Development and Biodistribution of a Nerve Growth Factor Radioactive Conjugate for PET Imaging.

PURPOSE: The purpose of these studies was to develop a nerve growth factor (NGF) radiometal-chelator conjugate to determine the biodistribution and brain uptake of NGF by positron emission tomography/computerized tomography (PET-CT). PROCEDURES: Purified NGF from llama seminal plasma was conjugated with FITC, and the chelator NOTA or DFO. NGF conjugates were evaluated for bioactivity. NOTA- and DFO-conjugated NGF were radiolabeled with gallium-68 or zirconium-89 ([68 Ga]GaCl3, half-life = 68 min; [89Zr]Zr(oxalate)4, half-life = 3.3 days). [89Zr]Zr-NGF was evaluated for biodistribution (0.5, 1, or 24 h), PET imaging (60 min), and brain autoradiography in mice. RESULTS: Cell-based in vitro assays confirmed that the NGF conjugates maintained NGF receptor-binding and biological activity. Zirconium-89 and gallium-68 radiolabeling showed a high efficiency; however, only[89Zr]Zr-NGF was stable in vitro. Biodistribution studies showed that, as with most small proteins < 70 kDa, [89Zr]Zr-NGF uptake was predominantly in the kidney and was cleared rapidly with almost complete elimination of NGF at 24 h. Dynamic PET imaging from 0-60 min showed a similar pattern to ex vivo biodistribution with some transient liver uptake. Interestingly, although absolute brain uptake was very low, at 24 h after treatment, cerebral cortex uptake was higher than any other brain area examined and blood. CONCLUSIONS: We conclude that conjugation of DFO to NGF through a thiourea linkage allows effective radiolabeling with zirconium-89 while maintaining NGF bioactivity. Following intravenous administration, the radiolabeled NGF targets non-neuronal tissues (e.g., kidney, liver), and although absolute brain uptake was very low, the brain uptake that was observed was restricted to the cortex.

Soil particles in the tissues of the foot in endemic elephantiasis of the lower legs.

The presence of microparticles of clay is demonstrated in the dermis of the foot in a patient with endemic elephantiasis. The particles are seen to be in the phagosomes of macrophages or in the cytoplasm of other cells. The conducting lymphatic in the subdermal tissue is found to be impermeable to Patent Blue Violet dye and to be fibrosed. The failure to conduct lymph to the node produces a permanent deposit of silica in the dermal tissues; a parallel is drawn with similar deposits in the lung in pneumoconiosis.

Endemic elephantiasis as a paediatric problem in the tropics.

Endemic (non-filarial) elephantiasis of the lower legs is a disease of worldwide distribution in which the first signs commonly occur in childhood, at a time when the disease can be arrested and even reversed. Failure to recognize this stage exposes the patient and his family to increasing disability. The distribution, pathology and clinical appearance are summarized with illustrative cases. The management of these cases is outlined. Public health education, especially that of parents, plays a major part in control of the disease.

The effects of silica on lymph nodes and vessels--a possible mechanism in the pathogenesis of non-filarial endemic elephantiasis.

Non-filarial tropical elephantiasis, which occurs in certain volcanic areas of the world, has been postulated to be an obstructive lymphopathy due to the fibrogenic effects of silica absorbed through the plantar skin of bare-footed people. Animal experiments involving the direct intralymphatic injection of fine silica particles have been carried out in order to assess the extent to which this substance can engender lymphatic obstruction and to determine its main site of action. Intralymphatic silica provoked an immediate and intense macrophage reaction with later fibrosis both within lymph vessels and to a lesser extent within lymph nodes. Lymphography indicated that the consequent obstruction resulted more from the effects of silica on vessels than on nodes.

Environmental factors in the etiology of endemic elephantiasis of the lower legs in tropical Africa.

