An overview of existing mesothelioma registries worldwide,and the need for a US Registry

The association between asbestos exposure, mainly in occupational settings, and malignant mesothelioma has been well established; this has prompted several countries to establish mesothelioma epidemiologic surveillance programs often at the request of national agencies. This review compares currently existing mesothelioma registries worldwide to develop a concept model for a US real-time case capture mesothelioma registry. Five countries were identified with a mesothelioma specific registry, including Italy, France, UK, Australia, and South Korea. All, except the UK, used interviews to collect exposure data. Linkage with the national death index was available or was in future plans for all registries. The registries have limited information on treatment, quality of life, and other patient-centered outcomes such as symptoms and pain management. To thoroughly collect exposure data, “real-time” enrollment is preferable; to maximize the capture of mesothelioma cases, optimal coverage, and a simplified consent process are needed.     

Increased bone formation in mice lacking plasminogen activators.

Plasminogen activators tPA and uPA are involved in tissue remodeling, but their role in bone growth is undefined. Mice lacking tPA and uPA show increased bone formation and bone mass. The noncollagenous components of bone matrix are also increased, probably from defective degradation. This study underlines the importance of controlled bone matrix remodeling for normal endochondral ossification. INTRODUCTION: Proteolytic pathways are suggested to play a role in endochondral ossification. To elucidate the involvement of the plasminogen activators tPA and uPA in this process, we characterized the long bone phenotype in mice deficient in both tPA and uPA (tPA-/-:uPA-/-). MATERIALS AND METHODS: Bones of 2- to 7-day-old tPA-/-:uPA-/- and wild-type (WT) mice were studied using bone histomorphometry, electron microscopy analysis, and biochemical assessment of bone matrix components. Cell-mediated degradation of metabolically labeled bone matrix, osteoblast proliferation, and osteoblast differentiation, both at the gene and protein level, were studied in vitro using cells derived from both genotypes. RESULTS: Deficiency of the plasminogen activators led to elongation of the bones and to increased bone mass (25% more trabecular bone in the proximal tibial metaphysis), without altering the morphology of the growth plate. In addition, the composition of bone matrix was modified in plasminogen activator deficient mice, because an increased amount of proteoglycans (2x), osteocalcin (+45%), and fibronectin (+36%) was detected. Matrix degradation assays showed that plasminogen activators, by generating plasmin, participate in osteoblast-mediated degradation of the noncollagenous components of bone matrix. In addition, proliferation of primary osteoblasts derived from plasminogen activator-deficient mice was increased by 35%. Finally, osteoblast differentiation and formation of a mineralized bone matrix were enhanced in osteoblast cultures derived from tPA-/-:uPA-/- mice. CONCLUSIONS: The data presented indicate the importance of the plasminogen system in degradation of the noncollagenous components of bone matrix and suggest that the accumulation of these proteins in bone matrix--as occurs during plasminogen activator deficiency--may in turn stimulate osteoblast function, resulting in increased bone formation.     

A 1463 gene cattle-human comparative map with anchor points defined by human genome sequence coordinates

A second-generation 5000 rad radiation hybrid (RH) map of the cattle genome was constructed primarily using cattle ESTs that were targeted to gaps in the existing cattle-human comparative map, as well as to sparsely populated map intervals. A total of 870 targeted markers were added, bringing the number of markers mapped on the RH(5000) panel to 1913. Of these, 1463 have significant BLASTN hits (E < e(-5)) against the human genome sequence. A cattle-human comparative map was created using human genome sequence coordinates of the paired orthologs. One-hundred and ninety-five conserved segments (defined by two or more genes) were identified between the cattle and human genomes, of which 31 are newly discovered and 34 were extended singletons on the first-generation map. The new map represents an improvement of 20% genome-wide comparative coverage compared with the first-generation map. Analysis of gene content within human genome regions where there are gaps in the comparative map revealed gaps with both significantly greater and significantly lower gene content. The new, more detailed cattle-human comparative map provides an improved resource for the analysis of mammalian chromosome evolution, the identification of candidate genes for economically important traits, and for proper alignment of sequence contigs on cattle chromosomes.     

Paracytosis of Haemophilus influenzae through cell layers of NCI-H292 lung epithelial cells.

