Obstructive sleep apnea and dementia: A role to play?

A growing number of studies, in animal models and humans, have highlighted the link between sleep and Alzheimer's disease (AD) pathophysiology. Among sleep disorders, obstructive sleep apnea (OSA) appears to be a potentially interesting comorbidity, as it is highly prevalent in the middle-aged and elderly population, often associated with some cognitive impairment, associated with an increased risk of developing cognitive decline and dementia including AD, and indeed treatable. The association between OSA and cognition varies according to the studies, but OSA is more frequent in older people with AD than those who are cognitively normal. People with OSA suffer from daytime sleepiness, impaired cognitive function and an increased risk of developing mild cognitive impairment, dementia and AD than those without OSA. Finally, the literature suggests a link between OSA and AD biomarkers. Whether screening and treating OSA could have positive impact on the levels of AD biomarkers and slow or even prevent incident dementia remain to be investigated. It therefore seems essential to understand the role of OSA in the pathophysiology of AD, as there is still no effective treatment to slow or halt its progression. At present, treating the risk factors that can promote the development and/or worsening of AD represents a promising strategy for delaying or even thwarting the onset of symptoms.

Nonconvulsive status epilepticus in the elderly.

There is a higher incidence of status epilepticus in the older adult population that commonly presents as nonconvulsive status epilepticus (NCSE). NCSE most often corresponds to prolonged focal seizures with impaired consciousness with three main clinical presentations: i) an unexplained acute confusional state, ii) subtle eye, motor or behavioral signs or mood changes and iii) typical temporal or frontal seizures with impaired consciousness. Focal seizures without impaired consciousness or de novo absence status of late onset may also be met. The identified risk factors for NCSE onset are: a precession by a generalized tonic-clonic seizure, a known history of epilepsy, female gender, and an acute symptomatic cause or a known brain injury (especially a stroke sequelae). Diagnosis in this population may be difficult, as the clinical presentation is often not very suggestive (stupor, confusion, even coma), and requires an unrestricted use of EEG with an EEG diagnosis based on the EEG with now accepted criteria (so-called Salzburg EEG criteria). The treatment is based first on the injection of benzodiazepines and in the second line on intravenous or oral or gastric tube administration of antiepileptic drugs. It is not recommended to resort to an intubation-ventilation (except necessary to treat respiratory distress, multi-organ failure…). Prognosis is poor with about 30% mortality.

Effects of bosentan on nondigital ulcers in patients with systemic sclerosis.

BACKGROUND: Bosentan is an oral dual endothelin receptor antagonist, which has been shown to be efficacious for preventing new digital ulcers in patients with systemic sclerosis (SSc) in two high-quality randomized controlled trials. However, its efficacy for nondigital ulcers in SSc remains unknown. OBJECTIVES: To evaluate the efficacy of bosentan on nondigital ulcers in patients with SSc. METHODS: Bosentan was administered to five patients with SSc with pulmonary arterial hypertension, who also had nondigital ulcers refractory to conventional treatments. The efficacy of bosentan on nondigital ulcers and its association with clinical features of ulcers were analysed. RESULTS: The nondigital ulcers refractory to conventional treatments were significantly improved by the administration of bosentan in cases surrounded with severe cyanosis. In contrast, nondigital ulcers without cyanosis were still refractory to bosentan therapy. CONCLUSIONS: Bosentan may be efficacious for accelerating the healing of nondigital ulcers with severe cyanosis, suggesting that nondigital ulcers caused by severely impaired peripheral circulation are highly responsive to this treatment.

Immediate-early gene induction and MAP kinase activation during recovery from metabolic inhibition in cultured cardiac myocytes.

