A humanized mouse model of liver fibrosis following expansion of transplanted hepatic stellate cells.

Hepatic stellate cells (HSCs) are major contributors to liver fibrosis, as hepatic injuries may cause their transdifferentiation into myofibroblast-like cells capable of producing excessive extracellular matrix proteins. Also, HSCs can modulate engraftment of transplanted hepatocytes and contribute to liver regeneration. Therefore, understanding the biology of human HSCs (hHSCs) is important, but effective methods have not been available to address their fate in vivo.

Alternative Means of Estimating I Maximum Permissible Activity to Treat Thyroid Cancer.

To protect bone marrow from overirradiation, the maximum permissible activity (MPA) of I to treat thyroid cancer is that which limits the absorbed dose to blood (as a surrogate of marrow) to less than 200 cGy. The conventional approach (method 1) requires repeated γ-camera whole-body measurements along with blood samples. We sought to determine whether reliable MPA values can be obtained by simplified procedures.

Kupffer Cell Transplantation in Mice for Elucidating Monocyte/Macrophage Biology and for Potential in Cell or Gene Therapy.

Kupffer cells (KC) play major roles in immunity and tissue injury or repair. Because recapitulation of KC biology and function within liver will allow superior insights into their functional repertoire, we studied the efficacy of the cell transplantation approach for this purpose. Mouse KC were isolated from donor livers, characterized, and transplanted into syngeneic recipients.

Diagnosis of abnormal biliary copper excretion by positron emission tomography with targeting of (64)Copper-asialofetuin complex in LEC rat model of Wilson's disease.

Identification by molecular imaging of key processes in handling of transition state metals, such as copper (Cu), will be of considerable clinical value. For instance, the ability to diagnose Wilson's disease with molecular imaging by identifying copper excretion in an ATP7B-dependent manner will be very significant. To develop highly effective diagnostic approaches, we hypothesized that targeting of radiocopper via the asialoglycoprotein receptor will be appropriate for positron emission tomography, and examined this approach in a rat model of Wilson's disease.

Directly acting drugs prostacyclin or nitroglycerine and endothelin receptor blocker bosentan improve cell engraftment in rodent liver.

Unlabelled: To optimize strategies for liver-directed cell therapy, prevention of initial transplanted cell losses is particularly important for subsequent liver repopulation. After cell transplantation in hepatic sinusoids, perturbations in hepatic microcirculation along with changes in various liver cell types are among the earliest changes. Therefore, for advancing further concepts in cell engraftment we studied vascular and related events in the liver after transplanting syngeneic hepatocytes into dipeptidyl peptidase IV-deficient rats.

PET with 64Cu-histidine for noninvasive diagnosis of biliary copper excretion in Long-Evans cinnamon rat model of Wilson disease.

Unlabelled: Excretion of copper into bile requires the copper transporter Atp7b, which is deficient in Wilson disease. We hypothesized that a radiocopper-histidine complex would be effective for diagnosing Wilson disease by molecular imaging and tested this hypothesis in the Long-Evans cinnamon (LEC) rat model with Atp7b deficiency.

Methods: We complexed (64)Cu to l-histidine and analyzed clearance from blood, uptake in tissues, and excretion in bile of healthy Long-Evans agouti (LEA) rats versus LEC rats modeling Wilson disease.

Adenosine triphosphate-binding cassette subfamily C member 2 is the major transporter of the hepatobiliary imaging agent (99m)Tc-mebrofenin.

Unlabelled: The organic anion (99m)Tc-N-[2-[(3-bromo-2,4,6-trimethylphenyl)-amino]-2-oxoethyl]-N-(carboxymethyl)-glycine ((99m)Tc-mebrofenin) and its analogs are widely used for hepatobiliary imaging. Identification of the mechanisms directing bile canalicular transport of these agents will provide insights into the basis of their hepatic handling for assessing perturbations.

Methods: We performed studies in animals, including healthy Fischer 344 rats or rats treated with carbon tetrachloride or intrasplenic cell transplantation and healthy Wistar rats or HsdAMC:TR-Abcc2 mutant rats in Wistar background.

In vitro human leukocyte labeling with (64)Cu: an intraindividual comparison with (111)In-oxine and (18)F-FDG.

Unlabelled: We investigated labeling human leukocytes [white blood cells (WBCs)] in vitro with copper-64 (Cu) comparing labeling efficiency, viability and stability of Cu-WBCs with (111)In-oxine (In) WBCs and (18)F-FDG (FDG) WBCs.

