Effect of rikkunshito on gastric sensorimotor function under distention.

BACKGROUND: The herbal medicine rikkunshito is effective for the treatment of gastrointestinal symptoms in patients with functional dyspepsia. Although some basic studies on the effects of rikkunshito have been reported in rats, its effects on human gastric function have not yet been clarified. Psychosocial stress induces visceral hypersensitivity and elements of rikkunshito may reasonably affect or suppress this process. We conducted a study to verify the hypothesis that rikkunshito improves stress-induced gastric hypersensitivity and/or changes in gastric wall tone. METHODS: Nine healthy volunteers (five males, four females) participated in the study. The counterbalanced regimen consisted of a 2-week period of oral administration of 7.5 g day(-1) rikkunshito, then a 2-week period without treatment. Fundic sensorimotor function was examined using a gastric barostat twice on the day after each period. Virtual reality stress was imposed during the measurements of gastric tone and electrocardiogram. KEY RESULTS: Stress induced a significant increase in heart rate (P = 0.041), gastric volume (P = 0.008), and phasic volume events (P = 0.049) and a decrease in sensory (P = 0.038), discomfort (P = 0.011), and pain (P = 0.041) thresholds of the stomach. Rikkunshito significantly reduced epigastric fullness (P = 0.037) and perceived stress (P = 0.034) following stimulation of the pain threshold, regardless of stress without the drug. Stress reduced gastric volume at the sensory threshold and increased anxiety at the discomfort threshold, and these responses were significantly inhibited by rikkunshito (P = 0.026, P = 0.022, respectively). CONCLUSIONS & INFERENCES: These findings suggest that rikkunshito may improve symptoms and impaired gastric accommodation under distention stimuli of the proximal stomach superimposed by stress.

Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist.

BACKGROUND: Signalling of angiotensin II via angiotensin II type 1 receptor (AT1) promotes cardiac and renal fibrosis, but its role in lung fibrosis is little understood. Using a rat bleomycin (BLM) induced model of pulmonary fibrosis, we examined the expression of AT1 in the lung and the effect of an AT1 antagonist on pulmonary fibrosis. METHODS: Adult male Sprague-Dawley rats were given 0.3 mg/kg BLM intratracheally. Two days earlier they had received 10 mg/kg/day of the AT1 antagonist candesartan cilexetil mixed in the drinking water. AT1 expression in the lungs was examined by immunohistochemistry and immunoblot methods. The effect of the AT1 antagonist on pulmonary fibrosis was studied by analysis of bronchoalveolar lavage (BAL) fluid, histopathology, and hydroxyproline assay. RESULTS: Immunohistochemical studies showed overexpression of AT1 in inflammatory immune cells, alveolar type II cells, and fibroblasts. A quantitative assay for AT1 showed that AT1 expression was significantly upregulated in cells from BAL fluid after day 3 and in the lung homogenates after day 21. Candesartan cilexetil significantly inhibited the increase in total protein and albumin, as well as the increase in total cells and neutrophils in BAL fluid. On day 21 candesartan cilexetil also ameliorated morphological changes and an increased amount of hydroxyproline in lung homogenates. In addition, BLM increased the expression of transforming growth factor (TGF)-beta1 in BAL fluid on day 7; this increase was significantly reduced by candesartan cilexetil. CONCLUSION: AT1 expression is upregulated in fibrotic lungs. Angiotensin II promotes lung fibrosis via AT1 and, presumably, in part via TGF-beta1.

[New serum markers to monitor treatment of acute exacerbation of interstitial lung disease].

A 58-year-old woman was admitted to our hospital because of recurrent fever, severe cough and sputum. Chest radiological examinations showed diffuse reticulonodular opacities in both lung fields. Interstitial pneumonia with probable polymyositis was diagnosed. Serum surfactant protein (SP)-A, SP-D and KL-6, which are new interstitial lung disease markers, showed values significantly higher than cutoff levels. The markers increased more in parallel with the rapid development of respiratory insufficiency, CPK level, myalgia and proximal muscle weakness. Treatment with a high dose of corticosteroid and the following gradual decrease over 8 months led to clinical and radiological improvement, with normalization of values of the markers. These markers may therefore be reliable indicators of therapeutic success. However, these markers underwent different respective changes during the first 2 months. SP-A reached a maximum at the start of the treatment, while SP-D and KL-6 peaked at 5 and 10 days, respectively, after the treatment was initiated. This discrepancy demonstrates that the markers reach the bloodstream by diverse mechanisms and are useful for analyzing pathophysiological alterations in the lung in the early stages of treatment.

