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Biomedical subjects

V Bohr

Publications and source records attributed to V Bohr.

At least 19 recordsLinked to original sources
PubMed1998

Oxidative DNA damage processing and changes with aging.

Living organisms are constantly exposed to oxidative stress from environmental agents and from endogenous metabolic processes. The resulting oxidative modifications occur in proteins, lipids and DNA. Since proteins and lipids are readily degraded and resynthesized, the most significant consequence of the oxidative stress is thought to be the DNA modifications, which can become permanent via the formation of mutations and other types of genomic instability. Many different DNA base changes have been seen following some form of oxidative stress, and these lesions are widely considered as instigators for the development of cancer and are also implicated in the process of aging. Several studies have documented that oxidative DNA lesions accumulate with aging, and it appears that the major site of this accumulation is mitochondrial DNA rather than nuclear DNA. The DNA repair mechanisms involved in the removal of oxidative DNA lesions are much more complex than previously considered. They involve base excision repair (BER) pathways and nucleotide excision repair (NER) pathways, and there is currently a great deal of interest in clarification of the pathways and their interactions. We have used a number of different approaches to explore the mechanism of the repair processes, and we are able to examine the repair of different types of lesions and to measure different steps of the repair processes. Furthermore, we can measure the DNA damage processing in the nuclear DNA and separately, in the mitochondrial DNA. Contrary to widely held notions, mitochondria have efficient DNA repair of oxidative DNA damage and we are exploring the mechanisms. In a human disorder, Cockayne syndrome (CS), characterized by premature aging, there appear to be deficiencies in the repair of oxidative DNA damage in the nuclear DNA, and this may be the major underlying cause of the disease.

Aging↗
PubMed1993

Cisplatin sensitivity/resistance in UV repair-deficient Chinese hamster ovary cells of complementation groups 1 and 3.

We assessed the possible role of the human repair genes, ERCC1 and ERCC3, in resistance to cisplatin-induced cytotoxicity. The UV repair-deficient Chinese hamster ovary (CHO) 43:3B [designated ERCC1(-)] cell line and its paired subline 83-J5, which is stably transfected with the human DNA excision repair gene ERCC1 [designated ERCC1(+)], were used in this study. UV repair-deficient CHO 27-1 cells [designated ERCC3(-)] and its paired subline designated 'ERCC3(+)', which is stably transfected with the human DNA excision repair gene ERCC3, were also used. In each pair of cell lines, we assessed cisplatin cytotoxicity, cellular drug accumulation and platinum-DNA adduct repair after 1 h drug exposures. Drug accumulation and DNA repair were assessed by atomic absorption spectrometry with Zeeman background correction. ERCC1(+) cells (IC50 = 4.0 microM) were 5-fold more resistant to cisplatin than ERCC1(-) cells (IC50 = 0.75 microM). ERCC1(+) cells repaired 25% of DNA lesions in cellular DNA within a 6 h time period following an IC50 drug exposure and repaired 48% over 24 h. No DNA repair was observed in ERCC1(-) cells during the same time periods. Both cell lines showed similar patterns of drug accumulation. For ERCC3(-) cells (IC50 = 54 microM) and ERCC3(+) cells (IC50 = 49 microM), the profiles of cisplatin sensitivity and cellular drug accumulation were similar. When treated with 50 microM cisplatin, these cells showed similar patterns of drug accumulation, and were equally efficient at forming and repairing lesions in cellular DNA. These data show that in UV repair-deficient CHO cells, ERCC1 confers resistance to cisplatin and confers the ability to remove platinum from cellular DNA. In contrast, ERCC3 does not influence cisplatin drug sensitivity or adduct repair capability. This suggests that ERCC1 may be a determinant of cisplatin resistance, whereas ERCC3 is probably not.

Animals↗
PubMed1986

Comparative effects of growth inhibitors on DNA replication, DNA repair, and protein synthesis in human epidermal keratinocytes.

Cultured human epidermal keratinocytes were used as a model system for testing compounds with potential therapeutic effect against hyperproliferative skin disorders. We have investigated whether each test compound caused direct damage to the DNA or inhibited DNA repair and/or seminconservative replication of DNA, as well as its effect on the overall rate of protein synthesis and on expression of specific keratin genes. The following compounds were studied: (a) inhibitors of DNA polymerase alpha [aphidicolin and its derivative aphidicolin glycine], (b) inhibitors of topoisomerases [novobiocin, nalidixic acid, teniposide, etoposide, and 4'-(9-acridylamine) methanesulfon-m-anisidide], (c) modifiers of chromatin structure [sodium butyrate, 3-aminobenzamide, and nicotinamide], (d) inhibitors of calmodulin activation and protein kinase C [chlorpromazine and trifluoperazine]; and (e) drugs used in clinical dermatology [anthralin, fluocinolone acetonide, ketoconazole, and hydroxyurea]. The compounds were tested at concentrations at which they were known from the literature to be effective in their respective actions. Among the groups of compounds studied, the topoisomerase inhibitors were particularly interesting since they caused no detectable damage to DNA but exhibited maximal inhibitory effect on replication combined with minimal inhibition of DNA repair. In addition most of the topoisomerase inhibitors, particularly novobiocin, changed the pattern of gene expression by inhibiting the synthesis of certain keratins and inducing a Mr 67,000 protein in the prekeratin fraction. These properties combined with minimal systemic side effects may encourage the clinical exploration of some topoisomerase inhibitors for antiproliferative therapy of skin disorders.

