99mTc Uptake Research Articles

In Vivo Imaging of Retinoic Acid Receptor Activity using a Sodium/Iodide Symporter and Luciferase Dual Imaging Reporter Gene

Retinoic acids are natural derivatives of vitamin A, and play important roles in modulating tumor cell growth by regulating differentiation, thus suggesting the potential use of these derivatives in cancer therapy and prevention. To visualize the intranuclear responses of functional retinoic acid receptors, we have developed a dual-imaging reporter gene system based on the use of sodium/iodide symporter (NIS) and luciferase in cancer cell lines. NIS and luciferase genes were linked with an internal ribosome entry site, and placed under the control of an artificial cis-acting retinoic acid responsive element (pRARE/NL). After retinoic acid treatment, I-125 uptake by pRARE/NL transfected cells was found to have increased by up to about five times that of nontreated cells. The bioluminescence intensity of pRARE/NL transfected cells showed dose-dependency. In vivo luciferase images showed higher intensity in retinoic acid treated SK-RARE/NL tumors, and scintigraphic images of SK-RARE/NL tumors showed increased Tc-99m uptake after retinoic acid treatment. The NIS/luciferase imaging reporter system was sufficiently sensitive to allow the visualization of intranuclear retinoic acid receptor activity. This cis-enhancer imaging reporter system may be useful in vitro and in vivo for the evaluation of retinoic acid responses in such areas as cellular differentiation and chemoprevention.

In Vivo Imaging of Retinoic Acid Receptor Activity using a Sodium/Iodide Symporter and Luciferase Dual Imaging Reporter Gene

Retinoic acids are natural derivatives of vitamin A, and play important roles in modulating tumor cell growth by regulating differentiation, thus suggesting the potential use of these derivatives in cancer therapy and prevention. To visualize the intranuclear responses of functional retinoic acid receptors, we have developed a dual-imaging reporter gene system based on the use of sodium/iodide symporter (NIS) and luciferase in cancer cell lines. NIS and luciferase genes were linked with an internal ribosome entry site, and placed under the control of an artificial cis-acting retinoic acid responsive element (pRARE/NL). After retinoic acid treatment, I-125 uptake by pRARE/NL transfected cells was found to have increased by up to about five times that of nontreated cells. The bioluminescence intensity of pRARE/NL transfected cells showed dose-dependency. In vivo luciferase images showed higher intensity in retinoic acid treated SK-RARE/NL tumors, and scintigraphic images of SK-RARE/NL tumors showed increased Tc-99m uptake after retinoic acid treatment. The NIS/luciferase imaging reporter system was sufficiently sensitive to allow the visualization of intranuclear retinoic acid receptor activity. This cis-enhancer imaging reporter system may be useful in vitro and in vivo for the evaluation of retinoic acid responses in such areas as cellular differentiation and chemoprevention.

A Tc-99m-labeled long chain fatty acid derivative for myocardial imaging.

C-11- and I-123-labeled long chain fatty acid derivatives have been reported as useful radiopharmaceuticals for the estimation of myocardial fatty acid metabolism. We have reported that Tc-99m-labeled N-[[[(2-mercaptoethyl)amino]carbonyl]methyl]-N-(2-mercaptoethyl)-6-aminohexanoic acid ([(99m)Tc]MAMA-HA), a medium chain fatty acid derivative, is metabolized by beta-oxidation in the liver and that the MAMA ligand is useful for attaching to the omega-position of fatty acid derivatives as a chelating group for Tc-99m. On the basis of these findings, we focused on developing a Tc-99m-labeled long chain fatty acid derivative that reflected fatty acid metabolism in the myocardium. In this study, we synthesized a dodecanoic acid derivative, MAMA-DA, and a hexadecanoic acid derivative, MAMA-HDA, and performed radiolabeling and biodistribution studies. [(99m)Tc]MAMA-DA and [(99m)Tc]MAMA-HDA were prepared using a ligand-exchange reaction. Biodistribution studies were carried out in normal mice and rats. Then, a high initial uptake of Tc-99m was observed, followed by a rapid clearance from the heart. The maximum heart/blood ratio was 3.6 at 2 min postinjection of [(99m)Tc]MAMA-HDA. These kinetics were similar to those with postinjection of p-[(125)I]iodophenylpentadecanoic acid. Metabolite analysis showed [(99m)Tc]MAMA-HDA was metabolized by beta-oxidation in the body. In conclusion, [(99m)Tc]MAMA-HDA is a promising compound as a long chain fatty acid analogue for estimating beta-oxidation of fatty acid in the heart.