Diverged nuclear localization of Werner helicase in human and mouse cells.

Werner syndrome (WS) is a rare autosomal recessive genetic disorder causing premature aging and rare cancers. A gene responsible for WS (WRN) encodes a protein with 1432 amino acids (a.a.) homologous to the E. coli RecQ-type DNA helicase. Transcriptional activation facilitated nucleolar localization of human WRN protein (hWRNp) and serum starvation induced translocation of hWRNp from the nucleoli to the nucleoplasm in human cultured cells, suggesting a nucleolar-nucleoplasm trafficking of hWRNp depending on transcriptional state. Mutant hWRNp lacking the C-terminal 30 a.a. residues (Delta1403-1432) failed to localize in the nucleolus, whereas Delta1405-1432 can migrate into the nucleolus. Here we identify a region putative for nucleolar localization signal (NoLS) containing a sequence of two positively charged amino acids (Arg(1403)-Lys(1404)) in the C-terminal area of hWRNp. By contrast, the mouse homolog (mWRNp) exists only in the nucleoplasm. We show that the inability of mWRNp to migrate into the nucleolus is due to a difference of a sequence in the region corresponding to the NoLS of hWRNp. In addition, mouse cells cannot recognize the NoLS of hWRNp. Our study suggests that defect in nucleolar function of hWRNp may be linked to the premature aging which is not observed in mWRN(-/-) mice.

Diagnostic significance of surfactant proteins A and D in sera from patients with radiation pneumonitis.

Radiation pneumonitis (RP) is the most common complication of radiotherapy for thoracic tumours. The aim of this study was to evaluate the significance of pulmonary surfactant proteins (SP)-A and SP-D as new serum markers for RP. Twenty-five patients with lung tumour, who had received radiotherapy, were studied. At the completion of radiotherapy, the presence of RP was judged by chest plain radiography and chest high resolution computed tomography (HRCT). RP findings detected on chest plain radiography were seen in only three of 12 patients in whom RP was detected by HRCT. Nevertheless, both SP-A and SP-D concentrations in sera from the patients with RP were significantly higher than those from the 13 patients without RP (p = 0.0065, p = 0.0011, respectively). As with SP-A, ratios of SP-D at the completion, compared to at the initiation (1 week post/pre ratio), were also significantly higher in patients with RP than in patients without RP. When a post/pre ratio > 1.6 was considered positive, the SP-A and SP-D assays showed an 83% and 85% specificity, respectively. In conclusion, serum assays of surfactant proteins A and D may be of diagnostic value for detection of radiation pneumonitis, even when the radiographic change is faint.

IL-18 might reflect disease activity in mild and moderate asthma exacerbation.

BACKGROUND: IL-18, identified as an IFN-gamma-inducing factor, is a proinflammatory cytokine that plays an important role in TH1 cell activation. Recently, it was reported that histamine induced IL-18 and that IL-18 might act as a coinducer of TH1 and TH2 cytokines. OBJECTIVE: The aim was to evaluate the contribution of IL-18 to asthma exacerbation. METHODS: Serum IL-18, soluble IL-2 receptor, eosinophil cationic protein, and plasma IFN-gamma levels, as well as peak expiratory flow were measured in patients with stable asthma (n = 28), acute mild or moderate asthma (n = 23), or pulmonary sarcoidosis (n = 35) and in healthy subjects (n = 26). We compared the serum IL-18 levels between patients with acute asthma and those in remission and examined the time course in acute exacerbation after asthma therapy. RESULTS: Significantly higher serum IL-18 levels were found in patients with acute asthma (215 +/- 33 pg/mL, mean +/- SE; P = .02) and pulmonary sarcoidosis (239 +/- 27 pg/mL, P = .008) than in control subjects (127 +/- 11 pg/mL), but the plasma IFN-gamma level was significantly elevated in only pulmonary sarcoidosis (P < .001). In pulmonary sarcoidosis the IL-18 values significantly correlated with the IFN-gamma levels (r = 0.61, P < .001), but in acute asthma they did not. The IL-18 levels during acute asthma exacerbation were significantly higher (P = .01) than on remission days. In acute asthma, circulating IL-18 levels significantly correlated with serum soluble IL-2 receptor levels (r = 0.77, P < .0001) but not with serum eosinophil cationic protein levels. The IL-18 level had a tendency to inversely correlate with peak expiratory flow. The elevated IL-18 levels in acute asthma quickly decreased on day 3 (P = .02) and day 7 (P = .002) after therapy. CONCLUSION: It was suggested that IL-18 may play a potential role to activate immunologic responses and may reflect disease activity in mild and moderate asthma exacerbation.

