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

Minimum Cost of Transport in Asian Elephants: Do We Really Need a Bigger Elephant?

Body mass is the primary determinant of an animal’s energy requirements. At their optimum walking speed, large animals have lower mass-specific energy requirements for locomotion than small ones. In animals ranging in size from 0.8 g (roach) to 260 kg (zebu steer), the minimum cost of transport (COTmin) decreases with increasing body size roughly as COTmin∝body mass (Mb)–0.316±0.023 (95% CI). Typically, the variation of COTmin with body mass is weaker at the intraspecific level as a result of physiological and geometric similarity within closely related species. The interspecific relationship estimates that an adult elephant, with twice the body mass of a mid-sized elephant, should be able to move its body approximately 23% cheaper than the smaller elephant. We sought to determine whether adult Asian and sub-adult African elephants follow a single quasi-intraspecific relationship, and extend the interspecific relationship between COTmin and body mass to 12-fold larger animals. Physiological and possibly geometric similarity between adult Asian elephants and sub-adult African elephants caused body mass to have a no effect on COTmin (COTmin∝Mb0.007±0.455). The COTmin in elephants occurred at walking speeds between 1.3 and ∼1.5 m s–1, and at Froude numbers between 0.10 and 0.24. The addition of adult Asian elephants to the interspecific relationship resulted in COTmin∝M –0.277±0.046b. The quasi-intraspecific relationship between body mass and COTmin among elephants caused the interspecific relationship to underestimate COTmin in larger elephants

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-

Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer

Background Selective cyclooxygenase inhibitors may retard the progression of cancer, but they have enhanced thrombotic potential. We report on cardiovascular adverse events in patients receiving rofecoxib to reduce rates of recurrence of colorectal cancer. Methods All serious adverse events that were cardiovascular thrombotic events were reviewed in 2434 patients with stage II or III colorectal cancer participating in a randomized, placebo-controlled trial of rofecoxib, 25 mg daily, started after potentially curative tumor resection and chemotherapy or radiotherapy as indicated. The trial was terminated prematurely owing to worldwide withdrawal of rofecoxib. To examine possible persistent risks, we examined cardiovascular thrombotic events reported up to 24 months after the trial was closed. Results The median duration of active treatment was 7.4 months. The 1167 patients receiving rofecoxib and the 1160 patients receiving placebo were well matched, with a median follow-up period of 33.0 months (interquartile range, 27.6 to 40.1) and 33.4 months (27.7 to 40.4), respectively. Of the 23 confirmed cardiovascular thrombotic events, 16 occurred in the rofecoxib group during or within 14 days after the treatment period, with an estimated relative risk of 2.66 (from the Cox proportional-hazards model; 95% confidence interval [CI], 1.03 to 6.86; P = 0.04). Analysis of the Antiplatelet Trialists’ Collaboration end point (the combined incidence of death from cardiovascular, hemorrhagic, and unknown causes; of nonfatal myocardial infarction; and of nonfatal ischemic and hemorrhagic stroke) gave an unadjusted relative risk of 1.60 (95% CI, 0.57 to 4.51; P = 0.37). Fourteen more cardiovascular thrombotic events, six in the rofecoxib group, were reported within the 2 years after trial closure, with an overall unadjusted relative risk of 1.50 (95% CI, 0.76 to 2.94; P = 0.24). Four patients in the rofecoxib group and two in the placebo group died from thrombotic causes during or within 14 days after the treatment period, and during the follow-up period, one patient in the rofecoxib group and five patients in the placebo group died from cardiovascular causes. Conclusions Rofecoxib therapy was associated with an increased frequency of adverse cardiovascular events among patients with a median study treatment of 7.4 months’ duration. (Current Controlled Trials number, ISRCTN98278138.