Determination of extrarenal plasma clearance and hepatic uptake of technetium-99m-mercaptoacetyltriglycine in cats.

To determine maximum extrarenal plasma clearance of technetium-99m-mercaptoacetyltriglycine (99mTc-MAG3) and maximum extrarenal hepatic uptake of 99mTc-MAG3 in cats. 6 clinically normal adult cats. Simultaneously, baseline plasma clearance and camera-based uptake of 99mTc-MAG3 were determined in anesthetized cats. Double exponential curves were fitted to plasma clearance data. Injected dose was divided by area under the curve and body weight to determine 99mTc-MAG3 clearance. Regions of interest were drawn around kidneys and liver, and percentage dose uptake was determined 1 to 3 minutes after injection. After bilateral nephrectomy, simultaneous extrarenal plasma clearance and camera-based hepatic uptake of 99mTc-MAG3 were evaluated in each cat. Mean +/- SD baseline plasma clearance and extrarenal clearance were 5.29 +/- 0.77 and 0.84 +/- 0.47 mL/min/kg, respectively. Mean extrarenal clearance (as a percentage of baseline plasma clearance) was 16.06 +/- 7.64%. For right, left, and both kidneys, mean percentage dose uptake was 9.42 +/- 2.58, 9.37 +/- 0.86, and 18.79 +/- 2.47%, respectively. Mean hepatic percentage dose uptake before and after nephrectomy was 12.95 +/- 0.93 and 21.47 +/- 2.00%, respectively. Mean percentage change of hepatic uptake after nephrectomy was 166.89 +/- 23.19%. In cats, extrarenal clearance of 99mTc-MAG3 is higher than that of other species; therefore, 99mTc-MAG3 is not useful for estimation of renal function in felids. Evaluation of renal function in cats may be more accurate via camera-based versus plasma clearance-based methods because camera-based studies can discriminate specific organs.

POSTPARTUM THYROIDITIS PRESENTING AS A COLD NODULE AND EVOLVING TO GRAVES' DISEASE

SUMMARYWe describe the case of a 30‐year‐old woman who, five months after giving birth, was referred with a solitary nodule in her anterior neck. Laboratory analysis, ultrasonography, pertechnetate (Tc99m) thyroid scan and cytological examination of fine needle aspiration biopsy performed on the nodule led us to diagnose postpartum thyroiditis (PPT). Twenty‐eight months after parturition, overt hyperthyroidism developed, with raised thyroperoxidase and thyroid stimulating hormone receptor antibody titres, diffuse high uptake of Tc99m at thyroid scan, and high vascular flow throughout the gland at Color‐Power imaging. The diagnosis of Graves' disease (GD) was established. The differential diagnosis of thyrotoxicosis in the postpartum period, and the possible aetiological relationships between PPT and GD are discussed. To our knowledge, this is the first published report of a PPT presenting as a cold nodule, and evolving to GD.

Preoperative parathyroid localization: correlating false-negative technetium 99m sestamibi scans with parathyroid disease.

The recent trend toward minimally invasive directed parathyroid surgery has increased the surgeon's reliance on preoperative parathyroid localization. Technetium Tc 99m sestamibi scanning is generally viewed as the gold standard for preoperative localization, with reported sensitivities of 75% to 100% and specificities of 75% to 90%. However, in each reported series there exists a group of patients in whom preoperative localization is either equivocal or negative. We focused on a subset of patients from our parathyroid database with false-negative sestamibi (MIBI) scans, in an attempt to elucidate features that could affect these studies. We identified 20 patients with negative preoperative scans and confirmed parathyroid disease. We compared them with 22 consecutive patients with positive scans, correlating the following variables: patient age, gender, concomitant thyroid disease (Hashimoto's thyroiditis, papillary thyroid carcinoma, thyroid adenoma), preoperative parathyroid hormone values, location and number of enlarged parathyroid glands, parathyroid weight, and the relative proportion of chief cells, clear cells, oxyphil cells, and adipose tissue. Retrospective chart review of clinicopathological and radiological findings. We found that patients with false-negative scans were more likely to have an enlarged parathyroid containing a high proportion of clear cells (P =.01). A trend was seen (P =.1) correlating increased parathyroid fat content and false-negative scans. Conversely, positive preoperative scans were more likely to be associated with a higher percentage of oxyphil cells (P =.02). Univariate analysis for other variables, as well as logistic regression analysis, did not achieve statistical significance. To date, the present study is the largest clinicopathological review of patients with false-negative sestamibi scans. Technetium Tc 99m uptake correlates with parathyroid oxyphil cell content, and false-negative scans can occur with parathyroid glands containing predominantly clear cells.

