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Cytological changes in the urine in the form of inclusion-bearing cells, giant cells and haematuria after vaccination with inactivated influenza virus vaccine. A study with application of Millipore procedure and Papanicolaou staining.

Marked cellular reactions in the urine appeared after subcutaneous vaccination with inactivated influenza virus vaccine. Inclusion-bearing epithelial cells increased in 16 cases from 2.4 to 9.6% and erythrocytes from 2.5 to 16.2 per visual field. Pathological values for inclusion-bearing cells were found in 5 of 18 cases (28%), spherical giant cells in 3 (17%), and an abnormal number of erythrocytes in 7 (39%). Killed virus, lacking the capability of replication, thus gave rise both to the formation of inclusions and to fusion of cells within the epithelium of the kidneys and of the urinary tract, and also to haematuria. There was a striking resemblance to the reaction in 34 cases of uncomplicated influenza A2, but the inclusion-provoking effect of the vaccination dose was clearly weaker and the erythrocyturia somewhat less pronounced. As a rule the cellular changes after the vaccination quickly reverted to normal, but there were examples of elevated values still existing after 6 months. Two patients had a high inclusion content and haematuria persisting for 3 and 4 years, one of whom following influenza A2. Influenza and influenza vaccinations may be the cause of certain instances of chronic benign haematuria.

Adult

The differentiation of monocytes into macrophages, epithelioid cells, and multinucleated giant cells in subcutaneous granulomas. I. Fine structure.

The morphological changes occurring in monocytes during their differentiation into macrophages, epithelioid cells, Langhans-type giant cells, and foreign-body-type giant cells were investigated in foreign-body granulomas induced by subcutaneous implantation of pieces of Melinex plastic. Analysis based on Adams's (1974) criteria for discrimination between the several types of cell of the monocyte line, showed that each type has a characteristic type of granule. Primary and secondary granules, numerous in the Golgi area of monocytes were generally found close to the cell membrane and decreased in number in maturing macrophages. This was accompanied by an increase in the number of microtubules. Mature macrophages show numerous characteristic macrophage granules, which are round (average diameter: 280 nm) and have a halo between the limiting membrane and granular matrix. Mature epithelioid cells have characteristic epithelioid cell granules, and multinucleated giant cells a heterogenous population of granules. Fusing macrophages generally have their Golgi areas facing each other, and also show a reduced thickness of the cell coat. The morphology of the multinucleated giant cell is closely related to the number of nuclei present. In Langhans-type giant cells, which generally have two to ten nuclei, a giant centrosphere with numerous aggregated centrioles is found. In transition forms between Langhans-type and foreign-body-type giant cells, which generally contain 10--30 nuclei, the centrioles show less aggregation. In the foreign-body-type giant cells, which generally have more than 30 nuclei, centrioles are virtually absent and never aggregated. These differences between the Langhans-type giant cells, the foreign-body-type giant cells, and the transition forms, support our previous finding that Langhans-type giant cells are the precursors of foreign-body-type giant cells.

Animals

Are Langhans giant cells precursors of foreign-body giant cells?

Granulomas were induced in rats by subcutaneous implantation of pieces of Melinex plastic into the dorsum. The pieces of Melinex were removed at intervals varying from 16h to 14 days, and the adherent cells were studied morphologically and quantitatively. Giant cell formation started about 32h after implantation. The first giant cells to appear were of the Langerhans type. Two days after implantation, most of the giant cells are still Langhans-type cells. A few giant cells of the foreign-body type and transition forms between the Langhans and foreign-body types are also present. From the third day on, the foreign-body type gradually becomes predominant. Independent of the duration of implantation, giant cells with 3, 4, or 5 nuclei are virtually without exception of the Langhans type. The higher the number of nuclei between 6 and 30, the more cells are of the foreign-body type. Giant cells with 30 or more nuclei are all foreign-body type. The findings are discussed in the light of current knowledge concerning giant cell formation. It is concluded that under the present experimental conditions, Langhans-type giant cells are the precursors of foreign-body-type giant cells.

Animals

Are Langhans giant cells precursors of foreign-body giant cells?

