Effector mechanisms in allograft rejection. IV. In contrast to late cytotoxic cells, and early killer cells infiltrating mouse sponge matrix allografts are predominantly T lymphocytes.

We have earlier demonstrated that a mixed population of immunologically specific killer cells, including cytotoxic T lymphocytes, non-T (“B”) lymphocytes and monocytes, infiltrate “sponge matrix” allografts at the peak of rejection on Day 8 after transplantation. We have now performed a sequential study covering both early and late stages of the rejection response. We demonstrate that the early infiltrating killer cells are sensitive to anti-Ø and anti-T cell serum plus complement treatment but the late killer cells are not. This finding indicates that the first cytotoxic host cells infiltrating the allograft are predominantly T lymphocytes, whereas as the rejection process proceeds also cytotoxic non-T (“B”) lymphocytes and monocytes are recruited to the site of inflammation.     

Bone Cell-autonomous Contribution of Type 2 Cannabinoid Receptor to Breast Cancer-induced Osteolysis

The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumor growth, bone remodeling, and bone pain. However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here we found that the CB2-selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micromolar concentrations. Under conditions in which these ligands are used at the nanomolar range, HU308 and JWH133 enhanced human and mouse breast cancer cell-induced osteoclastogenesis and exacerbated osteolysis, and these effects were attenuated in cultures obtained from CB2-deficient mice or in the presence of a CB2 receptor blocker. HU308 and JWH133 had no effects on osteoblast growth or differentiation in the presence of conditioned medium from breast cancer cells, but under these circumstances both agents enhanced parathyroid hormone-induced osteoblast differentiation and the ability to support osteoclast formation. Mechanistic studies in osteoclast precursors and osteoblasts showed that JWH133 and HU308 induced PI3K/AKT activity in a CB2-dependent manner, and these effects were enhanced in the presence of osteolytic and osteoblastic factors such as RANKL (receptor activator of NFκB ligand) and parathyroid hormone. When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands depending upon cell type and concentration used. We, therefore, conclude that both CB2-selective activation and antagonism have potential efficacy in cancer-associated bone disease, but further studies are warranted and ongoing.     

Analysis of fidelity mechanisms with eukaryotic DNA replication and repair proteins

We are investigating the mechanisms for producing or avoiding errors during DNA synthesis catalyzed by DNA replication and repair proteins purified from eukaryotic sources. Using assays that monitor the fidelity of a single round of DNA synthesis in vitro, we have defined the error frequency and mutational specificity of the four classes of animal cell DNA polymerases (alpha, beta, delta, gamma), and the fidelity of an SV40 origin-dependent DNA replication complex in extracts of HeLa cells.     

Treatment of burns casualties after fire at Bradford City football ground.

On 11 May 1985 the main stand of Bradford City Football Club caught fire. Within four minutes the stand was alight from end to end. Fifty three people were burnt to death and about 250 injured; 83 required admission to hospital, and 55 of these were treated by primary excision of their burns and skin grafting. In such disasters the help of staff from other hospitals and areas is essential. Patients should be assessed to see whether they have burns that will ultimately be fatal; if they have they should not be sent to regional burns units, where they would take up beds that could be used for patients with treatable burns. All districts should ensure that their plans for accidents in which burns injuries predominate are adequate.     

Correlation of 19F-NMR spectra of halothane in rat tumor and non-tumor tissues with membrane alterations

The membrane environments in normal and tumor rat tissue and the effect of hyperthermia thereon are studied with 19F-NMR spectroscopy of the general anesthetic halothane. Normal and tumor cell types are clearly differentiated by the halothane resonance. A hydrophobic environment prominent in tumor tissue is more sensitive to heat treatment than the corresponding environments of normal cells. Studies of extracted lipids suggest that this may be due in part to the considerable difference in lipid temperature response which exists between normal and kidney tumor cells.     

Thrombolytic Therapy in Haemolytic-Uraemic Syndrome

The treatment of five children with the haemolytic-uraemic syndrome using streptokinase is described to illustrate the difficulties and limitations of thrombolytic therapy in this disease. This experience is germane to the design of multicentre clinical trials.A multivariate analysis relating clinical outcome to the data obtained at the time of admission was also carried out for 31 children with the disease treated in four centres. The results suggest that this technique may help to identify those patients likely to have a fatal outcome. An expanded form of this type of analysis should be incorporated in future clinical trials.