Haemophilus influenzae penetrates the respiratory epithelium during carriage and invasive disease, including respiratory tract infections. We developed an in vitro model system consisting of lung epithelial NCI-H292 cells on permeable supports to study the passage of H. influenzae through lung epithelial cell layers. The NCI-H292 cells formed tight layers with a Ca(2+)-dependent transepithelial resistance of around 40 omega.cm2. H. influenzae passed through the cell layers without affecting the viability of the cells and [3H]inulin penetration. The passage time was independent of the inoculum of H. influenzae in the apical compartment and was not influenced by the presence of capsule or fimbriae on H. influenzae or by the ability of the bacteria to adhere to the epithelial cells. However, highly adherent strains showed greater paracytosis. Different strains passed through the cell layer independently. The passage time was shorter for rapidly growing strains than for slowly growing strains (10 to 18 h and 30 h, respectively). Microscopic examination revealed the presence of clusters of H. influenzae bacteria between the epithelial cells, indicating that bacterial passage was due to paracytosis. After the addition of chloramphenicol, no bacteria were cultured from the basolateral side, and no bacterial clusters between the epithelial cells were seen, suggesting that de novo bacterial protein synthesis was needed for the bacteria to reach the intercellular space. We conclude that H. influenzae passes through viable cell layers of the human lung epithelial cell line NCI-H292 by paracytosis, requiring bacterial protein synthesis.     

Adequate Vitamin D Intake Cannot Be Achieved within Carbon Emission Limits Unless Food Is Fortified: A Simulation Study

This study applied linear programming using a Dutch “model diet” to simulate the dietary shifts needed in order to optimize the intake of vitamin D and to minimize the carbon footprint, considering the popularity of the diet. Scenarios were modelled without and with additional fortified bread, milk, and oil as options in the diets. The baseline diet provided about one fifth of the adequate intake of vitamin D from natural food sources and voluntary vitamin D-fortified foods. Nevertheless, when optimizing this diet for vitamin D, these food sources together were insufficient to meet the adequate intake required, unless the carbon emission and calorie intake were increased almost 3-fold and 2-fold, respectively. When vitamin D-fortified bread, milk, and oil were added as options to the diet, along with increases in fish consumption, and decreases in sugar, snack, and cake consumption, adequate intakes for vitamin D and other nutrients could be met within the 2000 kcal limits, along with a relatively unchanged carbon footprint. Achieving vitamin D goals while reducing the carbon footprint by 10% was only possible when compromising on the popularity of the diet. Adding vitamin D to foods did not contribute to the total carbon emissions. The modelling study shows that it is impossible to obtain adequate vitamin D through realistic dietary shifts alone, unless more vitamin D-fortified foods are a necessary part of the diet.     

Cytokines modulate contraction of periosteal explants from rabbit calvariae

Periosteal explants obtained from rabbit calvariae are introduced as a model system to study contraction of soft connective tissue. Culturing of these explants resulted in a substantial time-dependent decrease of the surface area which coincided with a similar decrease in volume. A 75% reduction of the initial explant surface area was observed after a culture period of 72h in the presence of 10% serum. Also in the absence of serum contraction of explants was found, indicating that serum components were not essential. Following devitalization of the explants no contraction did occur. A strong inhibition of contraction was found following interference with the formation of microfilaments, microtubules or intracellular cyclic-AMP levels by using cytochalasin B, colchicine or dibutyryl-cAMP, respectively. These data indicated that viable cells and an intact cytoskeleton were a prerequisite for contraction to occur. A number of cytokines (EGF, aFGF, bFGF, IGF-1, PDGF, TGF-beta and IL-1alpha) was tested for their ability to influence contraction. IL-1alpha was shown to inhibit contraction from the 48h culture period on. Anti-IL-1alpha-serum completely abolished this effect. The IL-1alpha-inducible inhibition of contraction was also partially blocked by indomethacin. TGF-beta enhanced contraction dose-dependently during the 24-48h culture period, whereas TGF-1 and IL-1alpha, added to the cultures in combination, proved to antagonize each other. The other growth factors did neither influence contraction not the IL-1alpha-induced inhibition of contraction.     

Side-effects of experimental pyrethroid applications for the control of tsetseflies in a riverine forest habitat (Africa)

During tsetse control operations near Bouaflé, Ivory Coast, Africa, a study was made of environmental side-effects of helicopter sprayings with permethrin and deltamethrin on a riverine forest. Terrestrial and aquatic arthropod populations and fish were observed for acute effects. The abundance of the species was assessed by various trapping devices before, during, and after the spraying cycle. Populations of mayfly-larvae and small shrimps (Caridina africana) were virtually eliminated after the spraying cycle. TheEphemeroptera recovered within the same season. Caddis-fly andSimulium-larvae populations were affected but they recovered within each spraying interval. Large shrimps (Macrobrachium vollenhovenii) were paralyzed by the insecticide. Recovery occurred within 48 hr. Among the terrestrial arthropods, the hymenopteran and dipteran populations were significantly affected. No effect was observed on bottom dwelling spiders. The ability of the ecosystems to recover from the disturbance is discussed.     

Intratumoral administration of recombinant human interleukin 12 in head and neck squamous cell carcinoma patients elicits a T-helper 1 profile in the locoregional lymph nodes.

