Acrylamide monomers in universal adhesives.

OBJECTIVES: The mono-functional monomer 2-hydroxyethyl methacrylate (HEMA) is often added to universal adhesives (UAs) to improve surface wetting and prevent phase separation. Nevertheless, HEMA promotes water sorption and hydrolysis at adhesive interfaces, hereby affecting long-term bonding to dentin. This study investigated if two acrylamide monomers could replace HEMA in an UA formulation applied in etch-and-rinse (2E&R) and self-etch (1SE) bonding mode. METHODS: Four experimental UAs were bonded to bur-cut dentin. In addition to 12 wt% 10-MDP, 25 wt% Bis-GMA and 10 wt% TEGDMA as common monomer composition, 20 %wt ethanol and 15 %wt water as solvent, and 3 wt% polymerization-related additives, the four formulations solely differed for either the acrylamide cross-linker monomer 'FAM-201' as TEGDMA alternative and HEMA replacement, the hydroxyethyl acrylamide monomer 'HEAA' as HEMA alternative, HEMA ('HEMA+'), or extra TEGDMA in a HEMA-free control ('HEMA-'), all added in a 15 wt% concentration. The split-tooth study design involved application in 2E&R mode on one tooth half versus 1SE mode on the corresponding half. Micro-tensile bond strength of half of the micro-specimens was measured upon 1-week distilled water storage ('immediate' 1w µTBS), with the other half measured after additional 6-month storage ('aged' 6 m µTBS). Statistics involved linear mixed-effects (LME) modelling (p < .05). Additionally, interfacial TEM characterization, thin-film (TF) XRD surface analysis, LogP determination, and a cytotoxicity assay were carried out. RESULTS: FAM-201 revealed significantly higher µTBS than HEMA+ at 1w and 6 m when applied both in E&R and SE bonding modes. HEAA's µTBS was significantly lower than that of HEMA+ at 1w when applied in SE mode. TF-XRD and TEM revealed similar chemical and ultrastructural interfacial characterization, including stable 10-MDP_Ca salt nano-layering. FAM-201 was least cytotoxic and presented with an intermediary LogP, while HEAA presented with the highest LogP, indicating high hydrophilicity and water-sorption sensitivity. SIGNIFICANCE: The acrylamide co-monomer FAM-201 could replace HEMA in an UA formulation, while HEAA not.

Pivotal role of signal transducer and activator of transcription (Stat)4 and Stat6 in the innate immune response during sepsis.

Signal transducer and activator of transcription (Stat)4 and Stat6 are transcription factors that provide type 1 and type 2 response, respectively. Here, we explored the role of Stat4 and Stat6 in innate immunity during septic peritonitis. Stat4-/- and Stat6-/- mice were resistant to the lethality compared with wild-type (WT) mice. At the mechanistic level, bacterial levels in Stat6-/- mice were much lower than in WT mice, which was associated with increased peritoneal levels of interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, macrophage-derived chemokine (MDC), and C10, known to enhance bacterial clearance. In Stat4-/- mice, hepatic inflammation and injury during sepsis were significantly ameliorated without affecting local responses. This event was associated with increased hepatic levels of IL-10 and IL-13, while decreasing those of macrophage inflammatory protein (MIP)-2 and KC. Sepsis-induced renal injury was also abrogated in Stat4-/- mice, which was accompanied by decreased renal levels of MIP-2 and KC without altering IL-10 and IL-13 levels. Thus, Stat6-/- and Stat4-/- mice appeared to be resistant to septic peritonitis by enhancing local bacterial clearance and modulating systemic organ damage, respectively, via balancing cytokine responses. These results clearly highlight an important role of local type 1 and systemic type 2 cytokine response in protective immunity during sepsis, which can be regulated by Stat proteins.

IL-8 is an essential mediator of the increased delayed-phase vascular permeability in LPS-induced rabbit pleurisy.

