Bloom's syndrome. XIII. DNA-polymerase activity of cultured lymphoblastoid cells.

The biochemical defect in Bloom's syndrome (BS) remains unknown, but two characteristic features of BS cells point to a disturbance of DNA replication, namely, an excessive number of sister-chromatid exchanges (SCEs) in bromodeoxyuridine (BrdU)-substituted cells and an abnormally slow rate of replicon elongation. The hypothesis of an abnormal DNA polymerase as the explanation for these observations was tested using an in situ assay system for DNA polymerase activity and to estimate molecular weights in cellular extracts of cultured BS cells. DNA polymerase subunits in cellular extracts from the BS cells when separated electrophoretically on polyacrylamide gels showed the same mobilities (i.

Lipoxygenase in trout gill tissue acting on arachidonic, eicosapentaenoic and docosahexaenoic acids.

Lipoxygenase activity was characterized in the gill tissue of fresh-water trout. Incubation of arachidonic acid with gill preparations yielded 12-hydroxyeicosatetraenoic acid as the major product, suggesting a 12-lipoxygenase. Eicosapentaenoic acid was similarly converted to the 12-hydroxyeicosapentaenoic acid.

The heat-shock response in vivo: experimental induction during mammalian organogenesis.

According to the embryonic stress hypothesis of teratogenesis, anatomical malformation can be the consequence of the induction of a heat-shock response (HSR) in the embryo at some critical stage during the determination or differentiation of organs. This hypothesis states that a teratogen is any agent that is capable of inducing a HSR and that can reach the developing embryo. As a first step in determining whether the hypothesis is tenable, it was necessary to determine whether the embryo in fact is capable of making the HSR during the period of organogenesis.

Impaired immune function in patients with xeroderma pigmentosum.

The development of contact allergy in sun-exposed skin is markedly impaired in patients with xeroderma pigmentosum as compared to the responses in healthy control subjects. The degree of this immunological impairment is directly related to the severity of the cutaneous disease. These findings raise the possibility that sunlight-induced alterations of immune function may be involved in the marked susceptibility of these patients to the development of nonmelanoma skin cancer.

Evidence for chromosome instability in vivo in Bloom syndrome: increased numbers of micronuclei in exfoliated cells.

The incidence of exfoliated epithelial cells containing micronuclei was determined in two small human populations, one homozygous and the other heterozygous for the Bloom syndrome gene (bl). The objectives of the study were two: to learn whether the chromosome instability featured so prominently by Bloom syndrome (BS) cells proliferating in vitro also occurs in vivo, and as part of a broad survey of various cancer-prone populations, to determine whether estimating micronucleus frequencies in exfoliated cell samples might be useful for identifying individuals with genetically determined chromosome instability. Eight individuals homozygous (bl/bl) for the BS gene, i.

Hybridization with human cells corrects the elevated SCE frequency and BrdU hypersensitivity of hamster cell line EM9.

Cells of the Chinese hamster line EM9 exhibit an elevated SCE frequency and a decreased proliferative response in bromodeoxyuridine (BrdU)-containing medium. Here, these phenotypic features were examined experimentally using polyethylene glycol fusion of EM9 and normal human cells. EM9/human hybrids exhibited both normal SCE frequencies and normal proliferative responses in BrdU-containing medium, suggesting that SCE elevation and BrdU hypersensitivity in EM9 have a common molecular basis.

Werner's syndrome: proliferation in vitro of clones of cells bearing chromosome translocations.

Each of several cultures of Werner's syndrome (WS) fibroblasts and lymphoblasts examined was found to be composed of one or several clones of cells with mutated chromosome complements. Two "sister" fibroblasts cell lines (FCLs) that were derived from a mixture of explants cut from the same WS skin biopsy were found to have completely different rearranged chromosome complements. Daily observation of the skin explants from which these two sister FCLs were derived revealed not only that no more than a few fibroblasts ever migrated from a given explant but also that fibroblasts migrated from only a few of the explants.

Bloom's syndrome XI. Progress report for 1983.

During the 30 years since its description as a clinical entity, Bloom's syndrome has been diagnosed in more than 100 persons. It is believed that most of these have been accessioned to the Bloom's Syndrome Registry, which now includes 103 persons. Of those 103, 80 are alive, with a mean age of 18.

