Increased extra-cardiac background uptake on immediate and delayed post-stress images with 99Tcm sestamibi: determinants, independence, and significance of counts in lung, abdomen and myocardium

Extra-cardiac activity on stress scans with 99Tcm sestamibi (MIBI) may influence scan interpretation. Lung uptake represents a potential sign of severe disease, whereas abdominal uptake may interfere with visualization of myocardial defects. We assessed myocardial, lung and infradiaphragmatic abdominal activity on images at 4 min (IMM) and 1 h (DEL) post-stress in 1800 consecutive studies. Potential variation among patients in organ activity was reduced with a weight-based dosing protocol. Multifactorial analysis was used to compare organ activity, and background ratios, i.e lung/heart or abdomen/heart, on stress images to (1) result of tomography, (2) peak workload, and (3) protocol (same-day versus separate-day rest/stress). Lung/heart ratios were primarily related to tomographic abnormalities, and abdomen/heart ratios to low stress workload; neither was related to protocol, and the two measurements appeared independent. Elevated lung/heart ratios (compared to angiographic normals), present on 16% and 10% of IMM and DEL images respectively, were determined primarily by increases in regional lung activity. Lung activity (normalized for dose) was higher in cases with disease than in normals (P<0.0001 as assessed by tomography, P<0.05 in the subset with correlating angiography). Increased abdominal/heart ratios derived primarily from increased abdominal activity, but were partially dependent on reciprocal decreases in myocardial activity. Elevated MIBI lung uptake ratios on abnormal scans can be attributed primarily to increased lung persistence of the radiotracer, and would thus be consistent with their use as a sign of left ventricular failure. Elevated abdominal background is associated with both higher splanchnic activity and lower myocardial activity, and is a non-specific finding related to suboptimal exercise intensity.     

Adrenal response to angiotensin II in black hypertension: lack of sexual dimorphism

Adrenal responsiveness to angiotensin (Ang) II is markedly blunted in black hypertensive patients compared with white hypertensive patients. One characteristic of this blunted adrenal response in whites is a powerful sexual dimorphism: premenopausal white women rarely show blunted responses. This abnormality, most evident when the system is activated by a low-salt diet, is a cardinal feature of the syndrome of nonmodulation, affecting a large percentage of white hypertensive patients. Nonmodulation is also marked by an increase in cardiovascular risk beyond that from hypertension itself. This study investigated whether young black women are likewise spared its expression or whether the adrenal unresponsiveness common among black hypertensive patients is unaccompanied by a gender bias. We compared the adrenal response to Ang II in 382 hypertensive patients (313 white, 69 black; 238 male, 144 female). Ang II was infused when subjects were in balance on a 10-mmol Na(+) intake. As anticipated, white hypertensive patients showed a very strong sexual dimorphism, with women having twice the aldosterone response of men (P=0.0001). Blacks, on the other hand, showed no gender difference (P=0.9). Increasing age had the dramatic effect of reducing responsiveness in white women but not in blacks. Young black women demonstrated the same blunting of adrenal responsiveness as older black women and black men of all ages. Mechanisms protecting against a blunted adrenal response to Ang II in young white women are absent in blacks. These differences may contribute to the markedly increased prevalence of hypertension in young black women.     

Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade

We have previously shown that antibodies to CTLA-4, an inhibitory receptor on T cells, can be effective at inducing regression of transplantable murine tumors. In this study, we demonstrate that an effective immune response against primary prostate tumors in transgenic (TRAMP) mice can be elicited using a strategy that combines CTLA-4 blockade and an irradiated tumor cell vaccine. Treatment of TRAMP mice at 14 weeks of age resulted in a significant reduction in tumor incidence (15% versus control, 75%), as assessed 2 months after treatment. Histopathological analysis revealed that treated mice had a lower tumor grade with significant accumulation of inflammatory cells in interductal spaces when treated with anti-CTLA-4 and a granulocyte-macrophage colony-stimulating factor-expressing vaccine. Vaccination of nontransgenic mice with this regimen resulted in marked prostatitis accompanied by destruction of epithelium, indicating that the immune response was, at least in part, directed against normal prostate antigens. These findings demonstrate that this combinatorial treatment can elicit a potent antiprostate response and suggest potential of this approach for treatment of prostate cancer.     

Opiate effects on 5-fluorouracil disposition in mice

 Purpose: This study was performed to investigate the effects of morphine on the disposition of 5-fluorouracil (5-FU). Methods: Mice were injected subcutaneously (s.c.) with saline or morphine, 20 mg/kg. 5-FU was administered intravenously (i.v.) 30 min later as a single bolus or by constant infusion. Blood samples were obtained by orbital sinus puncture. Urine samples were obtained from the bladder after ligation of the external urethra. 5-FU concentrations in plasma and urine were determined by HPLC. Results: Morphine markedly elevated plasma levels of 5-FU given at doses of 100 to 860 mg/kg. The plasma clearance rate of a bolus dose of 100 mg/kg 5-FU was significantly reduced from 54 to 28 ml/min per kg and the elimination half-life was increased from 6.9 to 12.2 min by prior administration of morphine. When 5-FU was infused at 0.5 mg/kg per min, morphine reduced its plasma clearance rate from 145 to 94 ml/min per kg. Mice made tolerant by prior morphine administration required higher doses of this opiate to raise 5-FU levels as well as to cause analgesia. The effects of morphine on 5-FU disposition were antagonized by naltrexone. Excretion of 5-FU in urine was not affected by morphine treatment. Conclusions: The plasma clearance rate of 5-FU in mice is significantly reduced by concomitant use of morphine. This effect of morphine is due to reduced hepatic elimination of 5-FU rather than to a decrease in its renal excretion. Received: 22 December 1995 / Accepted: 25 May 1996