Cancer continues to be a focus for action at national, European and international levels.
Explore the source record for details and available documents.
Europe↗
Biomedical subjects
P Webb
Publications and source records attributed to P Webb.
The third action plan of the Europe Against Cancer.
Explore the source record for details and available documents.
Europe↗
Eukaryotic regulatory elements lurking in plasmid DNA: the activator protein-1 site in pUC.
Explore the source record for details and available documents.
Animals↗
Heat storage and body temperature during cooling and rewarming.
During calorimetric experiments with forced cooling and rewarming, changes in rectal temperature (Tre) and mean skin temperature (Tsk) allowed calculations of Burton's (1935) weighting coefficient "a", which relates body temperature change to change in mean body temperature (delta Tb). Calculating delta Tb from change in body heat content (delta Hb), which was determined from direct and indirect calorimetry, included individualized values for body specific heat based on body fat content. In five different cooling procedures there were two with cooling by exposure to cold water and three with cooling in a tubing suit; two of the procedures included mild exercise. The delta Hb ranged from -335 to -1600 kJ; rewarming restored body heat content. The mean (SEM) value of "a" in 119 determinations was 0.75 (0.01). This small variability in the coefficient probably came from the large values of delta Hb and from the use of maximal changes in Tsk and Tre, including afterdrop. Change in Tre by itself correlated with delta Tb, but with much variability. In forced body cooling and rewarming, 0.75 (delta Tre) + 0.25 (delta Tsk) gives an accurate estimate of delta Tb, hence change in body heat storage.
Adult↗
Daily activity and body temperature.
Body temperature varies between 36 and 39 degrees C in states ranging from sleep to high levels of sustained exercise, but it is not known whether this continuum of body temperature is related to a continuum of activity. Calorimetric studies of sedentary days were undertaken with four levels of food intake, men doing mild sustained exercise, and men and women walking and cycling vigorously. Steady states of metabolism were followed by slow exponential changes to steady states of heat loss (sigma Q), followed in turn by changes in rectal temperature (T(re)). Regression analysis showed a continuous, curvilinear relationship between sigma Q and T(re) from the low end of the activity spectrum (50 W) to progressively higher levels of exercise (600 W). These related continua of activity and body temperature appear to be the result of heat regulation.
Adult↗
Positive and negative modulation of Jun action by thyroid hormone receptor at a unique AP1 site.
We have characterized the putative AP1 site in the backbone of pUC plasmids and found unique regulatory effects. The site, which mapped to a 19-bp region around nucleotide 37, conferred transcriptional activation by Jun or Jun/Fos that was boosted up to fivefold by unliganded thyroid hormone receptor (TR). Thyroid hormone changed potentiation of the Jun response by TR into repression. Although the plasmid sequence is a near-perfect consensus AP1 site, the perfect consensus AP1 site from the human collagenase promoter did not show the same effects. Deletion of the ligand binding domain of the TR eliminated the ability of the receptor to boost Jun activity, and deletion, mutation, or changes in specificity of the DNA binding domain eliminated both its ability to potentiate Jun activity and repress with hormone. In vitro Jun/Fos complexes bound the operative plasmid fragment, and the presence of TR interfered very little with Jun/Fos binding activity. Protein interaction studies in the absence of DNA showed that TR bound Jun protein in solution either in the presence or in the absence of hormone. These observations suggest a mechanism for synergy and repression by TR through modulation of Jun activity: positive when TR is unliganded, and negative when hormone is bound. They also suggest that the presence of the plasmid element can confound studies of the regulation of linked promoters.
Animals↗
Metabolic response to graded downhill walking.
Compared with level walking or running, progressive downhill walking or running requires a decreasing energy cost to some minimum where the cost again increases with further decrements in grade. Margaria estimated this minimum occurs at a -9% grade. In this study an attempt was made to more precisely track the energy cost curve in progressive downhill treadmill walking. Ten men, mean age 22.0 +/- 2.5 yr, volunteered as subjects. After VO2max determinations the subjects attended two downhill walking sessions. Each subject performed 14 randomly ordered walking bouts of 6 min in duration, at speeds of 90 and 105 m.min-1. The grades used were 0, -3, -6, -9, -12, -15, and -18%. Gas exchange measurements were obtained by open circuit spirometry during each work bout. Heart rate was monitored continuously and the stride frequency was counted by direct observation during each walking bout. Net VO2 values decreased with decrements in grade to -9, -12% for the respective speeds of 90 and 105 m.min-1. The group mean net VO2 minimums at -9 and -12%, however, were not significantly different (P > 0.05) from the group mean values at -6 and -15% at 90 m.min-1, or between -9 and -15% grades at 105 m.min-1, Group mean net VO2 values at 0, -3, and -18% were significantly different (P < 0.05) from net VO2 values for the other grades at 90 m.min-1 walking. At 105 m.min-1, mean net VO2 values at 0, -3, -6, and -18% were significantly different (P < 0.05) from net VO2 values at the other grades.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
A six-cylinder model of human thermoregulation for general use on personal computers.
