ABSTRACT
Ischemia-reperfusion injury-mediated primary graft dysfunction substantially hampers short- and long-term outcomes after lung transplantation. This condition continues to be diagnosed based on oxygen exchange parameters as well as radiological appearance, and therapeutic strategies are mostly supportive in nature. Identifying patients who may benefit from targeted therapy would therefore be highly desirable. Here, we show that C-C chemokine receptor type 2 (CCR2) expression in murine lung transplant recipients promotes monocyte infiltration into pulmonary grafts and mediates graft dysfunction. We have developed new positron emission tomography imaging agents using a CCR2 binding peptide, ECLi1, that can be used to monitor inflammatory responses after organ transplantation. Both 64 Cu-radiolabeled ECL1i peptide radiotracer (64 Cu-DOTA-ECL1i) and ECL1i-conjugated gold nanoclusters doped with 64 Cu (64 CuAuNCs-ECL1i) showed specific detection of CCR2, which is upregulated during ischemia-reperfusion injury after lung transplantation. Due to its fast pharmacokinetics, 64 Cu-DOTA-ECL1i functioned efficiently for rapid and serial imaging of CCR2. The multivalent 64 CuAuNCs-ECL1i with extended pharmacokinetics is favored for long-term CCR2 detection and potential targeted theranostics. This imaging may be applicable for diagnostic and therapeutic purposes for many immune-mediated diseases.
Subject(s)
Lung Transplantation/methods , Molecular Imaging/methods , Receptors, CCR2/physiology , Reperfusion Injury/diagnostic imaging , Animals , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/immunology , Monocytes/metabolism , Peptide Fragments/metabolism , Positron-Emission Tomography/methods , Reperfusion Injury/immunology , Reperfusion Injury/metabolism , Signal TransductionABSTRACT
Published data suggest that the average concentration of busulfan at steady state (Bu Css) is critical for successful engraftment in children receiving busulfan as a conditioning agent for bone marrow transplantation (BMT). We previously found in children that a Bu Css <600 ng/ml correlated with autologous recovery/mixed chimerism; there was no correlation between Bu Css and regimen-related toxicity (RRT). In a cohort continuous with the previous trial, we prospectively evaluated targeted busulfan concentrations in 32 pediatric patients (age 0.6-18.5 years) with AML (n = 6), CML (n = 6) and non-malignant disorders (n = 20) receiving HLA-closely matched donor grafts. In this trial, individual busulfan pharmacokinetics were performed prior to admission. Busulfan doses were then adjusted to achieve a Bu Css target range of 600-900 ng/ml +/- 10% depending on donor source and disease. A repeat study was done following dose 1 of the conditioning regimen. Thirty of thirty-two (94%) patients achieved target concentrations. Total busulfan doses ranged from 10.9 to 29 mg/kg. Thirty of thirty-two patients (94%) have durably engrafted. Grade 3/4 RRT occurred in seven patients (21%). Targeting Bu Css ranges of 600-900 ng/ml significantly improved our rate of successful engraftment from 74% to 94% (P = 0.043). These results indicate that targeted busulfan dosing optimizes allogeneic engraftment in children.
Subject(s)
Bone Marrow Transplantation/methods , Busulfan/administration & dosage , Transplantation Conditioning/methods , Administration, Oral , Adolescent , Adult , Bone Marrow Transplantation/statistics & numerical data , Busulfan/adverse effects , Busulfan/pharmacokinetics , Busulfan/therapeutic use , Child , Child, Preschool , Cohort Studies , Drug Administration Schedule , Graft Rejection/diagnosis , Humans , Infant , Prospective Studies , Transplantation Conditioning/statistics & numerical dataABSTRACT
PIP: Considerable literature indicates that variation in macro-sociodemographic dependent variables such as quality of life indicators may be linked to erratic departures from trends in some macroeconomic determinants. The author explores the nature of the effects of excessive fluctuations in export earnings and income on infant mortality rate using single-country time series data on Sudan for the period 1954-91. Ordinary least squares model estimation findings indicate that instability in income has a systematic and significant adverse effect upon infant mortality, while instability in export earnings exhibits a consistent lack of significance. These results indicate that recent sociological studies of the Third World may have overlooked some aspects of development potentially capable of explaining declines in development or quality of life indicators.^ieng