Methods: Leukocytes from 10 volunteers were labeled with Cu, In and FDG. Forty milliliters of venous blood was collected and leukocyte separation was performed according to standard methods.

Molecular pathway-specific 99mTc-N-(3-bromo-2,4,6-trimethyacetanilide) iminodiacetic acid liver imaging to assess innate immune responses induced by cell transplantation.

Objectives: Inflammatory responses after cell transplantation impair engraftment of transplanted cells. We studied whether perturbations in specific molecular pathways after inflammation in a syngeneic cell transplantation model could be identified by noninvasive imaging.

Methods: After transplanting hepatocytes into the liver of dipeptidyl peptidase IV-deficient Fischer 344 rats, we imaged hepatobiliary excretion of ppmTc-N-(3-bromo-2,4,6-trimethyacetanilide) iminodiacetic acid (99mTc-mebrofenin).

Systemic and local release of inflammatory cytokines regulates hepatobiliary excretion of 99mTc-mebrofenin.

Objectives: Imaging agents capable of providing cell compartment-specific information will facilitate studies of pathophysiological mechanisms, natural history of diseases, and therapeutic development. To demonstrate the effects of liver injury on the disposal of the organic anion mebrofenin, we performed animal studies.

Methods: Acute liver injury was induced in Fischer 344 rats with 0.

Diagnosing prosthetic vascular graft infection with the antigranulocyte antibody 99mTc-fanolesomab.

Aim: The objectives of this retrospective investigation were to determine the accuracy of 99mTc-fanolesomab, an antigranulocyte antibody, for diagnosing prosthetic vascular graft infection, ascertain optimum imaging times for this indication, and assess safety of this agent.

Methods: Eighteen patients with 19 prosthetic vascular grafts were included. Indications for graft placement included peripheral vascular disease (8), haemodialysis (7), and aneurysm (4).

Monocrotaline promotes transplanted cell engraftment and advances liver repopulation in rats via liver conditioning.

Disruption of the hepatic endothelial barrier or Kupffer cell function facilitates transplanted cell engraftment in the liver. To determine whether these mechanisms could be activated simultaneously, we studied the effects of monocrotaline, a pyrollizidine alkaloid, with reported toxicity in liver sinusoidal endothelial cells and Kupffer cells. The effects of monocrotaline in Fischer 344 rats were examined by tissue morphology, serum hyaluronic acid levels, and liver tests (endothelial and hepatocyte injury) or incorporation of carbon and (99m)Tc-sulfur colloid (Kupffer cell damage).

PET with FDG-labeled leukocytes versus scintigraphy with 111In-oxine-labeled leukocytes for detection of infection.

Purpose: To compare prospectively the accuracy of positron emission tomography (PET) with leukocytes labeled in vitro with (18)F fluorodeoxyglucose (FDG) versus that of conventional scintigraphy with leukocytes labeled in vitro with (111)In oxine in patients suspected of having infection.

Materials And Methods: This HIPAA-compliant study had institutional review board approval; informed consent was obtained from all patients. Patients were 25 men and 26 women aged 32-86 years.

Hepatic targeting of transplanted liver sinusoidal endothelial cells in intact mice.

Targeting of cells to specific tissues is critical for cell therapy. To study endothelial cell targeting, we isolated mouse liver sinusoidal endothelial cells (LSEC) and examined cell biodistributions in animals. To identify transplanted LSEC in tissues, we labeled cells metabolically with DiI-conjugated acetylated low density lipoprotein particles (DiI-Ac-LDL) or (111)Indium-oxine, used LSEC from Rosa26 donors expressing beta-galactosidase or Tie-2-GFP donors with green fluorescent protein (GFP) expression, and tranduced LSEC with a GFP-lentiviral vector.

Regulation of hepatobiliary transport activity and noninvasive identification of cytokine-dependent liver inflammation.

Unlabelled: Many diseases are associated with cytokine release after inflammatory infiltration, which perturbs organ function. Radioligands capable of noninvasive tracking to assess the integrity of specific biochemical pathways offer potent ways to establish such perturbing mechanisms.

Methods: To demonstrate regulation of hepatobiliary transport in disease, we used (99m)Tc-mebrofenin in a carbon tetrachloride-induced liver injury model in Fischer 344 rats.

Diagnosing infection in the failed joint replacement: a comparison of coincidence detection 18F-FDG and 111In-labeled leukocyte/99mTc-sulfur colloid marrow imaging.

