Gerald M. Kolodny

Identification and importance of brown adipose tissue in adult humans.

BACKGROUND Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. METHODS We analyzed 3640 consecutive (18)F-fluorodeoxyglucose ((18)F-FDG) positron-emission tomographic and computed tomographic (PET-CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of (18)F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from the neck and supraclavicular regions in patients undergoing surgery. RESULTS Substantial depots of brown adipose tissue were identified by PET-CT in a region extending from the anterior neck to the thorax. Tissue from this region had UCP1-immunopositive, multilocular adipocytes indicating brown adipose tissue. Positive scans were seen in 76 of 1013 women (7.5%) and 30 of 959 men (3.1%), corresponding to a female:male ratio greater than 2:1 (P<0.001). Women also had a greater mass of brown adipose tissue and higher (18)F-FDG uptake activity. The probability of the detection of brown adipose tissue was inversely correlated with years of age (P<0.001), outdoor temperature at the time of the scan (P=0.02), beta-blocker use (P<0.001), and among older patients, body-mass index (P=0.007). CONCLUSIONS Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of (18)F-FDG PET-CT. Most important, the amount of brown adipose tissue is inversely correlated with body-mass index, especially in older people, suggesting a potential role of brown adipose tissue in adult human metabolism.

Cold but not sympathomimetics activates human brown adipose tissue in vivo

As potential activators of brown adipose tissue (BAT), mild cold exposure and sympathomimetic drugs have been considered as treatments for obesity and diabetes, but whether they activate the same pathways is unknown. In 10 healthy human volunteers, we found that the sympathomimetic ephedrine raised blood pressure, heart rate, and energy expenditure, and increased multiple circulating metabolites, including glucose, insulin, and thyroid hormones. Cold exposure also increased blood pressure and energy expenditure, but decreased heart rate and had little effect on metabolites. Importantly, cold increased BAT activity as measured by 18F-fluorodeoxyglucose PET-CT in every volunteer, whereas ephedrine failed to stimulate BAT. Thus, at doses leading to broad activation of the sympathetic nervous system, ephedrine does not stimulate BAT in humans. In contrast, mild cold exposure stimulates BAT energy expenditure with fewer other systemic effects, suggesting that cold activates specific sympathetic pathways. Agents that mimic cold activation of BAT could provide a promising approach to treating obesity while minimizing systemic effects.

Gallium 67 imaging in monitoring lymphoma response to treatment

The value of gallium 67 (Ga) imaging in monitoring lymphoma response to treatment was assessed in 25 patients with Ga‐avid tumors and compared to body computed tomography (CT), chest radiographs, and palpation of tumor infiltrated peripheral lymph nodes. Ga imaging was negative in 95% (20/21) of the patients who were clinically considered to be in remission and in whom treatment was stopped. The disease did not recur during a follow‐up of 12 to 26 months in 15 patients. Six patients developed recurrence of the disease 3 to 12 months after treatment was stopped. In all six patients Ga imaging became positive again at the time of the appearance of active disease. In the group of patients in remission, CT was negative in 57% (11/19), chest x‐rays in 55% (6/11) and peripheral lymph nodes were palpated in none of the patients (13/13). In four patients that did not achieve remission after treatment, Ga scans were positive. Ga imaging appears useful in monitoring lymphoma response to treatment. This is probably because Ga imaging monitors tumor cell viability, whereas body CT and chest radiographs show the tumor mass, which may consist of fibrotic or necrotic tissue.

Evidence for transfer of macromolecular RNA between mammalian cells in culture

Abstract Evidence is presented for transfer of macromolecular RNA between cells in culture. RNA of donor cells was labeled with 3 H- or 14 C-uridine and/or 3 H-methyl methionine. The donor cells were then cultured together with non-labeled recipient cells. After separation of the donor and recipient cells, radioactively labeled RNA was found in the recipient cells. The use of actinomycin to suppress RNA synthesis in the recipient cells had no effect on the apparent transfer of RNA and uridine/cytidine ratios of donor and recipient cell RNA were similar. Sucrose gradient analysis of the labeled RNA in the recipient cells showed that apparently representatives of all major cytoplasmic species were transferred. There was no evidence found for DNA transfer using 3 H-thymidine label. The donor and recipient cells were separated by a technique that involved making the donor cells heavier than the recipient cells by having the donor cells phagocytize tantalum particles. After coculture, the heavy donor and light recipient cells were separated by centrifugation on a Ficoll gradient.

