Bernd Bubeck

Residual 201Tl Activity in Irreversible Defects as a Marker of Myocardial Viability Clinicopathological Study

BACKGROUND The objective of the present study was to characterize the relation between the residual 201Tl activity in irreversible perfusion defects and the extent of irreversible myocardial damage indicated by the volume fraction of myocardial interstitial fibrosis in patients with chronic coronary artery disease. METHODS AND RESULTS Stress planar 201Tl scintigraphy with tracer reinjection at rest was performed in 37 patients with > or = 75% stenosis of the left anterior descending coronary artery, and anteroseptal 201Tl activity was quantified by computer-assisted placement of regions of interest from the serial myocardial images. During coronary artery bypass grafting (performed within 6 +/- 3 weeks after scintigraphy), two transmural biopsy specimens were taken from the anterior wall of the left ventricle and the amount of interstitial fibrosis was assessed by use of light microscopic morphometry. A wide spectrum of interstitial fibrosis was obtained, ranging from 15 vol% to 60 vol%. Interstitial fibrosis was similar in patients with reversible (n = 11) or irreversible (n = 15) tracer defects in conventional stress-redistribution images. However, interstitial fibrosis was significantly lower in patients who had enhanced regional 201Tl activity after tracer reinjection compared with those who did not have enhancement of tracer activity after reinjection (28 +/- 8 vol%, n = 7, versus 41 +/- 12 vol%, n = 8; P = .031). The correlation between relative poststenotic 201Tl activity and interstitial fibrosis after tracer reinjection was significantly improved compared with conventional redistribution images (r = -.622 versus r = -.851, n = 15; P < .01). CONCLUSIONS The present data demonstrate that the level of regional 201Tl activity in redistribution and, in particular, reinjection images is significantly related to the mass of preserved viable myocytes in poststenotic left ventricular myocardium. Therefore, the residual 201Tl activity provides information about viability within irreversible perfusion defects and may itself serve as marker of myocardial viability.

D2 Dopamine Receptor Up-Regulation, Treatment Response, Neurological Soft Signs, and Extrapyramidal Side Effects in Schizophrenia: A Follow-Up Study with 123I-Iodobenzamide Single Photon Emission Computed Tomography in the Drug-Naive State and after Neuroleptic Treatment

BACKGROUND Animal and postmortem studies indicate that neuroleptic therapy may induce D2 dopamine receptor up-regulation in the basal ganglia. METHODS To address this phenomenon in a clinical study, we investigated the D2 dopamine receptor binding in 15 DSM-III-R schizophrenics in the drug-naive state and 3 days after completion of a standardized neuroleptic therapy (benperidol 12-16 mg/day, for 25 days) using single photon emission computed tomography (SPECT). SPECT scans were obtained 2 hours after intravenous injection of 185 MBq 123I-iodobenzamide. For analysis, basal ganglia to frontal cortex (BG/FC) ratios were calculated and the patient sample was subgrouped into patients with a favorable versus a poor treatment response. RESULTS Neuroleptic treatment led to decreased BG/FC ratios in patients with a favorable response, but increased ratios in the poor responders (df = 1, F = 4.1, p = .06). Changes of BG/FC ratios were significantly correlated with extrapyramidal side effects but not with neurological soft signs. CONCLUSIONS Our findings suggest that neuroleptic therapy may induce D2 dopamine receptor up-regulation in a subgroup of patients characterized by poor treatment response and pronounced extrapyramidal side effects.

Report of the Radionuclides in Nephrourology Committee for evaluation of transplanted kidney (review of techniques).

Comprehensive evaluation of renal transplants has been important in differential diagnosis of medical and surgical complications in the early post-transplantation period and in the long-term follow-up. If performed well, it yields excellent functional and good anatomic information about the graft that can be effectively used in the patient. That includes selection of patients for biopsy and for various drug regimens. This is true especially in patients with anuric acute tubular necrosis (ATN) and in patients with developing chronic rejection. Improving indices of renal function (effective renal plasma flow, uptake of tubular tracers) can indicate resolution of tubular injury (ATN) while there is still no improvement in plasma creatinine. In patients with chronic rejection, plasma creatinine increases only after approximately 30% of renal function is lost due to graft fibrosis. Early recognition of this condition could permit treatment and delay of retransplantation. The protocol recommended at the Copenhagen meeting includes a flow study, scintigram of the kidneys, prevoid and postvoid bladder image, injection site image (quality control), time/activity curves of the graft and bladder, and quantitative data of perfusion, function, and tracer transit. The flow study obtained during the initial transit of the bolus through the graft could be performed either with 99mTc mercaptoacetyltriglycine, or 99mTc diethylenetriaminepentaacetate (DTPA). Quantitative analysis of perfusion facilitates interpretation of the study during the early post-transplantation period. ATN, common in cadaver transplants, typically shows adequate perfusion. The function phase should include images and time/activity curves. Images alone are insufficient. Quantitative data such as clearance or other indices of function and indices of tracer transit are essential for correct interpretation of the results. Normal images and normal graft function reliably exclude clinically important complications. A single scintigram demonstrating prolonged tracer transit with decreased function cannot separate acute rejection and ATN. On serial studies, decline in function and poor perfusion are indicative of acute rejection. A normally appearing scintigram without cortical retention, but with low function, is consistent with chronic rejection. Pharmacological intervention to exclude obstruction (diuretic renogram) or hemodynamically significant renal artery stenosis (angiotensin converting enzyme challenge) should be used whenever indicated.

