IntroductionParoxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disease characterized by intravascular hemolysis, thrombosis, and bone marrow (BM) failure. Although PNH is caused by ...excessive proliferation of hematopoietic stem cell (HSC) clones with loss of function mutations in phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) genes, what drives PNH clones to expand remains elusive.Case descriptionWe present a case of a 26-year-old female who presented with hemolytic anemia, thrombocytopenia, and leukopenia. Flow cytometry analysis of peripheral blood showed that 71.9% and 15.3% of the granulocytes and erythrocytes were glycosylphosphatidylinositol-anchored protein deficient (GPI-) cells. The patient was diagnosed with PNH with non-severe aplastic anemia. Deep-targeted sequencing covering 390 different genes of sorted GPI(-) granulocytes revealed three different PIGA mutations (p.I69fs, variant allele frequency (VAF) 24.2%; p.T192P, VAF 5.8%; p.V300fs, VAF 5.1%) and no other mutations. She received six cycles of eculizumab and oral cyclosporine. Although the patient's serum lactate dehydrogenase level decreased, she remained dependent on red blood cell transfusion. Six months after diagnosis, she received a syngeneic bone marrow transplant (BMT) from a genetically identical healthy twin, following an immune ablative conditioning regimen consisting of cyclophosphamide 200 mg/kg and rabbit anti-thymocyte globulin 10 mg/kg. After four years, the patient's blood count remained normal without any signs of hemolysis. However, the peripheral blood still contained 0.2% GPI (-) granulocytes, and the three PIGA mutations that had been detected before BMT persisted at similar proportions to those before transplantation (p.I69fs, VAF 36.1%; p.T192P, VAF 3.7%; p.V300fs, VAF 8.6%) in the small PNH clones that persisted after transplantation.ConclusionsThe PNH clones that had increased excessively before BMT decreased, but persisted at low percentages for more than four years after the immunoablative conditioning regimen followed by syngeneic BMT. These findings indicate that as opposed to conventional theory, immune pressure on HSCs, which caused BM failure before BMT, was sufficient for PIGA-mutated HSCs to clonally expand to develop PNH.
The dimensions of man-made mineral fiber whiskers are similar to those of some kinds of asbestos. Thus these mineral fibers raise the concern for potential health hazard for workers exposed in the ...occupational environments. This study was designed to define acute biological effects of intratracheally administered titanium dioxide whiskers (TO1) compared with nonfibrous titanium dioxide (TOP) and UICC amosite (Ams), and their relations to acute lung inflammation in rats. The observed geometric mean length (mum) and width (mum) and geometric standard deviation are: TO1(2.12.0, 0.141.53); Ams (4.33.3, 0.311.9); and TOP (50 nm, 1-2 mum aggregates). Ten-week-old Wistar-Jcl male rats received a single tracheal injection of test materials at doses between 0.05 and 1.0 mg/rat. Control animals were injected with the same volume of saline. Lung tissue and bronchoalveolar lavage (BAL) fluid were collected from rats on days 1, 3, and 7 after administration. In the group injected with TO1, total protein, cytokine-induced neutrophil chemoattractant (CINC)/growth-regulated gene product (GRO), interleukin (IL) 1, and tumor necrosis factor (TNF) increased on day 1. Subsequently, total elastolytic activity and fucose levels in BAL increased by day 3. All parameters, except for fucose in BAL, recovered to the normal levels. Animals in the Ams group showed increased total protein and CINC/GRO and decreased total elastolytic activity in a dose-dependent manner on day 1. The fucose level increased on day 3 in the Ams group. All parameters returned to their control levels on day 7. Animals in the TOP group did not show significant changes any of parameters during the experimental period. Gene expression of TNF- and mono cyte chemoattractant protein (MCP) 3 in the lung increased dose-dependently in the animals treated with the three materials. The mRNAs for eotaxin and MIP-1 were overexpressed in the lung of animals treated with Ams and TO1, while RANTES mRNA was overexpressed dose-dependently in the lung of animals treated with Ams on day 1. Onset of inflammatory response was more rapid in the Ams group than the TO1 group. Recovery of the fucose level in BAL was slower in the TO1 group than in the Ams group, though we observed similar histopathological changes in the lung of animals with TO1 or Ams. We conclude that whisker-induced acute biological effects in the lung may be related to the shape of the whiskers and not to their chemical composition or surface crystal structure, showing biological effects similar to those of UICC amosite.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This paper presents the biological effects of rare earth elements (REEs) on respiratory organs investigated by the research groups of National Institute of Industrial Health and others. REEs are such ...important components of current industry that the elucidation of the biological effects and environmental effects is a matter of course. In our study, animal experiments have been carried out employing both of intratracheal administration and inhalation exposure into rats for the sample materials: Y2O3, La2O3, Nd2O3, CeO2, and Sm2O3, in which CeO2 included two kinds of samples of different particle sizes. The acute toxicity of rare earth oxides was weak, but the pulmonary effects continued for a long time. The typical changes of lung tissues were pathologically observed as pulmonary alveolar proteinosis, granuloma and pulmonary fibrosis. The rats to which were injected CeO2 of coarse particle did not show any pulmonary lesion, but those of fine particles showed lung lesion at the same level as the other rare earth oxides. As a conclusion, subchronical pulmonary effects from rare earth oxides was observed to respiratory organs although it did not cause serious acute toxicity. Therefore, countermeasures, such as wearing respiratory mask, would be basically necessary for the dust workers using REEs.
We compared two procedures in the double labelling immunoelectron microscopic method of hormone-storing cells: one-faced and two-faced procedures. With the two-faced procedure we got convincing ...results consistent with morphological finding, while we often got false results with the one-faced procedure. By the misleading one-faced procedure, the cell storing any one hormone will be misinterpreted as a multihormone storing cell. Therefore, it is concluded that the two-faced method is safer for the double labelling immunoelectron microscopic study.
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