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Biomedical subjects

A Bredberg

Publications and source records attributed to A Bredberg.

At least 55 records · Page 3Linked to original sources
PubMed1986

Restricted ultraviolet mutational spectrum in a shuttle vector propagated in xeroderma pigmentosum cells.

A shuttle vector plasmid, pZ189, carrying a bacterial suppressor tRNA marker gene, was treated with ultraviolet radiation and propagated in cultured skin cells from a patient with the skin-cancer-prone, DNA repair-deficient disease xeroderma pigmentosum and in repair-proficient cells. After replication in the human cells, progeny plasmids were purified. Plasmid survival and mutations inactivating the marker gene were scored by transforming an indicator strain of Escherichia coli carrying a suppressible amber mutation in the beta-galactosidase gene. Plasmid survival in the xeroderma pigmentosum cells was less than that of pZ189 harvested from repair-proficient human cells. The point-mutation frequency in the 150-base-pair tRNA marker gene increased up to 100-fold with ultraviolet dose. Sequence analysis of 150 mutant plasmids revealed that mutations were infrequent at potential thymine-thymine dimer sites. Ninety-three percent of the mutant plasmids from the xeroderma pigmentosum cells showed G X C----A X T transitions, compared to 73% in the normal cells (P less than 0.002). There were significantly fewer transversions (P less than 0.002) (especially G X C----T X A) and multiple base substitutions (P less than 0.00001) than when pZ189 was passaged in repair-proficient cells. The subset of mutational changes that are common to ultraviolet-treated plasmids propagated in both repair-proficient and xeroderma pigmentosum skin cells may be associated with the development of ultraviolet-induced skin cancer in humans.

DNA Repair↗
PubMed1986

Hereditary dysplastic nevus syndrome: lymphoid cell ultraviolet hypermutability in association with increased melanoma susceptibility.

The hereditary dysplastic nevus syndrome (DNS) is a well-characterized disorder in which affected individuals have increased numbers of premalignant (dysplastic) nevi and a markedly increased risk of developing cutaneous melanoma. Seeking evidence of a systemic disorder in DNS, we examined the effect of ultraviolet radiation on cultured lymphoid cells. Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with hereditary DNS had similar survival values following treatment with 2.3 to 9.0 J of 254-nm ultraviolet radiation per m2 as did lines from control individuals. Mutagenesis at the hypoxanthineguanine phosphoribosyltransferase locus was assessed by measuring the induction of resistance to thioguanine using a microtiter well assay. Three lymphoblastoid cell lines from patients with hereditary DNS and melanoma had a 2- to 3-fold greater frequency of induced mutants per clonable cell than three normal lines following exposure to 4.5 to 9.0 J of ultraviolet radiation per m2. Expanded clones of mutated DNS lymphoblastoid cell lines had less than 6% of normal hypoxanthine-guanine phosphoribosyltransferase activity. Inhibition and recovery of DNA synthesis following ultraviolet exposure were similar in 2 DNS and 2 normal lines. Repair by DNS lines of ultraviolet-induced DNA damage was in the normal range as measured by alkaline elution. Thus, hereditary DNS exhibits in vitro hypermutability which may reflect increased susceptibility to ultraviolet-induced somatic mutations in vivo. This abnormality may be related to the increased melanoma susceptibility of patients with hereditary DNS.

Adult↗
PubMed1985

Normal rate of DNA breakage in xeroderma pigmentosum complementation group E cells treated with 8-methoxypsoralen plus near-ultraviolet radiation.

Treatment of normal and xeroderma pigmentosum complementation group E skin fibroblasts with 8-methoxypsoralen plus repeated doses of near-ultraviolet radiation elicited a marked increase in DNA strand breakage during a subsequent incubation. No such induction of breaks was noted with cells from xeroderma pigmentosum groups A and D. The results suggest that the gene product which is deficient in xeroderma pigmentosum group E cells is involved in a critical step of DNA repair of far-ultraviolet photoproducts but not so in the repair of psoralen cross-links.

DNA↗
PubMed1984

Effects of in vitro PUVA on human leukocyte function.

