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J Nishimura

Publications and source records attributed to J Nishimura.

At least 55 records · Page 3Linked to original sources
PubMed2000

Glucocorticoid-induced osteoporosis: pathogenesis and management.

Glucocorticoid- (GC-) induced osteoporosis and an increased risk of fractures are one of the most serious problems for patient using long-term GC therapy, such as those with rheumatoid arthritis, autoimmune diseases, inflammatory bowel diseases, bronchial asthma, and chronic lung diseases. GCs are known to affect both bone formation and resorption. In rheumatoid arthritis, the etiology of bone loss is multifactorial, including local inflammation around joints, release of bone-absorbing cytokines, physical inactivity, and malnutrition, in addition to the use of GC. Two guidelines have been published, by the American College of Rheumatology Task Force in 1966 and by the UK Consensus Group in 1998. Both guidelines recommend that patients 'receiving GC therapy at doses of 7.5 mg/day of prednisolone or more for 6 months or longer should have their bone mineral density measured and begin preventive therapies. Calcium and vitamin D supplements, sex hormone replacement, and weight-bearing exercise are the first-line therapies. For patients who are unable to take sex hormone replacement therapy (HRT), bisphosphonates are recommended by both guidelines. In this article, we briefly summarize the pathogenesis of GC-induced osteoporosis and its prevention and treatment.

Bone Development↗
PubMed2000

Primary macroglobulinemia with t(11;18)(q21;q21).

These are the first cases of primary macroglobulinemia (PMG) with t(11;18)(q21;q21) reported in the literature. The first case was a 77-year-old man with macroglobulinemia (serum IgM: 8.36 g/dL). Abnormal lymphoid cells were detected in the blood and bone marrow. Immunologic and karyotypic analyses revealed that abnormal cells were positive for surface IgM-k, CD19, and CD20, negative for CD5 and CD10, and all had a t(11;18)(q21;q21). The second case was a 57-year-old woman with macroglobulinemia (serum IgM: 12.0 g/dL). Abnormal lymphoid cells were detected in blood and marrow, and cells were positive for surface IgM-lambda, CD19, and CD20, and negative for CD5 and CD10. Plasma cells bearing cytoplasmic IgM-lambda were increased in pleural fluid. Karyotyping demonstrated t(2;11;18)(q21-23;q21;q21). Rearrangements within BCL2 and YES genes located at 18q21 were not detected. Sixteen other cases with t(11;18)(q21;q21) have been reported in marginal zone B-cell lymphoma. Therefore, our report is in agreement with the finding that part of primary macroglobulinemia is a variant of marginal zone B-cell lymphoma.

Aged↗
PubMed2000

Interleukin-6 sensitizes multiple myeloma cell lines for apoptosis induced by interferon-alpha.

OBJECTIVE: Interleukin-6 (IL-6) is a multifunctional cytokine affecting growth and survival of normal B cell lineage and multiple myeloma cells. To test the hypothesis that IL-6, as well as other hematopoietic growth factors, may enhance apoptosis of target cells, we investigated the effect of IL-6 on myeloma cells in the presence of IFN-alpha, which is prescribed for patients with multiple myeloma. MATERIALS AND METHODS: Four myeloma cell lines, PCM6, NOP-2, U266, RPMI8226 were tested. We determined the induction of apoptosis by flow cytometry, using an FITC-Annexin V. RESULTS: IFN-alpha induced apoptosis on myeloma cell lines, and this apoptosis was further enhanced in the presence of IL-6, via activation of caspase 3. During induction of this apoptosis, the expression of c-Myc and Fas increased. The addition of IL-6 further increased the expression of Fas, but not that of c-Myc. Bcl-2, Bcl-x, and p53 were not affected by the addition of IL-6 and/or IFN-alpha. Addition of a PI-3-K inhibitor interfered with the enhancing effect of IL-6 on the apoptosis induced by IFN-alpha. CONCLUSION: We propose that IL-6 has the death signal, as well as growth promoting effects, and that PI-3-K may play a key role in the induction of apoptosis by IL-6.

Antineoplastic Agents↗
PubMed2000

Stereocontrol in cyclophane synthesis: a photochemical method to overlap aromatic rings.

