Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: a reproducible predictor of outcome?

Rhabdomyosarcoma has 2 major histological subtypes, embryonal and alveolar. Alveolar histology is associated with the fusion genes PAX3-FKHR and PAX7-FKHR. Definition of alveolar has been complicated by changes in terminology and subjectivity. It is currently unclear whether adverse clinical behaviour is better predicted by the presence of these fusion genes or by alveolar histology. We have determined the presence of the PAX3/7-FKHR fusion genes in 91 primary rhabdomyosarcoma tumours using a combination of classical cytogenetics, FISH and RT-PCR, with a view to determining the clinical characteristics of tumours with and without the characteristic translocations. There were 37 patients with t(2;13)/PAX3-FKHR, 8 with t(1;13) PAX7-FKHR and 46 with neither translocation. One or other of the characteristic translocations was found in 31/38 (82%) of alveolar cases. Univariate survival analysis revealed the presence of the translocation t(2;13)/PAX3-FKHR to be an adverse prognostic factor. With the difficulties in morphological diagnosis of alveolar rhabdomyosarcoma on increasingly used small needle biopsy specimens, these data suggest that molecular analysis for PAX3-FKHR will be a clinically useful tool in treatment stratification in the future. This hypothesis requires testing in a prospective study. Variant t(1;13)/PAX7-FKHR appears biologically different, occurring in younger patients with more localised disease.     

Using cost-effectiveness league tables to compare interventions to prevent sexual transmission of HIV

Cost-effectiveness information is needed to help public health decision makers choose between competing HIV prevention programs. One way to organize this information is in a 'league table' that lists cost-effectiveness ratios for different interventions and which facilitates comparisons across interventions. Herein we propose a common outcome measure for use in HIV prevention league tables and present a preliminary league table of interventions to reduce sexual transmission of HIV in the US. Fifteen studies encompassing 29 intervention for different population groups are included in the table. Approximately half of the interventions are cost-saving (i.e. save society money, in the long run), and three-quarters are cost-effective by conventional standards. We discuss the utility of such a table for informing the HIV prevention resource allocation process and delineate some of the difficulties associated with the league table approach, especially as applied to HIV prevention cost-effectiveness analysis.     

Sexually transmitted diseases and the increased risk for HIV transmission: implications for cost-effectiveness analyses of sexually transmitted disease prevention interventions

We estimated the annual number and cost of new HIV infections in the United States attributable to other sexually transmitted diseases (STDs). We used a mathematical model of HIV transmission to estimate the probability that a given STD infection would facilitate HIV transmission from an HIV-infected person to his or her partner and to calculate the number of HIV infections due to these facilitative effects. In 1996, an estimated 5,052 new HIV cases were attributable to the four STDs considered here: chlamydia (3,249 cases), syphilis (1,002 cases), gonorrhea (430 cases), and genital herpes (371 cases). These new HIV cases account for approximately $985 million U.S. in direct HIV treatment costs. The model suggested that syphilis is far more likely than the other STDs (on a per-case basis) to facilitate HIV transmission. This analysis provides a framework for incorporating STD-attributable HIV treatment costs into cost-effectiveness analyses of STD prevention programs.     

Surfactant treatment effects on lung structure and type II cells of preterm ventilated lambs

We evaluated surfactant treatment effects on lung morphology and alveolar type II cells of preterm ventilated lambs. Lambs were ventilated for 10 h following treatment of the right lung with natural surfactant. Lung parenchyma from the surfactant-treated right and the untreated left lung was compared morphometrically. Mechanical ventilation without surfactant resulted in distention of alveolar ducts accompanied by shallowing and loss of well-defined alveoli without disruption of collagen or elastin fibers. Surfactant treatment almost completely prevented these changes. The percent of normal parenchyma was 82 +/- 7% in surfactant-treated lobes and 26 +/- 5% in the nontreated lobes (p < 0.05). Type II cells became flatter in lungs ventilated without surfactant, and cell shape was preserved by surfactant treatment. The volume densities of lamellar bodies and multivesicular bodies in alveolar type II cells were not changed by surfactant treatment. With or without surfactant treatment, mechanical ventilation was associated with a shift in lamellar body distribution to a smaller size and a decrease in glycogen content of type II cells. Surfactant treatment of the preterm lung prevents alveolar distortion and atelectasis, but does not result in changes in subcellular organelles in immature type II cells.     

