Biomedical subjects
Publications and source records attributed to M Saunders.
The (3)He NMR of (3)He@C(60)H(6), (3)He@C(70)H(2), (3)He@C(70)H(4), (3)He@C(70)H(8), and (3)He@C(70)H(10) have been investigated. A new, unidentified C(60)H(6) isomer has been found by using (3)He NMR. (3)He@C(70)H(10) shows the most downfield-shifted (3)He NMR resonance among the neutral C(70) derivatives.
Fullerene (C60) Diels-Alder adducts with perfluoroalkylated 1,3-cyclopentadiene (1a,b) were synthesized and studied. The perfluoroalkylated cyclopentadiene was found to be less reactive toward C60 than cyclopentadiene itself, possibly because of the electron-withdrawing effect of the side chain. Because of the same effect, the temperature of the retro-Diels-Alder reaction for the fluorinated adducts was lower (70 degrees C) than the reported value (95 degrees C) for the cyclopentadiene adducts of C60. Higher adducts of the fluorous diene and C60 were found to be soluble in perfluorohexane and to show visible partitioning between organic (toluene) and fluorous phases. Also, the Diels-Alder addition of the fluorous diene was accompanied by extensive oxidation of the fullerene core, as revealed by MALDI-TOF data.
Chromogenic assays, immunoblotting, and Northern blot hybridization methods were employed to assess the effects of various agonists on the production of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) by the lymphatic endothelium (LEC). Fibrin autography showed that plasminogen-dependent fibrinolytic activity occurred at M(r) of 110 kDa, which represents a complex of tPA with PAI-1, and 65- and 55-kDa bands corresponding to tPA and uPA, respectively. The fractionation of lymph collected from ovine lymphatic vessels also produced a prominent lytic band of approximately 110 kDa, suggesting the formation of PA/PAI complexes in lymph. The stimulation of various agonists produced large-scale increases in tPA mRNA, as shown by Northern blot hybridization analyses. The effects of ECGF, histamine, and LPS on the presence of tPA and on enhancing the levels of mRNA reached maximum activity at 4 h and declined to levels below that of controls by 8 h. However, phorbol-treated cells exhibited reduced levels of tPA mRNA at 4 h, but was significantly increased by 8 h. A large-scale increase in PAI-1 mRNA steady-state levels was also stimulated by the agonists used in these studies. Both the 3.4- and 2.4-kb species of PAI-1 mRNA were increased. These observations demonstrated that tPA and PAI-1 are produced and secreted by LEC monolayer cultures and are also present in lymph.
Renal cell carcinoma (RCC) is an angiogenic tumor resistant to standard cytotoxic chemotherapeutic agents. Although often responsive to immunomodulatory agents including interleukin 2 and IFN-alpha, the overall results in randomized Phase III studies are disappointing with only modest improvements in overall survival. This Phase II study evaluated the efficacy and tolerability of razoxane, an antiangiogenic topoisomerase II inhibitor, in 40 patients (32 men, 8 women; age: range, 31-76 years; median, 58 years) with inoperable RCC. Twenty patients received razoxane 125 mg p.o., twice a day for 5 days each week for 8 weeks (one cycle). This was repeated in patients with stable disease (StD), but was discontinued after 16 weeks if there was no evidence of an objective response. Because minimal toxicity was seen, subsequent patients (n = 20) were treated until progressive disease (PD) was documented. Of 38 evaluable patients, 11 (29%) had StD for a minimum of 4 months, and the remainder had PD. Median overall survival was 7.3 months. Duration of survival was significantly better in patients with StD compared with those with PD (P = 0.003). The effect of treatment on six potential surrogate serum/plasma (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), urokinase plasminogen activator soluble receptor (uPAsr), E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand's factor (vWF) and two urinary (VEGF and bFGF) markers of angiogenesis was evaluated before and after 1 cycle of treatment. Pretreatment serum VEGF and E-selectin levels above the median value were associated with a poor prognosis. Serum VCAM-1 levels and urinary VEGF levels rose significantly after one cycle in patients with PD but not in those with StD. Serum VEGF, bFGF, VCAM-1 and vWF, plasma uPAsr and urinary bFGF levels were significantly higher in PD patients compared with StD patients before and/or after 1 cycle of treatment. In conclusion, razoxane is an antiangiogenic agent that has minimal toxicity and that requires further evaluation in combination with other active agents in the treatment of RCC. Surrogate serum and urinary markers of angiogenesis may have a role to play in predicting disease response and overall survival in RCC.