Differential regulation of human RecQ family helicases in cell transformation and cell cycle.

Three human RecQ DNA helicases, WRN, BLM and RTS, are involved in the genetic disorders associated with genomic instability and a high incidence of cancer. RecQL1 and RecQL5 also belong to the human RecQ helicase family, but their correlation with genetic disorders, if any, is unknown. We report here that in human B cells transformed by Epstein-Barr virus (EBV), human fibroblasts and umbilical endothelial cells transformed by simian virus 40, the expression of WRN, BLM, RTS and RecQL1 was sharply up-regulated. In B cells this expression was stimulated within 5-40 h by the tumor promoting agent phorbol myristic acetate (PMA). Interestingly, RecQL5beta, an alternative splicing product of RecQL5 with a nuclear localization signal, is expressed in resting B cells without significant modulation of its synthesis by EBV or PMA, suggesting it has a role in resting cells. We also roughly determined the number of copies per cell for the five RecQ helicase in B cells. In addition, levels of the different RecQ helicases are modulated in different ways during the cell cycle of actively proliferating fibroblasts and umbilical endothelial cells. Our results support the view that the levels of WRN, BLM, RTS and RecQL1 are differentially up-regulated to guarantee genomic stability in cells that are transformed or actively proliferating.

Serum surfactant proteins A and D as prognostic factors in idiopathic pulmonary fibrosis and their relationship to disease extent.

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening, interstitial lung disease of unknown etiology. For optimal therapeutic management of IPF an accurate tool is required for discrimination between reversible and irreversible types of the disease. However, such noninvasive tools are few, and even with high-resolution computed tomography (HRCT), which is the most trusted method for doing so, the nature of the disease activity in IPF cannot always be accurately predicted. The aims of the present study were to assess the values of surfactant protein (SP)-A and SP-D in semiquantifying the extent of disease in IPF and in predicting deterioration in restrictive pulmonary function and survival over a follow-up period of 3-yr. SP-A and SP-D in sera were measured with enzyme-linked immunosorbent assays as previously described. Fifty-two IPF patients were studied to evaluate the association between serum SP-A and SP-D and disease extent on HRCT, deterioration in pulmonary function, and survival during 3 yr of follow-up. Both SP-A and SP-D concentrations were significantly correlated with the extent of alveolitis (a reversible change), whereas they did not correlate with the progression of fibrosis (an irreversible change). The SP-D concentration, unlike that of SP-A, was also related to the extent of parenchymal collapse and the rate of deterioration per year in pulmonary function. The concentrations of SP-A and SP-D in patients who died within 3 yr were significantly higher than in patients who were still alive after 3 yr. We propose that assays of SP-A and SP-D in sera from IPF patients are useful tools for understanding some pathologic characteristics of the disease, that SP-D may be a good predictive indicator of the rate of decline in pulmonary function, and that a combination of the assays for SP-A and SP-D may be helpful in predicting the outcome of patients with IPF.

Sgs1 helicase activity is required for mitotic but apparently not for meiotic functions.

The SGS1 gene of Saccharomyces cerevisiae is a homologue for the Bloom's syndrome and Werner's syndrome genes. The disruption of the SGS1 gene resulted in very poor sporulation, and the majority of the cells were arrested at the mononucleated stage. The recombination frequency measured by a return-to-growth assay was reduced considerably in sgs1 disruptants. However, double-strand break formation, which is a key event in the initiation of meiotic DNA recombination, occurred; crossover and noncrossover products were observed in the disruptants, although the amounts of these products were slightly decreased compared with those in wild-type cells. The spores produced by sgs1 disruptants showed relatively high viability. The sgs1 spo13 double disruptants sporulated poorly, like the sgs1 disruptants, but spore viability was reduced much more than with either sgs1 or spo13 single disruptants. Disruption of the RED1 or RAD17 gene partially alleviated the poor-sporulation phenotype of sgs1 disruptants, indicating that portions of the population of sgs1 disruptants are blocked by the meiotic checkpoint. The poor sporulation of sgs1 disruptants was complemented with a mutated SGS1 gene encoding a protein lacking DNA helicase activity; however, the mutated gene could suppress neither the sensitivity of sgs1 disruptants to methyl methanesulfonate and hydroxyurea nor the mitotic hyperrecombination phenotype of sgs1 disruptants.