We investigated the involvement of IL-8 in the delayed vascular permeability (VP) in rabbit lipopolysaccharide (LPS)-pleurisy. Maximal level of interleukin-8 (IL-8) was detected in pleural fluid at 2 h after LPS injection and anti-IL-8 inhibited the delayed VP by 90%. Injection of homologous IL-8 induced VP, the time-course of which preceded that of LPS-induced delayed VP. Production of IL-8 in LPS-pleurisy was inhibited with anti-tumor necrosis factor alpha (TNF-alpha), whereas the production of TNF-alpha was not affected with anti-IL-8. Injection of IL-8 did not induce TNF-alpha production and anti-TNF-alpha had no effect on IL-8-induced VP. Injection of homologous TNF-alpha induced IL-8 production and VP, and TNF-alpha-induced delayed VP was blocked with anti-IL-8. These results indicate important roles of IL-8 in LPS-induced delayed VP and that TNF-alpha causes the delayed VP through the production of IL-8.

Functional roles of MCP-1 in Propionibacterium acnes-induced, T cell-mediated pulmonary granulomatosis in rabbits.

The immunological manifestation of granuloma formations in humans largely depends on the delayed-type hypersensitivity response. We investigated the involvement of monocyte chemoattractant protein-1 (MCP-1) in a rabbit model of T cell-mediated pulmonary granulomatosis. Intravenous injection of Propionibacterium acnes (P. acnes) into sensitized rabbits induced massive and diffuse pulmonary granulomas. Levels of MCP-1 in sera and bronchoalveolar lavage fluids (BALF) peaked before the granuloma formation reached the peak (on days 1 and 3 after challenge, respectively). Chemotactic activities toward monocytes and T cells in BALF were inhibited by anti-MCP-1 IgG by 80 and 36%, respectively. The phenotypic analysis of the migrating T cells revealed that activated and memory T cells rather than naive cells were preferentially attracted to the BALF. Administration of anti-MCP-1 antiserum inhibited the development of granuloma formation in both size and number, the numbers of infiltrating leukocytes in BALF, the expression of adhesion molecules on peripheral monocytes/T cells, and on macrophages/T cells in BALF, and the production of TNF-alpha in the lung. Anti-MCP-1 resulted in a trend toward decreased level of IL-1beta in the lung. The inhibition of the production of these cytokines appeared to be induced indirectly through the inhibition of the recruitment of macrophages that produce these cytokines. The results suggest important roles of MCP-1 in the development of granuloma formation in this model through the attraction and activation of specific types of cells.

Therapeutic use of chemokines.

Chemokines are involved in a number of pathological processes, and therefore represent important targets. However, it has also become apparent that chemokines have exciting therapeutic applications in inflammatory, infectious and cancer-related diseases. The following review will highlight the application of novel therapies including viral-encoded, recombinant, and genetically engineered chemokines to a number of diseases or disorders. Advances in the application of novel chemokine delivery procedures both at the research bench and the clinical bedside will also be discussed. Overall, the utilization of chemokines to prevent and treat disease has tremendous potential.

Interleukin-1 receptor antagonist: characterisation of its gene expression in rabbit tissues and large-scale expression in eucaryotic cells using a baculovirus expression system.

The gene expression of rabbit interleukin-1 receptor antagonist (RbIL-lra) was examined in rabbit tissues. RNA was isolated from heart, lung, kidney, muscle, liver, spleen, brain, and peripheral blood monocytes (PBMs), and RbIL-lra mRNA was identified as a single species by Northern analysis using a RbIL-lra probe. RbIL-lra was abundantly expressed in lung, brain, heart, and liver, expressed at low levels in spleen, and undetectable in kidney and unstimulated PBMs. Expression of large scale recombinant production of RbIL-lra was achieved by subcloning the cDNA into a baculovirus expression vector. Recombination of this vector was completed with the BacPAK6 baculovirus genome. The recombinant virus, containing the RbIL-lra cDNA, was used to infect Spodoptera frugiperda (Sf21) insect cells in a spinner flask system and in monolayers in cell culture flasks. Recombinant rabbit IL-lra (rRbIL-lra) was secreted into the culture medium in this system at very high levels (35 mg/l). The protein was identified by reducing SDS-PAGE electrophoresis, was variably glycosylated and had a molecular weight between 19-25 kDa. It was then purified by size exclusion HPLC on a Du Pont Gf-250 column. The rRbIL-lra was demonstrated to be functionally active by inhibiting recombinant human IL-1 alpha in a mouse thymocyte proliferation assay. 20 ng/ml (6.7 U/ml) of rRbIL-lra inhibited 95% of the activity of 2 ng/ml IL-1 alpha.

Neutrophils as a source of cytokines in inflammation.