The bases of the left and right aortae in snakes are joined by the interaortic foramen. Previous anatomical and physiological studies have raised the possibility of blood flow through this foramen playing an important role in the redistribution of blood throughout the body, particularly during periods of hemostatic stress. Echocardiography was employed to view the heart of unanesthetized specimens of the eastern diamondback rattlesnake, Crotalus adamanteus. The echocardiographic images, and particularly the color Doppler imaging, revealed that the patency of the interaortic foramen changes during the cardiac cycle, and that blood regularly flowed through the interaortic foramen between the two aortae. J. Exp. Zool. 284:742-745, 1999. Copyright 1999 Wiley-Liss, Inc.
The zone-axis CBED pattern-matching technique ZAPMATCH [Bird & Saunders (1992). Ultramicroscopy, 45, 241-251] has been applied to low-order structure-factor measurements in nickel and copper. Considerable disagreement exists between previously published results obtained with a variety of solid-state theories and experimental techniques. The nickel ZAPMATCH results confirm previous electron-diffraction critical-voltage measurements and are in excellent agreement with FLAPW (full-potential linearized augmented plane-wave) theory calculations. This is further proof of the accuracy achievable with ZAPMATCH analysis. For copper, however, while the results support the findings of previous experimental measurements, they are consistently higher than those given by a range of solid-state theories, perhaps demonstrating some limitation in the existing theory. Two extensions to the ZAPMATCH technique are also considered. First, rules are developed to determine the number of structure factors that can be refined accurately from a given CBED pattern. Second, the imaginary potential generally introduced to account for the effects of thermal diffuse scattering (TDS) is also refined. It is shown that, while the widely used Einstein model is a useful approximation, the refined values are consistently higher than the model predicts. In addition, the importance of a second-order (real) TDS correction arising from the Einstein model is investigated. Although its effects are limited in this instance, it may prove to be more significant at lower beam energies or for materials of higher atomic number.
Quantitative CBED techniques, such as the ZAPMATCH zone-axis pattern-matching method [Bird & Saunders (1992). Ultramicroscopy, 45, 241-251], have been applied with great success to the accurate refinement of low-order structure factors. The major limitation on the accuracy of the structure-factor measurements is uncertainty in the Debye-Waller factors describing the temperature-dependent atomic vibrations. While X-ray and neutron diffraction tech-niques are both capable of accurate measurements of Debye-Waller factors, the frequent use of liquid-nitrogen-cooled samples in CBED experiments means that previous measurements are rarely available at the temperatures required. This has prompted attempts to determine Debye-Waller factors from electron diffraction data obtained under experimental conditions that match those used for the quantitative CBED work. In this paper, the possibility of extracting accurate Debye-Waller factors from the low-order reflections of a zone-axis CBED pattern is investigated. In this way, the Debye-Waller factors and structure factors could be obtained from the same data set. With this new approach, it is shown that errors lower than +/-0.02 Å(2) can be obtained for the measurement of Debye-Waller factors from room- and liquid-nitrogen-temperature nickel and copper <110> zone-axis data. The results obtained are compared with previous measurements and theoretical predictions.
BACKGROUND AND PURPOSE: An analysis of the 366 patients treated with conventional radiotherapy in the CHART randomized trial was performed to determine whether prolongation of treatment time had any influence on tumour control or survival and to assess if this could have influenced the results of the randomized comparison of CHART against conventional radiotherapy. METHOD: After a preliminary analysis the cases were divided into two groups according to duration of treatment. RESULTS: Survival and primary tumour control showed small margins of deterioration when the 232 patients who had been treated up to 48 days were compared with 127 patients who had been treated in 49 or more days. These differences were not large with an estimated difference in 2-year survival of 8% and not conventionally statistically significant (P=0.25); furthermore, the survival difference was considerably reduced when the prognostic factors were taken into consideration in a Cox model. CONCLUSION: With a mean difference in treatment duration of 5.8 days, the marginal differences observed between patients treated for longer and shorter times are compatible with that which has been suggested in previous publications for the prolongation of treatment time in head and neck cancer. We conclude that the randomized comparison of CHART with conventional radiotherapy is unlikely to be affected by conventionally treated patients who took longer than 48 days to complete their treatment.
