Frederic H. Fahey

Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment

Osteoblasts and endothelium constitute functional niches that support haematopoietic stem cells in mammalian bone marrow. Adult bone marrow also contains adipocytes, the number of which correlates inversely with the haematopoietic activity of the marrow. Fatty infiltration of haematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia. To explore whether adipocytes influence haematopoiesis or simply fill marrow space, we compared the haematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. Here we show, by flow cytometry, colony-forming activity and competitive repopulation assay, that haematopoietic stem cells and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 ‘fatless’ mice, which are genetically incapable of forming adipocytes, and in mice treated with the peroxisome proliferator-activated receptor-γ inhibitor bisphenol A diglycidyl ether, which inhibits adipogenesis, marrow engraftment after irradiation is accelerated relative to wild-type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone-marrow microenvironment, and indicate that antagonizing marrow adipogenesis may enhance haematopoietic recovery in clinical bone-marrow transplantation.

Skeletal PET with 18F-Fluoride: Applying New Technology to an Old Tracer

Although 18F-labeled NaF was the first widely used agent for skeletal scintigraphy, it quickly fell into disuse after the introduction of 99mTc-labeled bone-imaging agents. Recent comparative studies have demonstrated that 18F-fluoride PET is more accurate than 99mTc-diphosphonate SPECT for identifying both malignant and benign lesions of the skeleton. Combining 18F-fluoride PET with other imaging, such as CT, can improve the specificity and overall accuracy of skeletal 18F-fluoride PET and probably will become the routine clinical practice for 18F-fluoride PET. Although 18F-labeled NaF and 99mTc-diphosphonate have a similar patient dosimetry, 18F-fluoride PET offers shorter study times (typically less than 1 h), resulting in a more efficient workflow, improved patient convenience, and faster turnarounds of reports to the referring physicians. With the widespread availability of PET scanners and the improved logistics for the delivery of 18F radiopharmaceuticals, prior limitations to the routine use of 18F-fluoride bone imaging have largely been overcome. The favorable imaging performance and the clinical utility of 18F-fluoride PET, compared with 99mTc-diphosphonate scintigraphy, support the reconsideration of 18F-fluoride as a routine bone-imaging agent.

Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease.

Osteosarcoma is the most common primary malignant tumor of bone. Analysis of familial cancer syndromes and sporadic cases has strongly implicated both p53 and pRb in its pathogenesis; however, the relative contribution of these mutations to the initiation of osteosarcoma is unclear. We describe here the generation and characterization of a genetically engineered mouse model in which all animals develop short latency malignant osteosarcoma. The genetically engineered mouse model is based on osteoblast-restricted deletion of p53 and pRb. Osteosarcoma development is dependent on loss of p53 and potentiated by loss of pRb, revealing a dominance of p53 mutation in the development of osteosarcoma. The model reproduces many of the defining features of human osteosarcoma including cytogenetic complexity and comparable gene expression signatures, histology, and metastatic behavior. Using a novel in silico methodology termed cytogenetic region enrichment analysis, we demonstrate high conservation of gene expression changes between murine osteosarcoma and known cytogentically rearranged loci from human osteosarcoma. Due to the strong similarity between murine osteosarcoma and human osteosarcoma in this model, this should provide a valuable platform for addressing the molecular genetics of osteosarcoma and for developing novel therapeutic strategies.

Dexmedetomidine-Induced Sedation in Volunteers Decreases Regional and Global Cerebral Blood Flow

Dexmedetomidine is a selective &agr;2-agonist approved for sedation of critically ill patients. There is little information on the effects of dexmedetomidine on cerebral blood flow (CBF) or intracranial hemodynamics, despite considerable other pharmacodynamic data. We hypothesized that therapeutic doses of dexmedetomidine would decrease CBF. Therefore, nine supine volunteers, aged 24–48 yr, were infused with a 1 &mgr;g/kg IV loading dose of dexmedetomidine, followed by an infusion of 0.2 &mgr;g · kg−1 · h−1 (LOW DEX) and 0.6 &mgr;g · kg−1 · h−1 (HIGH DEX). Hemodynamic and CBF (via positron emission tomography) measurements were determined at each experimental time point. Dexmedetomidine decreased both cardiac output and heart rate during and 30 min after drug administration. Blood pressure decreased from 12% to 16% during and after the dexmedetomidine administration. Global CBF was decreased significantly from baseline (91 mL · 100 g−1 · min−1 [95% confidence interval, 72–114] to 64 mL · 100 g−1 · min−1 [51–81] LOW DEX and 61 mL · 100 g−1 · min−1 [48–76] HIGH DEX). This decrease in CBF remained constant for at least 30 min after the dexmedetomidine infusion was discontinued, despite the plasma dexmedetomidine concentration decreasing 40% during this same time period (628 pg/mL [524–732] to 380 pg/mL [253–507]).