To investigate how cardiac myocytes recover from a brief period of ischemia, we used a metabolic inhibition (MI) model, one of the in vitro ischemic models, of chick embryo ventricular myocytes, and examined the induction of immediate-early (IE) genes mRNAs and the activity of mitogen-activated protein (MAP) kinase. We performed Northern blot analysis to study the expression of c-jun, c-fos, and c-myc mRNAs during MI using 1 mM NaCN and 20 mM 2-deoxy-d-glucose, and also during the recovery from MI of 30 min. The c-fos mRNA was induced transiently at 30 and 60 min during the recovery. The expression of c-jun mRNA was significantly augmented at 30, 60, 90, and 120 min during the recovery (3.0-, 4.7-, 2.4-, and 1.9-fold induction, respectively) and so did the expression of c-myc mRNA (1.4-, 1.7-, 1.8-, and 2.0-fold induction, respectively). In contrast, the levels of these mRNAs remained unchanged during MI. The electrophoretic mobility shift assay revealed that AP-1 DNA binding activity markedly increased at 120 min during the recovery. When the cells were pretreated with protein kinase C (PKC) inhibitors, 100 microM H-7 or 1 microM staurosporine, the induction of c-jun mRNA at 60 min during the recovery was markedly suppressed (95 or 82% reduction, respectively). The c-jun induction was partially inhibited when the cells were treated with 2 mM EGTA during MI and the recovery (42% reduction). MAP kinase activity quantified with in-gel kinase assay was unchanged during MI, but significantly increased at 5, 10, and 15 min during the recovery (3.0-, 4.1-, and 3.4-fold increase, respectively). S6 kinase activity was also augmented significantly at 15 min during the recovery. Thus, these data suggest that IE genes as well as MAP kinase may play roles in the recovery process of cardiac myocytes from MI, and that the augmentation of c-jun expression needs the activation of PKC and to some extent, [Ca2+]i.

Cerebrovascular Accident Rate Is Different Between Centrifugal and Axial-Flow Pumps, but Survival and Driveline Infection Rates Are Similar.

OBJECTIVES: We analyzed the outcome of patients with implantable left ventricular assist devices (LVADs) at the University of Tokyo Hospital to compare those with centrifugal pumps (CE group: Duraheart and Evaheart) and those with axial-flow pumps (AX group: Heartmate II and Jarvik 2000). METHODS: A total of 68 patients who underwent implantation of LVADs (Duraheart: n = 15; Evaheart: n = 23; Heartmate II: n = 22; Jarvik 2000: n = 8) as a bridge to transplantation at our institution from May 2011 to April 2015 were retrospectively reviewed. All patients were followed through December 2015. RESULTS: The mean follow-up time of the CE group was 1.95 ± 0.92 year (total 74.1 patient-years) and that of the AX group was 1.56 ± 0.56 year (total 46.8 patient-years). Whether the patients underwent centrifugal or axial-flow pump implantations was not associated with survival or driveline infection according to log-rank test (1-year survival rate: 89% vs 100% [P = .221]; 1-year freedom rate: 40% vs 43% [P = .952]). The rates of freedom from cerebrovascular accident (CVA) at 1 year after LVAD implantation in the CE and AX groups were 70% and 96%, respectively (P < .001). The CE group showed a higher frequency of CVA (0.472 vs 0.021 event per patient-year). CONCLUSIONS: Our findings indicate that overall survival and driveline infection rates are similar between centrifugal and axial-flow pumps, but they suggest that patients with centrifugal pumps are more likely to develop CVAs than those with axial-flow pumps.

Association of the Number of HLA-DR Mismatches With Early Post-transplant Acute Cellular Rejection Among Heart Transplantation Recipients: A Cohort Study in Japanese Population.

BACKGROUND: Although many risk factors are reported about graft rejection after heart transplantation (HTx), the effect of HLA mismatch (MM) still remains unknown, especially in the Japanese population. The aim of the present study was to investigate the influence of HLA MM on graft rejection among HTx recipients in Japan. METHODS: We retrospectively investigated the association of the number of HLA MM including class I (A, B) and class II (DR) (for each locus MM: 0 to 2, total MM: 0 to 6) and the incidence of moderate to severe acute cellular rejection (ACR) confirmed by endomyocardial biopsy (International Society for Heart and Lung Transplantation grade ≥ 3A/2R) within 1 year after HTx. RESULTS: Between 2007 and 2014, we had 49 HTx cases in our institute. After excluding those with insufficient data and positive donor-specific antigen, finally 35 patients were enrolled. Moderate to severe ACR was observed in 16 (45.7%) patients. The number of HLA-DR MM was significantly associated with the development of ACR (ACR+: 1.50 ± 0.63, ACR-: 1.11 ± 0.46, P = .029). From univariate analysis, DR MM = 2 was the only independent risk factor for ACR episodes (P = .017). The frequency of ACR within 1 year was significantly higher in those with DR MM = 2 (DR MM = 0 to 1: 0.3 ± 0.47, DR MM = 2: 1.17 ± 1.34 times, P = .007). CONCLUSIONS: The number of HLA-DR MMs was associated with the development and recurrence of ACR episodes among HTx recipients within 1 year after transplantation in Japanese population.

Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy.