Rothmund-thomson syndrome responsible gene, RECQL4: genomic structure and products.

RECQL4 is the fourth gene identified as a member of the human DNA helicase RecQ gene family including the genes for Werner syndrome (WRN) and Bloom syndrome, both of which are characterized by genomic instability. Recently, RECQL4 was identified as the gene responsible for some cases of Rothmund-Thomson syndrome (RTS), a rare autosomal recessive genetic disorder that shows chromosomal instability, premature aging, and a high risk of mesenchymal tumors. In this study, we show the genomic organization of the RECQL4 gene, including the exon-intron boundaries, the transcription initiation sites, and the potential promoter sequences, which facilitates further mutation analysis of the RECQL4 gene and studies to elucidate the pathogenesis behind RTS. The RECQL4 gene is in a small genome of 6.5 kb and consists of 21 exons. In the 5' upstream region, one Sp1 site and several AP 2 sites exist near the capping site, suggesting that the expression of RECQL4 is regulated by a housekeeping-type promoter similar to WRN. By comparative Northern blot analysis, we show that the RECQL4 transcripts are severely down-regulated in the cells from RTS patients, similar to our previous observation for WRN transcripts in cells from Werner patients. Immunocytochemical analysis indicated that the RECQL4 protein expressed in HeLa cells is in the nucleus and appears to be localized mainly in the nucleoplasm similar to WRN helicase.

Immunological diagnosis of Werner syndrome by down-regulated and truncated gene products.

Although immunological methods are widely used to diagnose various infectious diseases, they have rarely been employed to detect genetic diseases. In this study, we have established an immunoblot analysis system for the diagnosis of Werner syndrome (WS), a recessive genetic disorder causing premature aging and an enhanced risk of rare cancers. The method uses an immunoblot technique with specific monoclonal antibodies to WS gene product, and B-lymphoblastoid cell lines (LCLs) transformed by Epstein-Barr virus; these cell lines express an increased level of normal WS gene product DNA helicase. The method clearly distinguishes normal from patient LCLs containing any of the mutation types found so far in Japan, primarily because of the drastically reduced levels of mutated gene products, and secondarily because of the truncated product sizes. A comparison of this immunological diagnosis with the symptom-based clinical diagnosis has narrowed down the criteria of symptoms essential for WS diagnosis. This procedure is compatible with, and has some advantage over, the genetic method, because WS patients can be diagnosed without determining the mutated gene sequences. The method exemplified in WS may also be applied to detect some other genetic diseases.

Werner syndrome helicase contains a 5'-->3' exonuclease activity that digests DNA and RNA strands in DNA/DNA and RNA/DNA duplexes dependent on unwinding.

We show that WRN helicase contains a unique 5'-->3' exonuclease activity in the N-terminal region. Adeletion mutant lacking 231 N-terminal amino acid residues, made in a baculovirus system, did nothave this activity, while it showed ATPase and DNA helicase activities. This exonuclease activity was co-precipitated with the helicase activity using monoclonal antibodies specific to WRN helicase, indicating that it is an integral component with WRN helicase. The exonuclease in WRN helicase does not digest free single-stranded DNA or RNA, but it digests a strand in the duplex DNA or an RNA strand in a RNA/DNA heteroduplex in a 5'-->3' direction dependent on duplex unwinding. The digestion products were identified as 5'-mononucleotides. Our data show that WRN helicase needs a single-stranded 3' overhang region for efficient binding and unwinding of duplex molecules, while blunt-ended or 5' overhang duplex molecules were hardly unwound. These findings suggest that the WRN helicase and integral 5'-->3' exonuclease activities are involved in preventing a hyper-recombination by resolving entangled structures of DNA and RNA/DNA heteroduplexes that may be generated during rep-lication, repair and/or transcription.

Detection by epitope-defined monoclonal antibodies of Werner DNA helicases in the nucleoplasm and their upregulation by cell transformation and immortalization.

