Temporal and spatial relations between age specific mortality and ambient air quality in the United States: regression results for counties, 1960-97

Objective: To investigate longitudinal and spatial relations between air pollution and age specific mortality for United States counties (except Alaska) from 1960 to the end of 1997.     

Is less more? Rethinking the extent of surgery for invasive cervical cancer

The surgical treatment of early-stage cancer of the cervix is undergoing renewed scrutiny in an effort to minimize complications, preserve fertility when desired by the patient, and yet avoid any compromise of therapeutic efficacy. With regard to radical hysterectomy, the extent of the parametrial resection and lymphadenectomy are two topics of particular interest. A review of the relevant literature concerning radical hysterectomy and cervical cancer that supports a less radical approach is discussed. For women with stage I cervical cancer, a less radical resection appears to offer more when considered in the context of fewer immediate and long-term complications and comparable long-term survival.     

Suppression of the contact hypersensitivity response following topical exposure to 2-butoxyethanol in female BALB/c mice

The effects of route of exposure, time of exposure and metabolism of 2-butoxyethanol (BE) on the contact hypersensitivity response (CHR) were evaluated in female BALB/c mice. Mice were either orally exposed to 50, 150 or 400 mg BE/kg or topically exposed to 0.25, 1.0, 4.0 or 16.0 mg BE on the ear and the oxazolone (OXA)-induced CHR evaluated by measuring ear thickness before and after OXA challenge. While no modulation was observed following oral exposure to BE, topical exposure resulted in a significant decrease in the CHR. Application of 4.0 mg BE in 4:1 acetone and olive oil (AOO) vehicle at the time of sensitization, challenge or both, decreased the CHR by 18%, 18% and 22%, respectively. A time course study of the effects of topical exposure to 4.0 mg BE/ear during the challenge phase of the CHR revealed that BE must be applied at the time of OXA challenge to significantly reduce the ear swelling response. In order to determine if metabolism of topically applied BE was required for suppression of the CHR, butoxyacetic acid (BAA), the primary metabolite of BE, was applied to the ear immediately following OXA challenge. No topical dose of BAA (2.0,4.0 and 8.0 mg BAA/ear) administered in this study altered the CHR. Blocking the metabolism of BE by oral administration of 4-methylpyrazole (MP), further reduced OXA-induced ear swelling when compared to mice exposed to BE without MP treatment. Taken together, these studies indicated that suppression of the CHR in mice following topical exposure to this glycol ether was due to the activity of BE itself and was not dependent on metabolic activation of the compound. Further studies were undertaken to identify a potential mechanism of BE-induced reduction of the CHR. Epidermal cells from untreated BALB/c mice were isolated and exposed to BE in vitro (10(-12), 10(-10), 10(-8), 10(-6) and l0(-4) M BE). In vitro exposure to BE at these concentrations did not significantly affect expression of MHC class II surface protein or protein synthesis in epidermal Langerhans cells, failing to provide in vitro evidence that BE-associated suppression of the CHR is associated with a reduction in MHC class II expression.     

Pharmacokinetics of alemtuzumab used for in vivo and in vitro T-cell depletion in allogeneic transplantations: relevance for early adoptive immunotherapy and infectious complications

Persistence of alemtuzumab at lympholytic concentrations after reduced-intensity conditioning allogeneic stem cell transplantations (RITs) could impair immune reconstitution and reduce donor T-cell-mediated graft-versus-leukemia/lymphoma (GVL) effects, derived from the graft or subsequent adoptive immunotherapy. We have studied the pharmacokinetics of alemtuzumab in 2 different groups: RIT (100 mg alemtuzumab in vivo over 5 days) and myeloablative allografts (20 mg alemtuzumab added in vitro to the stem cells prior to return). Alemtuzumab concentrations in RIT patients were in excess of that required to kill infused donor CD52+ cells at the time of transplantation and remained at potentially lympholytic levels (> 0.1 microg/mL) for approximately 56 days after transplantation, 26 days longer than for the myeloablative group. Total lymphocyte counts were significantly lower in the RIT group persisting beyond 6 months after transplantation (P =.005), and median absolute CD4 counts higher than 200 x 106/L were delayed until 9 months after transplantation.     

