Mitochondrial damage in patients with long-term corticosteroid therapy: development of oculoskeletal symptoms similar to mitochondrial disease

Two patients with long-term corticosteroid administration sporadically developed limb muscle wasting followed by ophthalmoplegia, and the skeletal muscle pathology revealed ragged-red fibers (RRFs) with abnormal mitochondria, in addition to the findings of corticosteroid myopathy. The oculoskeletal symptoms of the present cases resemble those of chronic progressive external ophthalmoplegia, a type of mitochondrial disease. The ocular muscles have more RRFs than limb muscles, and large multiple deletions of mitochondrial DNA was detected in ocular and limb muscles of the two patients by PCR but not by Southern blotting. Immunohistochemistry demonstrated that 8-hydroxy-deoxyguanosine (8-OH-dG) and 4-hydroxy-2-nonenal were intensely stained in skeletal muscles of these patients particularly in RRFs. High-performance liquid chromatography with electrochemical detection analysis revealed an increase in 8-OH-dG from mitochondrial DNA. These findings may suggest that long-term corticosteroid administration potentially induces oxidative stress-mediated mitochondrial damage, resulting in the development of the oculoskeletal symptoms in some patients.


Potent induction of activin A secretion from monocytes and bone marrow stromal fibroblasts by cognate interaction with activated T cells

Activin A is a multifunctional cytokine essential for cell differentiation and apoptosis including erythroid cell differentiation in the bone marrow. In addition, activin A is induced by inflammation and exerts anti-inflammatory effects. However, the mechanism of activin A induction is still unclear, especially by inflammatory processes. Here we show that activin A secretion from monocytes and bone marrow stromal fibroblasts, its major sources in the bone marrow, is markedly enhanced by cognate interaction with activated T cells. This process is mediated by CD40/CD40 ligand interaction as well as concomitantly secreted T cell-derived cytokines, granulocyte macrophage-colony stimulating factor, and interferon-gamma. Furthermore, stromal fibroblasts as well as monocytes provide a costimulatory signal to anti-CD3-treated T cells via CD80 and CD86 to maintain the enhanced activin A production. These findings suggest that activin A is potently induced in the bone marrow and may play a role in the suppression of inflammatory or immune processes.


Chronic corticosteroid administration causes mitochondrial dysfunction in skeletal muscle

Corticosteroid myopathy is a major clinical problem in patients undergoing chronic corticosteroid treatment and shows insidious and progressive muscle atrophy in proximal limbs. Although several mechanisms underlying the pathophysiology of muscle injury have been postulated, precise pathogenesis is still not clear. We evaluated the mitochondrial functions in patients receiving corticosteroids compared with those in healthy controls or patients not receiving corticosteroids. The serum levels and total production of lactate were investigated by an aerobic exercise test using a bicycle ergometer. Mitochondrial respiratory activities and oxidative damage in biopsied skeletal muscles were also studied. The results of aerobic exercise tests revealed a significant overproduction of lactate in patients treated with corticosteroids ( p < 0.005), which was positively correlated with total corticosteroid doses administered ( p < 0.0001). In these patients, mitochondrial enzyme activity in complex I was significantly decreased ( p < 0.05) and oxidative damage of biopsied skeletal muscle was remarkable both in mitochondrial and nuclear DNAs ( p < 0.001). The results suggest that chronic corticosteroid administration induces mitochondrial dysfunction and oxidative damage in skeletal muscles, which may be the pathogenesis, at least in part, of corticosteroid-induced myopathy.


Apoptosis-related changes in skeletal muscle of patients with mitochondreal disease.