Physiological and pathological cardiac hypertrophy have directionally opposite changes in transcription of thyroid hormone (TH)-responsive genes, including alpha- and beta-myosin heavy chain (MyHC) and sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), and TH treatment can reverse molecular and functional abnormalities in pathological hypertrophy, such as pressure overload. These findings suggest relative hypothyroidism in pathological hypertrophy, but serum levels of TH are usually normal. We studied the regulation of TH receptors (TRs) beta1, alpha1, and alpha2 in pathological and physiological rat cardiac hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH target genes, alpha- and beta-MyHC and SERCA. All 3 TR subtypes in myocytes were downregulated in 2 hypertrophy models with a hypothyroid-like mRNA phenotype, phenylephrine in culture and pressure overload in vivo. Myocyte TRbeta1 was upregulated in models with a hyperthyroid-like phenotype, TH (triiodothyronine, T3), in culture and exercise in vivo. In myocyte culture, TR overexpression, or excess T3, reversed the effects of phenylephrine on TH-responsive mRNAs and promoters. In addition, TR cotransfection and treatment with the TRbeta1-selective agonist GC-1 suggested different functional coupling of the TR isoforms, TRbeta1 to transcription of beta-MyHC, SERCA, and TRbeta1, and TRalpha1 to alpha-MyHC transcription and increased myocyte size. We conclude that TR isoforms have distinct regulation and function in rat cardiac myocytes. Changes in myocyte TR levels can explain in part the characteristic molecular phenotypes in physiological and pathological cardiac hypertrophy.

Signaling pathways responsible for fetal gene induction in the failing human heart: evidence for altered thyroid hormone receptor gene expression.

BACKGROUND: We have previously demonstrated that changes in myosin heavy chain (MHC) isoforms that occur in failing human hearts resemble the pattern produced in rodent myocardium in response to hypothyroidism. Because thyroid hormone status is usually within normal limits in these patients, we hypothesized that failing/hypertrophied human myocardium might have a defect in thyroid hormone signaling due to alterations in expression of thyroid hormone receptors (TRs). METHODS AND RESULTS: To examine this hypothesis, we used RNase protection assay to measure mRNA levels of TRs in failing left ventricles that exhibited a fetal pattern of gene expression, ie, decreased expression of alpha-MHC with increased beta-MHC expression compared with left ventricles from age-matched controls. We detected expression of TR-alpha(1), -alpha(2), and -beta(1) isoforms in human left ventricles. In failing left ventricles, TR-alpha(1) was downregulated, whereas TR-alpha(2), a splice variant that does not bind thyroid hormone but inhibits responses to liganded TRs, was increased. Expression levels of TR-beta(1) did not differ significantly between the 2 groups. According to linear regression analysis, expression levels of TR-alpha(1) and -alpha(2) were positively and negatively correlated with those of alpha-MHC, respectively. CONCLUSIONS: We conclude that decreases in TR-alpha(1) and increases in TR-alpha(2) may lead to local attenuation of thyroid hormone signaling in the failing human heart and that the resulting tissue-specific hypothyroidism is a candidate for the molecular mechanism that induces fetal gene expression in the failing human ventricle.

Ca(2+)-growth coupling in angiotensin II-induced hypertrophy in cultured rat cardiac cells.

OBJECTIVES: There remain some controversies about the effect of angiotensin II on intracellular Ca2+ concentration ([Ca2+]i) in cardiac myocytes. The aim of this study was to investigate different roles of intracellular Ca2+ in the responses to angiotensin II between cardiac myocytes and nonmyocytes. METHODS: Primary cultures of neonatal rat cardiac myocytes and nonmyocytes were prepared. [Ca2+]i was measured with indo-1. Cellular growth was assayed by [3H]thymidine uptake, RNA content, [3H]phenylalanine incorporation and protein content. Induction of immediate-early gene was examined by Northern blot analysis. RESULTS: In myocytes, angiotensin II decreased [Ca2+]i transients, induced c-fos mRNA, and accelerated hypertrophy. These effects were completely suppressed by AT1 receptor blockade or protein kinase C inhibition. After chelation of extracellular Ca2+, angiotensin II caused no change in [Ca2+]i or no induction of c-fos in myocytes. Phorbol 12-myristate 13-acetate also decreased [Ca2+]i transients, caused c-fos induction, and provoked hypertrophy in myocytes. In nonmyocytes, angiotensin II increased [Ca2+]i transiently, induced c-fos mRNA and hypertrophy. These effects of angiotensin II were not fully abolished by protein kinase C inhibition. Extracellular Ca2+ chelation did not completely inhibit the effects of angiotensin II on [Ca2+]i or c-fos induction in nonmyocytes. Phorbol 12-myristate 13-acetate did not affect [Ca2+]i or cellular growth in nonmyocytes but did cause c-fos induction. CONCLUSIONS: These results suggest that angiotensin II induces cellular hypertrophy and immediate-early genes through the activation of protein kinase C in myocytes, although angiotensin II decreases [Ca2+]i transients via this signaling pathway. Induction by angiotensin II of hypertrophy and immediate-early genes in nonmyocytes may be in part mediated by a transient increase in [Ca2+]i which acts synergistically with protein kinase C activation.

