ABSTRACT
Leukopenia and anaemia are observed in about a fifth of all patients with systemic lupus erythematosus (SLE) and may be due either to the destruction of blood cells or their decreased production. The former may be humoral or cell-mediated or result from apoptosis of peripheral blood cells. Several observations suggest the occurrence of the latter reduced in vitro proliferation of pluripotent bone marrow progenitors from the bone marrow aspirates of SLE patients,reduced counts of CD34+ cells in bone marrow aspirates in SLE patients, apoptosis of lymphopoietic progenitors and apoptosis of bone marrow cells. The aim of our study was to investigate whether humoral factors may induce suppression of haematopoiesis by increased apoptosis of CD34+ cells. For this purpose, we incubated allogeneic CD34+-enriched cells with sera of 18 leukopenic SLE patients. Apoptosis was induced by four of 18 sera. This effect was independent of complement-inhibition and FAS-blockade. Although reduced proliferation of autologous pluripotent bone marrow progenitors has been attributed to an IgG serum inhibitor, removal of IgG from these four proapoptotic sera had no effect on apoptosis of allogeneic CD34+ cells. The proapoptotic effect was associated with high titres of anti-dsDNA antibodies and low haemoglobin concentrations, but not with high titres of antinuclear antibodies, TNF-alpha and IFN-alpha of the sera tested.
Subject(s)
Antigens, CD34/immunology , Apoptosis/physiology , Bone Marrow Cells/immunology , Hematopoiesis/physiology , Leukopenia/blood , Lupus Erythematosus, Systemic/blood , Cells, Cultured , Hematopoiesis/immunology , Humans , In Situ Nick-End Labeling , Interferon-alpha/analysis , Sensitivity and Specificity , Tumor Necrosis Factor-alpha/analysisABSTRACT
Acute tumour-lysis syndrome (ATLS) is a frequently fatal complication after cytoreductive leukaemia therapy. Lactic acidosis is associated with ATLS and its extent is correlated with the severity of ATLS. In the course of cytoreductive therapy, apoptosis is induced in tumour cells, which results in loss of mitochondrial function. We hypothesize that loss of mitochondrial function leads to compensatory glycolysis, which is the main cause of lactate accumulation and acidosis. We tested this hypothesis using the model of glucocorticoid-induced apoptosis in the human acute lymphoblastic leukaemia cell line CCRF-CEM. After induction of glucocorticoid-induced apoptosis, a biphasic course of lactate production was observed. Prior to the onset of apoptosis, i.e. prior to the loss of membrane potential, lactate production was reduced. However, subsequent to loss of mitochondrial membrane potential a massive increase in lactate production was observed (15.5 +/- 0.5 versus 10.17 +/- 0.09 mmol/10(6) cells, P = 0.001). We also demonstrated that inhibition of respiratory chain activity by antimycin A resulted in excess lactate production. In the model cell line used, conditional bcl-2 expression delayed glucocorticoid-induced apoptosis by protecting against loss of mitochondrial membrane potential; bcl-2 expression delayed the increase in lactate production and had no effect on the pre-apoptotic drop in lactate production. Apoptosis-induced lactate production was also observed in other cell lines (HL60, THP1 and OPM2) with various cytotoxic agents [doxorubicin, gemcitabine and vumon (VM26)]. Thus, the data suggest that lactate acidosis can be caused by apoptotic loss of mitochondrial function and massive apoptosis of a tumour mass via lactic acidosis may be the essential pathological event in ATLS.
Subject(s)
Lactic Acid/metabolism , Leukemia, T-Cell/metabolism , Mitochondria/metabolism , Antineoplastic Agents, Hormonal/pharmacology , Apoptosis/drug effects , Dexamethasone/pharmacology , Gene Expression , Humans , Membrane Potentials/drug effects , Polymerase Chain Reaction , Proto-Oncogene Proteins c-bcl-2/metabolism , Time Factors , Tumor Cells, CulturedABSTRACT
Tropical South America is one of the three main centres of the global, zonal overturning circulation of the equatorial atmosphere (generally termed the 'Walker' circulation). Although this area plays a key role in global climate cycles, little is known about South American climate history. Here we describe sediment cores and down-hole logging results of deep drilling in the Salar de Uyuni, on the Bolivian Altiplano, located in the tropical Andes. We demonstrate that during the past 50,000 years the Altiplano underwent important changes in effective moisture at both orbital (20,000-year) and millennial timescales. Long-duration wet periods, such as the Last Glacial Maximum--marked in the drill core by continuous deposition of lacustrine sediments--appear to have occurred in phase with summer insolation maxima produced by the Earth's precessional cycle. Short-duration, millennial events correlate well with North Atlantic cold events, including Heinrich events 1 and 2, as well as the Younger Dryas episode. At both millennial and orbital timescales, cold sea surface temperatures in the high-latitude North Atlantic were coeval with wet conditions in tropical South America, suggesting a common forcing.
Subject(s)
Antipsychotic Agents/therapeutic use , Risperidone/therapeutic use , Schizophrenia/drug therapy , Diagnosis, Dual (Psychiatry) , Drug Therapy, Combination , Humans , Schizophrenia/epidemiology , Schizophrenic Psychology , Substance-Related Disorders/diagnosis , Substance-Related Disorders/epidemiology , Treatment OutcomeSubject(s)
Cyproheptadine/therapeutic use , Depressive Disorder/drug therapy , Fluoxetine/therapeutic use , Schizophrenia/drug therapy , Schizophrenic Psychology , Adult , Aged , Antipsychotic Agents/adverse effects , Antipsychotic Agents/therapeutic use , Chronic Disease , Cyproheptadine/adverse effects , Depressive Disorder/psychology , Drug Therapy, Combination , Fluoxetine/adverse effects , Humans , Male , Middle Aged , Psychiatric Status Rating ScalesABSTRACT
We have isolated and characterized a new human cDNA, coding for a protein kinase, related to the protein kinase C (PKC) gene family. Although this protein kinase shares some homologous sequences and structural features with the four members of the PKC family initially isolated (alpha, beta I, beta II, and gamma), it shows more homology with the recently described PKC-related subfamily, encoded by the cDNAs delta, epsilon, and zeta. The transcript for this gene product, termed PKC-L, is most abundant in lung tissue, less expressed in heart and skin tissue, and exhibited very low expression in brain tissue. Thus, its tissue distribution is different from that described for other mammalian members of the PKC gene family, their expression being enriched in brain tissues. PKC-L is also expressed in several human cell lines, including the human epidermoid carcinoma line A431. The ability of phorbol esters to bind to and stimulate the kinase activity of PKC-L was revealed by introducing the cDNA into COS cells.
Subject(s)
Protein Kinase C/genetics , Amino Acid Sequence , Base Sequence , Cloning, Molecular , DNA/genetics , Humans , Lung/enzymology , Molecular Sequence Data , Myocardium/enzymology , Phorbol Esters/metabolism , Phosphorylation , Precipitin Tests , Protein Binding , Protein Kinase C/classification , Protein Kinase C/metabolism , Recombinant Proteins/metabolism , Restriction Mapping , Skin/enzymology , TransfectionABSTRACT
Eight subjects with persistent tardive dyskinesia were treated with vitamin E and placebo in a randomized, double-blind crossover study. Their mean score on the Abnormal Involuntary Movement Scale (AIMS) was significantly lower after treatment with vitamin E than after placebo administration.