Induction of DNA adducts and mutations in spleen, liver and lung of XPA- deficient/lacZ transgenic mice after oral treatment with benzo[a]pyrene: correlation with tumour development

We were interested to study the relationship between DNA lesions, DNA repair, mutation fixation, and tumour development. Therefore, mice harbouring lacZ reporter genes and being either wild-type or defective in the DNA excision repair gene XPA, were treated with the genotoxic carcinogen benzo[a]pyrene at an oral dose of 13 mg/kg b.w. (3 times/week). At different time points, i.e. 1, 5, 9 or 13 weeks after start of the oral administration, levels of BPDE-N2-dG adducts (the major formed DNA adduct by benzo[a]pyrene in mice), and lacZ mutation frequencies were measured both in target (spleen) and non-target (lung and liver) tissues. Both in wild-type and XPA-deficient mice, benzo[a]pyrene treatment resulted in increased BPDE-N2-dG adduct levels in all three tissues analysed. In XPA-deficient mice, BPDE-N2-dG adduct levels still increased up to 13 weeks of oral benzo[a]pyrene treatment, whereas in DNA repair proficient mice steady-state levels were reached after 5 weeks of treatment. After 13 weeks, the BPDE-N2-dG adduct levels observed in XPA-/- mice, were 2- to 3-fold higher than the steady state levels observed in XPA+/+ mice in the same tissues. Mutation frequencies in the lacZ reporter gene were the same in wild- type and XPA-deficient mice that were treated with the solvent only. Oral benzo[a]pyrene treatment resulted in an increase in mutation frequency in the lacZ marker gene in all three tissues, but this increase was most profound in the spleen. After 13 weeks of treatment, a 7-fold increase in lacZ mutation frequency was detected in the spleen of wild-type mice as compared to mutation frequencies in control mice. At the same time point, a 15-fold increase in lacZ mutation frequency was observed in the spleen of XPA-deficient mice. The data presented here show, that a defect in NER mainly results in enhanced mutation frequencies in lymphocytic cells after oral treatment with the genotoxic compound benzo[a]pyrene. Interestingly, as we established in a previously performed carcinogenicity assay, the same oral treatment with benzo[a]pyrene induced lymphomas residing in the spleen of XPA- deficient mice.      

Recurrence of unexpected infant death

Families which had experienced two or more unexpected infant deaths were the subject of detailed confidential enquiries, including necropsy examination. Cases were derived from two main sources: first, deaths occurring during a nationwide programme of support for families with a subsequent baby (8 families) plus 2 families from a scries of confidential enquiries in Sheffield, and second, direct referrals from paediatricians (17 families). Fifty-seven deaths were studied. Twenty-four families had experienced 2 and three had experienced 3 deaths: 11 deaths (19%) were found to be adequately explained by history or post-mortem findings; 7 (12%) were probably accidental; 31 (55%) were most probably due to an action by one of the parents (filicide); only 5 (9%) were considered to be true or idiopathic sudden infant death syndrome; in 3 (5%) cases there was insufficient information to draw a conclusion. Five (18%) of the families lived in circumstances of serious social deprivation. A history of psychiatric illness was present in one or both parents in 18 (67%) of the families.     

MR cisternography and myelography with Gd-DTPA in monkeys

To enhance the contrast between cerebrospinal fluid (CSF), brain, spinal cord, and surrounding meninges and bone on magnetic resonance (MR) images, as well as to study CSF flow, gadolinium-DTPA was injected in the subarachnoid space of eight monkeys. Six doses of progressively higher concentrations (from .125 mmol to 250 mmol) were injected every 30-40 minutes. Images of head and spine were obtained at .26 T or .5 T in sagittal and axial planes, using both spin-echo and inversion-recovery sequences in 13 imaging experiments. Marked, consistent changes of signal intensity in the CSF cavities were observed following the injections. These changes were dose related and occurred at different times in the areas close to the injection site versus those distant, a disparity that obviously was related to CSF flow. Gd-DTPA cisternography and myelography may be valuable in MR imaging of central nervous system disease, such as tumors adjacent to the CSF cavities, abnormal CSF collections (e.g., arachnoidal cysts), CSF rhinorrhea and otorrhea, syringohydromyelia, and studies of hydrocephalus and CSF flow dynamics.     

Depressed NK cell activity of peripheral blood mononuclear cells in untreated Hodgkin's disease: Enhancing effect of interferon in vitro

Natural killer (NK) cell activity of unseparated peripheral blood mononuclear cells from 30 untreated patients with Hodgkin's disease and 22 age- and sex-matched normal controls was evaluated using the classical K 562 cells as targets. A significant defect was demonstrated in the patients with stage I-II and seemed to be more profound in patients with advanced disease (stage III-IV) and in those with B symptoms. The differences between subgroups of patients, however, were not statistically significant, mostly because of the wide dispersion of individual data. Pre-incubation of effector cells with alpha A leucocyte recombinant interferon led to a clear increase in NK cell activity in 4 of 6 patients tested, showing that depressed NK activity in Hodgkin's disease is still susceptible to the enhancing effect of interferon, at least in some patients.—