Platelet-derived growth factor induces cellular growth in cultured chick ventricular myocytes.

OBJECTIVES: Platelet-derived growth factor (PDGF) stimulates growth in various types of cells, but little is known about its effect on cardiac myocytes. Therefore, we examined whether PDGF had a direct effect on cardiac myocytes and investigated their intracellular signaling pathways. METHODS: A primary culture of chick embryonic (Hamburger and Hamilton stage 36) ventricular myocytes was prepared. Cellular growth was estimated by 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyltetrazolium bromide assay and 5-bromo-2'-deoxyuridine incorporation assay. The number of PDGF binding sites was measured by binding assay. Induction of c-fos mRNA was analyzed by Northern blot analysis. The binding activity of activator protein (AP)-1 was examined by electrophoretic mobility shift assay. The activation of mitogen-activated protein kinase (MAPK) and signal transducers and activators of transcription (STATs) was analyzed by Western blot analysis, immunoprecipitation, and immunocytochemistry. Furthermore, intracellular Ca2+ concentration ([Ca2+]i) was measured with indo-1 and L-type Ca(2+)- channel current (ICa) was recorded with the patch clamp technique. RESULTS: PDGF-AB and -BB, but not PDGF-AA, increased viable cell number (5 ng/ml of PDGF-AA, -AB, -BB: 101 +/- 4%, 115* +/- 4%, 122* +/- 4%, respectively, n = 4, *P < 0.05) and DNA synthesis (104 +/- 11%, 202* +/- 18%, 295* +/- 25%, respectively, n = 4, *P < 0.05). Scatchard analysis demonstrated that the maximal number of PDGF-AA, -AB, -BB binding sites was 5 +/- 1, 63 +/- 12, 126 +/- 24 fmol/10(6) cells, respectively. PDGF-BB provoked induction of c-fos mRNA and increases in binding activity to the AP-1 site. PDGF-BB also induced tyrosine phosphorylation and nuclear translocation of MAPK. The c-fos induction, the increased AP-1 binding activity and the acceleration of DNA synthesis were all attenuated by genistein (100 microM) or MAPK kinase inhibitor (10 or 50 microM PD98059). Interestingly, protein kinase C inhibitor (250 nM calphostin C) attenuated the increases of AP-1 binding activity to some extent, but did not inhibit the c-fos induction at all. The phosphorylation states of STATs were not significantly affected by PDGF-BB. PDGF-BB did not alter [Ca2+]i or ICa. CONCLUSIONS: We conclude that PDGF can exert direct effects on embryonic cardiac myocytes and induce their growth. MAPK cascade may play an important role in the PDGF-induced embryonic myocardial growth.

Molecular cloning and expression of inducible nitric oxide synthase in chick embryonic ventricular myocytes.

OBJECTIVE: Inducible nitric oxide synthase (iNOS) has been implicated to contribute to myocardial dysfunction in various settings, but considerable species differences have been noted in the levels of iNOS expression and its function in several tissues. The aim of this study was to elucidate evolutional changes in myocardial iNOS expression and function. METHODS: An iNOS cDNA clone was isolated by RT-PCR from the 10-day old cultured chick embryonic ventricular myocytes stimulated with 10 micrograms/ml of lipopolysaccharide. Expression of the iNOS mRNA was analyzed with Northern blot analysis and RNase protection assay. The iNOS activity was estimated from conversion rates of L-arginine to L-citrulline and intracellular cGMP contents were measured with radioimmunoassay. Furthermore, both [Ca2+]i (fluorescent dye indo-1) and cell contraction (video motion detector) were simultaneously recorded. RESULTS: Aside from the primer sequences, the insert (1026 bp) of the cDNA clone showed 66.4% identity at the deduced amino acid level to the human iNOS cDNAs. Northern blot analysis revealed that chicken iNOS mRNA of approximately 4.5 kb was induced by lipopolysaccharide within 6 h in the cultured myocytes. RNase protection assay also showed that lipopolysaccharide provoked 14.6 +/- 5.1-fold increases (n = 6, p < 0.05) in the iNOS mRNA signals within 6 h. The iNOS activity (+300%, P < 0.05) as well as the intracellular cGMP contents (+75%, P < 0.01) were significantly augmented in the lipopolysaccharide-stimulated cells. Both the cell contraction and [Ca2+]i were significantly reduced after the administration of a large amount (10 mM) of L-arginine in the myocytes pretreated with both lipopolysaccharide and NG-monomethyl-L-arginine (100 microM). CONCLUSION: As like as the nucleotide and amino acid sequences, the myocardial effects of the iNOS may also be evolutionary conserved.