To overlap aromatic rings in cyclophanes, the inter- and intramolecular [2 + 2] photocycloaddition of vinylarenes has been developed. It gives cyclophanes, naphthalenophanes, phenanthrenophanes, thiophenophanes, and carbazolophanes in reasonable to excellent yields. The structures and properties of cyclophanes obtained are reviewed; especially the excimer emission of phenanthrenophanes, naphthalenophanes, and carbazolophanes stressed that many intriguing cyclophanes can be obtained through the fine molecular design of precursors.

Cyclobutanes↗
PubMed2000

Changes in the cytosolic Ca2+ concentration and Ca(2+)-sensitivity of the contractile apparatus during angiotensin II-induced desensitization in the rabbit femoral artery.

1. To investigate the underlying mechanism for the angiotensin II-induced desensitization of the contractile response during the prolonged stimulation of the vascular smooth muscle, we determined the effects of angiotensin-II on (1) cytosolic Ca2+ concentration ([Ca2+]i) and tension using fura-2-loaded medial strips of the rabbit femoral artery, (2) 45Ca2+ influx in ring preparations, and (3) Ca(2+)-sensitivity of the contractile apparatus in alpha-toxin permeabilized preparations. 2. In the presence of extracellular Ca2+, high concentrations of angiotensin-II elicited biphasic increases in [Ca2+]i and tension, which consisted of initial transient and subsequent lower and sustained phases. 3. The 45Ca2+ influx initially increased after the application of 10(-6) M angiotensin-II, and thereafter gradually decreased. At 20 min after the application, there was a discrepancy between the level of [Ca2+]i and the extent of 45Ca2+ influx. 4. The relationships between [Ca2+]i and tension suggested that the angiotensin-II-induced increase in the Ca(2+)-sensitivity of the contractile apparatus was maintained during the desensitization of smooth muscle contraction. 5. When 10(-6) M angiotensin-II was applied during the sustained phase of contraction induced by 118 mm K(+)-depolarization, at 10 min after the application, the [Ca2+]i levels were significantly lower and the tension levels were significantly higher than those prior to the application of angiotensin-II. 6. In conclusion, the decrease in [Ca2+]i, which is partially due to the inhibition of the Ca2+ influx, is mainly responsible for the desensitization evoked by high concentrations of angiotensin-II, and angiotensin-II seems to activate additional mechanisms which inhibit Ca2+ signaling during prolonged stimulation.

Angiotensin II↗
PubMed2000

The mechanism of the decrease in cytosolic Ca2+ concentrations induced by angiotensin II in the high K(+)-depolarized rabbit femoral artery.

1. Using front-surface fluorometry of fura-2-loaded strips, and measuring the transmembrane 45Ca2+ fluxes of ring preparations of the rabbit femoral artery, the mechanism underlying a sustained decrease in the cytosolic Ca2+ concentration ([Ca2+]i) induced by angiotensin II (AT-II) was investigated. 2. The application of AT-II during steady-state 118 mM K(+)-induced contractions caused a sustained decrease in [Ca2+]i following a rapid and transient increase in [Ca2+]i, while the tension was transiently enhanced. 3. When the intracellular Ca2+ stores were depleted by thapsigargin, the initial rapid and transient increase in [Ca2+]i was abolished, however, neither the sustained decrease in [Ca2+]i nor the enhancement of tension were affected. 4. Depolarization with 118 mM K+ physiological salt solution containing 1.25 mM Ba2+ induced a sustained increase in both the cytosolic Ba2+ concentration ([Ba2+]i) level and tension. However, the application of 10(-6) M AT-II during sustained Ba(2+)-contractions was found to have no effect on [Ba2+]i, but it did enhance tension. 5. After thapsigargin treatment, AT-II neither decreased nor increased the enhanced Ca2+ efflux rate induced by 118 mM K(+)-depolarization, whereas AT-II did increase the enhanced 45Ca2+ influx and the 45Ca2+ net uptake induced by 118 mM K(+)-depolarization. 6. Pretreatment with calphostin-C, partially, but significantly inhibited the decrease in [Ca2+]i induced by AT-II. 7. These findings therefore suggest that AT-II stimulates Ca2+ sequestration into the thapsigargin-insensitive Ca2+ stores, and thus induces a decrease in [Ca2+]i in the high external K(+)-stimulated rabbit femoral artery.