Human polymorphonuclear and monomorphonuclear leukocytes (PMNL and MMNL) were exposed in vitro to 8-methoxypsoralen (8-MOP, 0.1-80 micrograms/ml) and/or UV-A radiation (0.03-2 J/cm2) and then analysed for the following functions: chemotaxis, bactericidal activity and proliferation in response to mitogen stimulation. The functions of PMNL became depressed only at a high PUVA dose level (about 20 micrograms/ml of 8-MOP plus 2 J/cm2 of UV-A), whereas with MMNL chemotaxis was inhibited at 1 microgram/ml of 8-MOP plus 2 J/cm2 of UV-A and lymphocyte proliferation was diminished at 0.1 microgram/ml plus 0.1 J/cm2. Since with the MMNL, as compared with the PMNL, a longer time period was present between PUVA exposure and analysis, and since no difference between these cell types in trypan blue exclusion could be seen, the relative sensitivity of the MMNL functions was taken as evidence of DNA damage being a mechanism for the observed PUVA-induced effects.

Cells, Cultured↗
PubMed1983

Induction of SCE by DNA cross-links in human fibroblasts exposed to 8-MOP and UVA irradiation.

To study the SCE-inducing effect of psoralen cross-links in the DNA of normal, human fibroblasts, cell cultures were exposed to PUVA (0.2-1 micrograms of 8-MOP per ml, followed by UVA irradiation at 0.04 J/cm2) and carefully washed to remove non-covalently bound psoralen. Some cell cultures were then given a second dose of UVA (1.1 J/cm2), either immediately after PUVA or 1-3 days later. By this type of treatment, cells with different proportions of DNA cross-links are obtained. The initial PUVA treatment will mainly give rise to psoralen monoadducts and only few cross-links in the DNA, and the second UVA irradiation will convert a number of the psoralen monoadducts into cross-links. SCE analysis was carried out on cells grown for 2 cell cycles in the presence of BrdUrd (10 mumoles/1). PUVA treatment alone did not induce an increase in the SCE frequency, whereas a clear increase of SCE was observed in cells treated with PUVA immediately followed by the second UVA dose. This PUVA + UVA-induced increase of SCE was also observed after incubation of the cells for 3 days at confluency, as well as when a period of 3 days at confluency was introduced between the PUVA exposure and the second irradiation with UVA. In contrast, the SCE frequency gradually returned to the normal level when PUVA + UVA-treated cells were allowed to proliferate for 1-2 days, or when a proliferation period of 2-4 days was introduced between the PUVA exposure and the second irradiation. Because the SCE frequency was not changed by the initial PUVA treatment but markedly increased by PUVA + UVA, it is concluded that psoralen cross-links are considerably more effective at inducing SCE than monoadducts. The results also indicate that SCE-inducing PUVA damage is removed very slowly if at all from the DNA of confluent cells. In contrast, repair functions that eliminate cross-links as well as monoadducts seem to become activated during cell proliferation.

Bromodeoxyuridine↗
PubMed1983

Studies of DNA and chromosome damage in skin fibroblasts and blood lymphocytes from psoriasis patients treated with 8-methoxypsoralen and UVA irradiation.

Exposure of human lymphocytes and skin fibroblasts in vitro to a single, clinically used dose of PUVA, i.e., 0.1 micrograms/ml of 8-methoxypsoralen (8-MOP) plus 0.9-4 J/cm2 of longwave ultraviolet radiation (UVA), lead to the formation of DNA damage as determined by alkaline elution, and to chromosome aberrations and sister chromatid exchanges (SCE). When lymphocyte-enriched plasma was obtained from psoriasis patients 2 h after oral intake of 8-MOP and then UVA irradiated (1.8-3.6 J/cm2) in vitro, an increased frequency of chromosome aberrations and SCE was observed. Normal levels of chromosome aberrations and SCE were found in lymphocytes of psoriasis patients after 3-30 weeks of PUVA treatment in vivo. A small but statistically significant increase in the SCE frequency was observed in the lymphocytes of psoriasis patients treated for 1-6 years with PUVA (mean 18.0 SCE/cell) as compared with before PUVA (mean 15.8, p less than 0.05). Skin fibroblasts of psoriasis patients analyzed 5 years after the start of PUVA treatment showed a normal number of SCE but a high fraction of filter-retained DNA in the alkaline elution assay, suggesting the presence of cross-linked DNA.

Chromosome Aberrations↗
PubMed1982

Induction and repair of psoralen cross-links in DNA of normal human and xeroderma pigmentosum fibroblasts.