Technetium-99m labeled renal function and imaging agents: III. Synthesis of 99mTc-MAG3 and biodistribution of by-products

99mTc-MAG3, a new 99mTc radiopharmaceutical with biological properties similar to o-iodohippuric acid (OIH), is expected to find wide clinical application for renal function studies. Therefore it is important to make a kit formulation available which provides reproducibly the desired product in high radiochemical yields. Some differences between the biokinetic data of kit prepared 99mTc-MAG3 and HPLC-purified 99mTc-MAG3 were reported by different authors. The subject of this paper is the isolation of the by-products which are formed with our own kits, the evaluation of their biological behaviour and the comparison with the main product 99mTc-MAG3 in rats. The results suggest that the radiochemical purity of 99mTc-MAG3-preparations should be not less than 95%.

Renal clearance determination with one blood sample: Improved accuracy and universal applicability by a new calculation principle

A sufficiently accurate quantification of renal function requiring only one plasma sample without an additional gamma camera study has until now only been possible in adults. A new principle has been developed that allows the universal application of known algorithms, irrespective of the clearance substance used, by normalizing the plasma concentrations with respect to individual body dimensions of adult as well as infant patients. In this respect, algorithms are established for clearance determinations using technetium-99m mercaptoacetyltriglycine which are based on steady-state studies as the reference. They allow the calculation of quantitative clearance values in infants and require the drawing of only one blood sample at any time between 25 and 40 minutes postinjection. The comparison with a combined-camera/two-plasma-sample technique performed in 46 children ranging in age from 9 days to 14 years (mean, 6.05 years) resulted in a standard deviation of 8.5% from the line of identity (r = 0.94). Moreover, this procedure also increases accuracy in adult patients, especially those with impaired renal function.

Benzodiazepine receptor distribution and diazepam binding in schizophrenia: an exploratory study

Clinical studies indicate that patients with acute schizophrenia may benefit from benzodiazepine treatment. Therefore we investigated the benzodiazepine receptor distribution and diazepam binding in 20 patients with DSM-III schizophrenia using single photon emission computed tomography (SPECT) with iomazenil as the ligand. In each patient, two SPECT images were obtained: SPECT 1 was obtained 2 h after intravenous injection of 200 MBq I-123-iomazenil. Following SPECT 1, patients received 10 mg diazepam intravenously. Twenty min later, SPECT 2 was started. The highest iomazenil uptake was found in the occipital cortex followed by the frontal and temporal cortices. Baseline iomazenil uptake in the medial frontal cortex was significantly (P < 0.05) correlated with the BPRS total score (r = 0.46). Diazepam injection led to a significant activity decrease in iomazenil binding which was greatest in the frontal regions of interest. With respect to the medial frontal cortex, this effect was significantly (P < 0.05) more pronounced in patients with a remitting than a chronic course of the disorder. These findings suggest that changes of the benzodiazepine receptor system in the frontal cortex may be associated with severity and chronicity of schizophrenia.

Gender differences in D2 dopamine receptor binding in drug-naive patients with schizophrenia: an [123I]iodobenzamide single photon emission computed tomography study.

Recent studies have described a left lateralized striatal asymmetry of D2 dopamine receptors in male patients with schizophrenia. To replicate this finding and to explore its potential functional consequences, we investigated the D2 dopamine receptor system in 23 drug-naive patients with schizophrenia using single photon emission computed tomography (SPECT). Patients were examined in the drug-naive state and 72 h after completing a standardized neuroleptic treatment with benperidol (12-16 mg/day) for 25 days. Each SPECT examination comprised two scans: the first scan was taken 2 h after intravenous injection of 185 MBq [123I]iodobenzamide. After completion of the first scan, patients received benperidol (8 mg) intravenously. The second scan was started 20 min later. For analysis, basal ganglia to frontal cortex ratios were calculated. Fifteen of the 23 patients originally recruited completed the study on day 28. When compared to female patients, male patients showed a left lateralized asymmetry of striatal D2 dopamine receptor binding in the drug-naive state with an almost significant (P = 0.07) sex x hemisphere interaction. In the male patients, benperidol challenge led to a reversal of asymmetry patterns. These findings support previous reports of a left lateralized striatal D2 receptor binding in drug-naive male patients with schizophrenia and suggest that this asymmetry may affect the binding of conventional neuroleptics such as benperidol at the D2 dopamine receptor.

