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Radionuclide imaging for the detection of inflammation in vulnerable plaques.

Imaging of atheromatous plaques has traditionally centered on assessing the degree of luminal stenosis. More recently it has become clear that the vulnerable atherosclerotic plaques responsible for the majority of life-threatening syndromes are characterized by high numbers of inflammatory cells and proteins. This has highlighted the urgent need for suitable imaging techniques that can identify and quantify levels of inflammation within atheromatous lesions. Positron emission tomography and single-photon emission computed tomography imaging hold promise in this regard. Tracer compounds capable of assessing macrophage recruitment, foam cell generation, matrix metalloproteinase production, macrophage apoptosis, and macrophage metabolism have been developed and tested in the carotid and peripheral circulation. The identification of inflamed lesions within the coronary circulation, however, remains elusive owing to small plaque size, cardiac and respiratory motion, and lack of a suitable specific nuclear tracer.

Animals↗

Evaluation of SPECT quantification of radiopharmaceutical distribution in canine myocardium.

UNLABELLED: This study evaluates the quantitative accuracy of SPECT for in vivo distributions of 99mTc radiopharmaceuticals using fanbeam (FB) and parallel-beam (PB) collimators and compares uniform and nonuniform attenuation correction methods in terms of quantitative accuracy. METHODS: SPECT quantification of canine myocardial radioactivity was performed followed by well counter measurements of extracted myocardial tissue samples. Transmission scans using a line source and an FB collimator were performed to generate nonuniform attenuation maps of the canine thorax. Emission scans with two energy windows were acquired. Images were reconstructed using a filtered backprojection algorithm, with a dual-window scatter subtraction combined with either no attenuation compensation or single iteration Chang attenuation compensation based on an uniform attenuation map (mu = 0.152 cm-1) or the nonuniform transmission map. RESULTS: The measured mean counts from the SPECT images were converted to radionuclide concentrations (MBq/g) using a standard source calibration and were compared with those obtained using the well counter. CONCLUSION: The experimental results demonstrate that, compared with well counter values, the in vivo distributions of 99mTc were most accurately determined in FB and PB SPECT reconstructions with nonuniform attenuation compensation, under-estimated without attenuation compensation and overestimated with uniform attenuation compensation.

Animals↗

Normal pharmacokinetics of 99mTc-diphosphonate after intravenous administration.

In the past several years bone imaging has become a routine diagnostic tool for the nuclear medicine clinician. However, increased information may be derived by determining the ratio-pharmacokinetic parameters associated with blood, urine, and bone. In an adult male population of normals (N = 5--6) blood clearance, urinary excretion, and skeletal uptake of 99mTc-Diphosphonate were determined as a function of time after intravenous (i.v.) administration. The quantitative imaging studies (lower lumbar region) were performed up to 1 h post administration with a scintillation camera interfaced to a computer. Blood levels exhibited a triexponential clearance pattern and urinary excretion of the radiopharmaceutical was essentially complete by 4 h. The computer-generated images showed an initial early uptake in bone, kidneys, and soft tissue. Thereafter, a parallel fall-off in activity was observed in kidneys and soft tissue, with a concomitant increase in bone.

Adult↗

True-positive exercise electrocardiogram/false-negative thallium-201 scintigram: a proposal of a mechanism for the paradox.

A 72-year-old man with exertional angina had a strongly positive exercise electrocardiogram (EECG) with a negative thallium-201 myocardial perfusion scintigram (Tl). Arteriography revealed triple-vessel coronary artery disease, for which he underwent aortocoronary bypass grafting. Repeat EECG was negative, and it was again associated with a negative Tl. The false-negative Tl on the first test was felt to be due to a rare phenomenon of homogeneously distributed reversible exercise-induced myocardial ischemia, leading to a uniform radiotracer count density. The even distribution of ischemia would also be expected to render a false-negative EECG, due to electrocardiographic cancellation, and this is frequently the case. However, in the patient presented herein, we propose that the ischemic cardiac apex rendered the EECG strongly positive because its position was not opposed by an ischemic muscular region, and thus an uncancelled ischemic ST-segment vector was generated. This hypothesis is supported by our recent work showing the unique role of the ischemic apex (among all the other myocardial territories) in rendering the EECG positive.