The Voltage–gated Proton Channel, Hv1, Enhances Brain Damage from Ischemic Stroke

Phagocytic cell NADPH oxidase (NOX) generates reactive oxygen species (ROS) as part of innate immunity. Unfortunately, ischemia can also induce this pathway and inflict damage on native cells. The voltage-gated proton channel Hv1 enables NOX function by compensating cellular loss of electrons with protons. Accordingly, we investigated whether NOX-mediated brain damage in stroke can be inhibited by suppression of Hv1. We found that mouse and human brain microglia, but not neurons or astrocytes, expressed large Hv1-mediated currents. Hv1 was required for NOX-dependent ROS generation in brain microglia in situ and in vivo. Mice lacking Hv1 were protected from NOX-mediated neuronal death and brain damage 24 h after stroke. These results indicate that Hv1-dependent ROS production is responsible for a substantial fraction of brain damage at early time points after ischemic stroke and provide a rationale for Hv1 as a therapeutic target for the treatment of ischemic stroke.

Minimizing and Communicating Radiation Risk in Pediatric Nuclear Medicine

The value of pediatric nuclear medicine is well established. Pediatric patients are referred to nuclear medicine from nearly all pediatric specialties including urology, oncology, cardiology, gastroenterology, and orthopedics. Radiation exposure is associated with a potential, small, risk of inducing cancer in the patient later in life and is higher in younger patients. Recently, there has been enhanced interest in exposure to radiation from medical imaging. Thus, it is incumbent on practitioners of pediatric nuclear medicine to have an understanding of dosimetry and radiation risk to communicate effectively with their patients and their families. This article reviews radiation dosimetry for radiopharmaceuticals and also CT given the recent proliferation of PET/CT and SPECT/CT. It also describes the scientific basis for radiation risk estimation in the context of pediatric nuclear medicine. Approaches for effective communication of risk to patients’ families are discussed. Lastly, radiation dose reduction in pediatric nuclear medicine is explicated.

Early experience with fluorine-18 sodium fluoride bone PET in young patients with back pain.

Purpose: Skeletal positron emission tomography (PET) with fluorine-18 (18F) sodium fluoride (18F NaF) is an alternative to technetium-99m (99mTc)methylene diphosphonate (MDP) scintigraphy. Experience with pediatric PET is sparse, primarily in oncology. This study assesses the role of 18F NaF in evaluating young patients with back pain. Methods: Ninety-four 18F NaF PET scans were performed in 94 patients (27 males, 67 females; mean age, 15 years; range, 4-26 years) with back pain. Three-dimensional PET acquisition was performed 30 minutes after administration of 18F NaF (2.1 MBq/kg; maximum, 148 MBq). Radiation doses are presented for 18F NaF and 99mTc MDP. Results: 18F NaF PET revealed a possible cause of back pain in 55% (52/94). Fifteen patients had 2 or more potential sources of back pain. Diagnoses by PET were pars interarticularis/pedicle stress (34%), spinous process injury (16%), vertebral body ring apophyseal injury (14%), stress at a transitional vertebra-sacral articulation (7%), and sacroiliac joint inflammation/stress (3%). Comparing 18F NaF PET with 99mTc MDP scintigraphy, time between injection and scanning was shorter (0.5 hours vs 3 hours), radiation dosimetry was similar (3.5 mGy vs 2.8 mGy effective dose for a 55-kg patient for 18F NaF and 99mTc MDP, respectively), and cost of radiopharmaceutical was higher. Conclusions: 18F NaF bone PET can detect a variety of skeletal abnormalities in young patients with back pain. Relative to 99mTc MDP, images are of higher resolution. Total time from tracer administration to completion is shorter, and radiation dosimetry is similar. Higher cost for 18F NaF may be offset by enhanced patient throughput.

