'Oxygen Level in a Tissue' - What Do Available Measurements Really Report?

The aim of the paper is to discuss what currently is feasible clinically to measure the level of oxygen and how that measurement can be clinically useful. Because oxygen in tissues is quite heterogeneous and all methods of measurement can only provide an average across heterogeneities at some spatial and temporal resolution, the values that are obtained may have limitations on their clinical utility. However, even if such limitations are significant, if one utilizes repeated measurements and focuses on changes in the measured levels, rather than 'absolute levels', it may be possible to obtain very useful clinical information. While these considerations are especially pertinent in cancer, they also pertain to most other types of pathology.

Clinical and Statistical Considerations when Assessing Oxygen Levels in Tumors: Illustrative Results from Clinical EPR Oximetry Studies.

The success of treatment for malignancies, especially those undergoing radiation therapy or chemotherapy, has long been recognized to depend on the degree of hypoxia in the tumor. In addition to the prognostic value of knowing the tumor's initial level of hypoxia, assessing the tumor oxygenation during standard therapy or oxygen-related treatments (such as breathing oxygen-enriched gas mixtures or taking drugs that can increase oxygen supply to tissues) can provide valuable data to improve the efficacy of treatments. A series of early clinical studies of tumors in humans are ongoing at Dartmouth and Emory using electron paramagnetic resonance (EPR) oximetry to assess tumor oxygenation, initially and over time during either natural disease progression or treatment. This approach has the potential for reaching the long-sought goal of enhancing the effectiveness of cancer therapy. In order to effectively reach this goal, we consider the validity of the practical and statistical assumptions when interpreting the measurements made in vivo for patients undergoing treatment for cancer.

Skeletal Muscle Oxygenation Measured by EPR Oximetry Using a Highly Sensitive Polymer-Encapsulated Paramagnetic Sensor.

We have incorporated LiNc-BuO, an oxygen-sensing paramagnetic material, in polydimethylsiloxane (PDMS), which is an oxygen-permeable, biocompatible, and stable polymer. We fabricated implantable and retrievable oxygen-sensing chips (40 % LiNc-BuO in PDMS) using a 20-G Teflon tubing to mold the chips into variable shapes and sizes for in vivo studies in rats. In vitro EPR measurements were used to test the chip's oxygen response. Oxygen induced linear and reproducible line broadening with increasing partial pressure (pO2). The oxygen response was similar to that of bare (unencapsulated) crystals and did not change significantly on sterilization by autoclaving. The chips were implanted in rat femoris muscle and EPR oximetry was performed repeatedly (weekly) for 12 weeks post-implantation. The measurements showed good reliability and reproducibility over the period of testing. These results demonstrated that the new formulation of OxyChip with 40 % LiNc-BuO will enable the applicability of EPR oximetry for long-term measurement of oxygen concentration in tissues and has the potential for clinical applications.

Calculation of dose conversion factors for doses in the fingernails to organ doses at external gamma irradiation in air.

Absorbed doses to fingernails and organs were calculated for a set of homogenous external gamma-ray irradiation geometries in air. The doses were obtained by stochastic modeling of the ionizing particle transport (Monte Carlo method) for a mathematical human phantom with arms and hands placed loosely along the sides of the body. The resulting dose conversion factors for absorbed doses in fingernails can be used to assess the dose distribution and magnitude in practical dose reconstruction problems. For purposes of estimating dose in a large population exposed to radiation in order to triage people for treatment of acute radiation syndrome, the calculated data for a range of energies having a width of from 0.05 to 3.5 MeV were used to convert absorbed doses in fingernails to corresponding doses in organs and the whole body as well as the effective dose. Doses were assessed based on assumed rates of radioactive fallout at different time periods following a nuclear explosion.

Radiation dose reconstruction from L-band in vivo EPR spectroscopy of intact teeth: Comparison of methods.

In vivo EPR tooth dosimetry is a more challenging problem than in vitro EPR dosimetry because of several potential additional sources of variation associated with measurements that are made in the mouth of a living subject. For in vivo measurement a lower RF frequency is used and, unlike in the in vitro studies, the tooth cannot be processed to optimize the amount and configuration of the enamel that is measured. Additional factors involved with in vivo measurements include the reproducibility of positioning the resonator on the surface of the tooth in the mouth, irregular tooth geometry, and the possible influence of environmental noise. Consequently, in addition to using the theoretical and empirical models developed for analyzing data from measurements of teeth in vitro, other unconventional and more robust methods of dose reconstruction may be needed. The experimental parameter of interest is the peak-to-peak amplitude of the spectrum, which is correlated to the radiation dose through a calibration curve to derive the reconstructed dose. In this study we describe and compare the results from seven types of computations to measure the peak-to-peak amplitude for estimation of the radiation induced signal. The data utilized were from three sets of in vivo measurements of irradiated teeth. Six different teeth with different doses were placed in the mouth of a volunteer in situ and measurements of each tooth were carried out on three different days. The standard error of dose prediction (SEP) is used as a figure of merit for quantifying precision of the reconstruction. We found that many of the methods gave fairly similar results, with the best error of prediction resulting from a computation based on a Lorentzian line model whose center field corresponds to the known parameter of the radiation-induced EPR spectra of teeth, with corrections from a standard sample that was measured as part of the data acquisition scheme. When the results from the three days of measurement were pooled, the SEP decreased dramatically, which suggests that one of the principal sources of variation in the data is the ability to precisely standardize the measurements conditions within the mouth. There are very plausible ways to accomplish improvements in the existing procedures.

Some previously unrecognized features of herpes simplex virus encephalitis.