Much interest has recently been shown in apoptosis-mediated roles in the pathophysiology of mitochondrial diseases, because mitochondrial defects are implicated in a wide variety of degenerative diseases. We investigated whether apoptotic events occurred in skeletal muscles of patients with mitochondrial diseases, including chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayer syndrome (KSS), and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). In a immunohistochemical study, stainings for 8-hydroxy-deoxyguanosine (8-OH-dG), 4-hydroxy-nonenal (4-HNE), Mn-SOD, Bcl-2, cytochrome c, DNase I and Bcl-x L showed a pronounced granular distribution in the cytochrome c oxidase (COX)-negative ragged-red fibers (RRFs). On the other hand, the signals for Bax, p53, Fas and caspase 3 were not obviously increased in RRFs. In situ labeling of DNA breaks demonstrated preferential signals not only in myonuclei but also in subsarcolemmal regions of RRFs, indicating that mitochondrial as well as myonuclear DNA is fragmented in RRFs. An immunoblotting study demonstrated that cytochrome c was increased in the cytosol of diseased muscles and that DNase I was increased in mitochondria, compared to that of normal muscles. No difference was observed between protein bands at 20 kDa corresponding to caspase 3 in diseased and normal muscles. These findings demonstrate that these mitochondrial diseases harbor unique apoptosis-related changes that differ from caspase 3-dependent apoptosis. It is thought that these changes are induced by superoxide overproduction and cytochrome c release resulting from an inherent mitochondrial defect and that the events are associated with DNase I activation.


Comparative study of incadronate and elcatonin in patients with malignancy-associated hypercalcaemia

The clinical usefulness of incadronate was compared with elcatonin in 26 patients with malignancy-associated hypercalcaemia. Data from 21 and 24 patients could be used to assess efficacy and safety, respectively. Eleven patients were given a single 10-mg intravenous infusion of incadronate and 10 received twice-daily intramuscular injections of 40 IU of elcatonin for 7 consecutive days. After treatment, corrected serum calcium levels decreased significantly in both groups. The anti-hypercalcaemic effect of elcatonin was characterized by its rapid onset, with serum calcium levels reduced 1 day after administration. In contrast, the anti-hypercalcaemic effect of incadronate was more sustained but only became apparent a few days after infusion. Evaluation of symptoms revealed significantly greater improvement rates in the incadronate group compared with the elcatonin group. Adverse drug reactions were observed in three patients in the incadronate group, i.e. mild and transient fever in two cases and exacerbation of disturbance of consciousness in one case. These findings suggest that incadronate produces more marked and sustained hypocalcaemic effects than elcatonin, and that co-administration of these two drugs may yield both rapid and sustained control of malignancy-associated hypercalcaemia.

The Journal of International Medical Research


Estrogen Promotes Early Osteoblast Differentiation and Inhibits Adipocyte Differentiation in Mouse Bone Marrow Stromal Cell Lines that Express Estrogen Receptor (ER) α or ß


Loss of postural reflexes in long-term occupational solvent exposure

Inhalation of organic solvents has long been known to damage various nervous systems, including cerebellum, brainstem, and pyramidal tract. However, little is known about the damage of the dopaminergic system. We report two patients with occupational long-term solvent exposure who developed postural instability without other features of parkinsonism. The concentration of HVA in CSF was decreased and the retropulsion was dramatically improved after the administration of levodopa. These findings indicate that the nigrostriatal dopaminergic neurons were disturbed by chronic solvent exposure, resulting in the loss of postural reflexes.


Aberrant Growth Plate Development in VDR/RXR Double Null Mutant Mice

VDR forms heterodimers with one of three RXRs, RXR alpha, RXR beta, and RXR gamma, and it is thought that RXR ligands can also modulate the trans-activation function of VDR/RXR heterodimers. In the present study we generated VDR/RXR gamma double null mutant mice to examine the convergent actions of vitamin D and vitamin A signaling and to explore the possibility of a functionally redundant VDR. Although RXR gamma(-/-) mice exhibited no overt abnormalities, VDR(-/-)/RXR gamma(-/-) mice appeared similar to VDR(-/-) mice, showing features typical of vitamin D-dependent rickets type II, including growth retardation, impaired bone formation, hypocalcemia, and alopecia. However, compared to VDR(-/-) mice, growth plate development in VDR(-/-)/RXR gamma(-/-) mutant mice was more severely impaired. Normalizing mineral ion homeostasis through dietary supplementation with high calcium and phosphorous effectively prevented rachitic abnormalities, except for disarranged growth plates in VDR(-/-)/RXR gamma(-/-) mutant mice, and alopecia in both VDR(-/-) and VDR(-/-)/RXR gamma(-/-) mutant mice. Histological analysis of VDR(-/-)/RXR gamma(-/-) growth plates revealed that development of the hypertrophic chondrocytes was selectively impaired. Thus, our findings indicated that the combined actions of VDR- and RXR gamma-mediated signals are essential for the normal development of growth plate chondrocytes, and raised the possibility that a functionally redundant VDR is present on chondrocytes as a heterodimer with RXR gamma.


