XRCC1-mediated repair of strand breaks independent of PNKP binding.

Repair of DNA-protein crosslinks and oxidatively damaged DNA base lesions generates intermediates with nicks or gaps with abnormal and blocked 3'-phosphate and 5'-OH ends that prevent the activity of DNA polymerases and ligases. End cleaning in mammalian cells by Tdp1 and PNKP produces the conventional 3'-OH and 5'-phosphate DNA ends suitable for completion of repair. This repair function of PNKP is facilitated by its binding to the scaffold protein XRCC1, and phosphorylation of XRCC1 by CK2 at several consensus sites enables PNKP binding and recruitment to DNA damage.

Coeliac disease: further evidence that biopsy is not always necessary for diagnosis.

Objectives: Growing evidence supports the view that the diagnosis of coeliac disease (CD) can be made by serological tests alone, although this approach is still not widely accepted. We previously showed in retrospective and prospective studies that in adults an IgA-tissue transglutaminase antibody cut-off can be defined above which the positive predictive value for CD is 100%. Following a change in the analytical method for measuring the antibody, our objectives were to re-examine this finding in a larger series of adults to ascertain whether a diagnosis of CD can be reliably made in a proportion of patients without the need for small bowel biopsy and to re-evaluate the diagnostic guidelines used in our centre.

Role of the oxidized form of XRCC1 in protection against extreme oxidative stress.

The multi-domain protein XRCC1 is without catalytic activity, but can interact with a number of known repair proteins. The interaction between the N-terminal domain (NTD) of XRCC1 and DNA polymerase β (pol β) is critical for recruitment of pol β to sites of DNA damage and repair. Crystallographic and NMR approaches have identified oxidized and reduced forms of the XRCC1 NTD, and the corresponding forms of XRCC1 have been identified in cultured mouse fibroblast cells.

Population screening for the common G985 mutation causing medium-chain acyl-CoA dehydrogenase deficiency with Eu-labeled oligonucleotides and the DELFIA system.

We have screened 10171 neonatal blood spots from the Trent and West Midlands regions of the UK for the common G985 mutation to more accurately establish the incidence of medium-chain acyl coenzyme (Co)A dehydrogenase (MCAD) deficiency. We have used a technique involving PCR and Eu-labeled allele-specific oligonucleotides detected by using time-resolved fluorometry on the dissociation-enhanced fluorescence immunoassay (DELFIA) system for the detection of the G985 mutation. We have also evaluated the feasibility of neonatal screening with this technique.

Glucocorticoid resistant asthma: T-lymphocyte steroid metabolism and sensitivity to glucocorticoids and immunosuppressive agents.

We have previously shown that T-lymphocytes from clinically glucocorticoid (GC) resistant asthmatics are more refractory to dexamethasone suppression in vitro than those of GC sensitive asthmatics. We wished to extend these observations to compare three GCs used topically for asthma therapy (budesonide, beclomethasone dipropionate and fluticasone 17 alpha-propionate) and three immunosuppressive drugs (cyclosporin A, FK506 (tacrolimus) and mycophenolate mofetil) with dexamethasone for their antiproliferative effects on T-lymphocytes from GC sensitive and resistant asthmatics, and also to compare the rates of steroid metabolism by T-lymphocytes from these patients. Antiproliferative activity of the drugs was measured on peripheral blood T-lymphocytes activated with phytohaemagglutinin (PHA) and anti-CD3 antibody in vitro.

Excretion and metabolism of tipredane, a novel glucocorticoid, in the rat, mouse, monkey, and human.

The excretion and metabolism of [3H]tipredane, a novel glucocorticoid, has been studied in mice, rats, marmosets, rhesus and cynomolgus monkeys, and humans. After oral administration, [3H]tipredane was rapidly absorbed, metabolized, and excreted into urine and feces. In mice and male rats, radioactivity was excreted primarily into feces or bile, whereas in female rats, monkeys, and humans, excretion was mainly via the renal route.

Bone sarcoma: treatment by irradiation, amputation, or a combination of the two.

A retrospective survey of all cases of osteosarcoma of the femur and tibia treated at the major centres in the United Kingdom during 1952-9 was carried out in an attempt to assess the respective value of treatment by surgery and radiotherapy and the feasibility of a larger prospective study. Of the 192 patients available for the comparison, those treated by radiotherapy alone did least well. A combination of the two treatments-radiotherapy followed by amputation-produced better results, in terms of survival, than amputation alone; however, the comparatively small numbers involved and the inadequacy of information about the factors dictating the choice of treatment make firm conclusions impossible.