Technetium-99m labeled renal function and imaging agents: I. Clinical evaluation of 99mTc CO2-DADS-A (99mTc N,N′-Bis-(Mercaptoacetyl)-2,3-Diaminopropanoate)

Animal experiments and preliminary clinical results showed that the N2S2-complex 99mTc CO2-DADS-A, which was claimed to be a potential replacement for o-I-hippurate as a renal function agent, had a lower affinity for the tubular transport system than o-I-hippurate. In order to evaluate if this finding offered the possibility of detecting decreases in tubular function with more sensitivity, or at earlier times, 6 patients in the early post-transplantation period were subjected to 53 simultaneous scintigraphic investigations with 131I o-I-hippurate and 99mTc CO2-DADS-A. The comparison of the renograms obtained with the respective agents showed that in almost all cases of acute graft rejection only o-I-hippurate yielded the typical, diagnostically useful accumulation curve which results from its high retention in the kidney parenchyma. 99mTc CO2-DADS-A did not reveal this effect. Additionally the plasma clearance of each agent was measured simultaneously under steady state conditions in nine patients. Although it was reported that relative to o-I-hippurate the analog images obtained with 99mTc CO2-DADS-A gave higher kidney-to-background ratios and the amount excreted in the urine at 30 min was slightly less, the clearance values obtained for 99mTc CO2-DADS-A were on average only 36% of those for o-I-hippurate. It is concluded that 99mTc CO2-DADS-A is not suitable as a substitute for o-I-hippurate.

Absorption of Vitamin B12 Administered to Continent Ileal Reservoirs for Urinary Diversion

Urinary diversion through intestinal segments is a widely used method after radical cystectomy. During the last few years, new methods of bladder substitution, continent ileal neobladders, were developed. We used the method described by Hautmann et al. in 1986. 70 cm of ileum is used to form a reservoir. The ureters are implanted into the reservoir, which is then anastomosed to the urethral stump. A known problem when intestine is used for urinary diversion is the absorption of urinary solutes leading to metabolic disturbances. Therefore, the absorption of vitamin B12, instilled into the neobladders of 20 patients, was measured and related to the postoperative interval. The results show a high absorption rate 2 weeks postoperatively that is reduced quickly and significantly (p < 0.001) within the first 10 months (from more than 30 to below 5%). One year to 23 months after the operation, some neobladders absorbed no vitamin B12 at all, whereas others still absorbed significantly but only small quantities. These results may probably be attributed to the loss of villous structure as well as atrophy of the epithelial surface.

Reduction of myocardial ischemia by gallopamil: a dual-isotope study with thallium-201 and iodine-123 phenylpentadecanoic acid.

The present study was performed for characterizing the effect of chronic oral treatment with the calcium antagonist gallopamil on regional myocardial perfusion and free fatty acid utilization in poststenotic human myocardium. Twenty-two patients with angiographically documented coronary artery disease and stable angina pectoris underwent consecutive dual-isotope studies following simultaneous injection of 80 MBq thallium-201 and 200 MBq iodine-123 phenylpentadecanoic acid (IPPA) during a symptom-limited stress test. Radionuclide studies were performed after 1 week of placebo treatment (baseline), 4 weeks after oral treatment with 50 mg of gallopamil t.i.d. and again after 1 week of double-blind treatment with gallopamil or placebo. As compared to baseline, initial (poststress) uptake of both tracers in poststenotic myocardial segments was significantly improved after 4 weeks of treatment with gallopamil [thallium-201, + 9.0%; p < 0.001; 95% confidence interval (CI), 4.3–13.6%; IPPA, +11.8%; p = 0.003; 95% CI, 4.2–19.3%]. Poststenotic IPPA-clearance was likewise significantly increased (+ 28.2%; p < 0.001; 95% CI, 12.4–44.0%) indicating a considerably enhanced myocardial fatty acid oxidation after treatment. In the final double-blind phase, myocardial uptake of both tracers as well as IPPA clearance remained enhanced in the subgroup of patients receiving gallopamil and returned to baseline values in patients receiving placebo. Thus, in poststenotic myocardium, chronic treatment with gallopamil provokes an improvement of both regional myocardial perfusion (as demonstrated by an increased tracer uptake in poststress scintigrams) and regional myocardial fatty acid utilization (as demonstrated by an increased uptake and clearance of IPPA).