Angiotensin II↗
PubMed2000

The mechanism of bradykinin-induced endothelium-dependent contraction and relaxation in the porcine interlobar renal artery.

The mechanism of endothelium-dependent regulation of vascular tone of bradykinin was investigated by simultaneously monitoring the changes in the cytosolic Ca(2+) concentration and the force of smooth muscle in fura-2-loaded strips of the porcine renal artery with endothelium. During phenylephrine-induced sustained contraction, bradykinin (>3x10(-9) M) caused endothelium-dependent triphasic changes in the force of the strips, composed of an initial relaxation, a subsequent transient contraction and a late sustained relaxation. At low concentrations (10(-10) - 10(-9) M), bradykinin caused an endothelium-dependent biphasic relaxation with no contraction. A thromboxane A(2) (TXA(2))/prostaglandin H(2) (PGH(2)) receptor antagonist (10(-5) M ONO-3708) completely inhibited, while a TXA(2) synthase inhibitor (10(-5) M OKY-046) only partially inhibited, the transient contraction induced by bradykinin. Under conditions where the bradykinin-induced contraction was inhibited by ONO-3708 during the phenylephrine-induced contraction, bradykinin induced only a transient relaxation in the presence of N(Omega)-nitro-L-arginine methyl ester (L-NAME). This transient relaxation was inhibited when the precontraction was initiated by phenylephrine plus 40 mM extracellular K(+). The removal of L-NAME from this condition caused a partial reappearance of the initial relaxation and a complete reappearance of the sustained relaxation. In conclusion, bradykinin caused the endothelium-dependent triphasic regulation of vascular tone in the porcine renal artery. The concentrations of bradykinin required to induce a contraction was higher than that required to induce relaxation. Both TXA(2) and PGH(2) were involved in the bradykinin-induced contraction. The initial relaxation was mediated by nitric oxide and hyperpolarizing factors while the sustained relaxation depended on nitric oxide.

Animals↗
PubMed2000

Mechanisms underlying the neurokinin A-induced contraction of the pregnant rat myometrium.

1. Using fura-PE3 fluorimetry and alpha-toxin permeabilization, the characteristics of the contractile responses to neurokinin A (NKA) were determined in the pregnant rat myometrium. 2. NKA induced contractions in rat myometrium in a concentration-dependent manner. There were no significant differences in the maximum contractions and EC(50) values between the pregnant and non-pregnant myometrium, however, the contraction of only the former was greatly enhanced in the presence of phosphoramidon (PPAD), an endopeptidase inhibitor. 3. In the pregnant myometrium, NKA induced sustained increases in [Ca(2+)](i) and tension in normal physiological saline solution, while only small transient increases in [Ca(2+)](i) and tension were observed in Ca(2+)-free solution. 4. Both diltiazem (10 microM) and SK-F 96365 (10 microM) significantly inhibited the NKA-induced elevations of [Ca(2+)](i) and tension. The effects were additive when these drugs were used together. 5. NKA induced a significant leftward shift of the [Ca(2+)](i)-tension curve obtained by changing the external Ca(2+) (0 - 2.5 mM) during depolarization with high K(+) solution. This Ca(2+)-sensitizing effect by NKA was also observed in the alpha-toxin permeabilized myometrium. 5. These results indicated that in the pregnant rat myometrium: (1) the responsiveness to NKA increased, although it was masked by the increase in the endopeptidase activity; (2) NKA induced contractions of the myometrium by increasing both [Ca(2+)](i) and the myofilament Ca(2+) sensitivity and (3) The NKA-induced [Ca(2+)](i) elevation was partly due to the intracellular Ca(2+) release and mainly due to the Ca(2+) influx, which was thought to be through both voltage dependent calcium channels and non-specification channels.

Animals↗
PubMed2000

Stimulus-specific alteration of the relationship between cytosolic Ca(2+) transients and nitric oxide production in endothelial cells ex vivo.

