7,12-Dimethylbenz[a]anthracene-induced bone marrow toxicity is p53-dependent.

Polycyclic aromatic hydrocarbons (PAHs) are known immunotoxins and carcinogens. Our laboratory and others have demonstrated that metabolism of these compounds by CYP1B1 is required for carcinogenicity and immunotoxicity to occur. Previously, our laboratory reported significantly decreased bone marrow cellularity in mice following 7,12-dimethlybenz[a]anthracene (DMBA) administration. In addition, we have observed that DMBA causes apoptosis via activation of both caspase-8 and -9 in pre-B cells co-cultured with bone marrow stromal cells in vitro. In this study, we investigated the importance of the p53 protein in the bone marrow response to DMBA. Through the use of p53 gene knockout mice, we demonstrated that the effect of DMBA on bone marrow cellularity is p53-dependent. In addition, apoptosis of primary cultures of progenitor B cells cultured with bone marrow stromal cells and DMBA is also p53-dependent. The results of this study provide evidence for the importance of p53 in the signaling pathways by which PAHs cause immunotoxicity.     

Long-chain polyunsaturated fatty acid transport across the perfused human placenta

The role of the placenta in controlling the supply of fatty acids to the fetus was investigated in term placentae (n=9) from normal pregnancies. The maternal side was perfused ex vivo for 90 min with a modified Krebs Ringer solution containing a physiological mixture of fatty acids and ratio of fatty acid to human albumin. There was no evidence of chain elongation and desaturation of the essential fatty acids. Relative to the value for oleic acid, the rate of transfer to the fetal circulation was: 1.30±0.02 (P<0.001) for linoleic acid, 1.61 ± 0.09 (P=0.002) for α-linolenic acid, 0.67 ± 0.10 (P=0.033) for arachidonic acid and 2.I0 ± 0.16 (P=0.003) for docosahexaenoic acid. For tissue accumulation the values were 1.47 ± 0.39 (P<0.001) for linoleic acid, 2.24 ± 0.37 (P=0.027) for α-linolenic acid, 9.84 ± 1.03 (P=0.001) for arachidonic acid, and 3.01 ± 0.79 (P=0.064) for docosahexaenoic acid. The order of selectivity for transfer from the maternal to the fetal circulation was docosahexaenoic>α-linolenic>linoleic>oleic>arachidonic acid. Such a mechanism would allow the preferential transfer of docosahexaenoic acid and the essential fatty acids to the fetal circulation, thereby protecting the polyunsaturated fatty acid supply to the fetus during a critical period of development.     

High dose oral tamoxifen and subcutaneous interferon alpha-2a for recurrent glioma

Chemotherapeutic regimens in present use for recurrent glioma have substantial toxicity. Activity against recurrent gliomas has been reported for both tamoxifen and interferon alpha, agents that have more acceptable toxicity profiles and that can be administered in an outpatient setting. We tested the efficacy and toxicity of the combination of high-dose tamoxifen and interferon alpha in adults with recurrent glioma in a phase II trial. Eligible patients had radiographically measurable recurrent gliomas of any grade after initial radiation therapy. Interferon-alpha (6 × 10⁶ U subcutaneously three times per week) and tamoxifen (240 mg/m²/day orally) were administered continuously. Treatment response was assessed at 6 week intervals using clinical and radiographic criteria. Eighteen patients (11 males and 7 females) were enrolled. Median age was 41 years (range 23–61 years). All patients had gliomas that progressed after radiation therapy and nitrosourea chemotherapy. The histologic diagnosis of the original tumor was glioblastoma multiforme in 8 patients, anaplastic astrocytoma in 5 patients, astrocytoma in 4 patients and mixed malignant glioma in 1 patient. Reversible moderate to severe neurological toxicity manifested by dizziness and unsteady gait was seen at tamoxifen doses of 240 mg/m²/day. Although the initial tamoxifen dose was reduced to 120 mg/m²/day, moderate neurotoxicity was noted at this dose as well and the trial was closed early. The combination of oral tamoxifen (120 to 240 mg/m²/day) and subcutaneous interferon-alpha (6 × 10⁶ U three times per week) was associated with significant neurotoxicity in this group of recurrent glioma patients, resulting in early study closure. Of 16 evaluable patients, 12 had progressive disease after one cycle of treatment, 3 had stable disease, and there was one minor response. Gradual dose escalation may be required if similar patients are to be treated with high dose tamoxifen in conjunction with interferon.     

Cd1d-restricted cellular lysis by peripheral blood lymphocytes: relevance to the inflammatory bowel diseases

The CD1d molecule has been implicated to play a role in inflammatory bowel diseases (IBD), possibly through its presentation of an intestinal antigen trigger. To understand the role of the CD1d class I-like protein in IBD, we investigated the molecule's expression in diseased intestinal tissue and determined its potential to undergo specific recognition by intraepithelial and peripheral blood lymphocytes (PBLs) derived from IBD patients. We have observed an increase in precipitable CD1d in inflamed tissues, which suggests CD1d up-regulation in IBD; this was not accompanied by the occurrence of CD1d-specific cytotoxicity by lymphocytes isolated from the same tissue sites. In contrast, we have observed CD1d-specific cytotoxicity by PBLs from both patients and normal controls mediated by a possibly unique type of lymphocytic cell. These observations support a model in which intestinal inflammation may be initiated by circulating PBLs following the tissue-specific upregulation of CD1d. These activated PBLs may then be the source of the extraintestinal manifestations observed with IBD. We therefore propose that the cells responsible for this activity may play a role in regulating immune responses through the specific recognition of CD1d-specific antigen(s).     

Obesity and bullying: different effects for boys and girls.

AIMS: To investigate whether weight category (underweight, average weight, overweight, and obese) at age 7.5 predicts bullying involvement at 8.5 years. Models were tested separately for boys and girls to investigate gender differences in association patterns. METHODS: Prospective cohort study in southwest England. Height and weight were measured in children at age 7.5 (n = 8210). BMI (kg/m2) was used to define underweight, average weight, overweight, and obese children, according to British age and gender specific growth reference data. Overt (n = 7083) and relational (n = 6932) bullying behaviour was assessed in children at age 8.5. RESULTS: After adjustment for parental social class, compared to average weight boys, obese boys were 1.66 (95% CI 1.04 to 2.66) times more likely to be overt bullies and 1.54 (1.12 to 2.13) times more likely to be overt victims. Obese girls were 1.53 (1.09 to 2.15) times more likely to be overt victims compared to average weight girls. CONCLUSIONS: Obesity is predictive of bullying involvement for both boys and girls. Preadolescent obese boys and girls are more likely to be victims of bullying because they deviate from appearance ideals. Other obese boys are likely to be bullies, presumably because of their physical dominance in the peer group.