Further insights into the no-reflow phenomenon after primary angioplasty in acute myocardial infarction: The role of microthromboemboli

We tested the hypothesis that when acute coronary occlusion is caused by thrombus, part of the no-reflow phenomenon may result from spontaneous or coronary angioplasty-induced microthromboemboli, and that this phenomenon may be partly or wholly reversible. Accordingly, a thrombus was created in the left anterior descending coronary artery of 6 dogs and was labeled in vivo with 99mTc-DMP-444 that binds to the IIb/IIIa platelet receptor. Angioplasty was then performed to obtain thrombolysis in myocardial infarction grade-3 flow. Myocardial contrast echocardiography was performed 15 and 60 minutes after recanalization to define perfusion defect size. 99mTc-autoradiography and infarct size (IS) measurement were performed postmortem. An additional 5 dogs with coronary artery ligation followed by reperfusion served as control animals. These dogs also underwent myocardial contrast echocardiography and in vivo labeling with 99mTc-DMP-44. 99mTc uptake was significantly higher in the reperfused bed in dogs with thrombus compared with control dogs (2.7 ± 0.9 vs 1.4 ± 0.3 counts/pixel−1/min−1, P =.01) indicating the presence of microthromboemboli. Perfusion defect size early (15 minutes) after recanalization was smaller than the hot spot on autoradiography and overestimated IS in dogs with thrombus. Perfusion defect size decreased with time and was closer to IS 60 minutes after recanalization. The dogs with thrombi demonstrated larger IS/risk area ratios compared with the 5 control dogs (46 ± 6% vs 27 ± 12%, P =.04). We conclude that part of the no-reflow phenomenon seen after angioplasty in acute coronary thrombosis is a result of microthromboemboli and is mostly reversible. No reflow late after reperfusion is a result of tissue necrosis. The thrombus burden also affects ultimate IS. (J Am Soc Echocardiogr 2003;16:15-21.)

Subacute Thyroiditis with Highly Positive Thyrotropin Receptor Antibodies and High Thyroidal Radioactive Iodine Uptake

A 48-year-old woman with transient thyrotoxicosis, having a slightly high thyroidal 99mTc uptake (3.9% at 20 m) or radioactive iodine uptake (RAIU) (17.3% at 4 hour) and subacute thyroiditis (SAT)-like symptoms, signs and histological diagnosis (extensive cellular destruction and granulomatous inflammatory change), showed positive TRAb (59.9%) and TSAb (194%) activity. The high levels of TRAb and slightly high RAIU were still observed after one month of prednisolone treatment. Nine months later, the TRAb and TSAb levels finally normalized and her thyroid function has remained normal since then. We suspect that the slightly high RAIU were due to the presence of both the TRAb and the TSAb and the course of this case might mimic neonatal Graves' disease.

(99m)Technetium pentavalent dimercaptosuccinic acid scintigraphy in the follow-up of clinically nonfunctioning pituitary adenomas after radiotherapy.