Pediatric radiation exposure and effective dose reduction during voiding cystourethrography.

PURPOSE To compare radiation exposure and effective dose in children who underwent voiding cystourethrography (VCUG) performed with grid-controlled variable-rate pulsed fluoroscopy (GCPFL) with radiation exposure and effective dose in children who underwent VCUG performed with continuous fluoroscopy (CFL) and to compare these effective doses with those estimated with radionuclide cystography (RNC). MATERIALS AND METHODS Institutional review board approval was obtained, and the informed consent requirement was waived for this HIPAA-compliant retrospective study. Radiation exposure and fluoroscopy time during VCUG were reviewed in 145 children (75 girls, 70 boys; age range, 3 days to 8 years) who underwent GCPFL or CFL between 2001 and 2002. Children were grouped on the basis of the fluoroscopy unit used and their supine anteroposterior abdominal diameter (group 1, 8.0-8.5-cm diameter; group 2, 10-11-cm diameter; group 3, 12-13-cm diameter). Analysis of variance was used to compare radiation exposure and fluoroscopy time between fluoroscopy units and patient diameter groups. Effective doses were calculated and compared for both fluoroscopes and for estimated RNC dose values. RESULTS GCPFL resulted in a significant reduction in total radiation exposure, which was at least eight times lower than that with CFL in all three groups (P < .001 for all). There was no significant difference in fluoroscopy time (P > .50). Effective radiation doses from GCPFL were approximately one order of magnitude lower than those from CFL but one order of magnitude higher than those from RNC. CONCLUSION In children, VCUG can be performed with a GCPFL unit that delivers radiation exposures that are at least eight times lower than those delivered by a conventional CFL unit. SUPPLEMENTAL MATERIAL http://radiology.rsnajnls.org/cgi/content/full/2492062066/DC1.

Cortical activity related to accuracy of letter recognition.

Previous imaging and neurophysiological studies have suggested that the posterior inferior temporal region participates in tasks requiring the recognition of objects, including faces, words, and letters; however, the relationship between accuracy of recognition and activity in that region has not been systematically investigated. In this study, positron emission tomography was used to estimate glucose metabolism in 60 normal adults performing a computer-generated letter-recognition task. Both a region of interest and a voxel-based method of analysis, with subject state and trait variables statistically controlled, found task accuracy to be: (1) negatively related to metabolism in the left ventrolateral inferior temporal occipital cortex (Brodmanns area 37, or ventrolateral BA 37) and (2) positively related to metabolism in a region of the right ventrolateral frontal cortex (Brodmanns areas 47 and 11, or right BA 47/11). Left ventrolateral BA 37 was significantly related both to hits and to false alarms, whereas the right BA 47/11 finding was related only to false alarms. The results were taken as supporting an automaticity mechanism for left ventrolateral BA 37, whereby task accuracy was associated with automatic letter recognition and in turn to reduced metabolism in this extrastriate area. The right BA 47/11 finding was interpreted as reflecting a separate component of task accuracy, associated with selectivity of attention broadly and with inhibition of erroneous responding in particular. The findings are interpreted as supporting the need for control of variance due to subject and task variables, not only in correlational but also in subtraction designs.

Administered Radiopharmaceutical Doses in Children: A Survey of 13 Pediatric Hospitals in North America

Universally applied standards for administering radiopharmaceutical doses in children do not presently exist. Hence, pediatric radiopharmaceutical dosimetry varies considerably from institution to institution and is generally based on the recommended adult dose adjusted for body mass. Methods: We surveyed 13 pediatric hospitals in North America to obtain objective data on dosimetry practices for 16 pediatric nuclear medicine examinations, including the minimum total radiopharmaceutical administered dose per examination, the total administered dose based on body mass, and maximum total doses in children. Results: The reported administered doses of radiopharmaceuticals to children vary over a relatively large range, especially with respect to minimum total administered doses. Conclusion: This survey has identified a broad range of administered doses directly leading to variability in radiation-absorbed doses to patients. The nuclear medicine community should develop pediatric standards for radiopharmaceutical administered doses and reduce radiation exposure in children, such as through the use of modern software reconstruction techniques.