Interleukin-1 β enhances and interferon-γ suppresses activin A actions by reciprocally regulating activin A and follistatin secretion from bone marrow stromal fibroblasts

Activin A is a multi-functional cytokine with a potent stimulation on erythroid cell differentiation in the bone marrow. The actions of activin A are determined by a balance of the levels of activin A and its inhibitor, follistatin (FS). However, the regulation of its actions in the bone marrow has been unclear. Here we show that bone marrow-derived stromal fibroblasts are the major source of activin A and FS in the bone marrow, and that the production of activin A is enhanced by interleukin-1beta (IL-1beta) and lipopolysaccharide (LPS), whereas interferon-gamma (IFN-gamma) inhibits the secretion of activin A by stromal fibroblasts. Concomitantly, IL-1beta as well as LPS inhibits and IFN-gamma stimulates FS secretion from stromal fibroblasts. Thus, these cytokines potently regulate activin A actions by reciprocal modulation of activin A and FS secretion from stromal fibroblasts. Because activin A exhibits anti-inflammatory effects in various tissues, up-regulation of activin A actions by IL-1beta and endotoxin in the bone marrow may play a protective role against inflammatory processes as well as anaemia. The present results also suggest that the inhibitory effect of IFN-gamma on erythropoiesis is mediated at least in part by a suppression of activin A actions in bone marrow.


Homozygous deletion mutation of the parkin gene in patients with atypical parkinsonism

Autosomal recessive juvenile parkinsonism (AR-JP) is characterised by homogenous clinical features and selective degeneration of nigral neurons. Recent progress in molecular genetic analyses of AR-JP has led to the identification of a novel ubiquitin-like protein, parkin, whose precise function still remains to be elucidated. Two unrelated Japanese families had levodopa unresponsive parkinsonism complicated with cerebellar and pyramidal tract dysfunction. Genetic analysis of the parkin gene and mRNA in both families disclosed identical mutations with large deletions extending from exons 3 to 4. These results suggest that the parkin protein possesses an important function not only in the substantia nigra but also in extranigral neurons of the CNS and that the phenotype of multiple system dysfunction can also be a complication in patients with AR-JP due to variations in sites of or changes in functions by parkin mutation.

Journal of Neurology, Neurosurgery, and Psychiatry


Superantigens and autoantigens may be involved in the pathogenesis of gastric mucosa-associated lymphoid tissue lymphoma

To clarify the origin of tumor cells and the possible role of antigens in the pathogenesis of mucosa-associated lymphoid tissue lymphoma (MALTL) of the stomach, we analyzed the DNA sequences of the immunoglobulin (Ig) variable region gene from tumor cells of 4 patients with low-grade and 2 patients with high-grade MALTL associated with Helicobacter pylori infection. There were few somatic mutations in the Ig variable region gene, but intraclonal variations were observed in 2 of the 4 low-grade MALTL cases. In the remaining 2 low-grade MALTL and 1 of the 2 high-grade MALTL cases, somatic mutations and intraclonal variations were evident. In contrast, somatic mutations in the Ig variable region gene were prominent, but intraclonal variation was absent in the other high-grade MALTL cases. The deduced amino acid sequences of the antigen-binding fragments (Fab) from 2 MALTL cases revealed homology with anti-thyroglobulin antibodies, 3 MALTL cases with lupus anti-DNA antibodies, and 1 MALTL case with a rheumatoid factor. Furthermore, the heavy-chain variable region 3 (V(H)3) family genes were used in 5 of the 6 MALTL cases and had conserved amino acid residues for binding to staphylococcal protein A (SpA), a superantigen of B cells. Considering that another superantigen, protein Fv, competes for binding to Fab with SpA and has been shown to play a major role in immune defenses against gut pathogens, SpA and possibly protein Fv may contribute to the development of MALTL. Thus, these observations suggest that most gastric MALTLs arise from memory B cells that are preliminarily activated by superantigens and autoantigens.