The paper describes the basics of a six-cylinder model of human thermoregulation, written in MS-FORTRAN for use on personal computers. The heat balance equations with respect to the radial coordinate, the initial and boundary conditions, and the controller equations are explained. A complete set of parameter values is given. Emphasis is laid on the problems and status of validation. Therefore conditions and methods, on which a standard set of experimental results (dynamics of 29 core, muscle, subcutaneous and skin temperatures) is based, are explained as well as possible deficiencies both of the experimental and the simulation results. It turned out that within the environmental conditions tested (15-45 degrees C), the model, although simplifying the complex geometry of the human body to six cylinders, gives reliable results, both for steady state and dynamics of body temperature topography.
Body Temperature Regulation↗
2-Nitroimidazole dual-function bioreductive drugs: studies on the effects of regioisomerism and side-chain structural modifications on differential cytotoxicity and radiosensitization by aziridinyl and oxiranyl derivatives.
A series of 2-nitroimidazoles bearing side chains terminating in or containing aziridinyl and oxiranyl groups has been prepared, and the compounds were evaluated in vitro as hypoxia-selective bioreductively-activated cytotoxins and selected compounds tested for their radiosensitizing properties toward hypoxic mammalian cells. Compounds were either the regioisomers of analogues of the potent dual-functional 2-nitroimidiazole alpha-[(1-aziridinyl)-methyl]-2-nitro-1H-imidazole-1- ethanol (RSU-1069, 1) with additional methyl groups or related oxiranes of varying side-chain length and type. Oxiranyl derivatives showed little differential toxicity, and those tested were less effective as radiosensitizers, and although these properties were influenced by side-chain length, differences were not great. Aziridinyl compounds related to 1 but with increased side-chain lengths were unstable. Methylation of 1 in various regions had little effect on radiosensitization and no clear advantages over 1 as differential cytotoxic drugs. Progressive methylation at C-3 was found to increase toxicity but decrease hypoxia selectivity. Incorporation of a cyclohexane side chain in 1,2-cis-2,3-trans-3-aziridin-1-yl-2-hydroxy-1-(2-nitroimidazol+ ++-1- yl)cyclohexane (26) abolished hypoxia-selective toxicity and unexpectedly reduced radiosensitizing efficiency. Of the aziridines, 1-(2-nitro-1-imidazolyl)-2-methyl-3-(1-aziridinyl)-2-propanol (20) was comparable in efficacy to 1 as a bioreductively-activated cytotoxin with slightly lower aerobic toxicity; however, the prodrugs of 1 remain as preferred candidates for clinical evaluation.
Antibiotics, Antineoplastic↗
Inhomogeneity correction for in vivo spectroscopy by high-resolution water referencing.
One of the most common sources of distortion in in vivo spectroscopy is the inhomogeneity of the main magnetic field. This effect is particularly problematic when performing spectroscopic imaging, as the shim cannot be simultaneously optimized for all voxels. In this paper we present a technique to measure inhomogeneity rapidly, then show how to use the measurement to improve the analysis of the spectrum. This technique can be applied in conjunction with any spectroscopic localization method and any spectral quantitation algorithm. We present results from spectroscopic imaging of phantoms, then show application to a single-voxel water-suppressed proton brain study. We find that the quantitation of the in vivo spectrum is made immune to inhomogeneous line broadening.
Brain↗
Temperatures of skin, subcutaneous tissue, muscle and core in resting men in cold, comfortable and hot conditions.
To examine the core-shell model of temperature distribution and the possible role of subcutaneous temperature in heat regulation, comprehensive temperature measurements were made on six nude resting men exposed for 2-3 h to comfort (27 degrees C), cold (15 degrees C) and heat (45 degrees C). Cold produced strong shivering and heat caused heavy sweating. Temperatures were recorded every 10 min from: esophagus, rectum and auditory canal; back muscle and thigh muscle at 20 mm and 40 mm depths; 6 subcutaneous sites; and 16 skin sites. Average temperatures at these 29 sites were tabulated at the ends of comfort, hot and cold and the onsets of sweating and shivering. Body temperature changes were slow to develop, the skin temperatures being fastest, and successively deeper tissues progressively slower. There was occasional after-drop and after-rise. The data were consistent with the core-shell concept. The temperature gradient from subcutaneous tissue to skin, which differed substantially with comfort, the onset of shivering and the onset of sweating, could serve as a regulatory signal. The data are now in computer format and may be of interest to biothermal modelers.
Adult↗
The limits of the cellular capacity to mediate an estrogen response.