Respiratory Gating Enhances Imaging of Pulmonary Nodules and Measurement of Tracer Uptake in FDG PET/CT

OBJECTIVE The aim of this study was to evaluate prospectively the effects of respiratory gating during FDG PET/CT on the determination of lesion size and the measurement of tracer uptake in patients with pulmonary nodules in a clinical setting. SUBJECTS AND METHODS Eighteen patients with known pulmonary nodules (nine women, nine men; mean age, 61.4 years) underwent conventional FDG PET/CT and respiratory-gated PET acquisitions during their scheduled staging examinations. Maximum, minimum, and average standardized uptake values (SUVs) and lesion size and volume were determined with and without respiratory gating. The results were then compared using the two-tailed Students t test and the nonparametric Wilcoxons test to assess the effects of respiratory gating on PET acquisitions. RESULTS Respiratory gating reduced the measured area of lung lesions by 15.5%, the axial dimension by 10.3%, and the volume by 44.5% (p = 0.014, p = 0.007, and p = 0.025, respectively). The lesion volumes in gated studies were closer to those assessed by standard CT (difference decreased by 126.6%, p = 0.025). Respiratory gating increased the measured maximum SUV by 22.4% and average SUV by 13.3% (p < 0.001 and p = 0.002). CONCLUSION Our findings suggest that the use of PET respiratory gating in PET/CT results in lesion volumes closer to those assessed by CT and improved measurements of tracer uptake for lesions in the lungs.

An Evaluation of 99mTc-Labeled Red Blood Cell Scintigraphy for the Detection and Localization of Gastrointestinal Bleeding Sites

99mTechnetium-labeled red blood cell scintigraphy was performed upon 39 patients with clinical evidence for acute lower gastrointestinal bleeding from an unknown source. Seventeen of 39 patients (44%) had a scan became positive 6 or more h after injection, consistent with intermittent bleeding, in 8 of 17 patients (47%). In the 11 patients in whom the bleeding site was definitely identified by arteriography, surgery, or colonoscopy, scintigraphy correctly localized the bleeding site in 10 of 11 patients (91%). Four of 11 patients (36%) had an active bleeding site identified by arteriography. Ten of 17 patients (58%) with a positive scan required either gelfoam embolization (4 patients) or surgery (6 patients) to control the bleeding, whereas only 1 of 22 patients (5%) required surgery when the scan was negative. Six deaths occurred in the scan-positive patients compared with no deaths in the scan-negative patients. None of the 8 patients who had arteriography and no active bleeding site by scintigraphy had arteriographically demonstrable active bleeding. Scintigraphy provides a reliable noninvasive test to screen patients in whom arteriography is being considered to localize active bleeding sites. If the arteriogram is negative, the scintigraphic findings alone may guide the surgical or arteriographic intervention. In addition, scintigraphy identifies two patient populations which have considerably different morbidity and mortality.

Method for Decreasing Uptake of 18F-FDG by Hypermetabolic Brown Adipose Tissue on PET

OBJECTIVE The purpose of this study was to determine whether use of a high-fat, very-low-carbohydrate protocol for preparing patients for PET decreases the frequency of (18)F-FDG uptake by hypermetabolic brown adipose tissue (BAT) on PET scans. MATERIALS AND METHODS In this HIPAA-compliant retrospective study, 741 FDG PET/CT scans obtained during the winter months (October 1-April 30) for patients who prepared with a high-fat, very-low-carbohydrate, protein-permitted protocol were compared with 1,229 FDG PET scans obtained during the winter months for patients who prepared by fasting. FDG uptake on PET scans co-localized with regions of fat identified on the CT scans was assumed to represent hypermetabolic BAT. The categoric variables frequency of occurrence of hypermetabolic BAT (present or not) and the sex ratios of the groups before and after the change in preparation were compared by use of a chi-square test. The continuous variables of age and blood glucose level were compared by use of a two-tailed Students t test. RESULTS In this intention-to-treat analysis, there was no difference between the fasting (n = 1,229) and the high-fat, very-low-carbohydrate, protein-permitted diet (n = 741) groups in terms of age and sex. Patients who prepared with the high-fat diet had a significantly lower frequency of hypermetabolic BAT uptake on FDG PET scans during the winter months (p<0.0002) and had lower blood glucose levels (p<<0.001). CONCLUSION In this intention-to-treat analysis, use of a high-fat preparation protocol significantly lowered the frequency of uptake of FDG by hypermetabolic BAT on FDG PET studies. Use of this protocol has the potential to decrease the rate of false-positive findings on oncologic FDG PET scans.