Crocidolite asbestos suppresses the differentiation of HL-60 cells induced by DMSO.

This study was undertaken to determine if the biological function of inducers for cell differentiation is affected by asbestos fibers, which are sometimes deposited in human tissues. Protein kinase C activity, c-myc protein expression and cell surface CR3 expression were used as the markers of cell differentiation. The function of dimethylsulfoxide (DMSO), an inducer of cell differentiation, was suppressed by the co-culturing of crocidolite asbestos, because DMSO reacted with the hydroxyl radical released after the stimulation with crocidolite and spent itself. Superoxide dismutase (SOD) inhibited the effect of crocidolite, reacting rapidly with .O2- before the secondary release of .OH. Asbestos fibers deposited in tissues may inhibit the function of inducers which stimulate immature cells to differentiate, because such inducers frequently are also radical scavengers.

Activation of human CD4+CD45RA+ T cells by chrysotile asbestos in vitro.

Chrysotile asbestos stimulates T lymphocyte subsets. Cell surface CD4 or CD45RA expression in peripheral blood mononuclear cells (PBMC) was downregulated after incubation with chrysotile asbestos in vitro temporarily. The percentage of CD4+CD45RA+ cells and mean fluorescence intensity in CD4 or CD45RA decreased after incubation with asbestos and returned to the original level after 24 h of incubation, which suggests that chrysotile asbestos activates CD4+CD45RA+ cells. No change was observed in CD29 expression. An increased percentage of IL-2R positive cells and an elevated intracellular Ca++ level were also indicative of the activation of PBMC by chrysotile asbestos.

Quantum effects on liquid dynamics as evidenced by the presence of well-defined collective excitations in liquid para-hydrogen

The origin of the well-defined collective excitations found in liquid para-H2 by recent experiments is investigated. The persistence of their relatively long lifetimes down to microscopic scales is well accounted for by calculations carried out by means of path-integral-centroid molecular dynamics. In contrast only overdamped excitations are found in calculations carried within the classical limit. The results provide fully quantitative evidence of quantum effects on the dynamics of a simple liquid.

Effects of a nonpeptide angiotensin II receptor antagonist (CV-11974) on [Ca2+]i and cell motion in cultured ventricular myocytes.

We studied the effects of angiotensin II and CV-11974 (a newly synthesized angiotensin II receptor antagonist) on cell contraction and [Ca2+]i in cultured neonatal rat ventricular myocytes. Exposure of these cells to 10 nM angiotensin II significantly decreased peak systolic cell position (60.1 +/- 3.3% of the control, P < 0.01) and peak systolic [Ca2+]i (from 1111 +/- 250 to 572 +/- 143 nM, P < 0.05) within 60 s. Pretreatment of ventricular myocytes with CV-11974 (10-100 nM) completely suppressed the angiotensin II-induced changes in peak systolic cell position and [Ca2+]i. These results suggest that CV-11974 inhibits cardiac angiotensin II receptors.

Selectivity of felodipine for depolarized ventricular myocytes: a study at the single-cell level.