Aged↗

Mononuclear and dinuclear complexes of 99mTc.

In the labeling of penicillamine (Pen) with 99mTc, various complexes were detected. Studies of the conditions for differentiating the product formed in order to understand the chemical and biological behavior were carried out. Marked roles of pH and SnCl2 concentration were observed. Controlled delivery of Sn2+ ion was obtained with the tin-adsorbed resin (Sn-resin) developed. Radiopharmaceutical and biological characterization of mononuclear and dinuclear complexes of Tc-Pen, under given sets of labeling condition, were established. Those studies provided a good basis in technetium chemistry which facilitated the development of new Tc-radiopharmaceuticals. Selection of the appropriate ligand offered a stable mononuclear complex of Tc-bleomycin for tumor detection, Tc-Pen-ethyl-ester for blood-element labeling and, above all, development of a bis-thiosemicarbazone derivative as a new bifunctional chelating agent to be coupled to proteins, fatty acids, glucose etc. On the other hand, various cholescintigraphic agents were better conceived of as dinuclear complexes and this created the possibility of generating a new agent, a phthalein derivative, Tc-PC, containing the required coordination environment for the technetium to be bridged in a dinuclear state.

Bleomycin↗

Pulsatile perfusion and cardiomyocyte viability in a solid three-dimensional matrix.

BACKGROUND: The manufacture of full thickness three-dimensional myocardial grafts by means of tissue engineering is limited by the impeded cellular viability in unperfused in vitro systems. We introduce a novel concept of pulsatile tissue culture perfusion to promote ubiquitous cellular viability and metabolism. METHODS: In a novel bioreactor we established pulsatile flow through the embedded three-dimensional tissue culture. Fibrin glue served as the ground matrix wherein neonatal rat cardiomyocytes were inoculated. Fluor-Deoxy-Glucose-Positron-Emission-Tomography (FDG-PET) and life/dead assays were employed for comparative studies of glucose uptake resp. cell viability. RESULTS: A solid 8 mm thick structure resulted. Cellular viability significantly increased in the perfused chambers. We observed centripetal migration of the embedded cardiomyocytes to the site of the core vessel. However, cellular viability was high in the periphery of the tissue block too. FDG-PET revealed enhanced metabolic activity in perfused chambers. CONCLUSIONS: The present concept is highly effective in enhancing cellular viability and metabolism in a three-dimensional tissue culture environment. It could be utilized for various co-culture systems and the generation of viable tissue grafts.

Animals↗

The use of targeted mouse models for preclinical testing of novel cancer therapeutics.

The use of genetically engineered cancer-prone mice as relevant surrogates for patients during the development of pertinent clinical applications is an unproven expectation that awaits direct demonstration. Despite the generally disappointing findings using tumor xenografts and certain early transgenic cancer models to predict therapeutic efficacy in patients, the dramatic progress of mouse models in recent years engenders optimism that the newest generation of mouse models will provide a higher standard of predictive utility in the process of drug development.

Adenocarcinoma↗

Effect of a chayotte (Sechium edule) extract on the labeling of red blood cells and plasma proteins with technetium-99m: in vitro and in vivo studies.