Interleukin 1β enhances and interferon-γ suppresses activin A actions by reciprocally regulating activin A and follistatin secretion from bone marrow stromal fibroblasts


17β-Estradiol stimulates expression of osteoprotegerin by a mouse stromal cell line, ST-2, via estrogen receptor-α

Osteoprotegerin (OPG) is a recently identified member of the tumor necrosis factor (TNF) receptor superfamily that regulates bone mass through an inhibitory action on osteoclast differentiation and function. To determine its potential roles of OPG in pathological changes in bone metabolism caused by estrogen deficiency, we investigated effects of estrogen on OPG expression by a mouse stromal cell line, ST-2, in vitro. Treatment of ST-2 cells with 17beta-E(2) resulted in up-regulation of OPG expression at both the messenger RNA and protein levels. The effect was time and dose dependent and steroid specific. The stimulatory action of 17beta-E(2) on OPG expression appeared to be mediated by the estrogen receptor-alpha (ERalpha) subtype because stable overexpression of ERalpha, but not of ERbeta, enhanced the OPG induction by 17beta-E(2). Moreover, estrogen withdrawal after 5-day pretreatment, mimicking the event occurring in vivo at menopause, dramatically diminished the expression of OPG. These findings suggest that down-regulation of OPG after estrogen withdrawal contributes to the enhanced osteoclastic bone resorption and bone loss after menopause by enhancing RANK ligand-RANK system that lies downstream of a large number of bone-resorbing cytokines.


Successful combination therapy--flunarizine,pentoxifylline, and cholestyramine--for spur cell anemia

Spur cell anemia, a hemolytic anemia observed in patients with alcoholic cirrhosis, is characterized by unusual erythrocyte morphology and an increased ratio of free cholesterol to phospholipid in the erythrocyte membrane. The prognosis of spur cell anemia is usually extremely poor, however, we describe here a patient with spur cell anemia who was successfully treated with combination therapy consisting of flunarizine, pentoxifylline, and cholestyramine. Initial therapy with flunarizine alone for 6 weeks did not significantly decrease the number of spur cells on peripheral blood smears. So pentoxifylline was added to the regimen. The patient recovered from the anemia, showed remarkable improvement with regard to the hyperbilirubinemia, and the changes were accompanied by a significant decrease in the number of spur cells in peripheral blood smears. To correct the hypercholesterolemia, cholestyramine was added to the regimen, which resulted in a reduction in the serum level of free cholesterol and an increase in the molar ratio of free cholesterol to phospholipid in erythrocyte membrane. However, 6 months later a skin eruption developed that was considered an adverse reaction to the drugs, so the flunarizine and pentoxifylline were discontinued. With cholestyramine therapy alone, the remission of spur cell anemia was maintained for more than 11 months. These observations suggest that non-invasive combination therapy with flunarizine, pentoxifylline, and cholestyramine is effective and valuable in the treatment of patients with spur cell anemia.


Solitary plasmacytoma with VEGF overproduction: report of a patient with polyneuropathy


Corticospinal tract involvement in a variant of Guillain-Barré syndrome

To determine the involvement of the corticospinal tract in Guillain-Barré syndrome (GBS), we examined central motor conduction in patients with GBS-like symptoms and hyperreflexia using a magnetic stimulation technique. The subjects were 3 patients who exhibited ascending muscle weakness 2-4 weeks after preceding infections. Deep tendon reflexes were exaggerated in all four limbs of the 3 patients. The results of cerebrospinal fluid examinations revealed protein elevation without pleocytosis. The serum anti-GM(1) antibody titer was elevated in 2 patients. The results of nerve conduction study revealed axonal motor neuropathy and normal F-wave conduction. Central motor conduction time (CMCT) in patients with hyperreflexia was significantly delayed compared to that in patients with GBS and areflexia (p < 0.001), and the delayed CMCTs were significantly improved in the recovery periods (p < 0.001). Although hyperreflexia is a controversial symptom in patients with GBS, these findings indicate that there is functional corticospinal tract involvement in patients with a GBS variant.