The recruitment of neutrophils into inflammatory foci is a fundamental process observed in inflammation. The function of neutrophils has long been regarded only as an effector cell that kills the invading pathogens. Recent evidence has demonstrated that neutrophils are capable of producing inflammatory cytokines. The findings are, however, mainly based on the findings obtained in vitro. It has not been fully elucidated if neutrophils could synthesize and secrete cytokines in vivo. Animal models of inflammation are essential to address the issue and provide insight into the involvement of neutrophils in producing cytokines.

III. Chemokines and other mediators, 8. Chemokines and their receptors in cell-mediated immune responses in the lung.

Chemokines constitute a large family of chemotactic cytokines that belong to a super-gene family of 8-10 kDa proteins. The chemokines are considered to be primarily beneficial in host defense against invading pathogens. However, the reactions induced by chemokines can be occasionally excessive, resulting in a harmful response to the host. Recent studies in chemokine biology have elucidated that chemokines are involved in the initiation, development, and maintenance of numbers of diseases including lung diseases. In addition to its chemotactic activity, evidence suggests that chemokines can modify the outcome of the cell-mediated immune responses by altering the Th1/Th2 cytokine profile. Chemokines are also capable of dictating the direction of specific immune responses. Chemokine action is mediated by a large super-family of G-protein coupled receptors, and the receptors are preferentially expressed on Th1/Th2 cells. Certain chemokine receptors are constitutively expressed in immune surveying cells such as dendritic cells and naive T cells. The corresponding chemokines are present in normal lymphoid tissues, suggesting a role of chemokines/receptors in cell homing and cell-cell communication in lymphoid tissue that can be an initial step for immune recognition. Thus, comprehension of the chemokine biology in immune responses appears to be fundamental for understanding the pathogenesis of T cell-mediated immune responses. The following review will highlight the current insight into the role of chemokines and their receptors in the cell-mediated immune response, with a special focus on lung diseases.

Lazaroid reduces production of IL-8 and IL-1 receptor antagonist in ischemic spinal cord injury.

BACKGROUND: 21-aminosteroids (lazaroids) have demonstrated the protective effect against cerebral ischemic injury through the inhibition of lipid peroxidation. We examined whether lazaroids affected the production of proinflammatory and antiinflammatory cytokines in ischemic spinal cord injury model. MATERIALS: Anesthetized New Zealand white rabbits underwent a 20-minute infrarenal aortic cross-clamping (AXC) with pretreatment of either an intravenous 3 mg/kg lazaroid U74389G (group L; n = 10) or the same volume saline (group P; n = 10). Sham operation group (group S; n = 6) underwent only exposure of the aorta. Plasma concentrations of interleukin (IL)-8, -1beta, -1 receptor antagonist (IL-1ra) and tumor necrosis factor (TNF)-alpha were measured at four time points. Functional assessment with Tarlov score at 24 and 48 hours after pretreatment, pathologic assessment of the spinal cord, and measurements of cytokine levels in the spinal cord were performed. RESULTS: The maximum elevation of plasma IL-8 and -1ra levels occurred at 1 hour after declamping in four measurement points. Plasma IL-8 and -1ra levels in group L were significantly lower than those in group P (*p < 0.05). Plasma TNFalpha peaked at 5 minutes after declamping, but decreased afterwards. Plasma TNFalpha levels were not different among three groups. Spinal IL-8 levels in group L (0.98 +/- 0.34 ng/g tissue) were lower than those in group P (7.26 +/- 2.26 ng/g tissue)(*p < 0.05). Spinal IL-1ra and TNFalpha were not significantly different. Tarlov score and pathologic assessment were better in group L. CONCLUSIONS: Lazaroid U-74389G reduced the production of systemic IL-8 and -1ra and spinal IL-8 when AXC caused spinal cord injury. These results indicate that lazaroids may attenuate ischemic endothelial cell injury or activation of leukocytes.

Effect of methylprednisolone on phospholipase A(2) activity and lung surfactant degradation in acute lung injury in rabbits.