Unlabelled: The objectives of this study were to investigate (18)F-FDG imaging, using a coincidence detection system, for diagnosing prosthetic joint infection and to compare it with combined (111)In-labeled leukocyte/(99m)Tc-sulfur colloid marrow imaging in patients with failed lower extremity joint replacements.

Methods: Fifty-nine patients--with painful, failed, lower extremity joint prostheses, 40 hip and 19 knee--who underwent (18)F-FDG, labeled leukocyte, and bone marrow imaging, and had histopathologic and microbiologic confirmation of the final diagnosis, formed the basis of this investigation. (18)F-FDG images were interpreted as positive for infection using 4 different criteria: criterion 1: any periprosthetic activity, regardless of location or intensity; criterion 2: periprosthetic activity on the (18)F-FDG image, without corresponding activity on the marrow image; criterion 3: only bone-prosthesis interface activity, regardless of intensity; criterion 4: semiquantitative analysis--a lesion-to-background ratio was generated, and the cutoff value yielding the highest accuracy for determining the presence of infection was determined.

Sestamibi is a substrate for MDR1 and MDR2 P-glycoprotein genes.

Technetium-99m sestamibi has attracted interest for assessment of the function of P-glycoproteins, which are well expressed in the liver and have roles in biliary transport and the removal of chemotherapeutic drugs. To further examine the cross-reactivity of (99m)Tc-sestamibi for P-glycoprotein family members, we conducted studies in animals. Hepatobiliary secretion of (99m)Tc-sestamibi was determined in normal FVB/N mice, mutant mice with specific P-glycoprotein deficiencies in the FVB/N background, normal Long-Evans Agouti (LEA) rats, and Long-Evans Cinnamon (LEC) rats with abnormal copper transport and liver disease but intact P-glycoprotein expression.

Pulmonary activity on labeled leukocyte images: physiologic, pathologic, and imaging correlation.

Accurate interpretation of labeled leukocyte images requires knowledge of pulmonary labeled leukocyte uptake: its prevalence and patterns and its correlation with technical, physiologic, and pathologic conditions as well as with other imaging findings. Images obtained shortly after injection of labeled cells are characterized by diffuse pulmonary activity, which decreases over time, until about 4 hours after injection when it becomes indistinguishable from background activity, remaining constant thereafter. Focal pulmonary uptake that is segmental or lobar in appearance is most often associated with bacterial pneumonia.

Kupffer cells participate in early clearance of syngeneic hepatocytes transplanted in the rat liver.

Background & Aims: Kupffer cells are activated shortly after deposition of hepatocytes in liver sinusoids, with clearance of a significant fraction of transplanted cells, especially when cells are entrapped in portal spaces. We determined whether perturbation of Kupffer cells would improve transplanted cell engraftment.

Methods: Dipeptidyl peptidase IV-deficient rats were used as recipients of syngeneic Fischer 344 rat hepatocytes.

Cyclophosphamide disrupts hepatic sinusoidal endothelium and improves transplanted cell engraftment in rat liver.

To determine whether disruption of the hepatic sinusoidal endothelium will facilitate engraftment of transplanted cells, we treated Fischer 344 (F344) rats lacking dipeptidyl peptidase IV (DPPIV) activity with cyclophosphamide (CP). Electron microscopy showed endothelial injury within 6 hours following CP, and, after 24 and 48 hours, the endothelium was disrupted in most hepatic sinusoids. CP did not affect Kupffer cell function.

Hepatic sinusoidal vasodilators improve transplanted cell engraftment and ameliorate microcirculatory perturbations in the liver.

After transplantation, hepatocytes entering liver sinusoids are engrafted, whereas cells entrapped in portal spaces are cleared. We studied whether hepatic sinusoidal dilatation will increase the entry of transplanted cells in the liver lobule, improve cell engraftment, and decrease microcirculatory perturbations. F344 rat hepatocytes were transplanted intrasplenically into syngeneic dipeptidyl peptidase IV (DPPIV)-deficient rats.

99mTc-mebrofenin scintigraphy for evaluating liver disease in a rat model of Wilson's disease.

Unlabelled: The purpose of this study was to establish whether (99m)Tc-mebrofenin could noninvasively assess liver function in Wilson's disease.

Methods: Long-Evans Cinnamon (LEC) rats, which reproduce Wilson's disease with copper toxicosis, and their normal counterparts, Long-Evans Agouti (LEA) rats, were studied. Scintigraphic findings were correlated with biliary mebrofenin excretion and residual organ counts and with hepatic copper content, histology, copper excretion capacity, and liver test results.