MRI assessment of the pre-vertebral soft tissues in acute cervical spine trauma

This pictorial review illustrates the MRI appearances of pre-vertebral haematoma in acute cervical spine trauma. The review is based on 31 patients who underwent MRI within 5 days of injury. MRI showed pre-vertebral haematoma in 24 cases; soft tissue thickening was detected on conventional radiographs in 14 cases. MRI is more sensitive than radiography for the detection of pre-vertebral haematoma.     

The effect of microcolony size, at time of irradiation, on colony forming ability

PURPOSE: To investigate the effect of irradiating microcolonies of various sizes on their subsequent ability to form colonies. MATERIALS AND METHODS: The location of individual HPV-G cells in tissue culture flasks was recorded using computerized microscopy. This allowed the cells' positions to be continually revisited, which enabled manual sizing of individual microcolonies both at the time of irradiation (between 0-5 Gy) and following an incubation period during which the microcolonies were assessed for cologenic survival. RESULTS: The experiments indicate that when irradiated as microcolonies, cells have plating efficiencies (PE) that are lower than expected when compared with the prediction from the PE values of cells irradiated individually. CONCLUSION: These data support the conclusions of Mothersill and Seymour (1997b) which challenge the concept of independent survival of certain types of cells following irradiation. The results indicate that interactions between cells can occur even in small aggregates.     

Raising the quality of cost-utility analyses: lessons learnt and still to learn.

Heightened awareness by health care funders of the need to find more efficient ways of using scarce health care resources has led to greater demand for evidence of cost-effectiveness. Implicit in this demand is that evidence is generated using clear reporting and accepted methods. The research reported here updates an earlier review of published cost-utility analyses (CUAs) to address whether previously identified gaps in reporting have diminished over time. Raising CUA standards requires systematic and regular reviews of published material to allow adequate monitoring and evaluation. There is also a need to 'appraise the appraisers' in the sense of reviewing peer-review processes. This is particularly so in those journals which are growing in importance as outlets for economic evaluation information. The findings from this study indicate continuing variation in the quality of reporting. At the lower end of this spectrum improvements could be made in the reporting of comparators, in the clarity of effectiveness evidence, in the assignment of utility weights to health states and in reporting of sensitivity analysis. CUAs published in peer-reviewed specialist medical journals were more likely to be lower in quality suggesting guidance on the appraisal of economic submissions needs to be extended to the editors of these particular journals. These findings could be used to help to target attempts to raise the quality of evidence-based CUA information.     

Evaluation of myocardial energy status in vivo by NMR spectroscopy

Summary NMR spectroscopy is a powerful and non-invasive technique with which to study cardiac energy metabolism in vivo. This mcthod makes use of the "spin" properties of certain atomic nuclei. The naturally occurring phosphorus nucleus (P-31) is visible by NMR and phosphorus-31 NMR spectra contain signals from the major components of energy metabolism. In vivo, the phosphocreatine to ATP ratio (PCr/ATP) is used as an index of the energy status and viability of the myocardium. However, it is the response of this metabolic index to differing physiological and pharmacological stresses that has helped to elucidate the mechanisms that regulate cellular respiration and to highlight abnormalities in heart failure. As there are many technical difficulties involved with cardiac NMR, 31-phosphorus studies of skeletal muscle have provided an indirect way of studying abnormalities in myocardial metabolism in vivo.One of the unique features of NMR is that it permits in vivo measurements of fluxes through key enzymes in energy metabolism using magnetization transfer. Determination of the rates of energy transfer through the creatine kinase reaction and energy turnover in vivo will provide new insights into the control of energy metabolism in health and disease. Alternatively, carbon-13 NMR can be used to measure fluxes through the different metabolic pathways of synthesis and catabolism following administration of selectively labelled carbon-13 substrates. In conclusion, the non-invasive and versatile nature of NMR spectroscopy makes it an ideal method to assess and evaluate energy metabolism in vivo.     

Reduced cardiotoxicity of doxorubicin given in the form ofN-(2-hydroxypropyl) methacrylamide conjugates: an experimental study in the rat

Summary A rat model was used to evaluate the general acute toxicity and the late cardiotoxicity of 4 mg/kg doxorubicin (DOX) given either as free drug or in the form of threeN-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. In these HPMA copolymers, DOX was covalently bound via peptide linkages that were either non-biodegradable (Gly-Gly) or degradable by lysosomal proteinases (Gly-Phe-Leu-Gly). In addition, one biodegradable conjugate containing galactosamine was used; this residue was targeted to the liver. Over the first 3 weeks after the i.v. administration of free and polymer-bound DOX, all animals showed a transient reduction in body weight. However, the maximal reduction in body weight seen in animals that received polymer-bound DOX (4 mg/kg) was significantly lower than that observed in those that received free DOX (4 mg/kg) or a mixture of the unmodified parent HPMA copolymer and free DOX (4 mg/kg;P<0.01). Throughout the study (20 weeks), deaths related to cardiotoxicity were observed only in animals that received either free DOX or the mixture of HPMA copolymer and free DOX; in these cases, histological investigations revealed marked changes in the heart that were consistent with DOX-induced cardiotoxicity. Sequential measurements of cardiac output in surviving animals that received either free DOX or the mixture of HPMA copolymer and free DOX showed a reduction of 30% in function beginning at the 4th week after drug administration. The heart rate in these animals was 12% lower than that measured in age-matched control rats (P<0.05). Animals that were given the HPMA copolymer conjugates containing DOX exhibited no significant change in cardiac output throughout the study (P<0.05). In addition, no significant histological change was observed in the hearts of animals that received DOX in the form of HPMA copolymer conjugates and were killed at the end of the study. However, these animals had shown a significant increase in heart rate beginning at 8 weeks after drug administration (P<0.01). This study demonstrates that covalent binding of DOX to HPMA copolymer conjugates via both stable and biodegradable peptidyl linkages considerably reduces both the general acute toxicity and the late cardiotoxicity of DOX in the rat and could offer the potential for improving the therapeutic index in the clinical application of DOX.     

