A Bayesian approach to aid in formulary decision making: incorporating institution-specific cost-effectiveness data with clinical trial results.

Pharmacy and therapeutics committees commonly cite a lack of generalizability as a reason for not incorporating cost-effectiveness information into decision making. To address this concern, many committees undertake site-specific economic evaluations, which are often limited by small sample sizes and nonrandomized designs. We show how 2 complementary approaches were used to minimize these limitations in an economic evaluation of abciximab at 1 institution. Using a propensity score methodology, we selected patients who did not receive abciximab for the comparison cohort. Then, we adopted a Bayesian, hierarchical, random-effects model to integrate site-specific and clinical trial data. We applied the posterior distributions of effectiveness with local cost data in a traditional decision-analytic model. In 74% of the simulations, abciximab was cost-effective at 1 institution at the $50,000 per life year saved threshold, assuming a 50:50 split of patients undergoing coronary stenting and angioplasty. Among patients undergoing coronary stenting, the cost-effectiveness ratio of the addition of abciximab was at or below the $50,000 per life year saved threshold in 66.0% of the simulations.     

Vasopressin stimulation of NaCl transport in the medullary thick ascending limb of Henle's loop is decreased in aging mice

The maximal urinary osmolality that can be reached by the kidney is reduced with age. This may be due to impaired NaCl transport by the medullary thick ascending limb of Henle's loop, which is part of the renal concentrating mechanism and is modulated by antidiuretic hormone (ADH). We therefore tested in vitro a possible age-related change in the transport capacity and in the response of this nephron segment to ADH in young (1–2 months) and old (20–24 months) mice. The transepithelial potential difference (V _te) was significantly higher in young mice (+8.5±0.4 mV, n=13) than in old ones (+6.6±0.5 mV, n=17). Addition of 0.1 nmol.l^–1 ADH to the bath solution significantly increased V _te by 5.2±0.5 mV in the young and by 3.1±0.6 mV in the old animals. Application of dibutyryl-cAMP (0.1 mmol.1^–1) did not further increase the hormonal response in both groups. The ADH-mediated increase in the corresponding equivalent short-circuit current (I _SC = V _te/R_te) was twice as great in young mice as in old, indicating that the stimulation of NaCl transport by ADH across the medullary thick ascending limb is significantly reduced with age. These results suggest that the previously reported age-related defect in the urinary concentrating ability of the kidney is partly due to a decreased response of the medullary thick ascending limb to ADH.     

Effect of ibuprofen and interleukin 2 on transfusion-induced suppression of cell-mediated immunity

Transfusion-induced immunosuppression has been associated with excessive production of prostaglandin E and decreased interleukin 2 (IL-2) production. In the present study, allogeneic blood-transfused mice were tested for cell-mediated immunity with the use of a delayed-type hypersensitivity assay. In vivo administration of a cyclo-oxygenase inhibitor, ibuprofen, and murine recombinant IL-2 was initiated on day 0 and continued daily throughout the delayed-type hypersensitivity assay. The results indicate that prostaglandin E may play a primary role in allogeneic blood transfusion-induced suppression, as manifest by normal responses in ibuprofen-treated mice. Supplementation of transfused mice with recombinant IL-2 also preserved immune response, indicating inadequate IL-2 production after transfusion, while receptor expression appears to remain intact.     

Noninvasive assessment of metabolism in wounded skin by 31P-NMR in vivo.

Phosphorus-31 nuclear magnetic resonance techniques using shallow penetrating coils have been used to noninvasively monitor severity and metabolic changes over time in skin wounds in rats. Ratios of phosphocreatine (PCr) to inorganic phosphate (Pi) indicate energy status in both thermal wounds and surgical flaps. In partial and full-thickness scald wounds, reductions in PCr/Pi ratios correlated with burn depth and improved over time postinjury, suggesting wound revascularization. No decrease in intracellular pH was noted in these wounds; the phosphate shifts may be primarily the result of tissue degradation followed by restoration of the microvasculature. Distal regions of caudally based dorsal 3 x 10 cm full-thickness skin flaps reveal progressively lower PCr/Pi ratios to 3-6 hours after elevation as well as drops in pH up to 0.5 units, presumably as a result of anaerobic glycolysis in these tissues. After 24 hours, the intracellular pH returned to normal (7.1-7.2) and the PCr/Pi ratios approached 70%-90% of the well-perfused proximal regions within 3-7 days. These results indicate the establishment of a microvasculature from the underlying bed as the distal regions survive as free grafts. The data demonstrate the potential usefulness of the technique in noninvasive measurement of the biochemical response to injury and wound healing in living organisms.     

Histoincompatibility-associated differences in the phenotypes of murine cardiac allograft infiltrating T cells.