Molecular mechanism of type I congenital heparin cofactor (HC) II deficiency caused by a missense mutation at reactive P2 site: HC II Tokushima

We found a 66-year-old Japanese patient with type I congenital heparin cofactor (HC) II deficiency manifesting multiple atherosclerotic lesions. To investigate the molecular pathogenesis of our patient, we performed sequencing analysis and expressed recombinant human wild-type and mutant HC II molecules in COS-1 and CHO-K1 cells. Sequencing analysis following amplification of each of all 5 exons and its flanking region showed a single C to T transition at nucleotide position 12,854 in exon 5, which changed a Pro443 codon (CCG) to Leu codon (CTG). Because this mutation generates a new Bhv I site, the Bbv I digestion pattern of the PCR-amplified exon 5 fragments from each family member was analyzed. In all cases, the patterns were consistent with the activities and antigen levels of plasma HC I1 in those members. Transient transfection, metabolic labeling and pulse-chase experiments followed by immunoprecipitation analysis showed that the recombinant mutant HC II molecules were secreted from COS-1 cells in reduced amounts compared with the wild-type, and that an enhanced intracellular association of the mutant molecules with a chaperone, GRP78/BiP, was observed in CHO-K1 cells. Northern blot analysis indicated that the mutant HC I1 mRNA was transcribed at a similar level as that of wild-type. Immunohistochemical staining of the transfected cells revealed that COS-1 cells expressing the mutant HC II molecules were stained mainly in the perinuclear area. We conclude that the impaired secretion of the mutant HC II molecules, due to intracellular degradation, is the molecular pathogenesis of type I congenital HC II deficiency caused by a Pro443 to Leu mutation at reactive P2 site.


冠動脈疾患の予防ならびに治療の観点からみた高コレステロール血症治療の現状とその問題点 --- 四国高脂血症スタディ


Effects of alendronate on bone metastases and hypercarcemia after surgery for hepatocellular carcinoma

Alendronate, a bisphosphonate compound, lowers serum calcium in patients with cancer-associated hypercalcemia through its inhibitory effect on bone resorption and as a result symptoms associated with hypercalcemia improve. This study was carried out to investigate the effects of alendronate in patients with hypercalcemia due to bone metastasis of hepatocellular carcinoma (HCC). Two patients were evaluated. Their corrected serum calcium and alpha-fetoprotein (AFP) levels and their computed tomography (CT), bone scintigraphy and magnetic resonance imaging (MRI) findings were evaluated before and during alendronate treatment. After treatment, not only the corrected serum calcium levels but also AFP levels and bone pain decreased; in addition, the regression of the metastatic focus was noted in the MRI analysis. These tumor inhibitory effects of alendronate have not been reported in HCC before; and alendronate might serve to prevent bone metastases in patients with HCC. In conclusion, two patients who developed hypercalcemia associated with bone metastasis after surgery for HCC were treated with alendronate and they experienced alleviation of the pain due to bone metastasis, improvement of their quality of life and a marked decrease in AFP levels with tumor regression.


Functional association between nicotinic acetylcholine receptor and sarcomeric proteins via actin and desmin filaments


Aspirin Reduces Apolipoprotein(a) (Apo(a)) Production in Human Hepatocytes by Suppression of Apo(a) Gene Transcription

High serum lipoprotein(a) (Lp(a)) is a risk factor for vascular disorders. Our preliminary observations suggest that, in some patients with coronary heart disease with high serum Lp(a) levels, administration of aspirin reduced Lp(a) levels. Therefore, we aimed to analyze the effects of aspirin on the production of apo(a), the expression of apolipoprotein(a) (apo(a)) mRNA and the transcriptional activity of apo(a) gene promoter. Aspirin (5 mM) reduced the apo(a) levels in culture medium of human hepatocytes and suppressed apo(a) mRNA expression to 73% and 85% of the controls, respectively. Aspirin also reduced the transcriptional activity of apo(a) gene transfected into HepG2 hepatoma cells in a dose-dependent manner, with a maximal effect at 5 mM (44.3 +/- 1.5% of the control). Sodium salicylate (5 mM) also reduced apo(a) gene transcription, whereas indomethacin (10 microM) had no effect. Deletion analysis of apo(a) gene promoter showed that promoter region extending from -30 to +138 is critical for the effect of aspirin. Furthermore, enhanced production, mRNA expression, and gene transcription of apo(a) by interleukin-6 were also inhibited by aspirin. These results demonstrate that aspirin reduces apo(a) production from hepatocytes via reduction of the transcriptional activity of apo(a) gene with suppression of apo(a) mRNA expression. The suppression of apo(a) production by aspirin may at least in part play a role in the anti-atherogenic effect of aspirin in vascular disorders.


