Positive Energy Functional for Massless Scalars in Rotating Black Hole Backgrounds of Maximal Ungauged Supergravity.

We outline a proof of the stability of a massless neutral scalar field ψ in the background of a wide class of four dimensional asymptotically flat rotating and "electrically charged" solutions of supergravity, and the low energy limit of string theory, known as STU metrics. Despite their complexity, we find it possible to circumvent the difficulties presented by the existence of ergo regions and the related phenomenon of superradiance in the original metrics by following a strategy due to Whiting, and passing to an auxiliary metric admitting an everywhere lightlike Killing field and constructing a scalar field ψ (related to a possible unstable mode ψ by a nonlocal transformation) which satisfies the massless wave equation with respect to the auxiliary metric. By contrast with the case for ψ, the associated energy density of ψ is not only conserved but is also non-negative.

Assessment of technical and biological parameters of volumetric quantitative computed tomography of the foot: a phantom study.

SUMMARY: Few studies exist for bone densitometry of the whole foot. A phantom study demonstrated the sources of error and necessary controls for accurate quantitative computed tomography of the foot. A loss in bone mineral density (BMD) in the small foot bones may be an early indicator of diabetic foot complications. INTRODUCTION: Volumetric quantitative computed tomography (vQCT) facilitates the assessment of pedal bone osteopenia, which, in the presence of peripheral neuropathy, may well be an early sign of diabetic foot deformity. To date, sources and magnitudes of error in foot vQCT measurements have not been reported. METHODS: Foot phantoms were scanned using a 64-slice CT scanner. Energy (in kilovoltage peak), table height, phantom size and orientation, location of "bone" inserts, insert material, location of calibration phantom, and reconstruction kernel were systematically varied during scan acquisition. RESULTS: Energy (in kilovoltage peak) and distance from the isocenter (table height) resulted in relative attenuation changes from -5% to 22% and -5% to 0%, respectively, and average BMD changes from -0.9% to 0.0% and -1.1% to 0.3%, respectively, compared to a baseline 120-kVp scan performed at the isocenter. BMD compared to manufacturer-specified values ranged, on average, from -2.2% to 0.9%. Phantom size and location of bone-equivalent material inserts resulted in relative attenuation changes of -1.2% to 1.4% compared to the medium-sized phantom. CONCLUSION: This study demonstrated that variations in kilovoltage peak and table height can be controlled using a calibration phantom scanned at the same energy and height as a foot phantom; however, error due to soft tissue thickness and location of bones within a foot cannot be controlled using a calibration phantom alone.

Near-field radiative heat transfer between macroscopic planar surfaces.

Near-field radiation allows heat to propagate across a small vacuum gap at rates several orders of magnitude above that of far-field, blackbody radiation. Although heat transfer via near-field effects has been discussed for many years, experimental verification of this theory has been very limited. We have measured the heat transfer between two macroscopic sapphire plates, finding an increase in agreement with expectations from theory. These experiments, conducted near 300 K, have measured the heat transfer as a function of separation over mm to µm and as a function of temperature differences between 2.5 and 30 K. The experiments demonstrate that evanescence can be put to work to transfer heat from an object without actually touching it.

Population pharmacokinetic analysis of bisoprolol.

The technique of population pharmacokinetic analysis was employed to study the variability in the dose concentration relationship of bisoprolol during its clinical development. The influence of demographic factors on the variability of clearance was investigated in 3 different populations: group I, patients (including an elderly group) with essential hypertension receiving multiple oral doses of bisoprolol 10 or 20mg for 3 months; group II, patients with different degrees of renal impairment and healthy controls; and group III, patients with different types of hepatic impairment and healthy controls. Patients and controls in groups II and III received only a single oral dose of bisoprolol 10mg. The 3 data sets were analysed separately, using a non-linear mixed effects model (the NONMEM program). A 2-compartment pharmacokinetic model with first-order absorption described the data adequately. The typical values of volume of central compartment, volume of distribution at steady-state and the absorption rate constant for the 3 populations were: for group I, 68L, 235L, and 0.7h-1; for group II, 28L, 179L, and 0.3h-1; and for group III, 55L, 256L, and 0.4h-1, respectively. Plasma clearance was related to age in group I, to serum creatinine in group II and to aspartate transaminase activity in group III. The 68% confidence limits for clearance and elimination half-life were 8.2 to 21.5 L/h and 7.6 to 19.7h, respectively, for 50-year-old patients in group I. The analysis predicted that progressive increases in serum creatinine or aspartate transaminase activity will result in only a 50% reduction of clearance.

