Feasibility of recruitment to an oral dysplasia trial in the United Kingdom

Background: Oral epithelial dysplasia (OED) has a malignant potential. Therapeutic options for OED remain both limited and without good evidence. Despite surgery being the most common method of treating OED, recurrence and potentially significant morbidity remain problematic. Consequently, there has been much interest in non-surgical treatments for OED. Cyclo-oxygenase (COX) up-regulation is known to occur in the dysplasia-carcinoma sequence and evidence now exists that COX-2 is a prognostic marker of malignant transformation in OED. COX-inhibitors are therefore considered a potential therapeutic strategy for treating this condition. We aimed to provide both proof of principal evidence supporting the effect of topical COX inhibition, and determine the feasibility of recruitment to an OED chemoprevention trial in the UK. Methods: Recruitment of 40 patients with oral leukoplakia to 4 study arms was planned. The total daily dose of Aspirin would increase in each group and be used in the period between initial diagnostic and follow-up biopsies. Results: During the 15-month recruitment period, 15/50 screened patients were eligible for recruitment, and 13 (87%) consented. Only 1 had OED diagnosed on biopsy. 16 patients were intolerant of, or already taking Aspirin and 16 patients required no biopsy. Initial recruitment was slow, as detection relied on clinicians identifying potentially eligible patients. Pre-screening new patient letters and directly contacting patients listed for biopsies improved screening of potentially eligible patients. However, as the incidence of OED was so low, it had little impact on trial recruitment. The trial was terminated, as recruitment was unlikely to be achieved in a single centre. Conclusion: This feasibility trial has demonstrated the low incidence of OED in the UK and the difficulties in conducting a study because of this. With an incidence of around 1.5/100,000/year and a high proportion of those patients already taking or intolerant of Aspirin, a large multi-centred trial would be required to fulfil the recruitment for this study. The ability of topical non-steroidal anti-inflammatory drugs to modify COX and prostaglandin expression remains an important but unanswered question. Collaboration with centres in other parts of the world with higher incidences of the disease may be required to ensure adequate recruitment. ISRCTN: 31503555

Inhibition of protein kinase C (PKC) induces apoptosis in COLO 205 human colon carcinoma cells

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Mortality study of 18 000 patients treated with omeprazole.

Background: The long term safety of potent gastric acid suppressive therapy has yet to be established. Method: General practice record review at a median interval of 26 months followed by retrieval of details of all deaths within four years using the UK National Health Service Central Registers in 17 936 patients prescribed omeprazole in 1993–1995. Death rates were compared with general population rates. Results: Records of 17 489 patients (97.5%) were examined. A total of 12 703 patients received further scripts for antisecretory drugs, 8097 for omeprazole only (65.6%): 3097 patients have died. All cause mortality was higher in the first year (observed/expected (O/E) 1.44 (95% confidence intervals (CI) 1.34–1.55); p<0.0001) but had fallen to population expectation by the fourth year. There were significant mortality increases in the first year, falling to or below population expectation by the fourth year, for deaths ascribed to neoplasms (1.82 (95% CI 1.58–2.08); p<0.0001), circulatory diseases (1.27 (95% CI 1.13–1.43); p<0.0001), and respiratory diseases (1.37 (95% CI 1.12–1.64); p<0.001). Increased mortality ascribed to digestive diseases (2.56 (95% CI 1.87–3.43); p<0.0001) persisted, although reduced. Increased mortality rates for cancers of the stomach (4.06 (95% CI 2.60–6.04); p<0.0001), colon and rectum (1.40 (95% CI 0.84–2.18); p=0.075), and trachea, bronchus, and lung (1.64 (95% CI 1.19–2.19); p<0.01) seen in the first year had disappeared by the fourth year but that for cancer of the oesophagus had not (O/E 7.35 (95% CI 5.20–10.09) (p<0.0001) in year 1; 2.88 (95% CI 1.62–4.79) (p<0.001) in year 4). Forty of 78 patients dying of oesophageal cancer had the disease present at registration. Twenty seven of those remaining cases had clinical evidence of Barrett’s disease, stricture, ulcer, or oesophagitis at registration (O/E 3.30 (95% CI 2.17–4.80)). Six deaths occurred in patients with hiatal hernia or reflux only (O/E 1.02 (95% CI 0.37–2.22)) and five in patients without oesophageal disease (O/E 0.77 (95% CI 0.25–1.80)). No relationships were detected with numbers of omeprazole scripts received. Conclusions: Increases in mortality associated with treatment are due to pre- existing illness, including pre-existing severe oesophageal disease. There was no evidence of an increased risk of oesophageal adenocarcinoma in those without oesophageal mucosal damage recorded at registration