We prepared several monoclonal antibodies (mAbs) specific for the NH2- and COOH-terminal regions of the DNA helicase (WRN helicase) responsible for Werner's syndrome known as a premature aging disease. With these antibodies, we detected by immunoblot analysis the endogenous WRN helicase of a relative mass of 180 kD in several lines of cultured cells, but not in patient cells with a defined mutation. Immunocytochemical staining of proliferating fibroblasts and tumor cells showed that the major part of WRN helicase is in the nucleoplasm and not in the nucleolus. Similar experiments with a rat mAb specific to the mouse homologue of human WRN helicase yielded an identical conclusion. Although this nucleoplasmic staining was evident in cells in interphase, the condensed chromatin structure in metaphase was not stained by the same mAbs, suggesting that WRN helicases exist perhaps in a soluble form or bound to the unfolded chromatin structure. From quantitative immunoblot analysis, higher levels of WRN helicase were observed in all transformed cells and tumor cells examined than those of normal cells. The expression of WRN helicase was enhanced consistently in fibroblasts and B-lymphoblastoid cells by transformation with SV-40 and Epstein-Barr virus, respectively, suggesting that rapidly proliferating cells require a high copy numbers of WRN helicase.

[Thymic anaplastic carcinoma successfully controlled by combination chemotherapy].

Thymic carcinomas are rare tumors for which the main treatments have been surgery, radiotherapy, or both. However, the role of chemotherapy is less well-defined. Here, we report a case of advanced thymic anaplastic carcinoma which was suspected to be the primary lesion, yet was successfully controlled despite brain metastases by EACUM combination chemotherapy consisting of cyclophosphamide, adriamycin, cisplatin, 5-FU, and methtrexate. Pathohistological findings on metastatic lesions of the right supracuravicular lymph nodes led to a diagnosis of anaplastic carcinoma. We could not give a diagnosis of thymic carcinoma because the biopsy specimen had not been taken from the thymus. There was no evidence of a primary neoplastic tumor other than thymoma. The patient was still alive 6 years and 9 months after the start of anticancer treatment and was working normally. The findings from this case should be of value to the establishment of effective combination chemotherapy regimens for advanced thymic carcinoma.

Suppressive effects of 4-acetylaminophenylacetic acid (actarit) on experimental autoimmune encephalomyelitis in rats.

To elucidate the efficacy of 4-acetylaminophenylacetic acid (actarit), an anti-rheumatic drug, on neuroinflammatory diseases such as multiple sclerosis, the effects of actarit on both actively induced and adoptively transferred experimental autoimmune encephalomyelitis (EAE) were studied. Daily intraperitoneal administration of actarit during the effector phase of active EAE and transferred EAE suppressed the clinical manifestation and pathological findings of EAE at doses of 300 mg/kg or higher. The percentages of CD4 and CD25 positive cells in the infiltrating cells in the CNS were reduced by this treatment. Semi-quantitative cytokine analysis revealed that the mRNA expression of TNF-alpha and INF-gamma in spinal cords and spleens of actarit treated active EAE rats was significantly reduced compared with vehicle treated EAE rats. The mRNA expression of IL-10 on day 17 in spleens of actarit-treated EAE rats was significantly upregulated. Actarit is potentially useful for the treatment of neuroimmunological disorders, such as multiple sclerosis.

Expression of HGF and cMet in the developing and adult brain.

Hepatocyte growth factor (HGF) was recently recognized as a potential neurotrophic factor in the developing brain. We studied expression of HGF and its receptor using Northern blot analysis and in situ hybridization for mRNA and double immunofluorescent laser confocal microscopy. HGF and cMet messages were abundant in the hippocampus of both human and rat brains. In this region, both messages were localized in the neuronal layer. Segregation of HGF predominantly in the hippocampal CA3-4 and cMet in CA1 supports the hypothesis that HGF may mediate important neurotrophic functions in both developing and adult brains.

Chorea-acanthocytosis with polyclonal antibodies to ganglioside GM1.

A patient with chorea-acanthocytosis presenting with axonal neuropathy showed an elevation in IgM polyclonal antibodies to the GM1 ganglioside, which were estimated by enzyme-linked immunosorbent assay and complement-mediated liposome immune lysis assay (LILA). This is the first demonstration of such antibodies in chorea-acanthocytosis. Anti-GM1 antibodies might have directly caused the axonal neuropathy by binding to GM1 or cross-reactive antigens in the nerves.

