Differences in quantitative EEG between frontotemporal dementia and Alzheimer's disease as revealed by LORETA.

OBJECTIVE: To determine the electrophysiological characteristics of frontotemporal dementia (FTD) and the distinction with Alzheimer's disease (AD). METHODS: We performed analyses of global field power (GFP) which is a measure of whole brain electric field strength, and EEG neuroimaging analyses with sLORETA (standardized low resolution electromagnetic tomography), in the mild stages of FTD (n = 19; mean age = 68.11 ± 7.77) and AD (n = 19; mean age = 69.42 ± 9.57) patients, and normal control (NC) subjects (n = 22; mean age = 66.13 ± 6.02). RESULTS: In the GFP analysis, significant group effects were observed in the delta (1.5-6.0 Hz), alpha1 (8.5-10.0 Hz), and beta1 (12.5-18.0 Hz) bands. In sLORETA analysis, differences in activity were observed in the alpha1 band (NC > FTD) in the orbital frontal and temporal lobe, in the delta band (AD>NC) in widespread areas including the frontal lobe, and in the beta1 band (FTD > AD) in the parietal lobe and sensorimotor area. CONCLUSIONS: Differential patterns of brain regions and EEG frequency bands were observed between the FTD and AD groups in terms of pathological activity. SIGNIFICANCE: FTD and AD patients in the early stages displayed different patterns in the cortical localization of oscillatory activity across different frequency bands.

Clinical associations with autoantibody reactivities to individual components of U1 small nuclear ribonucleoprotein.

The reactivities to individual U1 small nuclear ribonucleoprotein (snRNP) components and their relationship to clinical features in patients with anti-U1 snRNP antibodies were examined. We evaluated 114 patients with connective tissue disease whose sera were positive for anti-U1 snRNP antibodies, but negative for anti-Sm antibodies. Antibodies to the U1 snRNP polypeptides 70K, A, and C were detected using subunit-specific enzyme-linked immunosorbent assays and antibodies to U1 small nuclear RNA (snRNA) were identified by an immunoprecipitation assay using deproteinized HeLa cell extracts. The clinical features were retrospectively obtained by chart review and prospectively collected after study entry. The pattern of antibody reactivities to U1 snRNP components varied among patients. The frequency of anti-70K, anti-A, anti-C, and anti-U1 snRNA antibodies was 60%, 86%, 74%, and 46%, respectively. There was no relationship between each reactivity and the clinical findings, but the presence of reactivities to increasing numbers of U1 snRNP components was correlated with sclerodactyly, shortness of the sublingual frenulum, esophageal dysfunction, and a lack of persistent proteinurea (p < 0.05 for all comparisons). The detection of autoantibody reactivities to individual components of the U1 snRNP particle is potentially useful for predicting the clinical course in patients with connective tissue disease and anti-U1 snRNP antibodies.

Discovery and functional characterization of a novel small molecule inhibitor of the intracellular phosphatase, SHIP2.

BACKGROUND AND PURPOSE: The lipid phosphatase known as SH2 domain-containing inositol 5'-phosphatase 2 (SHIP2) plays an important role in the regulation of the intracellular insulin signalling pathway. Recent studies have suggested that inhibition of SHIP2 could produce significant benefits in treatment of type 2 diabetes. However, there were no small molecule SHIP2 inhibitors and we, therefore, aimed to identify this type of compound. EXPERIMENTAL APPROACH: The phosphatase assay with malachite green was used for high-throughput screening. The pharmacological profiles of suitable compounds were further characterized in phosphatase assays, cellular assays and oral administration in normal and diabetic (db/db) mice. KEY RESULTS: During high-throughput screening, AS1949490 was identified as a potent SHIP2 inhibitor (IC(50)= 0.62 microM for SHIP2). This compound was also selective for SHIP2 relative to other intracellular phosphatases. In L6 myotubes, AS1949490 increased the phosphorylation of Akt, glucose consumption and glucose uptake. In FAO hepatocytes, AS1949490 suppressed gluconeogenesis. Acute administration of AS1949490 inhibited the expression of gluconeogenic genes in the livers of normal mice. Chronic treatment of diabetic db/db mice with AS1949490 significantly lowered the plasma glucose level and improved glucose intolerance. These in vivo effects were based in part on the activation of intracellular insulin signalling pathways in the liver. CONCLUSIONS AND IMPLICATIONS: This is the first report of a small molecule inhibitor of SHIP2. This compound will help to elucidate the physiological functions of SHIP2 and its involvement in various diseases, such as type 2 diabetes.

Successful treatment of refractory polymyositis with the immunosuppressant mizoribine: case report.