It is still difficult to differentiate pituitary adenoma remnants from postradiotherapy fibrosis by computed tomography (CT) or magnetic resonance imaging (MRI), especially in patients with clinically nonfunctioning pituitary adenomas (NFA), lacking circulating markers to follow disease progression or cure. We investigated the usefulness of scintigraphy with technetium-99m pentavalent dimercaptosuccinic acid [(99m)Tc(V)DMSA], shown previously to detect most pituitary GH- and PRL-secreting adenomas and NFA, with tumour-to-background ratios (T/B) as high as 25-fold. Eighteen patients with NFA (study group), 10 patients with GH- and three patients with PRL-secreting adenomas (control group), all of whom had undergone previous surgery. The study was an open longitudinal design. Pituitary CT/MRI and (99m)Tc(V)DMSA scintigraphy was performed before and 1, 3 and 5 years after conventional radiotherapy. Tumour size was measured as maximal diameter of the residual lesion, while uptake of (99m)Tc(V)DMSA was measured as a T/B ratio. At study entry, pituitary (99m)Tc(V)DMSA uptake was found in 13 NFA (72.2%), seven GH-secreting (70%) and all PRL-secreting adenomas; remnant tumour was documented by CT/MRI in all 31 patients. Maximal remnant diameter was significantly higher in patients with positive (13.3 +/- 0.9 mm) than in those with negative scintigraphy (7.0 +/- 0.3 mm, P < 0.001). During the 5-year follow-up postradiotherapy, a significant decrease in (99m)Tc(V)DMSA uptake (9.7 +/- 0.8 vs. 3.2 +/- 0.5, P < 0.0001) occurred in all but three patients. Two NFA patients died of tumour invasion 19 and 36 months after radiotherapy and one acromegalic patient had no change in his hormone levels. In the eight negative patients (five NFA and three GH), scintigraphy remained negative throughout follow-up. A remarkable shrinkage of the remnant tumour was observed in both the patients with negative (from 7.0 +/- 0.3 to 1.9 +/- 0.6 mm, P < 0.001) and in those with positive scintigraphy (from 13.3 +/- 0.9 to 7.3 +/- 0.6 mm, P < 0.001). At the end of the study, CT/MRI showed evident remnant tumour in 13 of 16 NFA (81.2%), nine GH-secreting (90%) and all three prolactinomas (100%), while the scintigraphy was negative (T/B < 1) or faintly positive (T/B 1-2) in eight of 16 NFA (50%), five GH-secreting (50%) and one prolactinoma (33.3%). Functional imaging of pituitary remnant adenomas (> 10 mm in size) by (99m)Tc(V)DMSA depicts viable pituitary adenoma remnants. This approach may be of clinical value in patients with clinically nonfunctioning adenomas to monitor the effects of radiotherapy.

Early response to chemotherapy: a surrogate for final outcome of Hodgkin's disease patients that should influence initial treatment length and intensity?

Early adjustment of treatment may benefit the patient. In order to guide treatment adjustment, use of early response (ER) or early complete response (ECR), judged after the few initial cycles of chemotherapy, is common in pediatric and also adult Hodgkin's and non-Hodgkin's studies. Paradoxically, almost no data support this strategy. The influence of ECR on outcome was evaluated in three series of advanced Hodgkin's disease (HD), leading to a series of questions. The 1982 EORTC study assessed prospectively the time frame needed to reach an apparent complete response (CR) through repeated tumor measurements. In patients assessed at mid-treatment before the fifth cycle, both 15 year freedom from progression (FFP) and overall survival (OS) were superior in ECR patients compared with other patients continued on the same treatment (61% versus 37%; P < 0.001). A series of questions arise from these observations. Question 1: is the shortening of treatment detrimental? In a randomized Swedish trial, in one arm treatment was shortened in patients evaluated from the fifth cycle as ECR as compared with the standard eight cycles arm, 10 year cause-specific-survival (CSS) was 53 versus 69% [not significant (ns)]; 10 year OS 49% versus 58% (ns). Conversely, in the EORTC 20884 study, ECR patients given only six cycles did as well as patients entering CR later and, for this reason, given eight cycles (identical 6 year event-free survival 75%). Question 2: is early treatment adaptation in patients who failed to reach ER beneficial? In the French MDH 90 trial, 15% of children failed to reach ECR after four cycles; in these children only, anthracyclines plus alkylating agents were given and the dose of radiotherapy increased, improving the results observed in the previous trial. In the EORTC 20884 study, patients who failed to reach an ECR were switched earlier to involved field RT: their results matched those of ECR patients, at the difference of the previous trial. Question 3: is ER a predicting factor that can be used with any type of treatment? Probably not, based on the German Hodgkin's Lymphoma Study Group trial HD 9: ECR is highly dependent on specific interval from treatment start and on treatment intensity. More general questions stem from these results. Question 4: is the definition of ER secured? With conventional imaging, the different methods for response assessment at end treatment also lead to different response rates; the assessment in the middle of treatment itself and the use of newer imaging techniques may further increase the variation. Indeed, question 5 is: is ER a concept based on any biology? Correlation to markers, 99mTc uptake, PET and hematological tolerance might help to pinpoint how and why ER represents a surrogate for final outcome. ER is a surrogate for final outcome, reflecting both tumor burden and activity. This predictability may, and possibly should, impact on treatment.