Bayesian parameter estimation and population pharmacokinetics.

The widespread application of Bayesian parameter estimation in the area of therapeutic drug monitoring (TDM) has prompted the need for well conducted population studies to obtain relevant prior pharmacokinetic parameter estimates. In many cases the population has consisted of a relatively small number of subjects. This may be unavoidable for drugs used in cancer chemotherapy or in small, specific populations of patients. In contrast, information about drugs which are used extensively, such as the aminoglycosides, can be obtained by population studies which involve a large number of individuals. Indeed, this technique has proved particularly useful for determining parameter estimates which can be employed in neonatal TDM. Bayesian parameter estimation has been most frequently used for drugs with narrow therapeutic ranges such as the aminoglycosides, cyclosporin, digoxin, anticonvulsants (especially phenytoin), lithium and theophylline. However, the technique has now been extended to cytotoxic drugs, Factor VIII and warfarin. Bayesian methods have also been used to limit the number of samples required in more conventional pharmacokinetic studies with new drugs. Further advances in the use of these methods are likely to include measures of drug response and toxicity requiring population studies which also include relevant pharmacodynamic information.

Population pharmacokinetics. Theory and clinical application.

Good therapeutic practice should always be based on an understanding of pharmacokinetic variability. This ensures that dosage adjustments can be made to accommodate differences in pharmacokinetics due to genetic, environmental, physiological or pathological factors. The identification of the circumstances in which these factors play a significant role depends on the conduct of pharmacokinetic studies throughout all stages of drug development. Advances in pharmacokinetic data analysis in the last 10 years have opened up a more comprehensive approach to this subject: early traditional small group studies may now be complemented by later population-based studies. This change in emphasis has been largely brought about by the development of appropriate computer software (NONMEM: Nonlinear Mixed Effects Model) and its successful application to the retrospective analysis of clinical data of a number of commonly used drugs, e.g. digoxin, phenytoin, gentamicin, procainamide, mexiletine and lignocaine (lidocaine). Success has been measured in terms of the provision of information which leads to increased efficiency in dosage adjustment, usually based on a subsequent Bayesian feedback procedure. The application of NONMEM to new drugs, however, raises a number of interesting questions, e.g. 'what experimental design strategies should be employed?' and 'can kinetic parameter distributions other than those which are unimodal and normal be identified?' An answer to the later question may be provided by an alternative non-parametric maximum likelihood (NPML) approach. Population kinetic studies generate a considerable amount of demographic and concentration-time data; the effort involved may be wasted unless sufficient attention is paid to the organisation and storage of such information. This is greatly facilitated by the creation of specially designed clinical pharmacokinetic data bases, conveniently stored on microcomputers. A move towards the adoption of population pharmacokinetics as a routine procedure during drug development should now be encouraged. A number of studies have shown that it is possible to organise existing, routine data in such a way that valuable information on pharmacokinetic variability can be obtained. It should be relatively easy to organise similar studies prospectively during drug development and, where appropriate, proceed to the establishment of control systems based on Bayesian feedback.

Population analysis of the pharmacokinetic variability of high-dose metoclopramide in cancer patients.