Measurement of Human Brown Adipose Tissue Volume and Activity Using Anatomic MR Imaging and Functional MR Imaging

The aim of this study was to assess the volume and function of human brown adipose tissue (BAT) in vivo using MR imaging. Methods: BAT volumes under thermoneutral conditions in the cervical areas were assessed via water-fat contrast using the Dixon method and via water-saturation efficiency using fast spin-echo and T2-weighted images. The existence of cervical BAT was also assessed by 18F-FDG PET/CT scans in the same subjects. BAT functionality was assessed via functional MR imaging (fMRI) blood oxygenation level–dependent (BOLD) signal changes in response to a mild cold challenge. Results: Under thermoneutral conditions, we were able to distinguish BAT from white adipose tissue in the cervical and supraclavicular fat. BAT showed higher water-to-fat contrast and higher water-saturation efficiency in MR imaging scans. The location and volume of BAT assessed by MR imaging were comparable to the measurements by 18F-FDG PET/CT scans. During mild cold challenge, BOLD fMRI signal increased in BAT by 10.7% ± 1.8% (P < 0.01). Conclusion: We demonstrated the feasibility of using MR imaging and fMRI to assess BAT volume and BAT responses to mild cold stimulation in the cervical areas of human subjects.

Single-photon emission computed tomography quantitation of gallium citrate uptake for the differentiation of lymphoma from benign hilar uptake

PURPOSE To assess the role of quantitative gallium citrate (Ga 67) single-photon emission computed tomography (SPECT) in differentiating lymphoma from benign hilar uptake, concentrations of Ga 67 in 29 sites of documented lymphoma and in 75 benign lesions were compared. PATIENTS AND METHODS One hundred seven thoracic Ga 67 SPECT studies obtained in 101 consecutive lymphoma patients were reviewed. Fifty-nine studies detected Ga 67 uptake in the hilar and or mediastinal regions. Forty-eight studies showed no such abnormality. The concentration of Ga 67 in the thoracic lesions was measured using a quantitative SPECT technique and its nature was determined by correlation with computed tomographic (CT) scans and follow-up evaluation of the sites. RESULTS In 20 of 59 abnormal studies (34%), there was lymphoma in the hilar and or mediastinal regions. In the remaining 39 abnormal studies (66%), Ga 67 uptake was benign. There were 29 sites of lymphoma and 75 benign lesions. The concentration of Ga 67 in lymphoma was significantly higher than in benign hilar uptake (13.2 +/- 5.4 %ID/mL x 10(-3) v 5.6 +/- 1.5 % injected dose (ID)/mL x 10(-3); P < .001). A concentration value of 8.3 %ID/mL x 10(-3) was found to best separate lymphoma and benign uptake, with a sensitivity of 90%, a specificity of 93%, a positive predictive value of 84%, and a negative predictive value of 96%. CONCLUSION Lymphoma and benign hilar uptake differ significantly in their concentration of Ga 67. The present study shows that quantitative Ga-67 SPECT reliably differentiates lymphoma and benign uptake.

Assessment of regional cerebral blood flow (rCBF) in stroke using SPECT and N-isopropyl-(I-123)-p-iodoamphetamine (IMP).

In this study we assessed regional cerebral blood flow in patients with signs and symptoms of acute stroke using single-photon emission computed tomography (SPECT) and N-isopropyl 1-123 p-iodoam- phetamine (IMP). Twenty-five patients with acute cerebral infarction had both IMP brain perfusion studies and CT scans performed within one week of each other; 22 had positive and three had negative perfusion studies. Of the 22 patients who had positive perfusion studies, six had negative CT studies initially. In the 16 patients who had abnormal CT studies, eight of the studies depicted areas of edema that were smaller than the perfusion deficits noted on the IMP studies and eight had areas of edema that were approximately equal in size to the perfusion defect. Of the three patients with normal IMP studies, two had normal CT studies and one had a positive CT study showing a 3-ram lacunar infarction. Using eight control patients, mean count rates per tissue volume normalized for the injected dose was calculated. Similarly, the quantitative data from regions of interest in the stroke patients were calculated and compared to the control patients or to a normal region in the uninvolved hemisphere in the same patients. SPECT with IMP was used to assess regional brain perfusion in acute cerebral infarction. Perfusion abnormalities were seen in our patients when the CT scan was normal, and quantitative data could be used to approximate regional cerebral blood flow in these patients when compared to the normal patient population. Stroke Vol 15, No I, 1984