1. To investigate the quantitative relationship between elevation in the intracellular Ca(2+) concentration ([Ca(2+)](i)) and nitric oxide (NO) production, the changes in [Ca(2+)](i) and NO production were determined in parallel, using fluorimetry of fura-2 and 2, 3-diaminonaphthalene, respectively, in endothelial cells ex vivo of pig aortic valves. 2. The extent of [Ca(2+)](i) elevation was quantitatively assessed by two parameters: the level of peak [Ca(2+)](i) elevation and the area under the [Ca(2+)](i) curve during treatment (the integrated [Ca(2+)](i) elevation). The amount of NO production was expressed as a percentage of that obtained with 10 microM ATP for 3 min. 3. ATP, bradykinin, thrombin, and ionomycin were used as stimulation to induce NO production, and all these caused [Ca(2+)](i) increases and NO production in a concentration-dependent manner. 4. The relationships between the peak [Ca(2+)](i) and NO production or between the integrated [Ca(2+)](i) elevation and NO production were well described by a straight line. However, the slope value of the linear relationship in both cases varied with the type of stimulation, with thrombin giving the greatest value, followed by ATP, bradykinin and ionomycin. 5. These data suggest that in endothelial cells ex vivo: (1) [Ca(2+)](i) elevation regulates NO production, but (2) the peak [Ca(2+)](i) elevation- or the integrated [Ca(2+)](i) elevation-NO production relationships varies depending on the type of agonists. Our results thus demonstrate the presence of the agonists-dependent modulation of the relationship between [Ca(2+)](i) elevation and NO production in endothelial cells ex vivo.

Adenosine Triphosphate↗
PubMed2000

Mechanisms of the thapsigargin-induced Ca(2+) entry in in situ endothelial cells of the porcine aortic valve and the endothelium-dependent relaxation in the porcine coronary artery.

The mechanisms of the thapsigargin (TG)-induced capacitative Ca(2+) entry in in situ endothelial cells and its role in the regulation of arterial tone were investigated using front-surface fluorimetry and fura-2-loaded strips of porcine aortic valve and coronary artery. In the presence of extracellular Ca(2+), TG induced an initial rapid and a subsequent sustained elevation of cytosolic Ca(2+) concentration ([Ca(2+)](i)) in valvular strips. In the absence of extracellular Ca(2+), TG induced only a transient increase in [Ca(2+)](i). The TG-induced sustained elevation of [Ca(2+)](i) in endothelial cells was inhibited completely by 1 mM Ni(2+) and partly by 10 microM econazole and 30 microM ML-9, but not by 900 ng ml(-1) pertussis toxin or 100 microM wortmannin. Therefore, cytochrome P450 and protein phosphorylation are suggested to be involved in the TG-induced Ca(2+) influx in in situ endothelial cells. TG induced an endothelium-dependent large relaxation consisting of an initial and a late sustained relaxation in coronary arterial strip precontracted with U46619 (a thromboxane A2 analogue). Indomethacin alone had no effect, while indomethacin plus N(omega)-nitro-L-arginine (L-NOARG) markedly inhibited the sustained phase and slightly inhibited the initial phase of the TG-induced relaxation. TG induced a smaller but sustained relaxation during the 40 mM K(+)-induced precontraction than that seen during the U46619-induced precontraction. This relaxation was completely abolished by the pretreatment with indomethacin plus L-NOARG. In conclusion, both nitric oxide (NO) and endothelium-derived hyperpolarizing factor were suggested to mediate the TG-induced relaxation, while NO plays a major role in the sustained relaxation. The TG-induced sustained [Ca(2+)](i) elevation in endothelial cells was thus suggested to be mainly linked to the sustained production of NO.

Animals↗
PubMed2000

Alteration of the [Ca(2+)](i)-force relationship during the vasorelaxation induced by a Ca(2+) channel blocker SR33805 in the porcine coronary artery.

The mechanism of vasorelaxation induced by SR33805 was investigated by simultaneously monitoring the cytosolic Ca(2+) concentration ([Ca(2+)](i)) and force, and by determining level of myosin light chain (MLC) phosphorylation in the medial strip of the porcine coronary artery. SR33805 inhibited the sustained increases in [Ca(2+)](i) and force (IC(50); 3.2+/-1.0 and 49.4+/-27.5 nM, respectively) induced by 118 mM K(+)-depolarization. There was about a 10 fold difference in the inhibitory potency between [Ca(2+)](i) and force. SR33805 completely inhibited the [Ca(2+)](i) elevation induced by a thromboxane A(2) analogue, U46619 and histamine, at concentrations (1 microM) higher than those required for the complete inhibition of K(+)-depolarization induced [Ca(2+)](i) elevation. SR33805 had no effect on the [Ca(2+)](i) elevation induced by histamine or caffeine in the absence of extracellular Ca(2+). SR33805 caused a leftward shift of the [Ca(2+)](i)-force relationship of the contraction induced by cumulative application of extracellular Ca(2+) during 118 mM K(+)-depolarization. The relationship between [Ca(2+)](i) and MLC phosphorylation also shifted to the left by SR33805, while the relationship between MLC phosphorylation and force remained unaffected. In conclusion, SR33805 caused an apparent leftward shift of the [Ca(2+)](i)-force relationship, accompanied by a greater degree of MLC phosphorylation for a given level of [Ca(2+)](i). The mechanism of this leftward shift, however, still remains to be elucidated.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2000