Zinc chloride–mediated reduction of apoptosis as an adjunct immunosuppressive modality in cardiac transplantation

Background: Zinc (Zn) blocks caspase-3 activation in cardiac allografts and therefore may synergistically decrease apoptosis along with cyclosporine (CsA), which inhibits mitochondrial release of cytochrome c. Simultaneous treatment of rat recipients of heterotopic heart transplants with zinc chloride (ZnCl 2) thus may allow lower doses of CsA for immunosuppression. Methods: PVG (RT1 c) rat hearts were transplanted heterotopically into the abdomen of ACI (RT1 a) rats. Group 1 ( n = 15) rats received no treatment. Group 2 rats ( n = 8) received 2 mg/kg/day CsA (sub-therapeutic dose) by oral gavage. Group 3 rats ( n = 9) received 2 mg/kg/day oral CsA in addition to 1 mg/kg/day sub-cutaneous ZnCl 2 delivered by osmotic pump. All rats were imaged using Annexin V–bound 99mTechnetium ( 99mTc–Annexin V) on post-operative Day 4 and subsequently killed. Annexin V avidly binds apoptotic cells in vivo. Region of interest per whole body (WB) data were calculated using the images. The allograft survival study was conducted with n = 11, 6, and 5 in control, CsA, and CsA+Zn groups, respectively. Finally, percentages of allografts that reached tolerance were measured in both CsA-only and CsA+Zn groups ( n = 8 each). Results: Zinc chloride had an additive effect with CsA on apoptotic blockade and graft survival. The regions of interest per WB uptake of 99mTc–Annexin V were 2.43% ± 0.37%, 2.08% ± 0.52%, and 1.49% ± 0.29%*, and acute survivals were 6.4 ± 1.7, 7.2 ± 2.1, and 11.2 ± 2.5* days for control, CsA, and CsA+Zn groups, respectively (* p < 0.001 vs controls). In addition, 87.5% of allografts became tolerant and survived for 90 days in the CsA+Zn group compared with only 37.5% in the CsA-only group ( p = 0.049). Conclusion: Zinc-mediated reduction of apoptosis served as an effective adjunct immunosuppressive therapy to CsA in a rat model of cardiac transplantation.

Single tumor cell uptake and dosimetry of technetium-99m Fab' or minute anti-CD22 in low-grade B-cell lymphoma.

A patient with follicular lymphoma was investigated with 0.5 mg Fab' or minute anti-CD22 labeled with 1100 MBq technetium-99m ((99m)Tc). A computed tomography scan performed a week later revealed regression. This unexpected response prompted an investigation of single cell dosimetry of low-energy electron emitters. Another patient with low-grade, unclassifiable B-cell lymphoma with a low expression of CD22 was injected with (99m)Tc anti-CD22. Blood samples were drawn 30 minutes, 4 hours, and 24 hours after injection. Lymphoma cells (CD19+) and T cells (CD3+), which served as control cells, were separated using a flow cytometer. The radioactivity of the two cell populations was measured in an NaI(Tl) well-type detector. The mean uptake per cell and absorbed dose were calculated. The CD22 expression of the patient's cells and of a B-cell lymphoma cell line (Raji) were assessed by flow cytometry for the extrapolation of the absorbed dose from the patient's cells to a cell line with higher CD22 expression. The average number of (99m)Tc atoms per CD19+ and CD3+ cell 4 hours postinjection were 5.4 and 0.054, respectively. Depending on the assumed ratio between antibody and CD22 molecules (1:2 or 1:1), the CD22 expression on the patient's cells and Raji cells varied from 2800 to 5700 and from 37,000 to 74,000 per cell, respectively. The average absorbed dose per cell ranged from 4 x 10(-7) to 0.1 grays (Gy). It seems feasible to assess the mean single tumor cell uptake of (99m)Tc targeted by Fab' or minute anti-CD22 in a patient's lymphoma using sorted cell populations, thereby allowing single cell dosimetry. Extrapolation of the absorbed dose from (99m)Tc to cells with higher CD22 expression was made and under certain conditions absorbed doses of 0.1 Gy were obtained, indicating the potential relevance of low-energy electron emitters to therapy.

Plasminogen activator inhibitor type-1 deficiency attenuates murine antigen-induced arthritis.