Anthralin↗
PubMed1985

DNA repair in lymphocytes from patients with secondary leukemia as measured by strand rejoining and unscheduled DNA synthesis.

The ability to repair damage to DNA was compared in 2 groups of patients having undergone treatment for leukemia, one of which developed secondary leukemia (SL), and the other without signs of secondary malignancy (treated controls). Both were related to normal controls. DNA repair was assessed in isolated peripheral lymphocytes from the patients by measuring the rejoining of strand breaks following alkylation damage to the lymphocytes or by measuring unscheduled DNA synthesis. Day-to-day variability in the assays was considerable, but findings were that 5 out of 7 SL patients had repair deficiencies as measured by their ability to rejoin strand breaks, and 5 out of 7 had increased unscheduled DNA synthesis compared to treated and normal controls. All patients with SL and 4 out of 8 treated controls had inherent strand breaks in their DNA as compared to the normal controls when measured by alkaline elution.

Adult↗
PubMed1985

Pneumococcal meningitis: an evaluation of prognostic factors in 164 cases based on mortality and on a study of lasting sequelae.

During the period 1966-76, 164 patients with pneumococcal meningitis were admitted to the University Hospital, Copenhagen. Of 111 survivors 94 underwent a series of clinical examinations. The findings in each patient were assessed for their aetiological relationship to meningitis. Of these patients 54% had neurological sequelae, 42% had neuropsychological sequelae, 25% had otological sequelae and 16% had sequelae as judged by computer-assisted tomography of the brain. On the basis of the general clinical condition, each patient was evaluated for the presence of sequelae of meningitis by means of a rating of nil, mild, moderate or severe. These ratings and mortality rates were used to evaluate the prognostic significance of various features present during the acute illness. A fatal outcome was significantly associated with increasing age, concomitant pneumonia, altered consciousness on admission, transfer from another hospital and development of complications while in hospital. There was a statistically significant association between lasting sequelae and the female sex, the age group of 16-50 years, patients who had not received any pre-admission antibiotic therapy and those with positive bacterial cultures of specimens from sites other than blood or cerebrospinal fluid.

Adolescent↗
PubMed1984

Psoralen-DNA crosslink repair in human lymphocytes. Comparison of alkaline elution with electron microscopy.

Much interest has surrounded the question of the removal of psoralen interstrand crosslinks in DNA of eukaryotic organisms. A commonly employed method for the study of psoralen repair is alkaline elution. In this study we have used alkaline elution to assess psoralen crosslink repair in human lymphocytes. The lymphocytes were treated with 8-methoxypsoralen or 4,5',8-trimethylpsoralen and allowed to repair for different periods of time. Analysis by alkaline elution showed elution patterns compatible with crosslink removal. When the crosslink removal under comparable conditions was studied by the use of electron microscopy under totally denaturing conditions, no repair of the crosslinks could be detected.

DNA↗
PubMed1984

Pneumococcal meningitis. Late neurologic sequelae and features of prognostic impact.

We interviewed and neurologically reexamined 94 patients who had previous pneumococcal meningitis. The findings were allocated into groups with and without a causal relationship to the meningitis. The main sequelae after meningitis were dizziness (23%), tiredness (22%), mild memory deficits (21%), and gait ataxia (18%), whereas other focal neurologic signs were rare. By a rating (0 to 5) of the presence and severity of sequelae after meningitis, 54% of the patients were found to have sequelae. The clinical condition at the time of acute illness was studied in subgroups of patients who had different neurologic sequelae or high sequelae ratings. Gait ataxia was associated with a state of agitation and confusion when the patient was admitted for meningitis. High sequelae ratings on reexamination were associated with an affected consciousness at the acute stage of the disease and with high numbers of WBCs in the CSF at the time of hospitalization.

Adolescent↗
PubMed1983

Sequelae from bacterial meningitis and their relation to the clinical condition during acute illness, based on 667 questionnaire returns. Part II of a three part series.

During the years 1966-1976, 875 patients with bacterial meningitis were treated at the Department of Infectious Diseases, Rigshospitalet, Denmark. In late 1979 and early 1980 a survey by questionnaire was conducted among survivors concerning the impact of the disease. Replies were received from 667 patients (96.4 per cent). The most common complaints after meningitis were headache (32 per cent) inability to concentrate (31 per cent), altered working capability (33 per cent) and loss of memory (24 per cent). Approximately 20 per cent suffered from impaired hearing, visual disturbances and dizziness. Five per cent had convulsions. Each questionnaire was evaluated for sequelae, and when present these were rated as mild, medium or severe. One-third of the patients had sequelae and in 6 per cent these were severe. Sequelae were most commonly associated with drowsiness, coma, agitation and confusion on admission to hospital.