We describe a patient who presented with polymyositis with anti-Jo-1 antibodies at 18 years after the onset of rheumatoid arthritis and was successfully treated with the immunosuppressive drug mizoribine at the time of exacerbation. She had developed diabetes mellitus, cerebral infarction, and myocardial infarction after high-dose steroid therapy was initiated. Therefore, an immunosuppressant was preferred as the second-line agent. Treatment with 150 mg/day of mizoribine and 8 mg/day of prednisolone resulted in eventual normalization of muscle enzyme levels. Mizoribine is a purine antimetabolite that inhibits T cell activation/proliferation and B cell proliferation. The potential efficacy of mizoribine for polymyositis was suggested by this case.

Clinical characteristics of Japanese patients with anti-PL-7 (anti-threonyl-tRNA synthetase) autoantibodies.

OBJECTIVE: The clinical and laboratory features of seven Japanese patients with anti-aminoacyl-tRNA synthetase (ARS) autoantibodies against PL-7 (anti-threonyl-tRNA synthetase) were analyzed and compared with previously published findings. METHODS: Serum samples from 1,135 Japanese patients with various autoimmune diseases were screened for anti-PL-7 antibodies using RNA and protein immunoprecipitation assays. The patients whose sera contained anti-PL-7 antibodies were assessed regarding clinical symptoms and clinical course. RESULTS: Sera from seven patients were found to have anti-PL-7 antibodies. These autoantibodies were associated with polymyositis/dermatomyositis (PM/DM) and/or interstitial lung disease (ILD). The clinical diagnoses of these seven patients were PM - systemic sclerosis (SSc) overlap (5 patients), DM (1 patient) and idiopathic pulmonary fibrosis (IPF) (1 patient). All patients had ILD with a chronic course and six also had arthritis (85%) and five sclerodactyly (71%). CONCLUSIONS: These results indicate that anti-PL-7 autoantibodies are closely associated with PM-SSc overlap as well as ILD, arthritis and sclerodactyly in our series of Japanese patients.

Successful treatment of recurrent intracardiac thrombus in Behçet's disease with immunosuppressive therapy.

Behçet's disease (BD) is a chronic multisystem inflammatory disorder characterized by recurrent oral and genital ulcers, skin eruptions and uveitis. Neurological, gastrointestinal, and musculoskeletal systems are also involved. Although venous and arterial vasculitis occur in up to one-third of patients, intracardiac thrombus is a very rare complication. We herein report the case of a 46-year-old man with BD who presented with a large right atrial thrombus. Within a month after surgical removal, the thrombus recurred and was successfully treated with immunosuppressants that included prednisolone and cyclophosphamide.

Glucose catabolic gene mRNA levels in skeletal muscle exhibit non-coordinate expression in hyperglycemic mice.

To assess the correlation between hyperglycemia and glucose catabolic gene levels in diabetic and healthy mice, we determined mRNA levels of pivotal proteins such as glucose transporters, hexokinase II, glycogen synthase, glutamine:fructose-6-phosphate amidotransferase and uncoupling proteins. Both KK and KKAy mice showed marked decreases of Glut1 and Glut4 mRNA levels in soleus compared to C57BL; db/db and ob/ob mice exhibited significantly decreased Glut4 mRNA levels, but not Glut1, in soleus. KK and KKAy mice showed a decrease of soleus HKII gene level, which may indicate decreased intracellular catabolism of glucose. Likewise, GS mRNA level was decreased in soleus muscle tissue in KK and KKAy mice. GFAT mRNA levels was no different between hyperglycemic and normoglycemic mice. In contrast, UCP2 and UCP3 mRNA levels were higher in KK and KKAy mice. Conversely, db/db and ob/ob mice showed a significant decrease in UCP3 mRNA. Individual correlation analysis indicated that the decrease in Glut4 gene levels was only observed in hyperglycemic mice. The more important observation is that the glucose catabolic genes do not exhibit any clear coordinate expression. Abnormal expression of glucose catabolic genes may contribute to hyperglycemia and muscle insulin resistance in these four strains.

Autoantibodies from primary biliary cirrhosis patients with anti-p95c antibodies bind to recombinant p97/VCP and inhibit in vitro nuclear envelope assembly.