Sechium edule (chayotte) is used as food or as medication in popular medicine. The labeling of blood elements with technetium-99m (99mTc) has been altered by drugs (synthetic and natural). Some authors have reported biological effects concerning the chayotte. We have evaluated the influence of chayotte extracts (macerated and infusion) on the labeling of blood elements with 99mTc. In vitro study, blood was incubated with the extracts, (6.25, 12.5, 25, 50 and 100% v/v). In in vivo study, the animals were treated with the extracts (100% v/v), as drinking water (15 and 60 days) and samples of blood were withdrawn. The blood samples were incubated with stannous chloride and with 99mTc. Plasma (P) and blood cells (BC) were isolated, also precipitated with trichloroacetic acid and soluble (SF) and insoluble fractions (IF) separated. There was a (p < 0.05) decrease in the radioactivity in BC, IF-BC and IF-P with the infusion (100%) and a slight decrease in the uptake of 99mTc by BC and a strong decrease in the fixation in IF-P with the macerated when the extracts were administrated in vivo (15 days). In 60 days, there was a decrease in BC (98.77 to 53.53%), in IF-BC (90.36 to 21.20%) and in IF-P (77.20 to 11.01%). In vitro study no alterations on the labeling of blood elements were found, however, we have found alterations on the fixation of 99mTc in the in vivo study, probably, due to the metabolization of chayotte capable to induce the generation of active metabolites.

Animals↗

A ventilatory assistance device for use with Technegas.

The demand for high-quality ventilation imaging of the lungs has resulted in the advent of Technegas, which has proven its superiority to the more conventional agents in a number of clinical trials. Images of similar diagnostic quality have been difficult to obtain in patients who are uncooperative, intubated or very young. With this problem as the impetus, a ventilatory assistance device (VAD) was designed to exploit the superior imaging qualities of Technegas. The Technegas generator was interposed between the patient and the VAD, allowing the controlled movement of Technegas into the patient from the generator. Utilizing this device, the problems of increased dead space, turbulent gas flow and possible contamination were circumvented. Twenty patients, comprising nine children and eleven adults, were studied for various indications including assessment of pulmonary parenchymal disease, suspected pulmonary embolism and the lung clearance of modified Technegas. In all cases, images of diagnostic quality were obtained with ease, facilitating relevant clinical decision making. We conclude from this preliminary appraisal that the VAD is a simple, safe addition to the Technegas generator for imaging a group of patients in whom images of diagnostic quality have traditionally proven difficult to obtain.

Adolescent↗

[The determination of the ejection fraction of the left ventricle by the first passage of an indicator bolus. Comparison of two curve-fitting algorithms (author's transl)].

In 28 studies of the first left ventricular bolus passage, the end-systolic and end-diastolic phase were determined in the left ventricular time activity curve (4 msec per frame) by simply smoothing this curve 25 times. Comparing this method with a highly sophisticated curve-fitting algorithm (Sinusoidial Approximation), a very high correlation (r = 0.95) was found of the resulting ejection fractions. Thus, the two methods can be regarded as equivalent. In comparison with the ejection fractions evaluated by cineventriculoangiographic studies, a good correlation (r = 0.85) was obtained as well. To generate end-systolic and end-diastolic frames the two frames containing the highest left ventricular radioactivity were designated as end-diastolic, and the two frames containing the lowest radioactivity as end-systolic, for each heart cycle. This criterion was found to be very efficient although the temporal resolution was 8 msec per image. Furthermore, mean filling- and ejection-times of the left ventricle were derived from the extensively smoothed time activity curve. Those parameters seemed not to be of great clinical value. By employment of fast computing procedures, the evaluation time of a first passage (including image and curve generation) could be reduced to less than 10 min. Accuracy remained constant so that this method was introduced into our clinical routine diagnostics.

Cardiac Output↗

[Right ventricular function: physiological and physiopathological features].

Sinus and conus constitute the two cavities of the right ventricle. They are anatomically and functionally different. The sinus is a flow-generator and the conus a pressure-regulator. The coronary circulation of the right ventricle is provided by the right coronary artery and the left anterior descending artery. The right ventricle is perfused during systole and diastole. When oxygen demand increases, coronary arteries dilate and oxygen extraction rises. As for the left ventricle, right ventricular performance depends upon heart rate, rhythm, contractility and loading conditions. Ventricular interactions are very important for right ventricular function. Loading conditions and contractility of the left ventricle are of major significance for right ventricular performance. For the right ventricle, the end of the ejection is different from the end of the active contraction. The time between them allows to achieve ventricular emptying. This duration is linked to afterload. Presently, it is impossible to accurately and simply assess these conditions. Pressure and volume overloadings result in right ventricular failure. They are responsible for ventricular dilation and ischaemia with a decrease in cardiac output, generating a vicious circle. Treatment includes the removal of the cause, and the maintenance of systemic arterial pressure and biventricular contractility. It is difficult to assess the effects of intravenous vasodilators on right ventricular afterload.