To examine the role of plasminogen activator inhibitor type-1 (PAI-1), the major fibrinolytic inhibitor, in vivo during murine antigen-induced arthritis (AIA). AIA was induced in PAI-1-deficient mice and control wild-type mice. Arthritis severity was evaluated by technetium 99m (99mTc) uptake in the knee joints and by histological scoring. Intra-articular fibrin deposition was examined by immunohistochemistry and synovial fibrinolysis quantitated by tissue D-dimer measurements and zymograms. Joint inflammation, quantitated by 99mTc uptake, was significantly reduced in PAI-1(-/-) mice on day 7 after arthritis onset (P<0.01). Likewise, synovial inflammation, evaluated by histological scoring, was significantly decreased in PAI-1-deficient mice on day 10 after arthritis onset (P<0.001). Articular cartilage damage was significantly decreased in PAI-1(-/-) mice, as shown by histological grading of safranin-O staining on day 10 after arthritis onset (P<0.005). Significantly decreased synovial accumulation of fibrin was observed by day 10 in arthritic joints of PAI-1(-/-) mice (P<0.005). Accordingly, the synovial tissue content of D-dimers, the specific fibrin degradation products generated by plasmin, were increased in PAI-1(-/-) mice (P<0.02). Finally, as expected, PA activity was increased in synovial tissues from PAI-1(-/-) mice, as shown by zymographic analysis. These results indicate that deficiency of PAI-1 results in increased synovial fibrinolysis, leading to reduced fibrin accumulation in arthritic joints and reduced severity of AIA.

Role of Activatory FcγRI and FcγRIII and Inhibitory FcγRII in Inflammation and Cartilage Destruction during Experimental Antigen-Induced Arthritis

IgG-containing immune complexes, which are found in most RA joints, communicate with hematopoietic cells using three classes of Fc receptors(Fc gamma RI, -II, -III). In a previous study we found that if a chronic T-cell-mediated antigen-induced arthritis (AIA) was elicited in knee joints of FcR gamma-chain-deficient mice that lack functional Fc gamma RI and Fc gamma RIII, joint inflammation was comparable but severe cartilage destruction was absent. We now examined the individual role of the stimulatory Fc gamma RI and Fc gamma RIII and inhibitory Fc gamma RII in inflammation and functional cartilage damage in knee joints with AIA using Fc gamma RI-, Fc gamma RII-, and Fc gamma RIII-deficient mice. Three weeks after immunization with the antigen-methylated bovine serum albumin (BSA), cellular (T-cell responses as measured by lymphocyte proliferation) immunity raised against mBSA was comparable in all groups examined. Humoral (total IgG, IgG1, IgG2a, and IgG2b levels) immunity against mBSA was comparable in Fc gamma RI-/- and Fc gamma RIII-/- but higher in Fc gamma RII-/- if compared to controls. Joint swelling as measured by (99m)Tc uptake at days 1, 3, and 7 was similar in Fc gamma RI-/- and Fc gamma RIII-/- mice and significantly higher in Fc gamma RII-/-. Chronic inflammation and cartilage damage (depletion of proteoglycans, metalloproteinase (MMP)-induced neoepitopes, and matrix erosion) was studied histologically in total knee joint sections stained with hematoxylin or safranin-O. Histologically, at day 7 after AIA induction, exudate and infiltrate in the knee joint was similar in Fc gamma RI-/- and Fc gamma RIII-/- and significantly higher (230% and 340%) in Fc gamma RII-/- mice if compared to controls. Aggrecan breakdown in cartilage caused by MMPs and, which is related to severe irreversible cartilage erosion, was further studied by immunolocalization of MMP-mediated neoepitopes (VDIPEN) and image analysis. MMP-induced neoepitopes determined in various cartilage layers (tibia and femur) were primarily inhibited in Fc gamma RI-/- (79 to 87% and 87 to 88%, respectively) and comparable in Fc gamma RIII-/-. VDIPEN neoepitopes were much higher (82 to 122% and 200 to 250%, respectively) in Fc gamma RII-/- mice. Initial depletion of proteoglycans was similar (60 to 100%) in all groups. In the chronic phase, cartilage matrix erosion in the lateral and medial tibia was significantly elevated in Fc gamma RII-/- (222% and 186%, respectively) but not in Fc gamma RI-/- or Fc gamma RIII-/- mice. These results suggest that during T-cell-mediated AIA, Fc gamma RI and Fc gamma RIII act in concert in acute and chronic inflammation whereas Fc gamma RI is the dominant FcR involved in severe cartilage destruction. Fc gamma RII is a crucial inhibiting factor in acute and chronic inflammation and cartilage erosion.

Warthin's tumor of parotid gland on Tc-99m pertechnetate scintigraphy with lemon juice stimulation: Tc-99m uptake, size, and pathologic correlation.