The environmental factors including geography, geology and soil have been reviewed in areas of high prevalence of non-filariasis endemic elephantiasis surveyed in tropical Africa. These areas occur at altitudes above 1000 m where rainfall is seasonal and exceeds 1000 mm annually. The soil is a red clay, very slippery when wet and very adhesive if allowed to dry on the skin. These are also areas of past or present alkalic volcanism, the prevalence being highest in proximity to the volcanoes. The derived soils are notable for the high proportion of alumino-silicate particles of colloid size in the clays. The significance of these findings suggests that the number and small size of the clays. The significance of these findings suggests that the number and small size of the particles facilitates entry through the skin into the lymphatic tissues, where they exert the known irritant and fibrosing effects of silica and alumina.

Endemic elephantiasis of the lower legs in the United Cameroon Republic.

Evidence for an association of endemic non-filarial elephantiasis of the lower legs with areas of red clay soils around volcanoes has been noted in several countries bordering the Rift Valley in East Africa. It was of interest to observe whether the association is also present in an area of endemic prevalence of the disease in West Africa. Such an area occurs in the Cameroon highlands where it has been suggested that onchocerciasis might be an etiological factor. The present study describes the results of a survey in this area. There was no statistical evidence of a relationship with onchocerciasis and the content of mineral microparticles in lymphatic tissues of the lower legs was again established. Climatic, geological and soil characteristics were similar to those in East Africa. It is considered that the disease in the two widely separated non-bancrofti areas is of similar etiology and it is proposed that it may be interpreted as silicosis of peripheral lymphatics of the lower legs.

Silica and silicates in femoral lymph nodes of barefooted people in Ethiopia with special reference to elephantiasis of the lower legs.

Electron microscopy of femoral lymph nodes of barefooted Ethiopians show the presence of numerous particles of colloid-size and electron-density in the lysosomes of the macrophages in the gland. On diffraction analysis, the particles are found to be amorphous. Elemental microanalysis of the X-ray spectrum indicate the predominance of Si, Al and Fe. In elephantiasics some particles contain silicon alone, presumably silica. The distribution of the Al/Si ratios of the particles in subjects with elephantiasis of the lower legs show a difference from that of non-elephantiasics which is statistically "highly significant" at p less than 0.001. The importance of this as a possible aetiological factor in the disease is discussed. The hypothesis that the disease is discussed. The hypothesis that the disease is a silicosis of the peripheral lymphatics of the lower limbs is supported by the present study.

The site of lymphatic blockade in endemic (non-filarial) elephantiasis of the lower legs.

1. The femoral lymph nodes of 13 patients with endemic (non-filarial) elephantiasis of the lower legs are compared with those of 13 non-elephantiasic adults from the same area. 2. Features characteristic of the disease include reflux of darkly-staining lymphocytes into the afferent lymphatics, crowding of the small lymphocytes into the sinuses with sheets of similar cells in the periphery of the node. The phenomena occur in relation with endolymphangitis of afferent lymphatics in some cases. 3. The picture closely resembles that produced experimentally in animals by occlusion of the incoming lymphatics and is interpreted as indicating delay in, or absence of, transport of the lymphocytes through the node into the central circulation (Gowans cycle). In elephantiasis, the loss of lymph-flow results from endolymphangitis of the afferent lymphatics. 4. The presence of microgranulomata and of birefringent particles was also noted but is not discussed here. 5. The present study indicates that the lesion responsible for the irreversible elephantiasis of the lower legs is in the distal lymphatics.

Endemic elephantiasis of the lower legs in Rwanda and Burundi.

The distribution of non-filarial elephantiasis of the lower legs in Rwanda and Burundi in Central Africa has been studied in order to test the previous observation of an association between the disease and the volcanic rocks and soils on which the people live. Using the method of market counts, a total of 26,602 adults were observed in 23 markets; 189 had elephantiasis. In addition, 264 cases were observed in specially arranged clinics and a further 77 while travelling. Prevalence per thousand adults varied from 0.0 to 20.7. It was noted that the areas of high prevalence corresponded with the areas of volcanic lava. A differential market count at the edge of the red soils in two of these areas showed a raised prevalence among people living on these soils, similar to that observed in Ethiopia. The observations confirm that the disease occurs in barefooted people who dig in soil developed from volcanic rocks, under tropical conditions, at altitudes around 1500 m. It is suggested that the high proportion of iron and other transitional metals may be important as irritant or toxic to the lymphatic vessels of the legs after absorption.