Passive tumor targeting of soluble macromolecules and drug conjugates.

The biodistribution of soluble macromolecules is governed extensively by their ability to penetrate endothelial layers. Many solid tumors possess vasculature that is hyperpermeable to macromolecules, not always correlating with the presence of interendothelial cell fenestrations. The exact physiological mechanisms responsible for this nonspecific leakiness are not yet fully understood. Together with enhanced vascular permeability, however, tumors usually lack effective lymphatic drainage; consequently, they selectively accumulate circulating macromolecules (up to 10% of an i.v. dose per gram in mice). This "enhanced permeability and retention effect" (EPR effect) has been studied extensively, and it is thought to constitute the mechanism of action of SMANCS (styrene-maleic/anhydride-neocarzinostatin), now in regular clinical use in Japan for the treatment of hepatoma. It seems likely that EPR also contributes to the anticancer activity of the N-(2-hydroxypropyl)methacrylamide copolymer-anthracycline conjugates which are shortly to undergo clinical evaluation in the U.K.     

Treatment of a constellation of inappropriate sexual and social behaviors in a 20 year old man with Down's Syndrome

In 1983, a Down's Syndrome male (I.Q. 72) AB who resided in a community residence was charged by local police with Exposing his genitalia, as a result of an incident of exhibitionism. Upon investigation by the New Jersey Division of Mental Retardation (a State of New Jersey Agency now named the New Jersey Division of Developmental Disabilities), it was found that AB had a constellation of inappropriate sexual and social behaviors. A treatment plan was designed by a State Psychologist, a private Psychologist, a State Special Educator, a State Social Worker, and residential staff, with the full cooperation of AB's parents. The treatment approach combined traditional psychotherapy, a token economy plan, and vigorous social skills training. AB has been followed for 7 years and the treatment plan has been modified a number of times, as AB's behavior has continued to improve. Over the 7 years, AB has not had any more arrests on sexual charges and his overall social behavior has shown marked improvement.     

Dose- and time-response relationships for lethal mutations and chromosomal instability induced by ionizing radiation in an immortalized human keratinocyte cell line

PURPOSE: To investigate the relationship between two well-established delayed effects of ionizing radiation, experiments were conducted to determine the induction and expression of lethal mutations (delayed reproductive death) and chromosomal instability with respect to dose and time in a human immortalized keratinocyte cell line. METHODS: HPV-G cells were gamma- or alpha-irradiated and maintained in culture for up to 72 population doublings. At intervals, measurements were made of cloning efficiency and the cells examined for apoptosis and cytogenetic aberrations. RESULTS: The descendants of cells surviving 1 or 3 Gy gamma-irradiation, but not 0.5 Gy gamma-irradiation, exhibited a reduced colony-forming efficiency. The reduction persisted at a constant rate of 15-20% clonogenic cell loss per population doubling for up to 72 population doublings. Apoptosis was demonstrated in all colonies in the 1 and 3 Gy groups at 30 and 72 population doublings post-irradiation but not in the 0.5 Gy group. A significant persistent reduction in colony-forming ability (approximately 80%) was demonstrated in the progeny of cells irradiated with 0.5 Gy alpha-particles. After 30 population doublings, the proportion of chromosomally aberrant cells was significantly greater than control values for all doses of both high- and low-LET radiations. The major cytogenetic aberrations (chromatid breaks, chromosome fragments and minutes) were consistent with the transmission of chromosomal instability. The expression of instability declined between 30 and 72 population doublings in the 0.5 Gy and 3 Gy gamma-irradiation groups, but persisted up to 72 population doublings in the 1 Gy group. The expression of chromosomal instability was greater in the descendants of alpha-irradiated cells and showed little evidence of reduction with time. CONCLUSIONS: Unstable aberrations characteristic of radiation-induced chromosomal instability may commonly result in apoptosis and account for a component of the delayed reproductive death/lethal mutation phenotype in HPV-G cells. However, the absence of lethal mutations in the descendants of 0.5 Gy gamma-irradiated cells indicates a low-LET threshold effect for this particular endpoint. Overall, and particularly at low doses, there is no direct correlation between the two endpoints, indicating the absence of a simple relationship between these manifestations of radiation-induced genomic instability.