We have reported previously that p95c, a novel 95-kDa cytosolic protein, was the target of autoantibodies in sera of patients with autoimmune hepatic diseases. We studied 30 sera that were shown previously to immunoprecipitate a 95 kDa protein from [(35)S]-methionine-labelled HeLa lysates and had a specific precipitin band in immunodiffusion. Thirteen sera were available to test the ability of p95c antibodies to inhibit nuclear envelope assembly in an in vitro assay in which confocal fluorescence microscopy was also used to identify the stages at which nuclear assembly was inhibited. The percentage inhibition of nuclear envelope assembly of the 13 sera ranged from 7% to 99% and nuclear envelope assembly and the swelling of nucleus was inhibited at several stages. The percentage inhibition of nuclear assembly was correlated with the titre of anti-p95c as determined by immunodiffusion. To confirm the identity of this autoantigen, we used a full-length cDNA of the p97/valosin-containing protein (VCP) to produce a radiolabelled recombinant protein that was then used in an immunoprecipitation (IP) assay. Our study demonstrated that 12 of the 13 (93%) human sera with antibodies to p95c immunoprecipitated recombinant p97/VCP. Because p95c and p97 have similar molecular masses and cell localization, and because the majority of sera bind recombinant p97/VCP and anti-p95c antibodies inhibit nuclear assembly, this is compelling evidence that p95c and p97/VCP are identical.

A case of systemic lupus erythematosus presenting with rectal ulcers as the initial clinical manifestation of disease.

Gastrointestinal involvement is often seen in patients with systemic lupus erythematosus (SLE). All parts of the gastrointestinal tract may be affected. However, rectal involvement at onset is rare. We describe here a case of SLE in which rectal ulcers due to vasculitis occurred as the initial manifestation of the disease without involvement of any other organ. The ulcers worsened, along with the appearance of lupus nephritis 5 years later When steroid therapy was initiated, there was rapid clinical and radiographic improvement. Our case suggests that rectal ulcer is a rare but important complication of SLE and can represent the initial and sole clinical manifestation of the disease.

Cytokine and immunogenetic profiles in Japanese patients with adult Still's disease. Association with chronic articular disease.

OBJECTIVE: To determine cytokines and MHC class II alleles in Japanese patients with adult Still's disease (ASD) and clarify the association between those profiles and chronic articular disease. METHODS: Of 35 patients with ASD (13 men, 22 women, mean age at onset 34.0 yr), 17 (49%) had chronic arthritis (>6 months, chronic articular ASD) and 18 (51%) lacked chronic arthritis (systemic ASD). Cytokines and cytokine receptors in sera were measured by ELISA. Correlations of each cytokine with disease activity or C-reactive protein (CRP) were determined. MHC class II alleles were examined by polymerase chain reaction methods. RESULTS: In chronic articular ASD, female gender was more frequent and liver dysfunction and myalgia were rarer than in systemic ASD. In active disease, the white blood cell count was lower, but total IgG was greater in patients with chronic articular ASD than in those with systemic ASD. Tumour necrosis factor (TNF) alpha, soluble TNF receptor 2 and interleukin (IL)-18 were increased in both types of ASD, even in remission. Soluble IL-2 receptors, IL-4 and IL-18 levels were correlated with disease activity or CRP value only in chronic articular ASD. Interferon gamma and IL-8 remained increased only in chronic articular ASD, even when disease activity, including IL-6 and CRP, was low. DRB1*1501 (DR2) and DRB1*1201 (DR5) alleles were more frequent in chronic articular than in systemic ASD, whereas DQB1*0602 (DQ1) was frequently observed in both types of ASD. CONCLUSION: The present study suggests that ASD with chronic articular disease has distinct clinical, cytokine and immunogenetic profiles.

Hematopoietic stem cell transplantation for the treatment of autoimmune diseases.

Abstract Systemic autoimmune diseases that are resistant to conventional treatment cause considerable morbidity and mortality. Although aggressive new approaches to treating autoimmune diseases have been developed over the past decade, there are still patients with a severe, progressive, and life-threatening course. Based on animal studies and experience in the treatment of hematological disorders with preexisting autoimmune disease, hematopoietic stem cell transplantation has been proposed for the treatment of severe autoimmune diseases. Immunoablation and subsequent autologous peripheral blood stem cell transplantation using CD34(+) hematopoietic cells with T cell depletion have been used for selected severe autoimmune diseases at many institutes in Australia, Europe, and the United States. However, it is necessary to assess the efficacy and safety of this therapy compared with conventional and other newly emerging therapies.

[Hypersensitivity peumonitis in a patient with rheumatoid arthritis].