Green fluorescent protein as a genetic marker in transgenic Aedes aegypti

We report here the use of the enhanced green fluorescent protein (EGFP) from the jellyfish, Aequorea victoria, as a genetic marker for the genetic transformation of mosquitoes. The EGFP gene, under the control of the actin5C promoter of Drosophila melanogaster was inserted into the Hermes transposable element. Preblastoderm embryos of a wild-type strain of the yellow fever mosquito, Aedes aegypti, were microinjected with this plasmid, together with a helper plasmid containing the Hermes transposase placed under the control of the D. melanogaster hsp70 promoter. Somatic EGFP expression was observed during early instars in approximately one-half of all G0 individuals. Two G1 individuals arising from a G0 female displayed high levels of EGFP gene expression during all stages of development. EGFP was transmitted in a Mendelian fashion to the G2 and G3 generations and molecular analysis confirmed the presence of the Hermes[actin5C:EGFP] gene in these insects. These results clearly demonstrate that EGFP can be used as an effective genetic marker in wild-type Ae. aegypti and most likely in other mosquito species as well.     

Cost-effectiveness of an HIV risk reduction intervention for adults with severe mental illness

Small-group HIV prevention interventions that focus on individual behavioural change have been shown to be especially effective in reducing HIV risk among persons with severe mental illness. Because economic resources to fund HIV prevention efforts are limited, health departments, community planning groups and other key decision-makers need reliable information on the cost and cost-effectiveness (not solely on effectiveness) of different HIV prevention interventions. This study used an economic evaluation technique known as cost-utility analysis to assess the cost-effectiveness of three related cognitive-behavioural HIV risk reduction interventions: a single-session, one-on-one intervention; a multi-session small-group intervention; and a multi-session small-group intervention that taught participants to act as safer sex advocates to their peers. For men, all three interventions were cost-effective, but advocacy training was the most cost-effective of the three. For women, only the single-session intervention was cost-effective. The gender differences observed here highlight the importance of focusing on gender issues when delivering HIV prevention interventions to men and women who are severely mentally ill.     

Morphine and morphine-6-glucuronide in the plasma and cerebrospinal fluid of children

AIMS: To measure morphine and morphine-6-glucuronide in the plasma and cerebrospinal fluid of children following a single intravenous dose of morphine. METHODS: Twenty-nine paired samples of cerebrospinal fluid and plasma were collected from children with leukaemia undergoing therapeutic lumbar puncture. An intravenous dose of morphine was administered at selected intervals before the procedure. Concentrations of morphine and morphine-6-glucuronide (M6G) were measured in each sample. Morphine was measured using a specific radioimmunoassay (r.i.a.) and M6G was measured using a novel enzyme-linked immunosorbent assay (ELISA). RESULTS: The ELISA for measuring M6G was highly sensitive. The intra-and interassay variations were less than 15%. Using a two-compartment model for plasma morphine, the area under the curve to infinity (AUC, 7143 ng ml-1 min), volume of distribution (3.6 l kg-1 ) and elimination half-life (88 min) were comparable with those reported in adults. Clearance (35 ml min-1 ) was higher than that in adults. Morphine-6-glucuronide was readily synthesized by the children in this study. The elimination half-life (321 min) and AUC (35507 ng ml-1 min) of plasma M6G were much greater than those of morphine. CONCLUSIONS: Extensive metabolism of morphine to M6G in children with cancer has been demonstrated. These data provide further evidence to support the importance of M6G accumulation after multiple doses. There was no evidence that morphine passed more easily into the CSF of children than adults.     

Quantitation and localization of pulmonary manganese superoxide dismutase and tumor necrosis factor alpha following exposure to ozone and nitrogen dioxide.

Tumor necrosis factor a (TNFalpha) and manganese superoxide dismutase (MnSOD) are thought to play critical roles in the process of lung injury, repair, and disease. The induction of TNFalpha and MnSOD were examined in a model of progressive pulmonary fibrosis along the length of the alveolar duct in rats exposed for 1, 5, and 8 weeks to a combination of 0.8 ppm ozone and 14.4 ppm nitrogen dioxide. This oxidant injury model results in a triphasic response with an initial inflammatory stage during weeks 1-3, followed by a partial resolution at weeks 4-5, and a final stage of rapidly progressive fibrosis during weeks 6-8. Changes in TNFalpha and MnSOD labeling for the proximal and distal alveolar ducts of the lungs were quantified using immunohistochemistry and morphometric techniques at 1, 5, and 8 weeks of exposure. A significant elevation in MnSOD was noted in alveolar macrophages and interstitial cells of the proximal and distal portions of the alveolar duct following 8 weeks of exposure. Labeling for TNFalpha only in the proximal region of the alveolar duct, was significantly increased in alveolar macrophages after 1 and 8 weeks of exposure, while a significant increase in TNFalpha labeling of interstitial cells in proximal regions was noted at all time points. We conclude that MnSOD is elevated in areas of focal injury as well as the more distal protected areas of the lungs, while TNFalpha correlates strongly with both the temporal and spatial aspects of greatest cellular injury in the lungs.