Olfactory disturbances induced by the anti-cancer drug tegafur were studied in separate clinical and experimental investigations. Five patients with olfactory dysfunction after tegafur were studied and were found to have normal endoscopic findings of the olfactory cleft mucosa. The average period for drug administration was 22 months. Recovery from the olfactory disturbance was poor and biopsy of the olfactory mucosa revealed severely degenerated epithelium. In experimental studies in a guinea pig animal model, effects of oral tegafur on mitotic cells in the olfactory epithelium were examined using bromodeoxyuridine (BrdU) uptake as index. At the conclusion of 3 weeks' treatment, no pronounced morphological changes were seen, but the number of BrdU-incorporating cells decreased in proportion to the dose of tegafur used. Following long-term administration of tegafur 18 months, mitotic cells reacting to BrdU or proliferating cell nuclear antigen had virtually disappeared, indicating persistent inhibition of mitotic cell activity. Morphological changes present included decreased olfactory cell numbers, loss of cells in areas just above basal cells and degeneration of the mucous layer.
We used immunohistochemistry to investigate the expression of spot35/calbindin-D28k (calbindin) in mouse olfactory epithelium during development. Cell stages of immunopositive olfactory cells were determined by comparing the levels of proliferating cell nuclear antigen (PCNA). Calbindin-positive cells were abundant in the middle layer of the epithelium of animals before 2 weeks of age and gradually diminished during development. Only low levels were detectable near the basement membrane in the adult. Changes of calbindin-positive cells in terms of number and distribution were apparently compatible with localization changes of premature olfactory cells. PCNA overlapped calbindin in the nasal mucosa at lower magnifications on stained serial sections and immunohistochemical double staining revealed that calbindin-immunoreactive cells were located mainly just above PCNA-immunoreactive cells in the basal layer of the epithelium. This indicated that calbindin is expressed postmitotically in immature olfactory cells and is lost by mature cells. These findings suggest that calbindin might support the maturation of the olfactory cells, such as the projection of the neuronal processes, by stabilizing intracellular calcium ions in immature cells.
Summary Seven cases of myelodysplastic syndrome with myelofibrosis, which is defined using the following criteria: (1) pancytopenia with < 5% blasts in the peripheral blood; (2) minimal or no splenomegaly; (3) myelofibrosis with cellular marrow; (4) absence of diffuse proliferation of blasts in the bone marrow; and (5) presence of myelodysplastic features of bone marrow or peripheral blood cells, are presented. They were in the range of 52–82 years old and consisted of 3 males and 4 females. Six out of 7 cases developed into acute leukaemia after 5 to 8 months from the onset and died from between 2 weeks to 8 months from the evolution to leukaemia. The type of leukaemia was acute myeloblastic in 3 patients, and acute myelo‐megakaryoblastic in 3 patients. Another patient died of severe hepatic injury after 5 months from the onset of the disease. These findings revealed that the complication of myelofibrosis in the patients with myelodysplastic syndrome was an indicative sign of rapid progression to overt leukaemia or otherwise poor prognosis for survival. In addition myelodysplastic syndrome is thought to be major primary disorder for acute myelofibrosis. Myelodysplastic syndrome with myelofibrosis is closely associated with the neoplastic proliferation of megakaryoblasts in a considerable number of patients.
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