Fas ligand-induced apoptosis of hepatocytes in natural killer cell leukaemia

Neoplastic natural killer (NK) cells overexpress Fas ligand (FasL), which may cause damage of Fas-bearing tissues. We report a patient with NK cell leukaemia who developed liver injury after pharyngitis. The NK leukaemic cells expressed functional FasL. In addition to soluble FasL, serum levels of interleukin-6 and interferon-gamma were increased dramatically when liver injury was aggravated. Moreover, hepatocytes expressed Fas and apoptotic hepatocytes were detected in the portal areas. These findings are consistent with the notion that inflammatory cytokines enhance the sensitivity to FasL and trigger apoptosis of hepatocytes in NK cell malignancies.


Effect of Aspirin Treatment on Serum Levels of Lipoprotein(a) --- Analysis From the Apolipoprotein(a)Isoforms

高リポ蛋白(a)血症に及ぼすaspirinの影響 --- アポリポ蛋白(a)アイソフォームとの関連


Humanized anti-HM1.24 antibody mediates myeloma cell cytotoxicity that is enhanced by cytokine stimulation of effector cells

To develop a new immunotherapy for multiple myeloma, we have generated a monoclonal antibody (MoAb) that detects a human plasma cell-specific antigen, HM1.24. Our previous study has shown that mouse anti-HM1.24 MoAb inhibits the proliferation of human myeloma cells implanted into severe combined immunodeficiency mice. In this report, we evaluated the antitumor activity of the humanized anti-HM1.24 MoAb (IgG1kappa), which was constructed by grafting the complementarity-determining regions. In contrast to the parent mouse MoAb, humanized anti-HM1.24 MoAb mediated antibody-dependent cellular cytotoxicity (ADCC) against both myeloma cell lines and myeloma cells from patients in the presence of human peripheral blood mononuclear cells (PBMCs). The PBMCs from untreated myeloma patients exhibited ADCC activity as efficiently as those of healthy donors. Although decreased ADCC activity of PBMCs was observed in patients who responded poorly to conventional chemotherapy, it could be significantly augmented by the stimulation with interleukin-2 (IL-2), IL-12, or IL-15. There was a strong correlation between the percentage of CD16(+) cells and ADCC activity in the PBMCs of myeloma patients. Moreover, peripheral blood stem cell collections from myeloma patients contained higher numbers of CD16(+) cells than PBMCs and exhibited ADCC activity that was enhanced by IL-2. These results indicate that humanized anti-HM1.24 MoAb has potential as a new therapeutic strategy in multiple myeloma and that treatment of effector cells with immunomodulating cytokines can restore the effect of humanized anti-HM1.24 MoAb in patients with diminished ADCC activity.


Biclonal lymphoplasmacytic immunocytoma associated with Crohn's disease

A 33-year-old man with a 4-year history of Crohn's disease presented with marked ascites and an abdominal tumor. Two M-protein peaks, immunoglobulin (Ig) G-kappa and IgA-kappa, were detected in the serum. Neoplastic lymphoplasmacytic cells were infiltrated in the bone marrow and ascites. Histological examination of the abdominal tumor showed marked proliferation of lymphoplasmacytic cells that were positive for either IgG or IgA. Moreover, DNA sequences of the expressed IgG and IgA genes were different in the complementarity-determining region 3. These results suggest that chronic inflammation in Crohn's disease contributes to the simultaneous development of biclonal lymphoplasmacytic immunocytoma of the small intestine.


Quantitative analysis of immunofluorescent signals for dystrophin, beta-dystroglycan and myosin skeletal muscle by epifluorescence microscopy.