Keratinocyte growth factor and embryonic rat lung morphogenesis.

We examined possible roles of keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) in lung morphogenesis. By polymerase chain reaction, transcripts for both KGF and its receptor were detected early (rat gestational days 16 and 14, respectively) and their abundance increased during lung morphogenesis. To evaluate possible role of KGF in lung morphogenesis, day 14 lung explants were cultured in Dulbecco's modified Eagle medium + 10% fetal calf serum for 1 to 4 days in the presence (5-50 ng/ml) or absence of KGF (control). KGF (at 25 and 50 ng/ml) induced a marked reduction in the number of terminal branches and destination of the distal epithelium into cyst-like structures. These effects of exogenous KGF were progressively diminished by increasing concentrations of anti-KGF (2-16 micrograms/ml). Electron microscopic examination revealed that the epithelial cells of the cystic structures contained lamellar bodies, and were therefore type II cells and/or their progenitors. Northern blot analysis showed higher expression of surfactant protein C (SP-C) mRNA (a marker for alveolar epithelial type II cells) in KGF-treated fetal lungs. In situ hybridization of the KGF-treated lungs revealed that the SP-C mRNA-expressing cells were arranged distally in the form of linear arrays, a pattern distinctly different from that in control lungs. Acidic fibroblast growth factor, which also binds KGF receptors, in the presence of heparin mimicked the effect of KGF on branching. Transforming growth factor-beta(1) (TGF-beta 1) inhibited branching of fetal lungs in culture, and this effect dominated over that induced by KGF. Blocking of endogenous HGF with antibodies or addition of HGF to cultures of fetal lung explants had no significant effect on branching or growth. In conclusion, KGF markedly influences branching, and epithelial growth, differentiation, and patterning during lung morphogenesis.

Intrathecal administration of antibodies against LFA-1 and against ICAM-1 suppresses experimental allergic encephalomyelitis in rats.

The effects of intracerebroventricular administration of mAbs against LFA-1 and ICAM-1 on both active and passive experimental allergic encephalomyelitis (EAE) in rats were examined. Lewis rats were immunized with guinea pig myelin basic protein (MBP) or MBP 68-86 peptide in complete Freund's adjuvant to induce active EAE, or they were injected with encephalitogenic MBP-reactive lymphocytes for adoptive transferred EAE. LFA-1-specific mAbs and/or ICAM-1-specific mAbs or a control mAb or PBS were injected into the lateral ventricles via implanted needles. Intracerebroventricular administration of the specific mAbs together on Days 0, 2, 4, and 6 or on Days 4, 6, 8, and 10 after immunization almost completely suppressed the clinical signs of the actively induced EAE with reduced numbers of the infiltrating cells and reduced percentages of W3/25(+) and IA-29(+) cells in the central nervous system (CNS) of the rats. Pretreatment with both specific mAbs from 14 to 11 days prior to immunization also exhibited a considerable protective effect. However, daily injection from Day 10 to 13 after immunization did not suppress the clinical signs. In rats with adoptive transferred EAE, daily treatment from Day 0 to Day 4 after cell transfer completely abolished clinical signs of EAE, although comparison of histological findings was not remarkable. In conclusion, intrathecal administration of antibodies against LFA-1 and ICAM-1 may be useful for the treatment of human demyelinating diseases, such as multiple sclerosis.

[Long-term maintenance therapy of multifocal motor neuropathy by weekly administration of human immunoglobulin].

High-dose intravenous immunoglobulin therapy for multifocal motor neuropathy (MMN) exhibits a beneficial, but temporary effect in most cases. We experienced a patient with MMN having a high titer of anti-GM1 ganglioside antibody. He was weekly administered human immunoglobulin, and his muscle strength was successfully improved and maintained at the improved level after high-dose human immunoglobulin infusion. The pattern of improvement and maintenance by weekly administration of human immunoglobulin was variable among the muscles; e.g. only a minimal improvement was observed in the most severely involved brachioradial muscles. Successive measurements with a hand-held dynamometer revealed in detail the changes in the strength of each muscle during treatment. Anti-GM1 ganglioside antibody titers did not significantly change during the treatment, but a slight improvement in motor conduction amplitudes and velocities was observed in mildly affected nerves. Our findings suggest that weekly administration of human immunoglobulin is a safe and effective therapy for MMN and that the anti-GM1 ganglioside antibody titer may not be a good indicator for this therapy.