Granulomas were induced in rats by subcutaneous implantation of pieces of Melinex plastic into the dorsum. The pieces of Melinex were removed at intervals varying from 16 h to 14 days, and the adherent cells were studied morphologically and quantitatively. Giant cell formation started about 32 h after implantation. The first giant cells to appear were of the Langhans type. Two days after implantation, most of the giant cells are still Langhans-type cells. A few giant cells of the foreign-body type and transition forms between the Langhans and foreign-body types are also present. From the third day on, the foreign-body type gradually becomes predominant. Independent of the duration of implantation, giant cells with 3, 4, or 5 nuclei are virtually without exception of the Langhans type. The higher the number of nuclei between 6 and 30, the more cells are of the foreign-body type. Giant cells with 30 or more nuclei are all foreign-body type. The findings are discussed in the light of current knowledge concerning giant cell formation. It is concluded that under the present experimental conditions, Langhans-type giant cells are the precursors of foreign-body-type giant cells.

Animals

[Central giant cell granuloma. Histochemical and ultrastructural study on giant cell function (author's transl)].

Multinucleated giant cells in giant cell granuloma are formed by cell fusion of capillary pericytes. In our present study we tried to analyze cell function and activity by histologic, histochemical, and electronmicroscopic examination of giant cells. Lysosomal enzymes such as acid phosphatase and amino-peptidase were found in giant cells which is in agreement with former work. By their lysosomal system giant cells are proved phagocytic. In addition, giant cells being localized at trabecular surfaces of newly formed woven bone may develop osteoclastic functions. The enzymatic and funcational resemblance of giant cells and multinucleated osteoclasts points to the possibility of a similar cytogenesis of both cell types.

Bone Resorption

The differentiation of monocytes into macrophages, epithelioid cells, and multinucleated giant cells in subcutaneous granulomas. II. Peroxidatic activity.

The peroxidatic (PO) activity of monocytes differentiating into macrophages, epithelioid cells, and multinucleated giant cells in subcutaneous granulomas was investigated with three different media for the demonstration of PO activity. Irrespective of the stage of differentiation, these cells did not show PO activity in the rough endoplasmic reticulum (RER) or nuclear envelope. In addition, it was found that the morphologically characteristic types of granule of the various cells of the monocyte line (the primary granules and secondary granules of monocytes, the macrophage granules, and the epithelioid cell granules), all have distinct cytochemical characteristics. Monocytes lose their primary and secondary granules during differentiation into mature macrophages. Simultaneously, the granules of both types become elongated and the secondary granule lose their halo. In contrast to monocytes, mature macrophages may contain a few microperoxisomes. During the differentiation of macrophages into epithelioid cells or multinucleated giant cells there is an increase in the number of microperoxisomes.

Animals

An ultrastructural study of nuclear and centriolar configurations in multinucleated giant cells.

Multinucleated giant cells were examined with electron microscopy from (1) four peripheral giant cell granulomas of the jaws, (2) a central giant cell tumor of the maxilla, (3) five giant cell tumors of tendon sheath, (4) experimentally induced foreign body granulomas in rats, (5) a virus-induced sarcoma, and (6) osteoclasts from the mandibles of rats and (7) the femurs of hamsters. The purpose of the study was (1) to examine the location and arrangement of the nuclei and the centrioles of the multinuclueated cells and compare them with the osteoclast which has previously been thought to have a unique arrangement and (2) to observe whether the physical location of the centrioles and the nuclei were such that the nuclei could undergo mitosis within the cytoplasm. All of the multinucleated cells were found to have a similar arragnement of nuclear concentration areas and nucleus-free areas. A giant centrosphere containing multiple pairs of centrioles was found in the nucleus-free areas, unassociated with any particular nucleus. In the case of the foreign body giant cell and the osteoclast, this giant centrosphere was located very close to the foreign material or bone. When occasional single pairs of centrioles were found, they were located in the area of nuclear concentration, closely associated with a particular nucleus at the periphery. These findings have shown that a common centrosphere containing multiple centrioles is not an exclusive feature of the osteoclast as was previously thought. The findings suggest that a mononuclear cell containing a centriole pair fuses to the larger cell and maintains its centriole pair in close proximity to its nucleus for a short period of time, during which it may undergo mitotic activity. Eventually, the centrioles proceed to a common centrosphere whereas the nuclei aggregate in another area making further mitotic activity an unlikely possibility.

Adolescent

[Changes in the positive P.A.S. reaction of the cytoplasm of giant cells. Role of etiologic factors and the giant cell reaction].