Towards a Nonperturbative Path Integral in Gauge Theories

We propose a modification of the Faddeev-Popov procedure to construct a path integral representation for the transition amplitude and the partition function for gauge theories whose orbit space has a non-Euclidean geometry. Our approach is based on the Kato-Trotter product formula modified appropriately to incorporate the gauge invariance condition, and thereby equivalence to the Dirac operator formalism is guaranteed by construction. The modified path integral provides a solution to the Gribov obstruction as well as to the operator ordering problem when the orbit space has curvature. A few explicit examples are given to illustrate new features of the formalism developed. The method is applied to the Kogut-Susskind lattice gauge theory to develop a nonperturbative functional integral for a quantum Yang-Mills theory. Feynman's conjecture about a relation between the mass gap and the orbit space geometry in gluodynamics is discussed in the framework of the modified path integral.Comment: plain Latex, 12 pages, a few changes made and some comments added, a final version to appear in Phys. Lett.

A titanium-nitride near-infrared kinetic inductance photon-counting detector and its anomalous electrodynamics

We demonstrate single-photon counting at 1550 nm with titanium-nitride (TiN) microwave kinetic inductance detectors. Energy resolution of 0.4 eV and arrival-time resolution of 1.2 microseconds are achieved. 0-, 1-, 2-photon events are resolved and shown to follow Poisson statistics. We find that the temperature-dependent frequency shift deviates from the Mattis-Bardeen theory, and the dissipation response shows a shorter decay time than the frequency response at low temperatures. We suggest that the observed anomalous electrodynamics may be related to quasiparticle traps or subgap states in the disordered TiN films. Finally, the electron density-of-states is derived from the pulse response.Comment: 4 pages, 3 figure

Quantum Hamiltonian Reduction of the Schwinger Model

We reexamine a unitary-transformation method of extracting a physical Hamiltonian from a gauge field theory after quantizing all degrees of freedom including redundant variables. We show that this {\it quantum Hamiltonian reduction} method suffers from crucial modifications arising from regularization of composite operators. We assess the effects of regularization in the simplest gauge field theory, the Schwinger model. Without regularization, the quantum reduction yields the identical Hamiltonian with the classically reduced one. On the other hand, with regularization incorporated, the resulting Hamiltonian of the quantum reduction disagrees with that of the classical reduction. However, we find that the discrepancy is resolved by redefinitions of fermion currents and that the results are again consistent with those of the classical reduction.Comment: 23 pages, LaTeX file, UT-Komaba 94-

Chromoelectric Knot in QCD

We argue that the Skyrme theory describes the chromomagnetic (not chromoelectric) dynamics of QCD. This shows that the Skyrme theory could more properly be interpreted as an effective theory which is dual to QCD, rather than an effective theory of QCD itself. This leads us to predict the existence of a new type of topological knot, a twisted chromoelectric flux ring, in QCD which is dual to the chromomagnetic Faddeev-Niemi knot in Skyrme theory. We estimate the mass and the decay width of the lightest chromoelectric knot to be around $50 GeV$ and $117 MeV$.Comment: 4 page