The courses of 15 brain biopsy-proven cases of herpes simplex virus encephalitis (HSVE) were followed for 6 to 67 months. Convulsive disorders were often temporary, but paralysis was permanent. Patients usually entered the hospital free of paralysis or coma, in a potentially reversible febrile confusional state. Later, paralysis and coma fixed subsequent courses. Mortality was 53.3 percent but, at follow-up, 93.3 percent (14 patients) were dead or living a vegetative existence at home or in institutions. If a definitive diagnosis of HSVE could be made at the time of hospital admission, the prognosis might be remarkably changed.

Limitations of dual-photopeak window scatter correction for brain imaging.

UNLABELLED: A method for performing scatter corrections that would directly use the photopeak information and would be straightforward for use in clinical practice would be attractive in SPECT imaging. The dual-photopeak window method may be such a method. It relates the scatter fraction to the ratio of the lower to the total parts of a split-photopeak window. We investigated the use of this scatter correction method on a dedicated brain camera. METHODS: Calibration curves for the Ceraspect, a dedicated brain imaging camera, were obtained for four split-window combinations using point sources in air and water. Simulations of the Ceraspect calibration curves at several energy resolution values were obtained using a Monte Carlo simulation of the instrument. RESULTS: The calibration curves, experimental and simulated, revealed an ambiguous and unstable relationship between lower-to-total ratio and scatter fraction. CONCLUSION: The unsatisfactory calibration curves can be attributed to the limited scatter produced in a brain-sized phantom during the calibration process and inherent stability problems in the calibration process. The dual-photopeak window method is not usable for small-field imaging systems and may even be unstable for larger-field systems.

Determination of 3D positions of pacemaker leads from biplane angiographic sequences.

In vitro and in vivo analyses of stress on pacemaker leads and their components during the heart cycle have become especially important because of incidences of failure of some of these mechanical components. For stress analyses, the three-dimensional (3D) position, shape, and motion of the pacemaker leads must be known accurately at each time point during the cardiac cycle. We have developed a method for determination of the in vivo 3D positions of pacemaker leads during the entire heart cycle. Sequences of biplane images of patients with pacemakers were obtained at 30 frames/s for each projection. The sequences usually included at least two heart cycles. After patient imaging, biplane images of a calibration object were obtained from which the biplane imaging geometry was determined. The centerlines of the leads and unique, identifiable points on the attached electrodes were indicated manually for all acquired images. Temporal interpolation of the lead and electrode data was performed so that the temporal nonsynchronicity of the image acquisition was overcome. Epipolar lines, generated from the calculated geometry, were employed to identify corresponding points along the leads in the pairs of biplane images for each time point. The 3D positions of the lead and electrodes were calculated from the known geometry and from the identified corresponding points in the images. Using multiple image sets obtained with the calibration object at various orientations, the precision of the calculated rotation matrix and of the translation vector defining the imaging geometry was found to be approximately 0.7 degree and 1%, respectively. The 3D positions were reproducible to within 2 mm, with the error lying primarily along the axis between the focal spot and the imaging plane. Using data obtained by temporally downsampling to 15 frames/s, the interpolated data were found to lie within approximately 2 mm of the true position for most of the heart cycle. These results indicate that, with this technique, one can reliably determine pacemaker lead positions throughout the heart cycle, and thereby it will provide the basis for stress analysis on pacemaker leads.

Tetrazole analogs of phenylalanine derivatives as tyrosine hydroxylase inhibitors.

Eight new tetrazole analogs of phenylalanine derivatives in which the carboxyl group was replaced by a tetrazole ring were synthesized. At a concentration of 2.5 time 10(-5) M, each compound exhibited greater than 50% inhibition of tyrosine hydroxylase activity.

Antiviral activity in sera of patients with Crohn's disease.

Sera from patients with Crohn's disease were tested for antiviral activity using a microtiter assay with end points showing 50% reduction of cytopathic effects. Patients were significantly more likely to have serum antiviral activity equivalent to interferon levels of 20 or more units/ml than were control subjects. The mean antiviral activity in the patients' sera (34 +/- 20 (s.d.) units/ml) was significantly greater than that in the control subjects' sera (0.6 +/- 1.7 (s.d.) units/ml). Following acidification the mean antiviral activity of the patients' sera (28 +/- 17 (s.d.) units/ml) had not changed significantly while heat inactivation resulted in significant loss of activity (7.5 +/- 2.7 (s.d.) units/ml). These findings are suggestive of the presence of circulating leucocyte interferon in the sera of patients with Crohn's disease.

In vitro effects of listerial hemolysin on rat brain mitochondria.

Crude hemolysin derived from Listeria monocytogenes, strains 9-125 and 1122-3, reduced phosphate utilization of rat brain mitochondria in a succinate system. Oxidation rates were not altered by addition of hemolysin to a concentration of 42 hemolytic units/ml, with a mitochondrial protein concentration of 2.3 mg/ml. At a mitochondrial protein concentration of 1.8 mg/ml, 42 hemolytic units/ml of hemolysin increased the inhibition of phosphate utilization and also reduced the oxygen uptake. An age differential was apparent, with mitochondria from young rats demonstrating uncoupling at a lower concentration of hemolysin.

Viral chemotherapy.

New antiviral compounds are being tested constantly and may be of considerable value with increasing availability. More than 200 analogues of purines and pyrimidines have been found to inhibit DNA and RNA viruses. Adenine arabinoside is most effective against disseminated herpes simplex virus and disseminated herpes zoster. Idoxuridine is useful in treatment of herpetic keratitis. Interferon still is in the experimental stage, and, because of its short half-life and high cost, it probably will not be released in the near future. Amantadine appears to be useful in prevention of A2 influenza, but its value against swine flu has not been established. Methisazone is effective in prevention of smallpox and in the treatment of complications of vaccinia.