Skin fibroblasts from normal human subjects were exposed in vitro to long-wave ultraviolet radiation (UVA, 320-400 nm) alone, or in combination with 8-methoxypsoralen (8-MOP). DNA damage was analysed with the alkaline elution technique before and after post-treatment incubation of the cells at 37 degrees C for various times. Cells treated with UVA at 1.1 J/cm/ showed an increased DNA elution rate, which returned to the normal level within 30 min of post-treatment incubation. In cells treated with PUVA (8-MOP at 20 microgram/ml plus UVA at 0.04 J/cm2), the alkaline elution rate was not different from untreated control cells, either before or after post-treatment incubation for time up to 7 days. When the PUVA treatment was followed first by a washing, to remove any unbound 8-MOP, and then by UVA (PUVA + UVA) at 1.1 J/cm2, the alkaline elution rate decreased below the control level. During the post-treatment incubation of the PUVA + UVA-treated cells there was a gradual increase of the alkaline elution rate to a level significantly above that in control cells. This increase was observed after 30 min. It reached a maximum after 24 h and remained after 7 days of post-treatment incubation. Cells from a patient with xeroderma pigmentosum of complementation group A, which were given the same PUVA + UVA treatment, did not show any change in the alkaline elution rate during the post-treatment incubation. If, as seems likely, an increased alkaline elution rate indicates as increase of DNA breaks, and a decreased alkaline elution rate indicates the sealing of breaks and/or the formation of cross-links, and results would suggest the following: (1) UVA irradiation in itself is capable of inducing DNA breaks, which are rapidly sealed during post-treatment incubation; (2) PUVA treatment induces mono-adducts, some of which appear to remain in the DNA for at least 7 days of post-treatment incubation and can be activated to form DNA cross-links by a second dose of UVA; (3) DNA cross-links induced by PUVA + UVA can be recognized by a repair process that involves the formation of DNA breaks. This process is not observed in xeroderma pigmentosum cells of group A.

Cell Line↗
PubMed1982

Sister chromatid exchange in human populations: the effect of smoking, drug treatment, and occupational exposure.

Increased rate of sister chromatid exchange (SCE) in peripheral lymphocytes has been observed in smokers as compared to nonsmokers and in patients receiving certain cytostatic drugs. The increased SCE frequency in smokers was shown to depend on the number of cigarettes smoked per day, as well as on the duration of smoking. DNA cross-links caused by photochemotherapy against psoriasis, 8-methoxypsoralen plus UVA irradiation (PUVA), as well as by the anti-cancer chemotherapeutic agent CCNU, were shown to be more effective at inducing SCE's than other types of DNA damage caused by these treatments. These observations suggest that SCE analysis may be used as an indicator of genotoxic exposure in vivo, provided that the various types of DNA damage caused by genotoxic agents and the dose, as well as the time of exposure in relation to the time of sampling, are considered.

Crossing Over, Genetic↗
PubMed1981

DNA damage in human skin fibroblasts exposed to UVA light used in clinical PUVA treatment.

Human skin fibroblasts were irradiated with a clinically used UVA light source. The doses (1.1 and 3 J/cm2) were similar to those reaching the dermis during clinical PUVA treatment of psoriasis. DNA strand breaks, as determined by alkaline elution, were formed in a dose-dependent way and disappeared within 1 hr of postincubation at 37 degrees C. These findings have clinical implications since UVA-induced DNA damage may be accompanied by mutagenic and tumor promoting effects.

DNA↗
PubMed1981

Genetic aspects of psoriasis: mode of inheritance and action of PUVA on DNA.

The results of some family and experimental studies related to psoriasis are summarized. Complex segregation analysis of Lomholt's classical family material of psoriasis from the Faroe Islands gave clear evidence of a major locus (additive gene with a frequency of 0.07) plus a strong polygenic component (genetic heritability 0.87). An analysis of another family material showed complete linkage between the major locus for psoriasis and the HLA region. Treatment of cells with 8-methoxypsoralene plus a small dose of UVA induces monoadducts, some of which appear to remain in the DNA for at least 7 days of post-treatment incubation. These monoadducts can be activated to form DNA cross-links by a second, larger UVA dose. 8-Methoxypsoralene plus UVA-induced DNA cross-links can be modified by a repair process which involves the formation of DNA breaks. This process in not observed in XPA cells.

DNA↗
PubMed1978

Sister chromatid exchanges in lymphocytes from psoriasis patients treated with 8-methoxypsoralen and longwave ultraviolet light.