Mechanisms of graft rejection may be governed in part by the kind and degree of histocompatibility differences between donor and recipient. Cardiac allograft rejection was studied in three murine models selected to provide disparity at different major histocompatibility complex (MHC), minor lymphocyte stimulating (Mls) and other minor histocompatibility loci. Graft survival for the A.TL to A.TH combination (M3) was significantly longer (median day of rejection 15.0 days) than both the B10.A to AKR (M2) or the C57BL/6 to C3H/HeN (M1) donor-recipient combinations (median days of rejection: 9.0 days and 9.0 days respectively; P < 0.001). The infiltration of grafts by T cells was examined by removal of grafts serially post-transplantation and culturing mechanically disrupted graft tissue with interleukin-2 (IL-2). Recovery of T cells by this method revealed highly reproducible characteristics (kinetic and phenotypic), unique to each donor-recipient combination. Cultures from M1 and M2 grafts had differing CD4/CD8 T-cell ratios at days 2 (1.8 versus 0.7, respectively) and 4 (1.6 versus 0.1, respectively) post-transplantation. The M3 model differed from M2 (at days 4, 8 and 10) and from M1 (at days 8 and 10). At these times, cultures of M3 grafts contained a significantly increased percentage of CD4 cells and significantly decreased percentage of CD8 cells (CD4/CD8 ratios 0.9-1.3) by comparison with M1 (CD4/CD8 ratios 0.02-0.04) and M2 (CD4/CD8 ratios 0.1-0.02). Long-surviving M3 grafts (greater than 30 days post-transplantation) were compared with grafts removed immediately upon cessation of graft function (days 14, 15 and 18 post-transplantation). There was a significant difference between these groups in the ratios of CD4/CD8 T-cell ratios (1.1 versus 0.4, respectively). This study suggests that the cellular rejection mechanism of a graft is a variable process driven by the individual histocompatibility antigen disparity between donor and recipient. These findings may have diagnostic and therapeutic applications in organ transplantation.     

Screening protocol for Torulopsis (Candida) glabrata.

A screening test has been developed for the presumptive identification of Torulopsis (Candida) glabrata from other common clinical isolates of yeast-like fungi. An interlaboratory comparison of a protocol consisting of morphology on cornmeal Tween 80 agar and trehalose fermentation at 42 degrees C was successful in differentiating T. glabrata from other taxa that are frequent or possible clinical isolates. The screening results for 517 clinical yeast isolates, 241 of which were T. glabrata, were compared with their final identification via commercial systems (API20C Yeast Identification System [bioMERIEUX, Hazelwood, Mo.] and Rapid Yeast Identification Panel [Dade Microscan, Sacramento, Calif.]). The trehalose screening test has a sensitivity and a specificity of 97.8 and 95.8%, respectively, and a positive predictive value of 97.4% and a negative predictive value of 96.5%. Overall, the trehalose screen had an efficiency rating of 93.9% for ruling in or out T. glabrata. Since T. glabrata represents a substantial part of the workload in a clinical laboratory, a significant reduction in direct and indirect costs should be realized.     

Sister chromatid exchange analysis in lung and peripheral blood lymphocytes of mice exposed to methyl isocyanate by inhalation

Mice were exposed to 1, 3, or 6 ppm methyl isocyanate (MIC) for 6 hr/day for four consecutive days. Lung cells and peripheral blood lymphocytes (PBLs) were removed and cultured for analysis of sister chromatid exchange (SCE) and cell cycle kinetics. MIC caused a small but significant increase in SCE frequency of cultured lung cells from mice exposed to 1, 3, or 6 ppm MIC. MIC did not significantly increase SCE levels in PBLs of mice exposed to concentrations as high as 6 ppm. In cultured PBLs, MIC had a stimulatory effect on cell cycling rates as measured by the replicative index, and it caused a significant reduction in mononuclear leucocyte counts and the mitotic indices.     

Culture of menstrual endometrium with peritoneal explants and mesothelial monolayers confirms attachment to intact mesothelial cells

BACKGROUND: To evaluate adhesion of menstrual endometrium (ME) to intact peritoneal mesothelium. METHODS: Explants of peritoneum were cultured for 1 h with ME (n = 6). Specimens were serially sectioned for haematoxylin and eosin stain and immunohistochemistry using an anti-cytokeratin antibody to label mesothelium. Confocal laser scanning microscopy (CLSM) was performed to identify an intact layer of mesothelial cells (MC) underlying sites of ME attachment. Also, ME and MC were labelled with Cell-Tracker dyes. ME was cultured with mesothelial monolayers for 1 h (n = 10). Cultures were examined with differential interference contrast and CLSM. Optical sections were taken and a three-dimensional model was constructed. RESULTS: In the peritoneal explants, ME adhered to intact mesothelium. There was no evidence of transmesothelial invasion. CLSM of sections of the explants demonstrated an intact monolayer of cytokeratin positive cells below the sites of ME implantation. Cytokeratin negative and positive ME cells adhered to mesothelial cells. Likewise, the ME attached to cultured mesothelium. Orthogonal sections and three-dimensional reconstruction confirmed an intact monolayer of mesothelium underlying ME attachment sites. CONCLUSIONS: This study confirms that ME adheres rapidly to intact peritoneal mesothelium. Further studies are needed that characterize the mechanisms of ME adhesion to, and migration through, mesothelial cells.