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

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

Estudio de la operación de las agencias navieras en el Canal de Panamá y su contribución al desarrollo del sector marítimo.

El presente estudio se realizó con el objetivo de analizar la eficiencia operativa de las agencias navieras panameñas, que prestan sus servicios al mercado marítimo mundial. Con ese fin se realizó un estudio descriptivo que permitió conocer la forma como desarrollan estas agencias, sus funciones administrativas y el proceso administrativo en general, así como las características de Su operación para atender la demanda de servicios de tierra de las naves que llegan a Panamá. En la actualidad existen más de 30 agencias navieras que prestan diferentes servicios a las naves, y que entre ellas, generan más de 1500 empleos directos y un número no determinado de plazas indirectas. La actividad de las agencias navieras está regulada por el Código de Comercio, aunque en algunos casos existen normas de uso común que dictan la pauta en las relaciones con los clientes. Igualmente existen actividades que realizan estas empresas y que no están debidamente contempladas por las disposiciones legales panameñas, en cuyo caso es costumbre recurrir al uso supletorio de la legislación sajona como normativa para la regulación de estas actividades. La modernización y la globalización de la economía mundial plantean un importante reto a las agencias navieras panameñas. La competitividad que puedan alcanzar para mantenerse con reales oportunidades en el mercado marítimo depende de la eficiencia operativa que puedan lograr para transferir el efecto de la eficiencia a los precios, sin desmejorar las condiciones de redituabilidad de su funcionamiento. Nuestro informe consta de cuatro (4) capítulos a saber: el capítulo I contiene una breve descripción de la función de fas agencias navieras dentro del Campo Marítimo, en el que se abordan algunos conceptos de la actividad de representación y agenciamiento de naves, algunos datos generales sobre el origen y evolución de las agencias navieras en Panamá, la función que desarrollan en el campo marítimo y las perspectivas de la actividad ante la globalización. En el Capítulo II enumeramos en forma sistemática la importancia de la actividad de agenciamiento de naves en la economía panameña, desde los aspectos de su contribución a la eficiencia operativa del Canal y los puertos internacionales, el impacto directo sobre la economía local y el desarrollo del sector marítimo panameño. En el Capítulo III se presenta un análisis sobre los sistemas operación de las Agencias navieras panameñas y el efecto que tendrá a corto plazo sobre la competitividad de las mismas, ante la internacionalización de las operaciones comerciales y la globalización en general. En el Capitulo IV se detallan las conclusiones de la investigación y recomendaciones del autor. A través de nuestro estudio se ha podido determinar que la eficiencia de las agencias navieras panameñas se basa en la experiencia y pericia con la que se realizan procedimientos de tierra, especialmente los relacionados con las travesías por el Canal de Panamá. Este cúmulo de conocimientos adquiridos en base a muchos años de experiencia, supone una ventaja relativa, sobre cualquier empresa extranjera que desee establecer operaciones en suelo nacional. Sin embargo cabe resaltar que existen algunas áreas dentro de los esquemas de operación de las agencias navieras locales, que no se desarrollan, o que se desarrollan sin el soporte de las nuevas técnicas y mecanismos que utiliza la Administración Moderna para alcanzar los máximos niveles de eficiencia, calidad y competitividad de los servicios que prestan a los usuarios. Las agencias navieras panameñas deberán realizar a corto plazo una evaluación para determinar las necesidades actuales y proyectar las necesidades futuras del mercado marítimo internacional, para desarrollar los esfuerzos necesarios que les permitan satisfacer plenamente esas necesidades. Al hacerlo, estarán garantizando su continuidad, competitividad y rentabilidad en sus operaciones. Esperamos que nuestro aporte contribuya a orientar los esfuerzos de las agencias navieras en la búsqueda de la competitividad necesaria para enfrentar los retos de la globalización

Oestrogen inactivation in the colon: analysis of the expression and regulation of 17 β -hydroxysteroidehydrogenase isozymes in normal colon and colonic cancer

Epidemiological data suggest that oestrogen contributes to the aetiology of colonic cancer. Furthermore, recent studies have suggested that local hormone metabolism may play a key role in determining colonic responsiveness to oestrogen. To further clarify this mechanism we have characterized the expression and regulation of isozymes of 17β-hydroxysteroid dehydrogenase (17β-HSD) in vitro and in situ. Immunohistochemistry was used to confirm expression of the type 2 and 4 isozymes of 17β-HSD (17β-HSD2 and 4) in normal colonic epithelial cells. Parallel studies suggested that both isozymes were abnormally expressed in colonic tumours and this was confirmed by Western blot analyses. Abnormal expression of 17β-HSD2 and 4 proteins was also observed in Caco-2, HT-29 and SW620 colonic cancer cell lines, although the overall pattern of oestrogen metabolism in these cells was similar to that seen in primary colonic mucosal tissue. The predominant activity (conversion of oestradiol to oestrone) was highest in Caco-2>SW620>HT-29, which correlated inversely with the rate of proliferation of the cell lines. Regulatory studies using SW620 cells indicated that the most potent stimulator of oestradiol to oestrone inactivation was the antiproliferative agent 1,25-dihydroxyvitamin D 3(1,25D 3), whilst oestradiol itself inhibited 17β-HSD activity. Both oestradiol and 1,25D 3 decreased mRNA for 17β-HSD2 and 4. Data indicate that the high capacity for inactivation of oestrogens in the colon is associated with the presence of 17β-HSD2 and 4 in epithelial cells. Abnormal expression of both isozymes in colonic cancer cells and the stimulation of oestrogen inactivation by the antiproliferative agent 1,25D 3 highlights a possible role for 17β-HSD isozymes as modulators of colonic cell proliferation. © 2000 Cancer Research Campaig

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

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.

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