Metoclopramide infusions are used to prevent nausea and vomiting in cancer patients during chemotherapy. 47 patients received metoclopramide during 109 chemotherapeutic treatments as a loading (dose range = 0.55 to 4.5 mg/kg over 15 minutes) and maintenance (dose range = 0.57 to 4.8 mg/kg over 8 hours) infusion. During and up to 24 hours after the end of the maintenance infusion between 4 and 10 blood samples were collected per treatment. Metoclopramide was analysed in plasma by liquid chromatography. Pharmacokinetic and demographic data of 83 treatments were analysed by the NONMEM program using a linear 2-compartment model. It was found that bodyweight and serum alkaline phosphatase activity explain some of the interindividual variability in clearance (CL). The typical pharmacokinetic parameters for an average individual (70kg, alkaline phosphatase = 100 IU/L) were: CL = 20 L/h; volume of distribution at steady state (Vdss) = 190L; terminal half-life = 8h. The interindividual variabilities in clearance, volume of central compartment and Vdss were 50%, 35% and 35%, respectively. The residual variability in plasma concentrations was estimated as 13%.

Variability in the pharmacokinetics of epirubicin: a population analysis.

Population pharmacokinetic analysis of the anticancer agent epirubicin was carried out using the program NONMEM. Data were available from 36 patients aged 20-73 years, of whom 23 were women. All subjects exhibited normal liver and renal function. Epirubicin was given as a short-term i.v. infusion over the dose range of 25-100 mg/m2, and an average of 11 plasma samples/subject were taken for a period of up to 72 h after each dose. A Two compartment model was fitted to the data, characterised by the parameters clearance, volume of the central compartment, alpha and beta. Clearance was tested as a linear function of various demographic and/or biochemical features. A significant proportion of the variability in clearance could be attributed to sex, and also to age in women. For example, a 25-year-old man would display an average clearance of 95 l/h, whereas a 70-year-old woman would exhibit an average clearance of 64 l/h. Such differences in clearance might be important in the selection of epirubicin dose regimens.

Enhancement of methotrexate absorption by subdivision of dose.

A comparison was made in fasting patients between a single 100 mg oral dose of methotrexate formulated as its sodium salt in a palatable syrup and the same total quantity of drug administered in four divided doses of 25 mg taken at 2-h intervals. Allocation to the order of these treatment schedules was on a random basis. The area under the serum methotrexate concentration-time curve until 50 h was found to be considerably greater after the divided dose regimen, the mean ratio AUC 25 mg x 4/AUC 100 mg being 1.86 (+/- 0.90). There was no significant difference in peak serum methotrexate concentrations or methotrexate half-life estimates between the two regimens, however. The results of this study are consistent with saturation of an intestinal transport process when methotrexate is administered orally in a single large dose.

Bioavailability of methotrexate: implications for clinical use.

The absorption of oral methotrexate in syrup form has been compared in six patients with that of an identical IV dose (50 mg/m2). There was variable absorption amongst the group with respect to maximum levels achieved and the time taken to reach those levels. The area under the time-concentration curve was always smaller when the drug was given orally than after IV administration. A total of 33 patients receiving methotrexate for a variety of tumour types were followed for response to treatment and toxicity. A significantly longer methotrexate half-life (t1/2) was found in nine partial responders (9.2 +/- 1.6 h) than in the nonresponders (3.8 +/- 0.7 h). Severe methotrexate toxicity was not seen though occasional mucositis, conjunctivitis, and diarrhoea occurred in seven patients. The side effects could not be predicted from the dose, the bioavailability data, or the serum creatinine. Measurements of serum and urine methotrexate levels are useful in the assessment of absorption and bioavailability of the drug the prediction of tumour response.

Understanding the relative sensitivity of radiographic screens to scattered radiation.

This study compared the relative response of various screen-film and computed radiography (CR) systems to diagnostic radiation exposure. An analytic model was developed to calculate the total energy deposition within the depth of screen and the readout signal generated from this energy for the x-ray detection system. The model was used to predict the relative sensitivity of several screen-film and CR systems to scattered radiation as a function of various parameters, such as x-ray spectra, phantom thickness, phosphor composition, screen thickness, screen configuration (single front screen, single back screen, screen pair), and readout conditions. In addition, measurements of the scatter degradation factor (SDF) for different screen systems by using the beam stop technique with water phantoms were made to verify the model results. Theoretically calculated values of SDF were in good agreement with experimental data. These results are consistent with the common observation that rare-earth screens generally produce better image quality than calcium tungstate screens and the CR screen.

