Activation of Janus kinase/signal transducers and activators of transcription pathway involved in megakaryocyte proliferation induced by vanadium resembles some aspects of essential thrombocythemia.

Vanadium (V) is an air pollutant released into the atmosphere by burning fossil fuels. Also, it has been recently evaluated for their carcinogenic potential to establish permissible limits of exposure at workplaces. We previously reported an increase in the number and size of platelets and their precursor cells and megakaryocytes in bone marrow and spleen. The aim of this study was to identify the involvement of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and thrombopoietin (TPO) receptor, and myeloproliferative leukemia virus oncogene (Mpl), in megakaryocyte proliferation induced by this compound. Mice were exposed twice a week to vanadium pentoxide inhalation (0.02 M) and were killed at 4th, 6th, and 8th week of exposure. Phosphorylated JAK2 (JAK2 ph), STAT3 (STAT3 ph), STAT5, and Mpl were identified in mice spleen megakaryocytes by cytofluorometry and immunohistochemistry. An increase in JAK2 ph and STAT3 ph, but a decrease in Mpl at 8-week exposure was identified in our findings. Taking together, we propose that the morphological findings, JAK/STAT activation, and decreased Mpl receptor induced by V leads to a condition comparable to essential thrombocythemia, so the effect on megakaryocytes caused by different mechanisms is similar. We also suggest that the decrease in Mpl is a negative feedback mechanism after the JAK/STAT activation. Since megakaryocytes are platelet precursors, their alteration affects platelet morphology and function, which might have implications in hemostasis as demonstrated previously, so it is important to continue evaluating the effects of toxics and pollutants on megakaryocytes and platelets.

The methodology of self-controlled case series studies.

The self-controlled case series method is increasingly being used in pharmacoepidemiology, particularly in vaccine safety studies. This method is typically used to evaluate the association between a transient exposure and an acute event, using only cases. We present both parametric and semiparametric models using a motivating example on MMR vaccine and bleeding disorders. We briefly describe approaches for interferent events and a sequential version of the method for prospective surveillance of drug safety. The efficiency of the self-controlled case series method is compared to the that of cohort and case control studies. Some further extensions, to long or indefinite exposures and to bivariate counts, are described.

Chronic toxicity studies of piperonyl butoxide in F344 rats: induction of hepatocellular carcinoma.

Male and female F344 rats (30-33 rats/group) were administered piperonyl butoxide (alpha-[2-(2-butoxyethoxy)ethoxy]-4,5-methylenedioxy-2-propylto luene) in the diet at levels of 0 (control), 0.6, 1.2, and 2.4% for nearly 2 years. Beginning at about 40 weeks, 10 rats in the 1.2% treated male group died due to cecal hemorrhages. Piperonyl butoxide induced hepatocellular carcinoma in both sexes in a dose-dependent manner. Hepatocellular carcinoma was found even in the 1.2% treated male group (incidence, 26.7%), and incidences in the 2.4% groups of males and females were 80.0 and 57.7% respectively of all those surviving. Piperonyl butoxide also caused essential thrombocythemia with a dose-response relationship. Hemorrhages in stomach and cecum, anemia, degenerative lesions of alveoli, and nephrotoxicity were also observed related to exposure. These results indicate that piperonyl butoxide is a hepatocarcinogen to the rat.

Acute megakaryocytic leukemia following chemotherapy for a malignant teratoma.

A 20-year-old man underwent systemic chemotherapy (four cycles of vinblastine sulfate, bleomycin sulfate, and cisplatin) following full resection of a malignant mediastinal teratoma without evidence of metastatic spread. Five months following this resection, pancytopenia, circulating blast cells, and bone marrow necrosis developed. An autopsy disclosed a disseminated megakaryocytic neoplasm. Although a cause-effect relationship is suggested, the duration between the institution of therapy and the appearance of this megakaryocytic malignant neoplasm is less than the latent periods previously reported for cases of therapy-related leukemias. This case is also compared with other reports of therapy-related hematopoietic disorders with prominent megakaryocytic proliferations.

Fatal thrombocytopenic hemorrhagic diathesis associated with dapsone administration to a dog.

Dapsone was given for six days to a dog with chronic skin disease. The dog then became weak and anorectic, and it vomited and had purpura caused by severe thrombocytopenic hemorrhagic diathesis. Despite treatment, the dog died a week later. There were clinical and pathologic evidence that the dog's platelets and megakaryocytes had been destroyed during the first few days of dapsone therapy. It was concluded that the syndrome was dapsone-induced and that thrombocytopenia should be considered among the adverse reactions to dapsone in the dog.

Adverse drug reactions leading to hospitalization in children.

During a three-year period of prospective epidemiologic surveillance for adverse drug reactions in a pediatric population, 72 (2.0%) of 3,556 medical admissions were the result of adverse drug reactions. Antineoplastic drugs were most frequently cited as causing a reaction leading to admission. Approximately 40% of the reactions were severe, and four reactions contributed to death.

[Acute leukemia with megakaryoblasts. Incidence following immunosuppressive treatment of rheumatoid polyarthritis]. / Leucémie aiguë à mégacaryoblastes. Survenue après traitement immunodépresseur d'une polyarthrite rhumatoïde

The authors report the case of a man suffering from rheumatoid arthritis treated for almost 5 years with chlorambucil. Death occurred 9 years after the onset of the disease at the age of 55 years with a picture of acute megacaryoblastic leukaemia.