Coronary Circulation↗

Evaluation of the in vitro detection of the hypercoagulable state using the thrombin generation test and plasma clot impedance test.

This study reports the correlation of the thrombin generation test and the plasma clot impedance test with clinical evidence of hypercoagulability. Thrombin generation is increased and the rate of change of plasma from a liquid to a gel (clot impedance) is increased in situations where the risk of thrombosis is increased. These situations include increasing clinical signs and/or symptoms of thromboembolism, positive lung scans, postoperative total hip replacement, patients over 40 years old, low serum antithrombin III, thrombocytosis, transient cerebral ischemia, and positive isotope venogram for thrombosis. The two tests failed to indicate a significant effect of antiplatelet drugs on the hypercoagulable state. This study shows that the thrombin generation and plasma clot impedance tests are practical, rapid and useful tests for the detection and monitoring of the hypercoagulable state.

Adult↗

Interventional magnetic resonance imaging of the head and neck and new imaging techniques.

The use of magnetic resonance imaging to directly guide therapy is a new area of investigation. Clinical magnetic resonance imaging has the potential to evolve from a purely diagnostic tool into a guide for invasive procedures. The idea of using magnetic resonance to guide percutaneous biopsy developed one decade ago. Magnetic resonance-guided fine-needle aspiration for head and neck lesions has become a standard technique some institutions. Once the needle reaches a lesion in the head and neck, it is natural to explore the possibility of treatment in the same setting. The concept of interventional magnetic resonance imaging has generated interest among radiologists, surgeons, and manufacturers. This article provides an overview of interventional procedures of the head and neck and other new imaging techniques that have been developed.

Head and Neck Neoplasms↗

Malignant external otitis: review and personal experience.

Malignant external otitis (MEO) is an infrequent but severe infective disorder, generally due to Pseudomonas aeruginosa, which most often affects elderly diabetics patients. The clinical features rarely permit exact diagnosis of MEO to be made promptly, and initially at least they are difficult to distinguish from those of external otitis. This explains the frequent delay in diagnosis with respect to the onset of symptoms. Physical examination almost always reveals the presence of aspecific granulation tissue in the external auditory canal, while the most common laboratory finding is raised erythrocyte sedimentation rate (ESR). Imaging has great diagnostic relevance: CT and MRI are very useful for spatial resolution, while radionuclide scanning and, in our experience, SPECT are superior for detecting early osteitis and monitoring response to therapy. We present an extensive review of the literature and our personal experience. In particular, we stress the relevance of immunological study of MEO patients: all our 4 patients had defective immune defences. As regards therapy, like other authors we underline the fundamental importance of long-term antibiotic treatment. The availability of quinolones and latest generation cephalosporins has greatly simplified the choice of antibiotic treatment, although clinicians should be aware of the possibility of drug-resistant bacterial strains.

Aged↗

Evidence that in situ generated reactive oxygen species act as a potent stage I tumor promoter in mouse skin.

A body of indirect evidence has suggested the involvement of reactive oxygen species (ROS) in tumor promotion. However, direct evidence for the involvement of in situ generated ROS in tumor promotion is lacking at present. This study provides the first in situ evidence for the involvement of ROS in stage I tumor promotion. Earlier we have shown that parenteral administration of Photofrin-II (a mixture of porphyrins) to mice followed by their exposure to visible light generates ROS. In this study we further provide E.S.R. spectral evidence that both O2.- and .OH radicals are generated during tissue photosensitization. The free radicals/ROS generation is followed by the development of cutaneous inflammation which is maximum at six hours after photosensitization and develops in a dose dependent manner. The epidermal myeloperoxidase activity which represents neutrophil infiltration is also increased more than 160% of the control value. The histopathology of skin tissues of 7,12 dimethyl benz(a)anthracene initiated mice receiving multiple treatments of Pf-II and light for a period of four weeks indicates pronounced epidermal hyperplasia, glandular hyperplasia, dark basal keratinocytes induction characterized by the high uptake of the dye and frequent neutrophil infiltrations. Our data indicate that ROS generated in situ as a result of porphyrin-mediated cutaneous photosensitization results in the development of changes characteristic of stage I tumor promotion in murine skin.