X-ray CT metal artifact reduction using wavelets: an application for imaging total hip prostheses.

Traditional computed tomography (CT) reconstructions of total joint prostheses are limited by metal artifacts from corrupted projection data. Published metal artifact reduction methods are based on the assumption that severe attenuation of X-rays by prostheses renders corresponding portions of projection data unavailable, hence the "missing" data are either avoided (in iterative reconstruction) or interpolated (in filtered backprojection with data completion; typically, with filling data "gaps" via linear functions). In this paper, we propose a wavelet-based multiresolution analysis method for metal artifact reduction, in which information is extracted from corrupted projection data. The wavelet method improves image quality by a successive interpolation in the wavelet domain. Theoretical analysis and experimental results demonstrate that the metal artifacts due to both photon starving and beam hardening can be effectively suppressed using our method. As compared to the filtered backprojection after linear interpolation, the wavelet-based reconstruction is significantly more accurate for depiction of anatomical structures, especially in the immediate neighborhood of the prostheses. This superior imaging precision is highly advantageous in geometric modeling for fitting hip prostheses.

Deblurring subject to nonnegativity constraints when known functions are present with application to object-constrained computerized tomography.

The reconstruction of tomographic images is often treated as a linear deblurring problem. When a high-density, man-made metal object is present somewhere in the image field, it is a deblurring problem in which the unknown function has a component that is known except for some location and orientation parameters. We first address general linear deblurring problems in which a known function having unknown parameters is present. We then show how the resulting iterative solution can be applied to tomographic imaging in the presence of man-made foreign objects, and we apply the result, in particular, to X-ray computed tomography imaging used in support of brachytherapy treatment of advanced cervical cancer.

Evaluation of nonlinear regression with extended least squares: simulation study.

A new approach to nonlinear least-squares regression analysis using extended least squares (ELS) was compared with three conventional methods: ordinary least squares (OLS); weighted least squares 1/C (WLS-1) and weighted least squares 1/C2 (WLS-2). With Monte Carlo simulation techniques, 3 X 200 data sets were constructed with constant proportional error (5, 10, and 15% error) and 3 X 200 with constant additive error (0.05, 0.10, and 0.15 g/mL) from an initial (perfect) data set based on known parameters. Two sampling strategies were employed: one with 17 time points and one with 10 time points. All data sets were fitted by each of the four methods, and parameter estimation bias was assessed by comparing the mean parameter estimate with the known value. The relative precision of each method was investigated by examination of the absolute deviations of each individual parameter estimate from the known value. ELS performed as well as the appropriate weighting scheme (WLS-2 for constant proportional error sets and OLS for constant additive error sets) and was superior with regard to both bias and precision to less appropriate methods.

Health surveillance of Glasgow medical undergraduates pursuing elective studies abroad (1992-1998).

BACKGROUND: An integral part of the training for many UK medical undergraduates involves a period of elective study abroad. There is concern about the health risks this poses to the students, and uncertainty regarding the responsibility this places on medical schools. METHODS: Annually since 1992, medical undergraduates at Glasgow University have been asked to complete and return a confidential questionnaire on return from their elective studies. This records personal demographic details, the countries visited, and information about illnesses experienced. Analyses were conducted on the students' health experiences, lifestyle, the health precautions taken, and the climates experienced. RESULTS: Global statistics were compiled on 750 respondents. A subset of 267 completed a more extensive, post-1996, questionnaire enabling detailed study of comparative illness rates. A majority took pretravel health advice, visited only one country, stayed for 1 to 2 months, and experienced a tropical climate. Forty-five percent reported symptoms of illness, and alimentary symptoms predominated (77% of those ill). Higher illness rates were reported in those who experienced a hot desert or tropical climate compared with those who did not. There was correlation between taking professional pretravel health advice and exposure to a more hazardous climate. CONCLUSIONS: The attack rate for medical students on electives compares favorably to that for package holidaymakers; similarly the attack rate for students staying in the tropics compared with other travelers. A preexisting health problem did not predispose to a higher attack rate. Attack rates can be minimized by avoiding climatically extreme locations. This surveillance provides a focus of interest to the students, insight on minimizing avoidable health problems, evidences social responsibility by the Medical Faculty, and has the potential for expansion to other medical schools. Current Scottish medical school policies on HIV risk management would be strengthened by a more coordinated approach.

