Induction of macrophage-like differentiation of HL60 human myeloid leukemia cells by phorbol myristate acetate triggers an early decline in inositol lipid breakdown

We have studied the metabolism and cellular levels of inositol lipids and their breakdown products, the inositol phosphates and diacylglycerol (DAG), in HL60 human myeloid leukemia cells. Changes in these species during phorbol myristate acetate (PMA)-induced differentiation to a macrophage-like phenotype were quantitated by isotopic labeling techniques. The slow, autonomous breakdown of inositol lipids detectable in uninduced cells was almost completely abolished between 3 and 6 h of PMA addition. The intracellular levels of the inositol phosphates were detectably reduced 1 h after PMA addition and continued to decline during the next 24 h. Also consistent with the reduced breakdown of inositol lipids, the molar ratio of these species showed a small but significant increase relative to other membrane lipids 24 h following PMA addition. However, the cellular DAG content increased gradually after PMA addition, presumably due to the cessation of cell proliferation and reduced utilization of DAG as a precursor for lipid synthesis. The results here suggest that the slow, autonomous generation of inositol lipid-derived second messengers may contribute to the stimulation of proliferation of HL60 cells and that the rapid PMA-induced inhibition of this pathway may precede the triggering of cellular differentiation in this system.     

Non-specific arteritis of the aorta and its main branches

Four cases of non-specific arteritis involving the aorta and its main branches are described. Three of the cases were hypertensive and one of these had evidence of aortic incompetence. Cases 1, 2, and 3 had involvement of the aortic arch vessels and the descending aorta, whereas Case 4 presented as a coarctation of the abdominal aorta. There was a significant association with systemic disturbance such as polyarthritis, fever, weight loss, raised erythrocyte sedimentation rate, and hyperglobulinaemia. A detailed necropsy in Case 2 showed two large dissecting aneurysms. The nomenclature, the diagnostic criteria, and a probable pathogenesis of the disease are discussed with reference to the relevant published material.     

Magnetic resonance imaging: absence of in vitro cytogenetic damage

Human lymphocytes and Chinese hamster ovary (CHO) cells in culture were exposed for 12 1/2 hours to a magnetic resonance imaging apparatus with a 2.35-Tesla magnet and 100-MHz radio frequency emission. The cells were examined for cytogenetic damage manifested either as chromosome aberrations or sister chromatid exchanges (SCEs), which constitute very sensitive measures of genetic and cellular damage. In either unstimulated or stimulated human lymphocytes, as well as in exponentially growing CHO cells, no increase in either chromosome aberrations or SCEs was found as a result of exposure to these MR conditions. The data indicate that long-term exposure to MR imaging conditions far exceeding those to be found in the clinical situation does not cause cytogenetic damage.     

X-linked syndrome of platelet dysfunction, thrombocytopenia, and imbalanced globin chain synthesis with hemolysis

An unusual family is described with a congenital bleeding disorder present in four males belonging to three generations. Of the three surviving affected males, all had splenomegaly and petechiae. The three had moderate thrombocytopenia (55-90 X 10(9)/liter) and markedly prolonged Ivy-template bleeding times (greater than 30 min). They were also noted to have reticulocytosis and, upon further investigation, imbalanced globin chain synthesis resembling that of beta-thalassemia minor. Studies on nine additional family members in four generations were normal except for slight elevations of reticulocyte counts in female members, one of whom had the abnormal globin chain synthesis ratio. In male members, the bleeding tendency and clinical signs always occurred in the presence of the globin chain synthesis defect and reticulocytosis. This previously undescribed condition was apparently transmitted as an X-linked disorder.     

Interleukin-2 receptor common γ-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: Selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax,bcl-xS) gene expression

Cytokine deprivation from activated T cells leads to apoptosis associated with down-regulation of the bcl-2 gene product. It is not clear, however, how cytokines other than interleukin-2 (IL-2) may affect this process and regulate the involvement of other apoptosis-modulating genes. We show that a group of cytokines including IL-2, IL-4, IL-7 and IL-15, which can all signal through the γ chain of the IL-2R (IL-2Rγ), prevent the apoptosis of IL-2-deprived activated T cells. This rescue involves the induction of the anti-apoptosis genes (bcl-2 and bcl-x_L), but causes little change in expression of bax and bcl-x_S, which promote apoptosis. Furthermore, the prevention of apoptosis and induction of proliferation by the common γ chain cytokines can be dissociated. Thus, when proliferation is blocked, the common γ chain cytokines still induce up-regulation of bcl-2 relative to bax and retard apoptosis. These cytokines can thus regulate the persistence or removal of effector T cells by coordinating the balance between genes which promote and those which inhibit apoptosis, events which are probably mediated at least in part by signals through the common γ chain. These data also implicate inappropriate T cell apoptosis resulting from a dysfunctional common γ-chain as part of the pathophysiological defect in patients with X-linked severe-combined immunodeficiency (SCID).     

Chemokine expression and leucocyte infiltration in Sjogren's syndrome

OBJECTIVE: To investigate the expression and source of chemokines in minor salivary gland biopsies (MSGs) in patients with Sjogren's syndrome (SS). METHODS: Immunohistochemical analysis was used to determine the pattern of chemokine expression in MSGs from patients with (n=6) and without (n=5) SS, as well as to examine the phenotype of both resident and infiltrating cells expressing chemokines. RESULTS: Significant differences in the number of infiltrating mononuclear (MN) cells in patients with and without SS were noted. Ductal epithelial cells of SS biopsies expressed significantly increased levels of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, interleukin-8 (IL-8) and RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted). Biopsies from patients with SS showed that MIP-1beta was expressed by 51% of infiltrating cells, while 41% expressed MIP-1alpha, whereas 22 and 7% expressed RANTES and IL-8, respectively. CONCLUSION: Chemokines expressed by ductal epithelial cells may attract circulating leucocytes, in particular CD4+ T cells, towards the site of inflammation, thereby orchestrating the influx of MN cells characteristically seen in MSGs in SS. Chemokines may be induced directly by a putative triggering agent for SS, or secondary to the release of pro-inflammatory cytokines produced by epithelial cells. These findings further implicate epithelial cells as playing a major role in the pathogenesis of SS and implicate chemokines in the leucocyte recruitment in this setting.