While steroid response is generally restricted by the availability of steroid receptors, the theoretical limits of the response are not known. We have constructed a series of cell lines that stably express the estrogen receptor (ER) at levels up to 5,000,000 ERs per cell and employed these cells to explore the limits of the estrogen response. Several reporter genes with estrogen response elements upstream of the herpes thymidine kinase promoter showed hyperbolic saturation kinetics with increasing ER. Maximum response was 10 times that seen in cell lines with receptor titers comparable to physiological levels. Half-maximal responses required 500,000 receptors per cell, and cells with 5,000,000 ERs showed greater than 90% maximum induction. Estradiol dose-response studies indicated that the receptors are limiting below 500,000 ERs per cell, but at higher ER titers there are spare receptors. In contrast to most reporters, the widely used reporter pA2-CAT, which has 200 base pairs of Xenopus vitellogenin DNA between the response element and the promoter, showed squelching at ER levels beyond 500,000 per cell. Cell lines that expressed ER above this level activated pA2-CAT with a distorted hormone dependence, where saturating ligand concentrations were inhibitory. All reporters displayed squelching when the ER was provided by transient transfection at a level that we judge is 20,000,000 per cell by extrapolation from the behavior of stable cell lines. These findings suggest that saturation of the cellular capacity to mediate an estrogen response and ER-dependent squelching occur at receptor titers well above those encountered in nature. If current models of steroid hormone action are correct, the findings also imply that estrogen response elements are occupied to very small extents under normal conditions.
Animals↗
Rapid, fully automatic, arbitrary-volume in vivo shimming.
MR spectroscopy and many MR imaging methods benefit from a well-shimmed magnet. We have developed a pulse sequence which enables fast and accurate measurement of three-dimensional field maps in vivo, and a data analysis package that allows calculation of shim currents to optimally shim arbitrary selected volumes. A data link to the shim power supply allows automatic update of currents. No intervention by the operator is required. Typical in vivo shimming time is less than 5 min. Performance analysis, phantom, and in vivo results are presented.
Brain↗
Heat regulation during exercise with controlled cooling.
During heavy sustained exercise, when sweating is usually needed to dissipate the extra metabolic heat, controlled cooling caused heat loss to match total heat production with little sweating. The total heat produced and metabolic rate were varied independently by having subjects walk uphill and down. Heat loss was measured directly with a suit calorimeter; other measurements included metabolic energy from respiratory gas exchange and body temperatures. Thermoregulatory sweating was minimized by adjusting cooling in the calorimeter suit. Heat loss rose to match total heat, not metabolic rate, and there was a slow rise in rectal temperature. In the absence of major thermoregulatory response rectal temperature correlated most closely with total heat; it also correlated with the relative oxygen cost of exercise. Heat flow or heat content appeared to be the controlled variable and body temperature rise a secondary event resulting from thermal transport lag.
Adult↗
Synthesis of a series of nitrothiophenes with basic or electrophilic substituents and evaluation as radiosensitizers and as bioreductively activated cytotoxins.
A series of 2- and 3-nitrothiophene-5-carboxamides bearing N-(omega-aminoalkyl) side chains has been prepared by treatment of the thiophenecarbonyl chloride with the appropriate (protected) omega-aminoalkylamine. Analogous N-(oxiranylmethyl)nitrothiophene-5-carboxamides have been synthesized by epoxidation of the corresponding N-allylamide. Compounds in both classes were evaluated in vitro both as radiosensitizers of hypoxic mammalian cells and as selective bioreductively activated cytotoxins. The most potent radiosensitizers were those agents with strong tertiary amine bases or oxiranes in the side chain. Studies in vivo showed that 2-methyl-N-[2-(dimethyl-amino)ethyl]-3-nitrothiophene-5- carboxamide caused slight radiosensitization of the KHT sarcoma in mice given 0.34 mmol kg-1. However, administration of this and related tertiary amines at higher doses was precluded by systemic toxicity.
Animals↗
Sedentary daily expenditure: a base for estimating individual energy requirements.
As a base for estimating individual energy requirements, we propose using the energy expenditure of a sedentary day with regular meals and sleep at night. Ninety-five 24-h measurements of sedentary daily expenditure (SDE) by direct calorimetry on 37 men and women were analyzed, showing that fat-free mass combined with body mass index correlated highly with SDE (r2 = 0.92) with an SE of 5%. Weight and fat mass were better predictors for women and excellent predictors for men. We found that weight and height accurately predicted fat mass if suitable exponents were used in the expression wt/htx. Testing predictive equations with our own and other sets of data showed good agreement between estimated and observed SDEs. As a base for estimating individual energy requirements. SDE is more precise than basal metabolic rate and it can be predicted with useful accuracy from simple measures of weight and height.
Adipose Tissue↗
The measurement of energy expenditure.
This is a brief account of the development of energy expenditure measurements, from speculations by early philosophers on the nature of the "innate fire," through the beginnings of quantitative animal calorimetry and to the combined material and energy balances of Rubner and of Atwater and Benedict, which established the science of nutritional energy. The equivalence of oxidation rate and heat loss led to the simplification of indirect calorimetry, followed by the era of studies of basal metabolic rate. Current practices are reviewed for measuring energy expenditure by indirect calorimetry (respiration chambers, ventilated hoods, doubly labeled water) and direct calorimetry (rooms, suits). Because problems remain in the exact account of energy balance during weight change, growth, pregnancy and exercise, perhaps it may be time to combine once again carbon balance with energy balance, using modern methods.
Calorimetry, Indirect↗
Should DNR orders be suspended in OR?
Explore the source record for details and available documents.
Humans↗