Embryonic stress hypothesis of teratogenesis.

Cells and tissues of essentially all eukaryotes respond uniformly to a variety of stressful situations. Immediately following the onset of several types of environmental insult (e.g.

Bloom's syndrome and EM9 cells in BrdU-containing medium exhibit similarly elevated frequencies of sister chromatid exchange but dissimilar amounts of cellular proliferation and chromosome disruption.

Bloom's syndrome (BS) and EM9 cells both display elevated frequencies of sister chromatid exchange (SCE) following growth for two rounds of DNA replication in bromodeoxyuridine (BrdU)-containing medium. To learn whether hyperresponsiveness to BrdU itself might play a role in causing the SCE elevation, the effects of BrdU on two other parameters, cellular proliferation and chromosome disruption, were examined, comparing the responses of BS and normal lymphoblastoid cells and of EM9 and CHO cells. BS and normal cells responded similarly with respect to growth for 4 days in BrdU-containing medium (0, 1, 3, and 5 micrograms/ml).

Bloom's syndrome: evidence for an increased mutation frequency in vivo.

The incidence of lymphocytes resistant to the purine analog 6-thioguanine was studied in seven patients with Bloom's syndrome. The mean frequency was 17.3 X 10(-4).

Familial predisposition to cancer and age at onset of disease in randomly selected cancer patients.

Incidence of malignancy among close relatives was used to evaluate the relationship of early age at diagnosis and familial cancer predisposition in a general population of cancer patients. The occurrence of cancer and other conditions in families of more than 1,350 randomly selected patients with a wide variety of malignancies was ascertained. Each patient was assigned to one of four study groups based on comparison of his age at diagnosis with the distribution of ages at diagnosis for his cancer site compiled by the Third National Cancer Survey.

Bloom's syndrome cells have an abnormal serum growth response.

Certain growth responses of Bloom's syndrome (BS) dermal fibroblasts have been compared to those of normal human fibroblasts. By applying the principles of Michaelis-Menton kinetics to clonal dose-response data, serum and epidermal growth factor (EGF) requirements of the two cell types were found to be similar. However, the maximal clonal growth rate of BS cells was significantly lower than that of their normal counterparts.

Chronic renal disease, myotonic dystrophy, and gonadoblastoma in XY gonadal dysgenesis.

A patient with XY gonadal dysgenesis and gonadoblastoma showed myotonic dystrophy and chronic renal disease of unknown aetiology. The coexistence of renal disease and XY gonadal dysgenesis in this and two other subjects suggests a presently obscure aetiological relationship between the phenomena.

Xeroderma pigmentosum patients from Egypt: II. Preliminary correlations of epidemiology, clinical symptoms and molecular biology.

Xeroderma pigmentosum (XP) occurs with high frequency in Egypt and a continuation of our field studies has identified representatives of the 3 major complementation groups A, C, and variant. Group A patients, with one exception, showed very early onset of sun sensitivity and development of skin cancers, and microcephaly and mental retardation. The exceptional group A patient was 35 yr old, with normal stature and intelligence who had 2 normal children.

Fetal heart rate patterns in infants in whom necrotizing enterocolitis develops: a preliminary report.

Perinatal changes in fetal heart rate (FHR) were monitored in infants in whom necrotizing enterocolitis (NEC) developed. Eleven of 16 monitoring strips indicated severe FHR changes consistent with perinatal hypoxia, two indicated mild changes, two indicated tachycardia alone, and only one was normal. Severe variable FHR decelerations indicating umbilical cord compression occurred in four cases, persistent late FHR decelerations occurred in two cases, persistent late and severe variable FHR decelerations occurred in two cases, prolonged bradycardia occurred in two cases, and bradycardia with persistent late FHR decelerations occurred in one case.

Technical aspects in the management of the meconium aspiration syndrome with extracorporeal circulation.

Sixteen neonatal patients diagnosed as having the meconium aspiration syndrome were selected for management with extracorporeal circulation with a membrane oxygenator (ECMO) with 8 survivors over 4 yr. All patients weighed greater than 2 kg. Each was placed in the 100% mortality group according to a Neonatal Pulmonary Insufficiency Index (NPII) based on hourly pH and FiO2 determinations.