Glucocorticoids are the most potent and widely used anti-inflammatory agents, but they are not particularly effective against early phase of acute respiratory distress syndrome. We investigated whether methylprednisolone, a synthetic glucocorticoid, could inhibit increase of phospholipase A(2) activity in the lung and lead to protection against a model of acute respiratory distress syndrome in rabbits. Infusion of oleic acid (0.1 ml/kg/h, i.v. for 2 h) provoked pulmonary hemorrhage and edema, protein leakage and massive neutrophil infiltration, resulted in severe hypoxemia and impaired lung compliance, accompanying the increase of phospholipase A(2) activity and interleukin-8, and degradation of surfactant in the bronchoalveolar lavage fluid. Infusion of methylprednisolone (60 mg/kg/h, i.v. for 30 min before the oleic acid and then 0.5 mg/kg/h, i.v. for 6 h) did not improve the above described lung injury induced by oleic acid, nor did it suppress phospholipase A(2) activity and degradation of surfactant in bronchoalveolar lavage fluid, while it strongly reduced interleukin-8 levels in both plasma and bronchoalveolar lavage fluid. We conclude that methylprednisolone did not attenuate oleic acid-induced acute lung injury and this can be explained partly by its failure to reduce the increase of phospholipase A(2) activity and the surfactant degradation in the lung, which might also account for its clinical ineffectiveness against early acute respiratory distress syndrome.

Analysis of the cytokine interaction among interleukin-1beta, interleukin-8, and interleukin-1 receptor antagonist in the rabbit ovulatory process.

OBJECTIVE: To elucidate the regulation and involvement of interleukin (IL)-1beta, IL-8, and IL-1 receptor antagonist in the hCG-induced rabbit ovulatory process. DESIGN: Randomized, controlled animal study. SETTING: University research laboratory. ANIMAL(S): Mature female New Zealand white rabbits. INTERVENTION(S): After i.v. administration of 100 IU of hCG to rabbits, ovarian levels of IL-1beta. IL-8, and IL-1 receptor antagonist were determined at indicated times by ELISA. Anti IL-1beta, anti-lL-8, or anti-IL-1 receptor antagonist antiserum was given i.v. 30 minutes before hCG injection. MAIN OUTCOME MEASURE(S): Effects of each antiserum on the levels of the other cytokines and neutrophil accumulation, assessed by myeloperoxidase activity, were determined. Ovulation rate (rate of ruptured follicles) was also evaluated. RESULT(S): The maximal level of IL-8 was detected at 4 hours. which preceded that of IL-1beta and IL-1 receptor antagonist, detected at 6 hours after hCG injection. Administration of anti-IL-1beta antiserum resulted in a statistically significant reduction of the peak levels of IL-8 and IL-1 receptor antagonist. Administration of anti-IL-8 antiserum reduced the accumulation of IL-1beta and IL-1 receptor antagonist. Anti-IL-1 receptor antagonist antiserum significantly augmented the accumulation of IL-1beta and IL-8. Myeloperoxidase activity was reduced by anti-IL-8 antiserum. Anti-IL-1beta and anti-lL-8 antiserum reduced the hCG-induced ovulation rate, but a synergistic effect was not evident when these antisera were injected simultaneously. Anti-IL-1 receptor antagonist antiserum had no apparent effect on ovulatory efficiency. CONCLUSION(S): IL-1beta, IL-8, and IL-1 receptor antagonist may affect the accumulation of related cytokines in ovaries and may be involved in ovulation.

Interleukin-1beta in antigen-induced arthritis of the rabbit temporomandibular joint.

The aim was to investigate joint perfusate levels of interleukin-1beta (IL-1beta) in antigen-induced monoarthritis of the rabbit temporomandibular (TMJ) and knee joints. Twenty-four adult male New Zealand White rabbits were divided into three groups: a control group as well as TMJ arthritis and knee joint arthritis groups. After sensitization, unilateral arthritis was induced by intra-articular injection with ovalbumin and the contralateral joint was injected with saline 3 weeks after induction of arthritis. Joints were then perfused continuously with saline and samples were collected at 10-min intervals over a 50-min period. The IL-1beta concentrations in the samples were then analyzed. After killing the animals, the joints were examined histologically. The IL-1beta concentrations in the samples from the arthritic TMJs and knee joints were significantly higher than in the saline-injected and the control joints. Histological signs of chronic arthritis of similar severity were found in both joints. The IL-1beta levels in the samples from the arthritic TM and knee joints correlated with the histological severity of the arthritis, including pannus formation. In conclusion, this study shows that IL-1beta is released in the synovium of rabbit TMJs and knee joints during antigen-induced arthritis, and that high IL-1beta levels in synovial fluid are associated with histological signs of inflammation including, pannus tissue formation.