We report a case with rheumatoid arthritis and hypersensitivity pneumonitis. A 66-year-old female was admitted to our hospital because of fever, cough, and progressive dyspnea on October 10, 1997. She had a history of rheumatoid arthritis from 1987 and was treated with cyclophosphamide when she developed pulmonary symptoms in September 1997. On admission arthritis was subsided. Fine crackles on ausculation of lung, hypoxia, ground-glass appearance on chest X-ray were detected. The computed tomography of the chest disclosed diffuse interstitial shadow with patchy destruction of alveolar structures. Bronchoalveolar lavage demonstrated an increase in lymphocytes with predominance of suppressor-cytotoxic T cell subset (CD 8+). The histopathological examination of transbronchial lung biopsy showed interstitial inflammation with marked predominance of lymphocyte with intraalveolar exudate. Her condition got better and she discharged without definitive diagnosis and treatment for her respiratory symptoms. Eight hours after she went back home, she suddenly presented high fever and cough and gradually developed dyspnea. She was readmitted 5 days after the previous discharge. Although no specific precipitin antibody against various microorganisms was detected in her sera, the diagnosis of hypersensitivity pneumonitis was made. Thirty mg per day of prednisolone was resolved her symptoms promptly. There was no reported case with hypersensitivity pneumonitis and rheumatoid arthritis of other collagen diseases. The clinical course that arthritis and pulmonary symptoms appeared alternatively is of considerable interest to investigate for the pathogenesis of these two immune disorders.

A case of polymyositis associated with hepatitis B infection.

This report describes the case of a 47-year old man who developed myositis in association with hepatitis B surface antigen-positive hepatitis. Interestingly, the myositis repeatedly worsened 2 months after the exacerbation of hepatitis in this case, suggesting a close association between hepatitis B infection and myositis. The dose of prednisolone was increased twice in order to treat the exacerbating myositis, resulting in improvement of the muscle symptoms, but the patient eventually died of liver failure. Only 5 other myositis patients with hepatitis B antigenemia have been reported in the literature. We review these cases of the association between hepatitis B infection and myositis.

Vinexin forms a signaling complex with Sos and modulates epidermal growth factor-induced c-Jun N-terminal kinase/stress-activated protein kinase activities.

Vinexin, a novel protein that plays a key role in cell spreading and cytoskeletal organization, contains three SH3 domains and binds to vinculin through its first and second SH3 domains. We show here that the third SH3 domain binds to Sos, a guanine nucleotide exchange factor for Ras and Rac, both in vitro and in vivo. Point mutations in the third SH3 domain abolished the vinexin-Sos interaction. Stimulation of NIH/3T3 cells with serum, epidermal growth factor (EGF), or platelet-derived growth factor (PDGF) decreased the electrophoretic mobility of Sos and concomitantly inhibited formation of the vinexin-Sos complex. Phosphatase treatment of lysates restored the binding of Sos to vinexin, suggesting that signaling from serum, EGF, or PDGF regulates the vinexin-Sos complex through the Sos phosphorylation. To evaluate the function of vinexin downstream of growth factors, we examined the effects of wild-type and mutant vinexin expression on extracellular signal-regulated kinase (Erk) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activation in response to EGF. Exogenous expression of vinexin beta in NIH/3T3 cells enhanced JNK/SAPK activation but did not affect Erk activation. Moreover mutations in the third SH3 domain abolished EGF activation of JNK/SAPK in a dominant-negative fashion, whereas they slightly stimulated Erk. Together these results suggest that vinexin can selectively modulate EGF-induced signal transduction pathways leading to JNK/SAPK kinase activation.

Human RNA helicase A is a lupus autoantigen that is cleaved during apoptosis.

Proteolytic cleavage by caspases is the central event in cells undergoing apoptosis. Cleaved proteins are often targeted by autoantibodies, suggesting that the cleavage of self Ags enhances immunogenicity and is prone to induce an autoimmune response. We found autoantibodies that immunoprecipitated a 140-kDa RNA-associated protein, provisionally designated Pa, in 11 of 350 patient sera that were positive for antinuclear Abs in an immunofluorescence test. The Pa protein gave rise to three fragments with m.w. ranging from 120-130 kDa during anti-Fas-activated apoptosis. Pure caspase-3 cleaved the Pa protein into a 130-kDa fragment corresponding to the largest of these three products. Peptide sequence analysis of a tryptic digest from immunoaffinity-purified Pa showed 100% identity to human RNA helicase A (RHA). The identity of Pa with RHA was further confirmed by immunoblotting with rabbit anti-RHA Ab using anti-Pa immunoprecipitates as substrates. All 10 anti-RHA-positive patients who were clinically analyzed were diagnosed as having systemic lupus erythematosus, and 7 of them had lupus nephritis. RHA is a multifunctional protein with roles in cellular RNA synthesis and processing. Inactivation of RHA by cleavage may be an important part of the process leading to programmed cell death. The cleaved RHA fragments that are produced during apoptosis may trigger an autoimmune response in systemic lupus erythematosus.