Genetics University of Toronto Thrombophilia Study in Women (GUTTSI): genetic and other risk factors for venous thromboembolism in women

BACKGROUND: Women may be at increased risk for venous thromboembolism (VTE) as compared with men. We studied the effects of genetic and biochemical markers of thrombophilia in women, in conjunction with other established risk factors for VTE. METHOD: The present retrospective case-control study was conducted in a thrombosis treatment programme at a large Toronto hospital. The cases were 129 women aged 16-79 years with objectively confirmed VTE. Age-matched control individuals were women who were free of venous thrombosis. Neither cases nor control individuals had known cardiovascular disease. Participants were interviewed regarding personal risk factors for VTE, including smoking, history of malignancy, pregnancy, and oestrogen or oral contraceptive use. Blood specimens were analyzed for common single nucleotide polymorphisms of prothrombin, factor V and methylenetetrahydrofolate reductase (MTHFR; C677T, A1298C and T1317C), and the A66G polymorphism for methionine synthase reductase (MTRR).Fasting plasma homocysteine was also analyzed. RESULTS: Women with VTE were significantly more likely than female control individuals to carry the prothrombin polymorphism and the factor V polymorphism, or to have fasting hyperhomocysteinaemia. Homozygosity for the C677T MTHFR gene was not a significant risk factor for VTE, or were the A1298C or T1317C MTHFR homozygous variants. Also, the A66G MTRR homozygous state did not confer an increased risk for VTE. CONCLUSION: Prothrombin and factor V polymorphisms increased the risk for VTE in women, independent from other established risk factors. Although hyperhomocysteinaemia also heightens this risk, common polymorphisms in two genes that are responsible for homocysteine remethylation do not. These findings are consistent with previous studies that included both men and women

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

Prospective, double-blind, placebo-controlled randomized trial of cimetidine in gastric cancer

Cimetidine is thought to inhibit suppressor T-lymphocyte function and preliminary evidence from a randomized trial indicated that it might prolong survival for patients with operable and inoperable gastric cancer. The British Stomach Cancer Group conducted a randomized, double-blind, placebo-controlled trial examining the effects of cimetidine (400 mg or 800 mg twice a day) on the survival of patients with early (stages I, II and III: n = 229) and advanced (stages IVa and IVb: n = 201) gastric cancer. The primary end point was death. A total of 442 patients were randomized by 59 consultants in 39 hospitals between February 1990 and March 1995. Log-rank survival analysis was used to assess differences between the groups. Three hundred and forty patients died during the study: 166 (49%) in the cimetidine treatment groups and 174 (51%) in the placebo groups. Median survival for patients receiving cimetidine was 13 months (95% confidence interval (CI) 9–16 months) and 11 months in the placebo arm (95% CI 9–14 months). There was no significant difference in survival between the two treatment groups (P = 0.42) or between different doses of cimetidine tablets (P = 0.46). Five-year survival of those patients randomized to cimetidine was 21% compared to 18% for those patients randomized to placebo. Cimetidine at a dose of 400 mg or 800 mg twice a day does not have a significant influence on the survival of patients with gastric cancer compared to placebo. © 1999 Cancer Research Campaig

A model for hysteretic magnetic properties under the application of noncoaxial stress and field

Although descriptions of the effect of stress on spontaneous magnetization within a single domain already exist, there remains no adequate mathematical model for the effects of noncoaxial magnetic field and stress on bulk magnetization in a multidomained specimen. This article addresses the problem and provides a phenomenological theory that applies to the case of bulk isotropic materials. The magnetomechanical hysteresis model of Sablik and Jiles is thus extended to treat magnetic properties in the case of noncoaxial stress and magnetic field in an isotropic, polycrystalline medium. In the modeling, noncollinearity between magnetization and magnetic field is taken into account. The effect of roll‐axis anisotropy is also considered. Both magnetic and magnetostrictive hysteresis are describable by the extended model. Emphasis in this article is on describing properties like coercivity, remanence,hysteresis loss, maximum flux density, and maximum differential permeability as a function of stress for various angular orientations between field and stress axis. The model predictions are compared with experimental results