The search for alpha-amylase resistant, P.A.S. positive cytoplasm has been carried out in 206 giant cell lesions with or without specific inflammatory features and with neogenetic and degenerative plasmodia. It allowed to distinguish: --P.A.S. positivity in inflammatory cells of any nature, however with quantitative variations linked to etiologic factors (pathogen agent and disposition), to site, to the age of the plasmodia, and particularly, with negativation of the reaction in ancient lesions;--negativity of the neogenetic and degenerative plasmodia, save the giant cell articular lesions. Cells containing glycogen particularly (muscular tumors, renal or placental) are easily identified thanks to enzymatic digestion tests. Variations observed in the inflammatory cells seem to be the reflect of an active metabolism bringing about resorption phenomena but probably also immunization processes acting at the level of the cellular microenvironment.

Cytoplasm

Response to hormones of cells cultured from human giant cell tumors of bone.

Giant cell tumors of bone obtained from 7 patients were dispersed with clostridial collagenase and trypsin and adherent cells were maintained in culture. Early cultures contained both mononucleated and multinucleated cells presumably derived from the stromal and giant cells of the original tumor. The original multinucleated cells did not survive for greater than 7-10 days whereas the mononucleated cells persisted and could be passaged by trypsinization. In 5 of 7 early cultures exposed to parathyroid hormone (PTH) there was a rise in cAMP within 5-10 min in both cells and medium which averaged approximately 12-fold. None of the cells responded to calcitonin and a variable rise in cAMP was seen after incubation with prostaglandin E2. In cells cultured from 3 tumors the PTH response disappeared with passage of the cells, but in the remaining 2, PTH response persisted through multiple passages. The presence as well as the magnitude of the PTH-induced cAMP response in these cells is consistent with a skeletal origin.

Adult

Maxillary giant cell reparative granuloma.

"Giant cell reparative granuloma" was introduced into medical literature by Jaffe in 1953. Prior to that time most authors considered this lesion to be a variant of the benign giant cell tumor of the long bones, or a giant cell variant of osteitis fibrosa. Bernier and Cahn established the subdivision between the rare central giant cell reparative granuloma and the common peripheral epulis. In the past, considerable emphasis has been placed on the importance of differentiating the true giant cell tumor from the giant cell reparative granuloma of the jaw bones. Most authors now believe the true giant cell tumor does not appear in the jaw bones except in rare cases associated with Paget's disease of the skull. Developing from membranous, rather than cartilaginous, ossification might account for this. Both peripheral and central intraosseous lesions, parathyroid osteopathy and the pathologic tissue of cherubism show no appreciable histologic difference. These tumefactions are histologically a proliferative fibroblastic lesion with multinucleated giant cells. The histopathology of the giant cell tumor of the long bones is probably identical to the histopathology of the giant cell reparative granuloma of the jaw bones. The diagnosis of giant cell reparative granuloma must be made by physical examination, history, laboratory, X-ray parameters and clinical follow-up. Localized maxillary swelling is the most important clinical feature. The swelling is smooth and palpation can reveal a rubbery, elastic sensation where bone has been thinned. There are no specific radiographic signs. Conservative surgical management is indicated and adequate for giant cell reparative granulomas. Radiation is not indicated because of long term risks. Steroids have not been proven useful.

Adult

Regulation of hormone-induced cyclic AMP response to parathyroid hormone and prostaglandin E2 in cells cultured from human giant cell tumors of bone.

Cells dispersed from human giant cell tumors of bone and grown in monolayer culture increase intracellular cyclic AMP (cAMP) when incubated with parathyroid hormone (PTH) or prostaglandin E2 (PGE2). When cells are continuously exposed to PTH, cAMP levels increase acutely but then decrease rapidly to pretreatment values despite continued presence of hormone or addition of new hormone. Preincubation of cells with PTH for periods as short as 10 min results in a decrease in the capacity of cells to increase cAMP content when re-exposed to maximal stimulatory concentrations of PTH. The decrease in the magnitude of the PTH-induced cAMP response observed in cells pretreated with this hormone is dependent on the concentration of PTH present during the preincubation. The loss of cAMP response in cells pretreated with either PGE2 or PTH is hormone specific in that cells made refractory by pretreatment with one hormone still increase cAMP content when exposed to the other. Although the cells are not releasing measurable amounts of prostaglandins into the medium, pretreatment with indomethacin results in an increase in the magnitude of the cAMP response to PGE2. The PTH-induced cAMP response is not affected by indomethacin pretreatment. The loss of PTH responsiveness produced by hormone preincubation is consistent with the phenomenon of "down-regulation" observed with ligand-receptor interactions in a variety of tissues.