Reovirus oncolysis as a novel purging strategy for autologous stem cell transplantation

Hematologic stem cell rescue after high-dose cytotoxic therapy is extensively used for the treatment of many hematopoietic and solid cancers. Gene marking studies suggest that occult tumor cells within the autograft may contribute to clinical relapse. To date purging of autografts contaminated with cancer cells has been unsuccessful. The selective oncolytic property of reovirus against myriad malignant histologies in in vitro, in vivo, and ex vivo systems has been previously demonstrated. In the present study we have shown that reovirus can successfully purge cancer cells within autografts. Human monocytic and myeloma cell lines as well as enriched ex vivo lymphoma, myeloma, and Waldenstr?m macroglobulinemia patient tumor specimens were used in an experimental purging model. Viability of the cell lines or purified ex vivo tumor cells of diffuse large B-cell lymphoma, chronic lymphocytic leukemia, Waldenstr?m macroglobulinemia, and small lymphocytic lymphoma was significantly reduced after reovirus treatment. Further, [35S]-methionine labeling and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of cellular proteins demonstrated reovirus protein synthesis and disruption of host cell protein synthesis as early as 24 hours. Admixtures of apheresis product with the abovementioned tumor cells and cell lines treated with reovirus showed complete purging of disease. In contrast, reovirus purging of enriched ex vivo multiple myeloma, Burkitt lymphoma, and follicular lymphoma was incomplete. The oncolytic action of reovirus did not affect CD34+ stem cells or their long-term colony-forming assays even after granulocyte colony-stimulating factor (G-CSF) stimulation. Our results indicate the ex vivo use of an unattenuated oncolytic virus as an attractive purging strategy for autologous stem cell transplantations.     

Dexamethasone induces rapid serine-phosphorylation and membrane translocation of annexin 1 in a human folliculostellate cell line via a novel nongenomic mechanism involving the glucocorticoid receptor,protein kinase C,phosphatidylinositol 3-kinase,and mitogen-activated protein kinase

Our recent studies on rat pituitary tissue suggest that the annexin 1 (ANXA1)-dependent inhibitory actions of glucocorticoids on ACTH secretion are effected via a paracrine mechanism that involves protein kinase C (PKC)-dependent translocation of a serine-phosphorylated species of ANXA1 (Ser-P-ANXA1) to the plasma membrane of the nonsecretory folliculostellate cells. In the present study, we have used a human folliculostellate cell line (PDFS) to explore the signaling mechanisms that cause the translocation of Ser-P-ANXA1 to the membrane together with Western blot analysis and flow cytometry to detect the phosphorylated protein. Exposure of PDFS cells to dexamethasone caused time-dependent increases in the expression of ANXA1 mRNA and protein, which were first detected within 2 h of steroid contact. This genomic response was preceded by the appearance within 30 min of substantially increased amounts of Ser-P-ANXA1 and by translocation of the phosphorylated protein to the cell surface. The prompt membrane translocation of Ser-P-ANXA1 provoked by dexamethasone was inhibited by the glucocorticoid receptor, antagonist, mifepristone, but not by actinomycin D or cycloheximide, which effectively inhibit mRNA and protein synthesis respectively in our preparation. It was also inhibited by a nonselective PKC inhibitor (PKC(9-31)), by a selective inhibitor of Ca(2+)-dependent PKCs (Go 6976) and by annexin 5 (which sequesters PKC in other systems). In addition, blockade of phosphatidylinositiol 3-kinase (wortmannin) or MAPK pathways with PD 98059 or UO 126 (selective for MAPK kinse 1 and 2) prevented the steroid-induced translocation of Ser-P-ANXA1 to the cell surface. These results suggest that glucocorticoids induce rapid serine phosphorylation and membrane translocation of ANXA1 via a novel nongenomic, glucocorticoid receptor-dependent mechanism that requires MAPK, phosphatidylinositiol 3-kinase, and Ca(2+)-dependent PKC pathways.     

The Dental Cognitions Questionnaire in CBT for dental phobia in an adolescent with multiple phobias

A case of an adolescent boy with multiple phobias who was treated successfully for his dental phobia is described to illustrate the clinical utility of the Dental Cognitions Questionnaire (DCQ) in aiding effective cognitive-behavior therapy. The client showed drops in dental anxiety that coincided with the use of the DCQ in cognitive restructuring, and there was a close correlation between dental cognitions and degree of dental anxiety over the time-course of therapy and follow up.