An investigation on rheumatoid factor of different immunoglobulin classes in hepatitis B virus carriers.

Rheumatoid factor (RF) is known to be present very frequently in HB virus carriers. When RF was assayed in 140 asymptomatic carriers by agglutination method, 20.0% were found to be positive, whereas 2.7% in the controls (p less than 0.01). ELISA for detection of RF isotypes showed RF in carriers to be almost IgMRF only. IgMRF showed a tendency to react more readily to human IgG rather than to rabbit IgG. The incidence of IgMRF positivity was higher among anti-HBe antibody-positive carriers than among anti-HBe antibody negative ones, but the difference between the two populations was not significant. However, the incidence of IgMRF positivity in the group showing hepatic dysfunctions was found to be significantly higher than in the group with normal hepatic functions.

Arteriovenous malformation with an ulcer of the foot--report of a case.

An unusual case of arteriovenous malformation (AVM) associated with ulcer arising on the sole of the left foot is reported. This ulcer was precipitated by pregnancy. After a split thickness skin graft repaired the ulcer, diffuse AVM was found on the left lower leg by arteriography. All the involved vessels were totally excised and the course was comparatively good. Clinical manifestations of AVM, incidences of ulcer in AVM, histological differentiation from Kaposi sarcoma, and treatment of AVM are discussed.

A case of skin metastasis of lung carcinoma associated with superior vena cava syndrome.

An unusual case of lung carcinoma with both skin metastasis and superior vena cava syndrome (SVCS) is reported. The histological type of the primary lesion as taken by punch biopsy was small cell carcinoma consisting of relatively small cells with hyperchromatic nuclei and scanty cytoplasm. The cutaneous metastatic lesion consisted of large cells with light-staining nuclei and small cells with deep-staining nuclei; it had foci of glandular elements by light microscopy. Neurosecretory granules characteristic of small cell carcinoma were found in the tumor cell cytoplasm by electron microscopy. Cutaneous metastatic rates, complication rates of SVCS, and histological varieties of small cell lung carcinomas are discussed.

Warty dyskeratoma with multiple lesions.

A 63-year-old man with multiple nodules and pathological findings of acantholysis is reported as a case of warty dyskeratoma presenting with multiple lesions. The number of nodules is the highest in the records as far as we know. We conclude that warty dyskeratoma originates from the hair follicle.

[Preclinical and clinical studies on the efficacy of bifonazole in patients with tinea pedis at 10 years after approval. Part 1. Susceptibility to bifonazole of clinical isolates of dermatophytes].

An investigation was carried out to determine whether or not here had been any changes in the susceptibility of clinically isolated strains of Trichophyton metagrophytes and Trichophyton rubrum (both leading causes of tinea) to bifonazole, an imidazole derivative and antifungal for topical use. Susceptibility was measured in 107 strains of these fungi isolated from clinical samples during a study on the treatment of tinea pedis with Mycospor cream in 1995, 42 strains isolated and stored in 1990, and 39 strains isolated and stored prior to development of the drug. The results are as follows: (1) There was no distinct difference in the susceptibility to bifonazole of T. mentagrophytes strains isolated before 1986 and those isolated in 1990 or 1995. (2) T. rubrum strains isolated before 1986 were slightly more susceptible to bifonazole than those isolated in 1995, while the 1990 strains were slightly less susceptible than the 1995 strains, but the difference was not significant. (3) The highest MICs of bifonazole for all the T. mentagrophytes and T. rubrum strains isolated from before 1986 and those in 1995 were relatively low, being 2.5 micrograms/ml and 1.25 micrograms/ml, respectively. These results suggest that no resistance or reduced susceptibility to bifonazole has emerged among clinical isolates of dermatophytes since the development of the drug.

[Fundamental and clinical studies on the efficacy of bifonazole in patients with tinea pedis at 10 years after approval. Part 2. Clinical evaluation].