Clinical, pathological, and genetic features of limb-girdle muscular dystrophy type 2A with new calpain 3 gene mutations in seven patients from three Japanese families

We report on the clinical, pathological, and genetic features of 7 patients with limb-girdle muscular dystrophy type 2A (LGMD2A) from three Japanese families. The mean age of onset was 9.7+/-3.1 years (mean+/-SD), and loss of ambulance occurred at 38.5+/-2.1 years. Muscle atrophy was predominant in the pelvic and shoulder girdles, and proximal limb muscles. Muscle pathology revealed dystrophic changes. In two families, an identical G to C mutation at position 1080 the in calpain 3 gene was identified, and a frameshift mutation (1796insA) was found in the third family. The former mutation results in a W360R substitution in the proteolytic site of calpain 3, and the latter in a deletion of the Ca2+-binding domain.


Radioimmunodetection of human myeloma xenografts with a monoclonal antibody directed against a plasma cell specific antigen, HM1.24


Hepatosplenic gamma delta T-cell lymphoma associated with hepatitis B virus infection

Hepatitis B virus (HBV) infection has been implicated in the development of hepatocellular and hematopoietic malignancies. We describe a patient with chronic hepatitis B who developed hepatosplenic gamma delta T-cell lymphoma. A 45-year-old woman presented with marked hepatosplenomegaly and hepatic failure during the course of chronic hepatitis B. Peripheral blood examination revealed 57% abnormal lymphoid cells which expressed the gamma delta T-cell receptor. The cytogenetic analysis of tumor cells showed an abnormal karyotype; 47, XX, -13, +2mar in all 20 metaphases examined. A clonal rearrangement of the T-cell receptor genes was demonstrated by Southern blot analysis, showing monoclonal expansion of tumor cells. A liver biopsy specimen showed fibrosis of the portal areas and sinusoidal infiltration of tumor cells. HBV infection was documented by the presence of IgG anti-HBc and anti-HBs antibodies in serum. Although HBV-DNA was not detected in tumor cells by polymerase chain reaction analysis, there is a possibility that proliferation of gamma delta T cells in response to HBV infection played a role in the pathogenesis of hepatosplenic gamma delta T-cell lymphoma.

The Journal of Medical Investigation : JMI


Immunotherapy of multiple myeloma with a monoclonal antibody directed against a plasma cell-specific antigen, HM1.24


Current micro-and Macroangiopathic Complication of Diabetic Patients by Primary Care Physicians on Multicenter-study

プライマリ·ケア医による糖尿病合併症の調査

日本プライマリ·ケア学会誌

日本プライマリ·ケア学会誌


Part7. 2. 新規治療薬の開発と臨床応用の可能性を探る (抗RANKL抗体などを中心に). がん骨転移治療 ビスフォスフォネート治療によるBone Management

先端医学者 高橋俊二 編集

先端医学者 高橋俊二 編集


骨転移の分子標的治療薬 骨転移のバイオロジーとマネージメント

骨転移の分子標的治療薬 骨転移のバイオロジーとマネージメント

医薬ジャーナル社 米田俊之 編集

医薬ジャーナル社 米田俊之 編集


Anti-neuronal antibodies in acute pandysautonomia.

We encountered two patients with acute pandysautonomia who subacutely exhibited extensive autonomic dysfunction after antecedent infections. Although these patients had been suffering from autonomic disturbance for several months, they both had a good clinical course after plasma exchange and intravenous immunoglobulin therapy. Thin-layer chromatography (TLC)-immunostaining did not demonstrate any antibodies against gangliosides, but immunoblot analysis showed antibodies against a neuroblastoma cell line, SH-SY5Y, in serum samples. Furthermore, ganglionic acetylcholine receptor autoantibodies were detected in one patient. These findings suggest that neuronal antibodies against the autonomic nervous system play an important role in the pathogenesis of acute pandysautonomia.


末梢単核球細胞を用いた抹消動脈閉塞症に対する新たな血管新生治療の試み

末梢単核球細胞を用いた抹消動脈閉塞症に対する新たな血管新生治療の試み


Successful treatment of relapsed/refractory Hodgkin's lymphoma with tandem transplantation

Tandem transplantationが有効であった再発·難治性ホジキンリンパ腫の1例

The Journal of the Japanese Society of Internal Medicine


Effect of bisphosphonate on myeloma bone disease

The Japanese Journal of Clinical Hematology