The aim of this study was to evaluate the usefulness of technetium-99m (Tc-99m) pertechnetate scintigraphy with lemon juice stimulation in the diagnosis of Warthin's tumor and its correlation with Tc-99m uptake, tumor size, and histologic subtype. Tc-99m pertechnetate scintigraphy before and after lemon juice stimulation and pathologic specimens of 34 Warthin's tumors and 47 non-Warthin's lesions were retrospectively evaluated. Tc-99m uptake of Warthin's tumors before and after stimulation was visually graded as follows: absent; indeterminate; low grade; definite; and strong. Tumor size was defined as maximum diameter of the tumor measured from the surgical specimen. Warthin's tumors were classified into three histologic subtypes according to the ratio of epithelial and lymphoid stromal components: predominant epithelial; intermediate; and low-grade epithelial types. Eighteen of 34 (53%) Warthin's tumors and one benign lymphoepithelial cyst showed higher uptake than that of the normal parotid gland on Tc-99m scintigraphy before lemon juice stimulation. Thirty-two of the 34 (94%) Warthin's tumors, one benign lymphoepithelial cyst, one pleomorphic adenoma, and one oncocytoma revealed higher uptake than that of the normal parotid gland on Tc-99m scintigraphy after lemon juice stimulation. The mean size was 37 mm in strong uptake Warthin's tumors, 24 mm in definite uptake tumors, 19 mm in low-grade uptake tumors, and 12 mm in low-grade uptake tumors excluding those tumors with large cystic component. There was a significant correlation between tumor size and degree of Tc-99m uptake after lemon juice stimulation. However, there was no correlation between histologic subtype and Tc-99m uptake, and histologic subtype and tumor size in Warthin's tumors. Our study concludes that Tc-99m pertechnetate scintigraphy with lemon juice stimulation is useful for the detection and diagnosis of Warthin's tumor. The degree of uptake in Warthin's tumor on Tc-99m scintigraphy with lemon juice stimulation depends mainly on tumor size and the presence of large cystic component in it.

Primary mineralization at the surfaces of implants.

Osteogenesis around implants is affected by the physical and chemical characteristics of the biomaterials used. The osteoprogenitor cells must migrate to the implant site and synthesize and secrete a mineralizable extracellular matrix. Because this is neo-bone formation, the mechanism by which the cells calcify their matrix involves extracellular organelles called matrix vesicles in a process termed "primary mineralization". Two different methods for assessing the effects of implant materials on primary mineralization are presented in this report. In the first approach, different implant materials used in dentistry and orthopedic surgery were placed in rat tibial bones after marrow ablation. Two groups of implants were used, bone-bonding and non-bonding materials. We examined the effects of the materials on calcification morphometrically by quantitating changes in matrix vesicle morphology and distribution in endosteal tissue around implants as compared with normal endosteal bone healing. In addition, matrix vesicles were isolated from the endosteal tissue around the implant as well as from the contralateral limb and were examined biochemically. The results demonstrated that bone-bonding materials induced a greater increase in matrix vesicle enzyme activity than did non-bonding materials. However, all materials caused changes in matrix vesicles that were different from those seen in normal endosteal bone formation following injury. The effects of implant materials on biochemical markers of mineralization, including specific activities of matrix vesicle alkaline phosphatase and phospholipase A2 and phosphatidylserine content, demonstrated a high correlation with the morphometric observations with regard to enhancement and/or delay of primary mineralization. In the other approach, we used a radioisotopic method to evaluate the effects of implant materials on primary mineralization. This analysis revealed that implants alter bone healing, as shown by the differential uptake of 99mTc and 32P in different bone compartments. Decreased 32P uptake by the organic phase in the presence of bone-bonding implants suggests that cleavage of 99mTcMD32P into its technetium and methylene diphosphonate moieties was inhibited by the presence of the implants. In summary, these approaches to evaluating the effects of materials on primary mineralization demonstrate that the marrow ablation model can easily distinguish between bone-bonding and non-bonding materials. The use of this model can be valuable in the development of new materials.

Scatter and cross-talk corrections in simultaneous Tc-99m/I-123 brain SPECT using constrained factor analysis and artificial neural networks

Simultaneous imaging of Tc-99m and I-123 would have a high clinical potential in the assessment of brain perfusion (Tc-99m) and neurotransmission (I-123) but is hindered by cross-talk between the two radionuclides. Monte Carlo simulations of 15 different dual-isotope studies were performed using a digital brain phantom. Several physiologic Tc-99m and I-123 uptake patterns were modeled in the brain structures. Two methods were considered to correct for cross-talk from both scattered and unscattered photons: constrained spectral factor analysis (SFA) and artificial neural networks (ANN). The accuracy and precision of reconstructed pixel values within several brain structures were compared to those obtained with an energy windowing method (WSA). In I-123 images, mean bias was close to 10% in all structures for SFA and ANN and between 14% (in the caudate nucleus) and 25% (in the cerebellum) for WSA. Tc-99m activity was overestimated by 35% in the cortex and 53% in the caudate nucleus with WSA, but by less than 9% in all structures with SFA and ANN. SFA and ANN performed well even in the presence of high-energy I-123 photons. The accuracy was greatly improved by incorporating the contamination into the SFA model or in the learning phase for ANN. SFA and ANN are promising approaches to correct for cross-talk in simultaneous Tc-99m/I-123 SPECT.