Enhanced contractile response to thrombin in the pregnant rat myometrium.

Thrombin causes various cellular events by activating protease-activated receptors (PARs). Here, we showed, for the first time, that thrombin induced myometrial contraction. To determine the mechanism of thrombin-induced myometrial contraction, we simultaneously measured intracellular Ca(2+) concentration ([Ca(2+)](i)) and tension of fura-PE3-loaded rat myometrium using front-surface fluorimetry. The expression of thrombin receptor mRNA in the rat myometrium were determined by reverse transcription-polymerase chain reaction analysis (RT - PCR analysis). Thrombin (0.01 - 3 u ml(-1)) caused dose-dependent increase in [Ca(2+)](i) and tension in the rat myometrium, and this effect was greatly enhanced in the pregnant myometrium. PAR1-activating peptide mimicked the effects of thrombin. In Ca(2+)-free PSS, thrombin induced no increase in [Ca(2+)](i) and tension in the pregnant myometrium. Both diltiazem (10 microM) and SK-F 96365 (10 microM) significantly inhibited the thrombin-induced elevations of [Ca(2+)](i) and tension, and their effects were additive. RT - PCR analysis revealed an approximately 10 fold increase in the level of thrombin receptor mRNA in the pregnant myometrium compared to that obtained in the non-pregnant myometrium. In conclusion, the contractile response to thrombin was greatly enhanced in the pregnant myometrium, mainly due to the up-regulation of thrombin receptor. We propose that initiation of a post-parturitional myometrial contraction is one of the most important physiological roles of thrombin receptor.

Animals↗
PubMed2000

Thrombin causes endothelium-dependent biphasic regulation of vascular tone in the porcine renal interlobar artery.

Using a method employing front-surface fura-2 fluorometry to measure the cytosolic Ca(2+) concentration, [Ca(2+)](i), the mechanism of endothelium-dependent regulation of vascular tone by thrombin was studied in porcine renal interlobar arterial strips. At concentrations lower than 3 u ml(-1), thrombin evoked only early transient relaxation, while at 3 u ml(-1) and higher concentrations, thrombin caused an early relaxation and a subsequent transient contraction. Both thrombin-induced relaxation and contraction were abolished by removing the endothelium. Similar biphasic responses were observed with a protease-activated receptor-1-activating peptide. Early relaxation was associated with a decrease in [Ca(2+)](i), while the transient contraction was not associated with a change in [Ca(2+)](i) of smooth muscle cells. A thromboxane A(2) (TXA(2))/prostaglandin H(2) (PGH(2)) receptor antagonist (10(-5) M ONO-3708) completely inhibited the thrombin-induced contraction, whereas a thromboxane A(2) synthase inhibitor (10(-5) M OKY-046) only partly inhibited it. When the thrombin-induced contraction was inhibited by ONO-3708, either pretreatment with N(omega)-nitro-L-arginine methylester (L-NAME) or an increase in the amount of external K(+) to 40 mM did not abolish thrombin-induced relaxation during phenylephrine-induced sustained contraction. However, the combination of pretreatment with L-NAME and an elevation of external K(+) to 40 mM completely abolished the relaxation. There was no significant difference in the concentration-dependent effects of thrombin on the initial early relaxation between conditions in which the contractile components either were or were not inhibited. Thrombin is thus considered to mainly activate protease-activated receptor-1 and cause a biphasic response, early relaxation and a transient contraction, in the porcine renal interlobar artery in an endothelium-dependent manner. The thrombin-induced endothelium-dependent relaxation was mediated by nitric oxide and hyperpolarizing factors, while the contraction was mediated by TXA(2) and PGH(2).