PURPOSE: The aim of this study was to assess the potential of pre-treatment cell kinetic parameters to predict outcome in head and neck cancer patients treated by conventional radiotherapy. MATERIALS AND METHODS: Data from 11 different centers were pooled. Inclusion criteria were such that the patients received radiotherapy alone, and that the radiotherapy was given in an overall time of at least 6 weeks with a dose of at least 60 Gy. All patients received a tracer dose of either iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) intravenously prior to treatment and a tumor biopsy was taken several hours later. The cell kinetic parameters labeling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were subsequently calculated from flow cytometry data, obtained on the biopsies using antibodies against I/BrdUrd incorporated into DNA. Each center carried out their own flow cytometry analysis. RESULTS: From the 11 centers, a total of 476 patients conforming to the inclusion criteria were analyzed. Median values for overall time and total dose were 49 days and 69 Gy, respectively. Fifty one percent of patients had local recurrences and 53% patients had died, the majority from their disease. Median follow-up was 20 months; being 30 months for surviving patients. Multivariate analysis revealed that T-stage, maximum tumor diameter, differentiation grade, N-stage, tumor localization and overall time correlated with locoregional control, in decreasing order of significance. For the cell kinetic parameters, univariate analysis showed that only LI was significantly associated with local control (P=0.02), with higher values correlating with a worse outcome. Ts showed some evidence that patients with longer values did worse, but this was not significant (P=0.06). Tpot showed no trend (P=0.8). When assessing survival in a univariate analysis, neither LI nor Tpot associated with outcome (P=0.4, 0.4, respectively). Surprisingly, Ts did correlate with survival, with longer values being worse (P=0.02). In the multivariate analysis of local control, LI lost its significance (P=0.16). CONCLUSIONS: The only pretreatment kinetic parameter for which some evidence was found for an association with local control (the best end-point for testing the present hypothesis) was LI, not Tpot, and this evidence disappeared in a multivariate analysis. It therefore appears that pretreatment cell kinetic measurements carried out using flow cytometry, only provide a relatively weak predictor of outcome after radiotherapy in head and neck cancer.
Overall time is important in the curative treatment of head and neck cancer (Dische, S., Saunders, M.I., Barrett, A., Harvey, A., Gibson, D., Parmar, M., 1997, Radiother. Oncol., 44:123-136). Results are presented on outcome and morbidity in ten patients with head and neck cancer treated with external beam irradiation (CHART protocol) and interstitial implantation, completing treatment in 12 days. Local control and overall survival at 5 years was 67%. Acute and late morbidity was acceptable giving scope for dose escalation.
BACKGROUND AND METHOD: A randomised controlled trial in locally advanced non-small cell lung cancer (NSCLC), compared CHART which employs 36 fractions of 1.5 Gy 3 times per day to give 54 Gy in 12 consecutive days with conventional radiotherapy-30 fractions of 2 Gy to a total dose of 60 Gy in 6 weeks. A total of 563 patients were entered between April 1990 and April 1995. This report is based upon the data updated to 1 April 1998. RESULTS: The analysis of the mature data shows that the benefits previously reported have been maintained. Overall there was a 22% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2 year survival of 9% from 20 to 29% (P = 0.008) and a 21% reduction in the relative risk of local progression (P = 0.033). In the large subgroup of patients with squamous cell cancer which accounted for 81% of the cases, there was a 30% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2 year survival of 13% from 20 to 33% (P = 0.0007) and a 27% reduction in the relative risk of local progression (P = 0.012). Furthermore, in squamous carcinoma there was a 25% reduction in the relative risk of local and/or distant progression (P = 0.025) and 24% reduction in the relative risk of metastasis (P = 0.043). There was no evidence that CHART gave more or less benefit in any other subgroup. CONCLUSION: This analysis of mature data confirms that CHART is superior to conventional radiotherapy in achieving local tumour control and survival in locally advanced NSCLC. This demonstrates the importance of cellular repopulation as a cause of failure in the radiotherapy of NSCLC. The reduction in the risk of metastasis confirms that improved local tumour control, even in lung cancer, can reduce the incidence of metastasis. This trial shows that control of local tumour can lead to an improvement in long term survival.
Bootstrap resampling provides a versatile and reliable statistical method for estimating the accuracy of quantities which are calculated from experimental data. It is an empirically based method, in which large numbers of simulated datasets are generated by computer from existing measurements, so that approximate confidence intervals of the derived quantities may be obtained by direct numerical evaluation. A simple introduction to the method is given via a detailed example of estimating 95% confidence intervals for cumulated activity in the thyroid following injection of 99mTc-sodium pertechnetate using activity-time data from 23 subjects. The application of the approach to estimating confidence limits for the self-dose to the kidney following injection of 99mTc-DTPA organ imaging agent based on uptake data from 19 subjects is also illustrated. Results are then given for estimates of doses to the foetus following administration of 99mTc-sodium pertechnetate for clinical reasons during pregnancy, averaged over 25 subjects. The bootstrap method is well suited for applications in radiation dosimetry including uncertainty, reliability and sensitivity analysis of dose coefficients in biokinetic models, but it can also be applied in a wide range of other biomedical situations.