Adolescent↗
PubMed1983

Eight hundred and seventy-five cases of bacterial meningitis. Part I of a three-part series: clinical data, prognosis, and the role of specialised hospital departments.

Between 1966 and 1976, 875 patients with bacterial meningitis were treated at the Department of Infectious Diseases, Rigshospitalet. Among 495 patients admitted directly to the department, fatality rates were 0.4 per cent for meningococcal infections (including septicaemia), 3.7 per cent for haemophilus meningitis and 8.7 per cent for pneumococcal meningitis. The total fatality rate for directly admitted patients was 3.8 per cent, and 4.0 per cent had sequelae on discharge. Patients transferred from other hospitals often had complications, and their fatality rate (20.1 per cent) was markedly higher than that for directly admitted patients, but not significantly higher than that for patients treated elsewhere in Denmark (17.6 per cent). The low fatality at a specialised unit may reflect an open and swift admission procedure and the preparedness of staff familiar with the management of meningitis. During the first five years after discharge, the relative death risk was increased among meningitis patients but later declined to that found in the general population.

Adolescent↗
PubMed1983

875 cases of bacterial meningitis: diagnostic procedures and the impact of preadmission antibiotic therapy. Part III of a three-part series.

Data on the bacteriological findings, diagnostic measures and clinical course of 875 patients with bacterial meningitis are presented. Findings from the medical records and from a follow-up questionnaire survey of 667 of these cases revealed no significant difference between patients treated with antibiotics before admission (pretreated) and those who were not treated before admission (non-pretreated) with respect to clinical condition on admission, mortality and late sequelae. Pretreatment was, however, associated with a longer duration of symptoms. Apart from cases due to Neisseria meningitidis, there were no significant differences in diagnostic findings between pretreated and non-pretreated cases. In the group of pretreated meningococcal patients, however, positive blood cultures, pleiocytosis in the cerebrospinal fluid (CSF) and positive cultures from sites other than blood and CSF were less frequent than in the non-pretreated cases.

Anti-Bacterial Agents↗
PubMed1979

DNA in psoriatic epidermis.

An electron microscopic technique has been used to visualize crosslinks after total denaturation on DNA isolated from epidermis and dermis in patients with psoriasis treated with 8-methoxypsoralen (8-MOP) and irradiation with ultraviolet light at 360 nm (PUVA treatment). This technique facilitated accurate measurements of the number and density of DNA interstrand crosslinks. 30 biopsies from 14 patients were studied and a total of 9503 DNA molecules were scored in the electron-microscope, 6 patients were treated topically with 8-MOP and 10 were on systemic treatment. Two of the patients on topical treatment had previously been on systemic treatment. 1% of all DNA molecules contained 3 or more cross-links. The overall frequency of cross-links was almost identical in the epidermis (1.1%) and in the dermis (0.9%) and, furthermore, virtually the same in patients on topical and systemic PUVA treatment. The total number of crosslinks was of the same magnitude as that previously found in normal human skin. (V. Bohr et al., Acta Dermatovener, in press.) No significantly increased damage of the genetic material (DNA) was demonstrated in our study as a consequence of the PUVA treatment using 8-MOP. We have previously shown (V. Bohr & A. Lerche, Biochim Biophys Acta, in press) that 8-MOP induced crosslinks after irradiation at 360 nm in an in vitro system of pure DNA. In this system a correlation was established between the density of crosslinks formed and irradiation time, concentration of 8-MOP, and irradiation intensity.

DNA↗
PubMed1979

DNA interstrand crosslinks visualized by electron microscopy in PUVA-treated psoriasis.

An electron microscopic method has been used to visualize crosslinks after total denaturation of DNA isolated from epidermis and dermis in patients with psoriasis treated with 8-methoxypsoralen (8-MOP) and irradiation with ultraviolet light at 360 nm (PUVA treatment). This technique enabled accurate measurement of the number and density of DNA interstrand crosslinks. 30 biopsies were studied and a total of 9503 DNA molecules were scored in the electron microscope. 6 patients were treated topically with 8-MOP and 10 were on systemic treatment and biopsies were obtained immediately after irradiation. 1% of the total DNA molecules examined contained 3 or more crosslinks. The overall frequency of crosslinks was almost identical in the epidermis (1.1%) and in the dermis (0.9%) and, furthermore, virtually the same in patients on topical and systemic PUVA treatment. The total number of crosslinks was of the same magnitude as those previously found by us in normal human skin. Thus, though the formation of interstrand DNA crosslinks can be considered as an indicator of damage of the genetic material, we were unable to demonstrate this as being a consequence of PUVA treatment using 8-MOP.

Adult↗