The objective of this Phase II study was to evaluate the pharmacodynamic and immune effects of intratumorally administered recombinant human interleukin-12 (IL-12) on regional lymph nodes, primary tumor, and peripheral blood. Ten previously untreated patients with head and neck squamous cell carcinoma were injected in the primary tumor two to three times, once/week, at two dose levels of 100 or 300 ng/kg, before surgery. We compared these patients with 20 control (non-IL-12-treated) patients. Toxicity was high, with unexpected dose-limiting toxicities at the 300 ng/kg dose level. Dose-dependent plasma IFN-gamma and IL-10 increments were detected. These cytokine levels were higher after the first injection than after the subsequent injections. A rapid, transient reduction in lymphocytes, monocytes, and all lymphocyte subsets, especially natural killer cells, was observed, due to a redistribution to the lymph nodes. In the enlarged lymph nodes of the IL-12-treated patients, a higher percentage of natural killer cells and a lower percentage of T-helper cells were found compared with control patients. The same pattern was detected in the infiltrate in the primary tumor. Real-time semiquantitative PCR analysis of peripheral blood mononuclear cells in the peripheral blood showed a transient decrease of T-bet mRNA. Interestingly, the peripheral blood mononuclear cells in the lymph nodes showed a 128-fold (mean) increase of IFN-gamma mRNA. A switch from the Th2 to a Th1 profile in the lymph nodes compared with the peripheral blood occurred in the IL-12-treated patients. In conclusion, in previously untreated head and neck squamous cell carcinoma patients, recombinant human IL-12 intratumorally showed dose-limiting toxicities at the dose level of 300 ng/kg and resulted in measurable immunological responses locoregionally at both dose levels.     

Thallium-201 single-photon emission computed tomography as an early predictor of outcome in recurrent glioma.

PURPOSE: With limited response rates and potential toxicity of chemotherapeutic treatment in patients with recurrent glioma, reliable response assessment is essential. Currently, the assessment of treatment response in glioma patients is based on the combination of radiologic and clinical findings. However, response monitoring with computed tomography (CT) or magnetic resonance imaging (MRI) is hampered by several pitfalls and is prone to interobserver variability. The aim of this study was to establish the value of thallium-201 single-photon emission computed tomography (201Tl-SPECT) as a predictor of overall survival and response to chemotherapy in recurrent glioma, and to compare the value of 201Tl-SPECT with that of CT and MRI. PATIENTS AND METHODS: We studied patients who underwent CT or MRI and 201Tl-SPECT before chemotherapy (n = 57), and patients who also had undergone CT or MRI and 201Tl-SPECT after two courses of chemotherapy (n = 44). The value of the radiologic variables (CT-MRI tumor size, 201Tl-SPECT tumor size, and maximal tumor intensity) at baseline and at follow-up in predicting overall survival, and the percentage of patients alive and progression-free at 6 months (APF6) were examined using Cox regression and logistic regression analysis. RESULTS: Both at baseline and at follow-up, 201Tl-SPECT maximal tumor intensity was the strongest predictive variable and was inversely related to overall survival and APF6. In particular, progression of maximal tumor intensity after two courses of chemotherapy was a powerful predictor of poor outcome. CONCLUSION: 201Tl-SPECT is superior to conventional CT-MRI in the early prediction of overall survival and response to chemotherapy in patients with recurrent glioma.     

Nodal disease in purely glottic carcinoma: Is elective neck treatment worthwhile?

Objective: Although there is a generalized understanding of the relatively low overall incidence of nodal disease from purely glottic carcinoma, the exact role for elective neck treatment in the management of this disease remains controversial. The purpose of this study was to identify the incidence of occult nodal disease (including paratracheal) in patients who have glottic carcinoma without significant extra-glottic extension and to identify which patients are at risk for this. A retrospective chart review of 92 such patients who had either undergone neck dissection or been observed for a minimum of 2 years was performed. Results: For the 92 patients, neck treatment consisted of observation in 68 patients, paratracheal node dissection in four, unilateral neck dissection in four, unilateral neck dissection and excision of paratracheal nodes in 14, and bilateral neck dissection with paratracheal node excision in two. Of the 24 nodal dissections performed, four were positive for occult metastatic disease. No patient in the observation group developed nodal disease. Conclusion: The incidence of occult nodal disease in NO glottic carcinoma is low, 0% in early stage disease (T1–T2) and 19% in late stage disease (T3–T4). Nodes at highest risk included only the paratracheal, level II, and level III. Elective neck treatment should only be undertaken for advanced (T3–T4) disease and even then is of questionable benefit. If undertaken, it should have a low potential morbidity, such as selective neck dissection or radiation. Computed tomography was not useful in staging the neck for this subset of patients.