Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid

The recent finding that retinoic acid induces terminal granulocytic differentiation of the human promyelocytic leukemia cell line, HL-60, prompted an investigation of the sensitivity to this inducer of human myelocytic leukemia cells in primary suspension culture. Of the 21 leukemic specimens, only cells from the two patients with acute promyelocytic leukemia differentiated in response to retinoic acid. After an incubation period of 5--7 days in 1 microM retinoic acid, the cells from these two patients showed extensive morphological and functional maturation. Thus, because it appears that retinoic acid specifically induces granulocytic differentiation of leukemic promyelocytes, this compound may have therapeutic utility in the treatment of acute promyelocytic leukemia.     

Isolated thrombocytopenia after allogeneic bone marrow transplantation: existence of transient and chronic thrombocytopenic syndromes

Isolated thrombocytopenia after bone marrow transplantation was investigated in 65 fully engrafted patients surviving at least 60 days posttransplant. Twenty-four patients (37%) developed this complication, which occurred most frequently in patients receiving pretransplant preparation with total body irradiation or busulfan. Two distinct thrombocytopenic syndromes were identified: (1) transient thrombocytopenia (nine patients), in which a normal platelet count (greater than 100,000/microL) was initially established by day +40 but then diminished to less than 10,000 to 45,000/microL on day +40 to +70, with subsequent resolution of the thrombocytopenia by day +90; (2) chronic thrombocytopenia (15 patients), in which a platelet count greater than 100,000/microL was not achieved at any time during the first four months posttransplant, despite the simultaneous presence of normal granulocyte and reticulocyte counts. Although the transient syndrome did not adversely affect prognosis, the chronic syndrome carried a high mortality (21% actuarial survival at 1,000 days posttransplant compared with 67% survival for all patients, P less than .01) and had a high association with both severe (grades 3 to 4) acute graft-versus-host disease (GVHD) and chronic GVHD. In three of nine patients with transient thrombocytopenia, a temporal association with trimethoprim-sulfamethoxazole administration was observed, whereas in all other patients, no drug association could be found. Bone marrow biopsies in those patients with drug-associated thrombocytopenia showed decreased numbers of megakaryocytes, whereas biopsies in the remainder of the transiently thrombocytopenic patients demonstrated adequate numbers of platelet precursors, suggesting peripheral platelet destruction or ineffective thrombopoiesis. Biopsies in the chronic thrombocytopenic patients included those with and without adequate numbers of platelet precursors, although the association with chronic GVHD was strongest in patients demonstrating normal numbers of megakaryocytes. We conclude that isolated thrombocytopenia represents a significant complication of bone marrow transplantation, particularly in patients receiving hematopoietic ablative preparatory regimens, and that it is the chronic, not the transient, thrombocytopenic syndrome that is associated with an adverse patient prognosis.     

A mathematical model of calcium and phosphorus metabolism in two forms of hyperparathyroidism

Parathyroid hormone (PTH) plays a critical role in calcium and phosphorus metabolism. Interestingly, in two forms of hyperparathyroidism (excessive amount of PTH in the serum), the metabolic disturbances in patients with chronic kidney disease (CKD) significantly differ from those with primary hyperparathyroidism (PHP). Since an intuitive understanding of these PTH-linked regulatory mechanisms are hardly possible, we developed a mathematical model using clinical data (1586 CKD and 40 PHP patients). The model was composed of a set of ordinary differential equations, in which the regulatory mechanism of PTH together with other key factors such as 1,25-Dihydroxyvitamin D (1,25(OH)?D) and calcium was described in the tissues including bone, the kidney, the serum, and the parathyroid glands. In this model, an increase in PTH was induced by its autonomous production in PHP, while PTH in CKD was elevated by a decrease in feedback inhibition of 1,25(OH)?D in the serum, as well as an increase in stimulation by phosphorus in the serum. The model-based analysis revealed characteristic differences in the outcomes of hyperparathyroidism in CKD and PHP. The calcium exchange in bone, for instance, was predicted significantly higher in PHP than CKD. Furthermore, we evaluated the observed and predicted responses to the administration of calcimimetics, a recently developed synthetic drug that modulated efficacy of calcium-sensing receptors. The results herein support the notion that the described model would enable us to pose testable hypotheses about the actions of PTH, providing a quantitative analytical tool for evaluating treatment strategies of PHP and CKD.     

Regulation of lysyl oxidase in vascular cells: lysyl oxidase as a new player in cardiovascular diseases

Lysyl oxidase (LOX) plays a crucial role in the maintenance of extracellular matrix stability and could participate in vascular remodelling associated with cardiovascular diseases. Evidence from in vitro and in vivo studies shows that LOX downregulation is associated with the endothelial dysfunction characteristic of earlier stages of the atherosclerotic process. Conversely, upregulation of this enzyme in vascular cells could induce neointimal thickening in atherosclerosis and restenosis. In fact, LOX is chemotactic for vascular smooth muscle cells and monocytes, is modulated by proliferative stimulus in these cells, and could control other cellular processes such as gene expression and cell transformation. Furthermore, it is conceivable that LOX downregulation could underlie plaque instability and contribute to the destructive remodelling that takes place during aneurysm development. Overall, LOX could play a key role in vascular homeostasis and, hence, it emerges as a new player in cardiovascular diseases. This review addresses the experimental evidence related to the role of LOX in vascular disorders and the potential benefits of controlling its expression and function.     

The hierarchical organization of semantic memory: executive function in the processing of superordinate concepts

Research on the processing of objects at different hierarchical levels has suggested that understanding superordinate concepts (e.g. fruit), relative to basic level concepts (e.g. apple), requires greater semantic control demands. Yet, it is unclear which factors underlie this difference in executive processing. We built on previous research showing that superordinate concepts have less shared features among their members and therefore may involve higher semantic control requirements. To test this hypothesis, we developed an fMRI study in which we orthogonally manipulated feature sharedness (more shared vs. less shared) and concept level (superordinate vs. basic) in a sentence verification task. Sentences involving less shared features, relative to more shared features, significantly engaged the L lateral PFC. Importantly, sentences that included superordinate concepts, relative to those with basic level concepts, also revealed a stronger response in L lateral PFC, along with posterior temporal gyrus activation. There was also a significant interaction between feature sharedness and concept level in several PFC regions and L posterior temporal areas. The results suggest that relative to basic level concepts, processing superordinate concepts requires extra semantic control in L lateral PFC to coordinate information that is less shared by other members of the category level. These findings demonstrate that feature sharedness impacts the neural basis of semantic knowledge, and is a critical dimension in the processing of superordinate concepts.     

Embolie gazeuse cérébrale iatrogène d’origine veineuse sans signe respiratoire : un mécanisme rétrograde ?

IntroductionAir embolism is a rare complication of various invasive medical procedures. Venous cerebral air embolism is usually the consequence of paradoxical embolism. We report a case of isolated cerebral air embolism resulting from a non-paradoxical mechanism.Case reportA few minutes after his central venous catheter had been accidentally disconnected, a 63-year-old man developed left-sided rhythmic jerking movements followed by left hemiplegia. There were no associated cardiologic or pulmonary signs. Brain CT showed air bubbles in the right frontal cortical sulci. The brain MRI DWI and FLAIR sequences showed a high intensity right frontal cortical lesion without reduction in ADC. Transesophageal echocardiogram did not find a patent foramen ovale.ConclusionsIn this case of venous cerebral air embolism, the lack of any cardiopulmonary manifestation, the lack of a patent foramen ovale and the neuroradiological findings are not in favor of the hypothesis of paradoxical embolism. The hypothesis of retrograde venous cerebral air embolism is discussed.