The effect of cimetidine on the pharmacokinetics of epirubicin in patients with advanced breast cancer: preliminary evidence of a potentially common drug interaction.

Epirubicin is known to be metabolized in the liver. Therefore, drugs such as cimetidine, which inhibit the cytochrome P-450 enzyme system or reduce liver blood flow, may reduce the plasma clearance of epirubicin. In a small study, epirubicin 100 mg/m2 every 3 weeks was administered intravenously to eight patients, who also received oral cimetidine (400 mg b.d. for 7 days starting 5 days before chemotherapy) with either the first or second cycles. Epirubicin pharmacokinetics and liver blood flow (idocyanine green clearance) were assessed at each course. The areas under the plasma concentration time curves (AUCs) were used to compare the systemic exposure to epirubicin and its metabolites with each course. The estimated median percentage increase (95% confidence interval CI) in the AUC with cimetidine were: epirubicin 50% (95% CI -18 to 193, epirubicinol 41% (95% CI 1 to 92). Despite the small numbers studied, the increase in the active metabolite epirubicinol was significant (P < 0.05). These changes in exposure were not explained by reduced cytochrome P-450 activity as the 7-deoxy-doxorubicinol aglycone AUC was not reduced (357% increase: 95% CI 17 to 719) or by a decrease in liver blood flow (17% increase: 95% CI -39 to 104). Cimetidine is likely to be coprescribed or self-administered with epirubicin and therefore clinicians should be aware of this potential interaction.

Binding of [3H]mianserin to bovine serum albumin, human serum albumin and alpha 1-acid glycoprotein.

Scatchard plots which were curvilinear with negative slopes were obtained when the binding of [3H]mianserin to bovine serum albumin (BSA), human serum albumin (HSA), defatted human serum albumin (D-HSA) and alpha 1-acid glycoprotein (alpha 1-AGP) was studied with equilibrium dialysis with constant protein concentrations and various ligand concentrations. Binding parameters were estimated graphically and with a non-linear least-squares computer program, assuming two classes of independent binding sites. alpha 1-AGP had the highest binding affinity (K) and binding capacity (nK). The binding parameters, n and K were not independent of protein concentration when the BSA concentration was varied. Linear atypical Scatchard plots with positive slopes were obtained when the protein concentration was varied for BSA, HSA and D-HSA, at a fixed ligand concentration.

Dental photostimulable phosphor radiography.

Photostimulable phosphor radiography (PPR), a mature industry in medical imaging, became available in dentistry in 1994. At least three dental PPR systems have been made available commercially since that time. Although dental PPR offers a number of advantages over film-based methods, some aspects of dental PPR need improvement. Further research is needed to more fully compare and contrast this modality with film-based methods.

Digoxin therapy: a clinical pharmacokinetic approach.

Within certain limitations, digoxin can be prescribed for individual patients on a sound scientific basis. The use of pharmacokinetic principles and digoxin radioimmunoassay can improve the overall quality of treatment with this drug and reduce the incidence of adverse reactions. Variations in bioavailability and intestinal absorption are important factors in the determination of dosage and should be reduced to a minimum by improved pharmaceutical formulations.

Rhabdomyolysis and listeria monocytogenes.

Non-traumatic rhabdomyolysis occurs as a complication of a wide variety of infections and is often discovered as a result of the associated renal failure. We report a case of meningitis due to Listeria monocytogenes, an uncommon cause of infection in adults which was associated with rhabdomyolysis. This confirms a recent first case report of this association.