1-Methyl-3-isobutylxanthine

Giant cell stromal reaction in squamous cell carcinomata. Electronmicroscopic and ultrahistochemical observations on the genesis and functional activity of multinucleated giant cells in bleomycin-induced tumor regression.

Ten cases of oral squamous cell carcinoma, treated by bleomycin, were studied by electron microscopy with particular regard to the stromal reaction. The genesis and phagocytic function of multinucleated giant cells of foreign body type were observed. These cells phagocytize devitalized, keratinized tumor cells in particular. Their genesis from monocytic macrophages and endocytosis of large keratinized tumor cells are described in detail. Both phenomena are connected and the mode of formation of the cells results in functional specialization. The initial stages of intracellular digestion do not seem to take place within membrane limited vacuoles but in specialized cytoplasmatic areas which are formed around the ingested material. These contain high concentrations of hydrolases, sealed off from the rest of the cell by a clear zone of organell-free cytoplasm. This unique form of phagocytosis and digestion ("gigantophagocytosis*) is only possible in these highly specialized giant cells and explains their biological significance. It is likely that secondary lysosomes are formed in subsequent stages of digestion. The difference between our results and the experimental observations of other authors are discussed.

Bleomycin

Fusion of cytomegalovirus infected fibroblasts to form multinucleate giant cells.

Multinucleate giant cells have been observed to arise by cell fusion in cultures of human embryonic fibroblasts infected with human cytomegalovirus (CMV), strain AD 169. The infected cells develope intranuclear and intracytoplasmic inclusions and began to fuse three to four days postinfection when the majority of the cells were showing signs of a cytopathic effect.

Cell Fusion

Giant cell tumor of bone. Variations in patterns of appearance of different cell types.

Eleven benign giant cell tumors of bone were studied in the electron microscope, and the fine structural localization of acid phosphatase was elucidated. Three distinct cell types are always present in these tumors: stromal cells type 1; stromal cells type 2; and multinucleated giant cells. Small mononuclear cells may also occur, but are not likely to be actively participating in the neoplastic process. The range of variability in the fine structure of the different cell types constituting this tumor has been established. Variations in appearances include: a) presence of nuclear pseudoinclusions in stromal cells type 1 and multinucleated giant cells; b) aberrations in the structure of the rough surfaced endoplasmic reticulum in the same cell types; c) occurrence of ruffled borders, ectoplasmic layers and cytoplasmic labyrinths containing acid phosphatase in the giant cells. Some giant cells show evidence of marked phagocytic activity and contain large and numerous residual bodies carrying acid phosphatase. The significance of the interrelations between the different cell types are discussed and the possible role of stromal cells type 2 in immunological mechanisms directed against the tumor cells are mentioned.

Acid Phosphatase

[Partially common antigenicity of macrophages, epitheloid cells and foreign body giant cells. Experimental studies on rats].

QUESTION: By means of antimacrophage sera it is possible to demonstrate partially common antigenicity of monocytes with peritoneal macrophages, reticulum cells capable of phagocytosis, mast cells and Kupper's cells. The authors continued these studies important for the explantation of cytogenetical interrelations using a special method on epitheloid and giant cells of rats. The experiments aimed for the detection of possible partially common antigenicity with the above mentioned monocytes/macrophages system.

Animals

A biochemical profile of glass-adherent cell populations containing multinucleated foreign body giant cells.

Some biochemical characteristics of peritoneal macrophages, subcutaneous macrophages and subcutaneous cell populations containing multinucleate giant cells were compared. Subcutaneous macrophages possessed higher concentrations of succinate dehydrogenase, acid phosphatase, aryl hydroxylase, free RNase II, lecithin and free fatty acids than peritoneal macrophages, while the latter had higher concentrations of 5' -nucleotidase esterified cholesterol. These differences may be due to environmental variations depending on their anatomical position or more likely to their degree of activation. As significant numbers of multinucleate giant cells appear in the subcutaneous population the concentration aryl hydroxylase, 5' -nucleotidase lactate dehydrogenase, acid phosphatase, free ribonuclease II and esterified cholesterol falls. The concentration of succinate dehydrogenase decreases but then rises while the concentration of glucose-6-phosphate dehydrogenase increases. These highlight the differences between cell populations containing multinucleated giant cells and those composed from their precursor mononuclear phagocytes only.

Acid Phosphatase