Role of Fc receptor gamma chain in inflammation and cartilage damage during experimental antigen-induced arthritis.

To study the role of Fc receptor (FcR) gamma chain in inflammation and cartilage destruction during antigen-induced arthritis (AIA). FcR gamma-/- mice and controls were immunized with methylated bovine serum albumin (mBSA) in Freund's complete adjuvant, followed by induction of arthritis by local injection of mBSA into the right knee joint. Joint inflammation was studied by 99mTc uptake and by histology. Breakdown of proteoglycans from the cartilage matrix was determined by loss of red staining in Safranin O-stained knee joint sections, and matrix metalloproteinase (MMP)-mediated aggrecan degradation was determined by immunolocalization using anti-VDIPEN antibodies. Chondrocyte death was measured by determining empty lacunae in hematoxylin-stained sections and with the TUNEL assay in cryostat sections. Erosion was detected as ruffling of the cartilage surface. Joint swelling, as measured by 99mTc uptake on days 1, 3, and 7, was significantly decreased in FcR gamma-/- mice compared with controls. On day 7 after AIA induction, sustained joint inflammation, as seen histologically, was not significantly lower in FcR gamma-/- deficient mice. In various cartilage layers (femur, tibia, patella) of central arthritic knee joints, marked depletion of proteoglycans (40-70%), chondrocyte death (25-50%), and mild surface erosion were found. In FcR gamma-/- knee joints, depletion of proteoglycans was comparable (40-70%). Strikingly, chondrocyte death and matrix erosion were absent. Furthermore, MMP-induced aggrecan neoepitopes, which were abundantly found in controls, were also absent in FcR gamma-/-. Nevertheless, latent MMPs were present in the cartilage matrix as seen in APMA-activated patellae. FcR gamma chain is involved in the severity of acute and sustained inflammation and is a crucial factor in cartilage erosion during AIA, probably by regulating activation of latent MMPs present in the cartilage matrix.

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Oncocytoma of the parotid gland is a rare salivary gland tumor. The prognosis is usually favorable if the tumor can be removed surgically. We reported 2 cases of parotid gland oncocytoma and discussed the usefulness of radiographic findings in diagnosis. CT scans of the neck showed a well-defined homogenous parotid mass. MRI scans demonstrated a well circumscribed and lobulated mass of homogeneous intermediate signal intensity on T1-weighted images and hyperintensity on T2-images. The tumor was characterized by early enhancement following contrast injection. The tumor exhibited intense uptake and prolonged retention of Tc-99m pertechnetate.Radiographic study revealed no specific imaging characteristics of oncocytoma. This tumor was similar in imaging characteristics to Warthin's tumor. Thus, close attention to the differential diagnosis is important when imaging is used as a diagnostic technique.

Influence of background correction in the estimation of myocardial uptake of 99mTc labelled perfusion imaging agents

The effects of different corrections for background activity in the estimation of low organ uptake of radiopharmaceuticals have been examined using myocardial perfusion imaging agents. Estimates of myocardial uptake of Tc-labelled MIBI and tetrofosmin were made both at rest and after exercise. Patients were given one or other of the agents (12 MIBI; 17 tetrofosmin) and the measurements at rest and after exercise were made within a week of each other using a planar gamma camera method incorporating an attenuation-corrected, geometric mean technique. Myocardial uptakes were estimated using two different background corrections and also with no background subtraction. Mean values were in the range 1.3 to 3.0% and showed that, for both agents, uptakes estimated with and without background correction could differ by a factor of two. Although the study was not designed to compare myocardial uptakes of the two agents, a background correction which accounted separately for activity in tissue over- and under-lying the heart resulted in similar mean values for tetrofosmin (1.7% both at rest and after exercise) and for MIBI (1.8% rest; 1.9% exercise). For both agents, no significant difference was observed between myocardial uptakes at rest and after exercise measured at about two hours post-injection.