The usefulness of bifonazole (Mycospor), a topical imidazole antifungal agent approved 10 years ago, was evaluated for the treatment of tinea pedis. Mycospor cream was applied by 141 patients with tinea pedis once daily for 4 233ks, and the clinical efficacy and adverse reactions (as well as any correlations with susceptibility of isolates and the mycological activity of the agent against these isolates) were studied. The results were then compared to those of a previous study. The following results were obtained. 1. Mycological activity Mycological examination results became negative in 63.2% (36/57) of the patients with plantar tinea pedis, in 94.1% (32/34) of those with interdigital tinea pedis, and in 74.7% (68/91) of all tinea pedis patients. 2. Mycological activity and MIC No correlation was found between the MICs of bifonazole against the pathogenic fungi and the rate of eradication on mycological examination. 3. Improvement of symptoms The improvement rates for local symptoms were 82.5% for plantar tinea pedis, 85.7% for interdigital tinea pedis, and 83.7% for all tinea pedis. 4. Clinical efficacy Good clinical efficacies were found in 61.4% of the patients with plantar tinea pedis, in 88.6% of those with interdigital tinea pedis, and in 71.7% of all patients. 5. Safety Regarding adverse reactions, what seemed to be contact dermatitis was reported in 5 out of 127 cases (3.9%). The reaction decreased or disappeared in all cases. 6. Usefulness Mycospor was found to be useful in 64.9% of patients with plantar tinea pedis, in 88.6% of those with interdigital tinea pedis, and in 73.9% of all tinea pedis patients. 7. Comparison with former results The results obtained in the present clinical study were comparable to those obtained in patients with tinea pedis treated in a double-blind comparative study conducted during the development of as a new topical antifungal agent. From the above results, Mycospor cream was confirmed to be still useful, although it has been used widely for the topical treatment of cutaneous mycoses in the past 10 years since its approval.

[A simple method for differentiation of hydrogen sulfide-producing bacteria by the pH-dependent EDTA-sensitivity test].

The pH-dependent EDTA-sensitivity test was performed to differentiate several strains of bacteria forming black colonies by the production of hydrogen sulfide on TCBS (thiosulfate-citrate-bile salt-sucrose agar) medium (tentatively designated as hydrogen-sulfide production bacteria). Two halotorelant strains of 16 hydrogen sulfide-producing strains showed the same bacteriological properties and isoprenoid quinone type as did a reference strain of Proteus mirabilis and were classified into the EDTA-insensitive group as were P. mirabilis and P. vulgaris. On the other hand, the other 14 halophilic strains, showing similar but not identical bacteriological properties or the isoprenoid quinone type to those of Shewanella putrefaciens IFO 3908, were classified into the "EDTA-sensitive (at pH 5)" group as were some species of the genus Vibrio. By the same sensitivity test, S. putrefaciens IFO 3908 was classified into the "EDTA-sensitive (at any pH)" group. These results indicate that the pH-dependent EDTA-sensitivity test is useful for differentiation of bacterial isolates producing hydrogen sulfide and having similar bacteriological properties.

Erythroid and megakaryocytic differentiation of K562 erythroleukemic cells by monochloramine.

The induction of leukemic cell differentiation is a hopeful therapeutic modality. We studied the effects of monochloramine (NH2Cl) on erythroleukemic K562 cell differentiation, and compared the effects observed with those of U0126 and staurosporine, which are known inducers of erythroid and megakaryocytic differentiation, respectively. CD235 (glycophorin) expression, a marker of erythroid differentiation, was significantly increased by NH2Cl and U0126, along with an increase in cd235 mRNA levels. Other erythroid markers such as γ-globin and CD71 (transferrin receptor) were also increased by NH2Cl and U0126. In contrast, CD61 (integrin ß3) and CD42b (GP1bα) expression, markers of megakaryocytic differentiation, was increased by staurosporine, but did not change significantly by NH2Cl and U0126. NH2Cl retarded cell proliferation without a marked loss of viability. When ERK phosphorylation (T202/Y204) and CD235 expression were compared using various chemicals, a strong negative correlation was observed (r = -0.76). Paradoxically, NH2Cl and staurosporine, but not U0126, induced large cells with multiple or lobulated nuclei, which was characteristic to megakaryocytes. NH2Cl increased the mRNA levels of gata1 and scl, decreased that of gata2, and did not change those of pu.1 and klf1. The changes observed in mRNA expression were different from those of U0126 or staurosporine. These results suggest that NH2Cl induces the bidirectional differentiation of K562. Oxidative stress may be effective in inducing leukemic cell differentiation.