The frequency of sister chromatid exchanges (SCE) was analysed in peripheral lymphocytes from patients receiving 8-methoxypsoralen (8-MOP) and longwave ultraviolet light (UVA) against psoriasis. The average SCE frequency in 14 patients after 3-10 weeks of clinical treatment did not differ statistically from that before treatment. UVA irradiation in vitro of blood from patients receiving 8-MOP caused a significant increase in the number of SCE. Such an increase was not observed after systemic administration of 8-MOP excluding UVA irradiation in vitro, nor after UVA irradiation in vitro in the absence of 8-MOP. Thus, the combination of oral 8-MOP administration and subsequent UVA irradiation in vitro promotes SCE in peripheral lymphocytes. However, this effect is not seen after clinical irradiation to the skin in vivo. The reason for this may be that the accumulated dose of UVA light in circulating lymphocytes, even after several weeks of clinical therapy, is not large enough to produce a significant amount of DNA damage leading to SCE, or else that DNA damage caused by the treatment is efficiency repaired during the intervals between treatments.

Adolescent↗
PubMed1977

The binding of 8-methoxypsoralen to nuclear DNA of UVA irradiated human fibroblasts in vitro.

Human fibroblasts were exposed to tritium-labelled 8-methoxypsoralen (8-MOP) and longwave ultraviolet (UVA) light in vitro. The proportions of photochemically bound 8-MOP in the nucleus and cytoplasm were studied by autoradiography. The results show that UVA-irradiation of the cells in the presence of 8-MOP gives rise to a significant dose-dependent binding of 8-MOP in the cell nucleus.

Animals↗
PubMed1975

Treatment of psoriasis with oral psoralens and longwave ultraviolet light. Therapeutic results and cytogenetic hazards.

The purpose of the present investigation was to study the usefulness of oral treatment of psoriasis with psoralens and longwave ultraviolet light and the possible cytogenetic hazards of this therapy. 8-methoxypsoralen (8-MOP) in doses between 15 and 60 mg orally followed 2 hours later by UVA irradiation of one side of the body gave a healing of the irradiated side in 24 of 40 cases and an improvment in another 11 cases while only one case healed on the side of body that was not irradiated. The most common undesired side effect was pruritus on the irradiated side of the body. The cytogenetic study showed that 8-MOP and UVA treatment of lymphocytes in vitro gives rise to chromosomal aberrations. In a combined in vivo-in vitro study where the lymphocytes had been isolated from a patient 2 hours after intake of 60-80 mg 8-MOP and then irradiated with therapeutic UVA doses, a significant increase in chromosomal aberrations was found. When chromosome analyses were made on the patients whilst the 8-MOP treatment was temporarily withdrawn and when the lymphocytes were not irradiated in vitro, no increased frequency of chromosomal abberations was found on comparison with a group of psoriatic patients receiving dithranol therapy.

Administration, Oral↗
PubMedDate not supplied

Progress and regression within primary Sjögren's syndrome.

The purpose of this review is to give a modern view and an update of important areas in primary Sjögren's syndrome (SS), which may be the most common of the autoimmune systemic rheumatic diseases. Interest in aspects of primary SS including clinical manifestations, pathogenesis, aetiology, treatment, prognosis, etc has increased during the past three decades, the volume of scientific papers and the number of theses being the indicators. However, only a fraction of the money that is used for research into rheumatoid arthritis (RA) is used for SS, and the statement that SS is under-diagnosed, under-treated and under-researched will still be valid for several years to come. The topics that are focused on in this review are: (a) clinical areas with subsections on signs and symptoms, terminology, predictors for development of non-Hodgkin malignant lymphoma (NHML) and prognosis, (b) treatment, (c) the Danger model (aetiopathogenesis) and (d) pathology, including immunoglobulin G4 (IgG4)-positive cells.

Antibodies, Monoclonal↗
PubMedDate not supplied

Shuttle vector plasmid propagation in human peripheral blood lymphocytes facilitated by liposome-mediated transfection.

Transfection of human peripheral blood lymphocytes facilitated by a positively charged liposome preparation (Lipofectin, BRL) is 100-fold more efficient than the DEAE dextran technique for the uptake and replication of shuttle vector plasmid DNA. The yield of progeny plasmids obtained from 10 ml of blood was high enough for mutational analysis. A marked increase in the mutation frequency of the shuttle vector marker gene was noted in response to the induction of psoralen adducts in the vector. By using normal human lymphocytes, this method will permit shuttle vector analysis of DNA repair and mutagenesis in a large number of individuals. This method could also prove useful for studies of human lymphotropic viruses.

DNA Repair↗