A postal survey was conducted looking at the roles and experiences of General Practitioners on part-time contracts. This involved their perception of the attitudes of their colleagues and patients to their part-time status, and the consequences of these for their professional development. Of the 130 General Practitioners with part-time contracts in the one Regional Health Authority that was being surveyed 77.7% responded; 74.3% of the respondents were women. Of the women General Practitioners who responded to this particular question, the predominant age-bands were 31-40 years [41.4% (41)] and 41-50 [19.2% (19)], whilst male General Practitioners were more evenly spread across the age bands. The results showed that the majority of General Practitioners took up part-time contracts to enable them to look after their dependants, though a sizeable minority wished for free time or to relieve stress from a full-time contract. Forty percent said that they felt excluded from decision making about continuity of patient care and practice policy. Just under forty percent also stated that their workload was excessive in comparison with their full-time counterparts. Further, many expressed the opinion that they were financially penalised. The cost effective correlation between the increased availability of General Practitioners (particularly women) for patient care, and the costly medical education and training of such General Practitioners not being 'wasted' for several years was also noted together for the need for ongoing (or continual) medical education and training. The findings of this survey suggest there are many unresolved issues involved in satisfactory part-time contracting arrangements for General Practitioners. This particularly affects women General Practitioners. Whilst the RCP policy statement addresses education and training for general practice, the question of not losing out in relation to training opportunities and promotion is not addressed. The unresolved effects of the intra-professional differences in opportunities may affect the inter-professional functioning of the primary health care team and ultimately continuity and quality of care for patients.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
1. It is now accepted that uncontrolled proliferation of human airway smooth muscle (HASM) cells contributes, in many cases, to the chronic stages of asthma. However, the physiological and pathophysiological processes regulating cell growth and division in the airway are not clear. We have recently shown that the immediate early gene, cyclo-oxygenase-2, is induced by cytokines in HASM cells. Since cyclo-oxygenase metabolites, such as prostaglandin (PG) E2 have been shown to modulate HASM cell growth, we have investigated any autocrine action of endogenously released cyclo-oxygenase-1/2 products on the proliferative responses in these cells. 2. HASM cells were cultured from healthy tissue obtained at lung or heart/lung transplantation. HASM cell proliferation was measured by [3H]-methyl thymidine uptake by cells and by cell counts. Cyclo-oxygenase-2 expression was measured by Western blot analysis and activity measured by the release of PGE2, by radioimmunoasay. 3. HASM cells proliferated in response to foetal calf serum, a response that was greatly inhibited when cyclo-oxygenase-2 was induced with either interleukin-1beta plus tumour necrosis factor-alpha or interleukin-1beta, tumour necrosis factor alpha plus interferon gamma (each at 10 ng ml(-1)). The inhibitory effect of cytokines on HASM cell proliferation was reversed in a concentration dependent manner by either the mixed cyclo-oxygenase-1/-2 inhibitor, indomethacin or the selective cyclo-oxygenase-2 inhibitor, L-745,337 (each at 10 microM). 4. PGE2 or the stable analogue of prostacyclin, cicaprost concentration-dependently (0.1 pmol to 1 microM) inhibited serum induced proliferation of HASM cells. By contrast, the TP receptor agonist, U46619 stimulated proliferation of HASM cells when cells were cultured without but not with serum. Other cyclo-oxygenase products, PGD2, PGF2alpha had no effect on cellular proliferation at concentrations up to 1 microM. 5. These observations illustrate a profound inhibitory effect of cyclo-oxygenase-2 induction on HASM cell proliferation, possibly via IP or EP receptor activation. Cyclo-oxygenase-2 induction has, thus far, been associated with the pro-inflammatory responses of plasma exudation and oedema formation and is assumed to be an enzyme worthy of selective inhibition in many disease states. However, our observations suggest that cyclo-oxygenase-2 can have an anti-inflammatory, anti-proliferative function in the airways. These observations may have importance in the use and development of therapies for airway disease such as asthma.
Interleukin (IL)-8 is a C-X-C chemokine that potently chemoattracts and activates neutrophils. We determined whether IL-8 could be produced by human airway smooth muscle cells in culture and examined its regulation. TNF-alpha stimulated IL-8 mRNA expression and protein release in a time- and dose-dependent manner, whereas IFN-gamma alone had no effect. Both cytokines together did not induce greater IL-8 release compared to TNF-alpha alone. IL-1beta was more potent in inducing IL-8 release and, together with TNF-alpha, there was a synergistic augmentation of IL-8 release. IL-8 release induced by TNF-alpha and IFN-gamma was partly inhibited by the Th-2-derived cytokines IL-4, IL-10, and IL-13, as well as by dexamethasone. In addition to its contractile responses, airway smooth muscle cells have synthetic and secretory potential with the release of IL-8 and subsequent recruitment and activation of neutrophils in the airways. Release of IL-8 can be modulated by Th-2-derived cytokines and corticosteroids.