city in southern Sweden, and tests the hypothesis that the use of natural remedies is a strategy for coping with psychosocial stressors. METHODS: The study cohort consisted of 6545 men and women, aged 45-65 years, who during 1991 and 1992 participated in the Malmö Diet and Cancer Study, a large-scale prospective cohort study. Data on consumption of natural remedies were recorded during seven consecutive days, as part of a dietary assessment. Each participant also completed a questionnaire, covering education, work history, alcohol and smoking habits, perceived health, and psychosocial factors such as social network, social support, job strain and global control. Body composition was also measured. RESULTS: The prevalence of NR consumption was 26% among women and 17% among men. NR use was most common during winter and spring. The most popular products were ginseng, garlic, and various herb and plant extracts. Important determinants of NR usage were higher education, Swedish origin, and lifestyle factors like low body weight fat percentage and high alcohol consumption among women. Other determinants were higher age and non-smoking among men. None of the psychosocial factors appeared to influence the prevalence of NR consumption. CONCLUSIONS: The prevalence of NR consumption is influenced by sex, demographic factors, season of the year, and lifestyle. Use of NRs does not appear to be a common strategy for coping with psychosocial stress.

Journal Article↗
PubMed1996

Preoperative fine needle aspiration from human breast cancer is a valuable sampling material for progesterone receptor and cytometric DNA analysis.

In a breast cancer series (n = 54), preoperative fine needle aspiration (FNA) was compared with biopsy at primary surgery as a source of material for the determination of progesterone receptor (PgR) content by enzyme immuno assay. The respective results manifested a strong correlation (r(s) = 0.82). The fact that PgR content was usually higher in FNA samples than in the corresponding biopsy samples and the finding that 11% of the tumours were PgR positive in FNA but PgR negative in the corresponding biopsy samples suggest a greater proportion of malignant cells to be obtained with FNA than in surgical biopsy. In another breast cancer series (n = 50), corresponding comparisons for DNA flow cytometry showed concordance in ploidy status (diploid vs. non-diploid) in 84% of cases and a strong correlation in S-phase fraction values (r(s) = 0.70). At DNA image cytometry, concordant results (Auer I + II vs. Auer III + IV) were obtained in 87% of the cases. To sum up, FNA seems to be a useful sampling technique for PgR determination and DNA cytometry.

Aneuploidy↗
PubMed1996

Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden.

Nine different germ-line mutations in the BRCA1 breast and ovarian cancer susceptibility gene were identified in 15 of 47 kindreds from southern Sweden, by use of SSCP and heteroduplex analysis of all exons and flanking intron region and by a protein-truncation test for exon 11, followed by direct sequencing. All but one of the mutations are predicted to give rise to premature translation termination and include seven frameshift insertions or deletions, a nonsense mutation, and a splice acceptor site mutation. The remaining mutation is a missense mutation (Cys61Gly) in the zinc-binding motif. Four novel Swedish founding mutations were identified: the nucleotide 2595 deletion A was found in five families, the C 1806 T nonsense mutation in three families, the 3166 insertion TGAGA in three families, and the nucleotide 1201 deletion 11 in two families. Analysis of the intragenic polymorphism D17S855 supports common origins of the mutations. Eleven of the 15 kindreds manifesting BRCA1 mutations were breast-ovarian cancer families, several of them with a predominant ovarian cancer phenotype. The set of 32 families in which no BRCA1 alterations were detected included 1 breast-ovarian cancer kindred manifesting clear linkage to the BRCA1 region and loss of the wild-type chromosome in associated tumors. Other tumor types found in BRCA1 mutation/haplotype carriers included prostatic, pancreas, skin, and lung cancer, a malignant melanoma, an oligodendroglioma, and a carcinosarcoma. In all, 12 of 16 kindreds manifesting BRCA1 mutation or linkage contained ovarian cancer, as compared with only 6 of the remaining 31 families (P<.001). The present study confirms the involvement of BRCA1 in disease predisposition for a subset of hereditary breast cancer families often characterized by ovarian cancers.

Adult↗
PubMed1996

The prevalence of anaemia and mineral supplement use in a Swedish middle-aged population. Results from the Malmö Diet and Cancer Study.

OBJECTIVE: To describe dietary habits and use of mineral supplements in relation to nutrient recommendations and anaemia. DESIGN: a population-based cohort study. SUBJECTS: 2665 men and 3878 women, born between 1926 and 1945, randomly invited and participating in the prospective 'Malmö Diet and Cancer study' during 1991-1992. METHODS: The diet was assessed using a combined 7-day menu book for hot meals, beverages and supplements and a quantitative food frequency questionnaire for other foods. Anaemia was defined as haemoglobin < or = 131 g/l for men and < or = 115 g/l for women. RESULTS: Intake of mineral supplements were reported by 19% of the men and 31% of the women. Less than 0.2% had intakes of iron and selenium above highest recommended Swedish long-term intakes. The percentage of women with intake below nutrient recommendations were: zinc and selenium (60%); magnesium (35%); calcium (21%) and iron (70%, premenopausal). The corresponding values for men were: zinc, selenium and magnesium (33-47%); calcium and iron (5%). The median contribution of calcium from supplements was less than 110 mg. Supplement users had higher intakes of fish, fruits, vegetables and tea and lower intakes of coffee and meat. The iron intake was correlated to haemoglobin levels, and iron supplementation constituted about 45% of the intake. Three per cent of premenopausal women had anaemia as did less than 2% of postmenopausal women. CONCLUSION: A substantial number had mineral intake below present recommendations despite supplement use. The nutrient content of some supplements could be improved, especially calcium. Iron supplementation among postmenopausal women and men are questionable.

Aged↗
PubMed1995

Bioallethrin causes permanent changes in behavioural and muscarinic acetylcholine receptor variables in adult mice exposed neonatally to DDT.

We recently reported changes in the density of muscarinic acetylcholine receptors in cerebral cortex of mice treated neonatally with DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane) and receiving bioallethrin as adults. We also found behavioural aberrations in adult mice treated with bioallethrin, whether neonatally treated with DDT or the vehicle. To ascertain whether these changes were permanent, 10-day-old mice received an oral dose of DDT (0.5 mg/kg body weight) and at the age of 5 months they received bioallethrin orally (0.7 mg/kg body weight/day; 7 days). The animals were investigated at the age of 7 months. Here we report muscarinic acetylcholine receptor changes, additional behavioural disturbances and learning disabilities in mice receiving DDT as neonates and bioallethrin as adults, whereas the behavioural disturbances in mice receiving vehicle as neonates and bioallethrin as adults had diminished and changes in proportions of high- and low-affinity binding sites had developed. No changes in the density of nicotinic acetylcholine receptors were noted for any of the treated groups. In conclusion, exposure of neonates to DDT leads to increased susceptibility in adults to a short-acting pesticide with similar neurotoxic action. An adult exposure to this short-acting pesticide to mice neonatally exposed to DDT leads to irreversible muscarinic acetylcholine receptor changes and behavioural disturbances with additional changes 2 months after the exposure.

Allethrins↗