9,10-Dimethyl-1,2-benzanthracene↗

Comparison of methods for the generation of immunoreactive fragments of a monoclonal antibody (B72.3) reactive with human carcinomas.

Immunoglobulin fragments, whether of polyclonal or monoclonal antibodies, offer a number of advantages over the intact immunoglobulin. The generation of immunoreactive fragments from monoclonal antibodies (MAb) is not always a straightforward task. Both pepsin and papain can be used to digest MAb to a bivalent molecule with a Mr of 100,000. However, pepsin pepsin digestions does not always result in immunoreactive fragments and a stable consistent product by papain digestion is often difficult to obtain. MAb B72.3 is an example of both situations. MAb B72.3 reacts with a glycoprotein (TAG-72) with a molecular weight greater than 10(6). MAb B72.3 has been shown to exhibit a high degree of selective reactivity with colon, breast and ovarian carcinomas and has been used for radioimmunodiagnosis in model systems and in clinical trials. A third enzyme, bromelain, in the same family of sulfhydryl proteases as papain, has been used to generate a fragment of MAb B72.3, with a Mr of approximately 100,000. The bromelain-generated fragment of MAb B72.3 retained 100% immunoreactivity as measured in competitive solid-phase radioimmunoassays and could be generated with consistent results from one preparation to another. Both the bromelain- and papain-generated fragments were radiolabelled with 125I without significant loss of the MAb's reactivity to tumor extracts. Differences were observed between the bromelain- and papain-generated fragment when compared in vivo. Fragmentation of MAb B72.3 with bromelain has yielded a superior bivalent fragment for radioimmunolocalization.

Animals↗

Advances in breast imaging.

Although mammography remains the most widely used tool for the early detection of breast cancers and evaluation of palpable abnormalities, a number of other imaging tools are being developed and used. Ultrasonography (US) is an excellent adjunct to conventional mammography. In addition to identifying solid and cystic abnormalities, US can often distinguish benign and malignant solid nodules. Magnetic resonance imaging (MRI) also is useful in assessing the extent of disease within the breast, particularly in women with dense breasts. MRI may be a more sensitive screening tool in women at elevated breast cancer risk. Newer techniques based on the metabolic activity of breast tumors also have been developed. One such technique is scintimammography, which uses radiolabeled tracers to detect breast malignancies. Positron emission tomography (PET), which relies on the high metabolic rate of tumors, also has been described as a method to evaluate breast disease. Other techniques, such as optical tomography and thermography, rely on angiogenesis and generated heat to identify cancers. These and other tools may help to improve both the sensitivity and specificity of cancer detection. Ideally, this improved detection results in improved outcomes in those who have breast cancer and avoidance of unnecessary procedures in those who do not.

Breast↗

Functional renal imaging through factor analysis.

Functional images tend to be noisy, since they are formed from parameter values estimated from noisy time-activity curves. Factor analysis provides a rapid method for fitting smooth curves to these noisy curves. Noise in functional images is reduced by estimating parameter values from the smooth curves. The method is illustrated for three parameters: TMAX (time to maximum value), RISE (increase from first to maximum value), and RISMX (maximum increase between successive values). When curve-fitting through factor analysis is used to generate functional renal images from clinical studies or to estimate parameter values for simulated noisy renogram curves, noise is reduced for the TMAX and RISMX parameters and accuracy is improved for the RISE parameter.

Factor Analysis, Statistical↗