We studied the effects of felodipine (a second-generation dihydropyridine Ca2+ channel blocker) on excitation-contraction coupling (E-C coupling) in single isolated guinea-pig ventricular myocytes, using the whole-cell perforated patch-clamp technique or the Ca indicator, indo-1. Felodipine inhibited both L-type Ca2+ channel currents (ICa) and cell contractions in a concentration-dependent manner (10 pM to 100 nM) when we used a holding potential of -80 mV or -40 mV. The potency of felodipine was sharply dependent on a holding potential. Namely, use of a more depolarized holding potential markedly increased the potency of felodipine for inhibition of ICa and cell contraction. Next we current-clamped cells and obtained the resting membrane potential of -82 +/- 8 mV. When cells were current-injected at 0.1 Hz, exposure to 10 nM felodipine slightly but significantly diminished the amplitude of cell contractions (7.2 +/- 1.6 to 6.7 +/- 1.7 microns, P < 0.05) within 10 min. When cells were field stimulated, exposure of cells to 10 nM felodipine also slightly diminished the amplitude of cell shortening (5.1 +/- 2.0 to 4.6 +/- 1.9 microns, P < 0.05) and [Ca2+]i transients. We observed clear voltage-dependent blockade of E-C coupling by felodipine in ventricular myocytes. Thus, therapeutic concentrations (1-10 nM) of felodipine could inhibit E-C coupling in depolarized ventricular myocytes, which might simulate an ischemic or failing heart.

Embolism from intracranial aneurysms.

Embolism from an aneurysm is one of the mechanisms involved in the pathogenesis of ischemic symptoms associated with intracranial aneurysms. Four cases are reported in which aneurysms of the internal carotid arteries and middle cerebral arteries were the source of emboli resulting in cerebral infarction. In the treatment of these aneurysms, it is best to clip the neck of the aneurysm with great care to avoid embolism due to extrusion of clot into the distal artery.

Chronic total occlusion of the left main coronary artery.

We report 3 patients with chronic total occlusion of the left main coronary artery, which is considered to be very rare. In all three cases, coronary arteriograms showed a total occlusion of the left main coronary artery with good collaterals from the intact right coronary arteries. All of the patients underwent successful coronary artery bypass surgery; two of the cases were followed up for more than 10 years after the surgery. The Japanese literature is reviewed, and a comparison of foreign and Japanese cases is discussed.

[Effects of asbestos on the cell cycle of PHA-stimulated human peripheral blood lymphocytes].

It is well known that persons exposed to asbestos display systemic immunological alterations: impaired lymphocyte response to PHA, the appearance of autoantibodies and elevation of the serum immunoglobulin level. The authors intend in this report to determine whether asbestos fibres (crocidolite, chrysotile and amosite) have any effect on the cell cycle of human lymphocytes after PHA stimulation. Peripheral blood mononuclear (PBM) cells were incubated with 10 micrograms/ml PHA for 2 days. After PHA stimulation, a decrease in the percentage of cells in the G0 phase and an increase in that of cells in the G1A, G1B and S phases was observed. When asbestos fibres or titanium dioxide (TiO2) was added to the culture dish at the beginning of the experiment, the progression of the cell cycle was inhibited only by asbestos fibres, in which case the percentage of cells in the G0 phase was significantly increased, while those of cells in the G1B and S phases were significantly decreased. The experiment for determining the critical period for inhibition of blastogenic response revealed that no inhibition was demonstrable when crocidolite fibre was added at 24 hr after PHA stimulation. Although the mechanisms of asbestos-fibre-mediated suppression remain to be clarified, these results showed that asbestos fibres act at an early stage (G0 phase) of the cell cycle and suppress the PHA stimulation of PBM cells.

[Suppressive effect of crocidolite fibers on the differentiation of HL-60 cells induced with DMSO].

HL-60 cells were derived from a patient with myelocytic leukemia, and are known to be in the promyelocytic stage and to differentiate into myelocytes or granulocytes after induction with several materials, e.g., DMSO, retinoic acid, and interferons. The authors intended in this report to determine whether asbestos fibers have any effect on the differentiation processes of HL-60 cells induced with DMSO. The cells were induced to differentiate by incubation with 1.25% DMSO for 4 days. A decrease in the percentage of c-myc-protein-positive cells and an increase in the number of C3bi receptor (CD11b) positive cells were observed after differentiation. When crocidolite (50 micrograms/ml) was added to the culture dishes at the beginning of the experiments, the differentiation was inhibited. An increase in the percentage of c-myc-protein-positive cells and a decrease in that of C3bi-receptor-positive cells were observed compared with the cells induced with DMSO alone. It has been reported that DMSO activates phospholipid- and Ca2(+)-dependent protein kinase and induces the differentiation of HL-60 cells. The mechanisms of inhibition by crocidolite fibers of the effects of DMSO remain to be clarified, but the strength of activation of phospholipid- and Ca2(+)-dependent protein kinase may play an important role in the following induction of cell differentiation.