Animals↗
PubMed2000

Adult onset cyclic hematopoiesis in a patient with myelodysplastic syndrome.

A 75-year-old woman presenting with myelodysplastic syndrome showed cyclic oscillations in her white blood cell and platelet counts. Each cycle lasted for 5 to 6 months, with 4 cycles occurring over the course of a 2-year period. During successive cycles, the white blood cell count fluctuated from 10.1 to 2.6; 13.8 to 1.8; 11.0 to 1.6, and 8.6 to 1.3 x 10(9)/L. The platelet count fluctuated from 242 to 38, 199 to 11, 110 to 5, and 75 to 3 x 10(9)/L. The patient underwent red blood cell transfusions because of red blood cell aplasia; the frequency of the transfusions and the erythropoietin concentration in serum were inversely correlated. The number of circulating granulocyte-macrophage colony-forming units and CD34-positive cells in peripheral blood oscillated in phase with the white blood cell and platelet counts. These patterns suggested a periodic influx of progenitor cells from hematopoietic stem cells. The ratio of neutrophils to mononuclear cells remained essentially constant throughout the clinical course. Lymphocyte subset assessments using monoclonal antibodies showed an inverse CD4/CD8 ratio (less than 1) and extreme B cell lymphopenia throughout the fourth cycle. The percentage of CD3-positive cells oscillated inversely, suggesting that the cyclic cytopenia had an immune mechanism involving T lymphocytes.

Age of Onset↗
PubMed2000

Cytotoxic T-cell lymphoma diffusely involving the entire gastrointestinal tract associated with Epstein-Barr virus and tubercle bacilli infection.

We describe a rare case of cytotoxic gastrointestinal T-cell lymphoma with protein-losing enteropathy. Initial examination revealed the coexistence of T-cell lymphoma and tuberculosis in the mesenteric lymph node and liver. Despite anti-tuberculosis and anti-cancer treatment, the patient experienced chronic diarrhea and malabsorption and died approximately 3 years after onset. Autopsy specimens revealed medium-sized lymphoma cells, with a phenotype of CD3+, CD4-, CD7+, CD8+, CD30-, CD56-, CD103 (HML-1)-, TIA-1+, and granzyme B+, proliferating primarily and consistently in the mucosa of the entire bowel tract from esophagus to rectum. Interestingly, Epstein-Barr virus (EBV)-encoded small nuclear RNAs were detected in the tumors by in situ hybridization. Southern blot analysis revealed monoclonal proliferation in the EBV-infected T cells. Although the present case can possibly be categorized as an intestinal T-cell lymphoma according to the Revised European-American Lymphoma Classification, the case showed a unique clinical course and distribution of lymphoma cells. We present here an interesting case of gastrointestinal cytotoxic T-cell lymphoma and examine the possible association with infectious agents.

Digestive System↗
PubMed2000

Diffuse intervertebral disk calcification in a patient with rheumatoid arthritis.

A patient with seronegative rheumatoid arthritis (RA) who presented with intervertebral disk calcification (IDC) of several thoracic and lumbar intervertebral disks in herein described. There was no evidence of any other coexisting diseases such as ochronosis and hemochromatosis, but a remarkable degree of polyclonal hypergammaglobulinemia was observed as a notable finding. Although the appearance of IDC on T1-weighted images on magnetic resonance is controversial, no increased signal intensity was observed in our patient. To the best of our knowledge, this is the first report of IDC in RA.

Adult↗
PubMed2000

[Nonmyeloablative stem cell transplantation with low-dose total body irradiation (200 cGy) for a 55-year-old woman with acute lymphoblastic leukemia].

We describe a 55-year-old woman with acute lymphoblastic leukemia (ALL) in the first remission who underwent nonmyeloablative stem cell transplantation with conditioning consisting of low-dose total body irradiation and postgrafting cyclosporine and mycophenolate mofetil. Myelosuppression was mild, but on day 28 her bone marrow showed 8.8% lymphoblasts. We withdrew the cyclosporine, but the patient developed grade 2 acute GVHD and eosinophilia. The proportion of bone marrow lymphoblasts decreased transiently to 1.0% on day 40, but later increased again and the patient died on day 85. Application of this approach to patients with ALL needs to be examined on a large scale.

Cyclosporine↗