Associations of fat mass index with hot flashes and lean mass index with insomnia in middle-aged women.

OBJECTIVE: This cross-sectional study examined the relationship between body composition and physical and mental symptom severity in middle-aged women. METHODS: The first-visit records of 554 women aged 40-64 years were examined. The fat mass index (FMI) and lean mass index (LMI) were defined as fat mass and lean mass divided by the height squared, respectively. The participants were divided into two groups according to their median values. RESULTS: The only menopausal symptom with significantly different severity between the high and low FMI groups was hot flashes (HF) on the Menopausal Health-Related Quality of Life Questionnaire. The factors associated with severe HF were investigated using multiple logistic regression analysis. After adjusting, the FMI (kg/m2) was independently positively associated with severe HF (odds ratio, 1.08; 95% confidence interval, 1.02-1.15). Insomnia was the only menopausal symptom with significantly different severity between the LMI groups (defined as Athens Insomnia Scale score ≥10 points). The factors associated with moderate-to-severe insomnia were investigated using multiple logistic regression analysis. After adjusting, the LMI (kg/m2) was independently negatively associated with moderate-to-severe insomnia (odds ratio, 0.72; 95% confidence interval, 0.55-0.94). CONCLUSIONS: The FMI was positively associated with severe HF, whereas the LMI was negatively associated with moderate-to-severe insomnia in middle-aged women.

Chilliness in Japanese middle-aged women is associated with anxiety and low n-3 fatty acid intake.

Objective: This cross-sectional study investigated chilliness, which is the most prevalent sexual-vasomotor symptom in middle-aged Japanese women.Methods: First-visit records of 475 Japanese women (age 40-65 years) enrolled in the health and nutrition education program at a menopause clinic were analyzed. Chilliness was estimated based on responses to the Menopausal Symptom Scale. Effects of age, menopausal status, body composition, cardiovascular parameters, resting energy expenditure, physical fitness, menopausal symptoms, lifestyle, and estimated daily intake of nutrients were assessed using a multivariate logistic regression analysis.Results: Severe chilliness was found in 28.4% of women. It was not related to age, menopausal status, body mass index, or body fat percentage. The anxiety subscale score of the Hospital Anxiety and Depression Scale was the sole background characteristic independently associated with severe chilliness (adjusted odds ratio, 1.09; 95% confidence interval, 1.04-1.15 per point). Daily intakes of vitamin D and n-3 fatty acids were significantly lower in women with severe chilliness. Daily intake of n-3 fatty acids was negatively associated with severe chilliness after adjustment (odds ratio, 0.54; 95% confidence interval, 0.29-0.95 per g/1000 kcal intake).Conclusions: Chilliness is associated with anxiety and low intake of n-3 fatty acids.

Severity of hot flushes is inversely associated with dietary intake of vitamin B6 and oily fish.

Objectives: This study investigated the links between the severity of vasomotor symptoms (VMS) and the dietary consumption of a variety of nutrients. Method: A cross-sectional analysis of the first-visit records of 262 women aged 40-65 years was conducted. The severity of their hot flushes (HF) and night sweats (NS) and their dietary consumption of nutrients were evaluated using the Menopausal Health-Related Quality of Life Questionnaire and the brief-type self-administered Diet History Questionnaire, respectively. The relationships between severity of HF/NS and dietary intake were analyzed separately for 43 major nutrients. We then evaluated different food items as sources of the nutrients. Results: After adjustment for age, body mass index, menopausal status, and background factors significantly related to VMS, only vitamin B6 (VB6) was significantly related to severity of HF (adjusted odds ratio per 10 µg/MJ in VB6 intake, 0.92; 95% confidence interval, 0.86-0.97). Moreover, a significant inverse relationship was found between the consumption of oily fish as a source of VB6 and the severity of HF. Conclusions: VB6 and oily fish intake is inversely associated with the severity of HF in middle-aged women. Therefore, increased intake of VB6 could help attenuate HF.

Feelings of unattractiveness in peri- and postmenopausal women are associated with depressed mood, poor memory and unsatisfactory sexual relationships.

OBJECTIVES: This study aimed to investigate the prevalence of, and risk factors associated with, the feeling of unattractiveness in peri- and postmenopausal women. METHODS: The records of 351 women aged 40-76 who enrolled in a health and nutrition education program at a menopause clinic were analyzed in a cross-sectional manner. Perceptions of unattractiveness were estimated according to responses for the item 'feeling less attractive than before' on the Menopausal Health-Related Quality of Life Questionnaire. Age, menopausal status, body composition, cardiovascular parameters, physical fitness, and genitourinary, physical, and psychological symptoms of menopause were assessed for associations with feeling unattractive. RESULTS: The percentage of women who felt they were less attractive than before for more than half of the previous week was 33.6%. Multivariate logistic regression analysis revealed that independent risk factors for feeling unattractive included depression (adjusted odds ratio (OR) 1.35; 95% confidence interval (CI) 1.24-1.47), dissatisfaction with sexual relationship (adjusted OR 1.74; 95% CI 1.21-2.57), and poor memory (adjusted OR 1.89; 95% CI 1.46-2.49). CONCLUSIONS: Feelings of unattractiveness are highly prevalent in peri- and postmenopausal women. Such feelings are associated with depressed moods, poor memory, and unsatisfactory sexual relationships, rather than with age or body composition.

Association of IRF5 polymorphism with MPO-ANCA-positive vasculitis in a Japanese population.

Interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) are shared susceptibility genes for various autoimmune diseases. In this study, we investigated whether these genes also contribute to susceptibility to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a Japanese population. A case-control study was carried out on IRF5 rs10954213 and STAT4 rs7574865 in 232 Japanese myeloperoxidase (MPO)-ANCA-positive AAV patients, including 177 microscopic polyangiitis and 710 healthy controls. IRF5 rs10954213G was significantly increased in MPO-ANCA-positive AAV (additive model, P=0.023, odds ratio=1.27, 95% confidence interval=1.03-1.57). The risk allele was previously shown to be associated with lower mRNA level of IRF5. On the other hand, significant association of STAT4 rs7574865T with AAV was not detected. These observations suggested that IRF5 may contribute to susceptibility to MPO-ANCA-positive AAV in a Japanese population.

Systemic lupus erythematosus with cytophagic histiocytic panniculitis successfully treated with high-dose glucocorticoids and cyclosporine A.

A 37-year-old male with systemic lupus erythematosus (SLE) presented with high fever, subcutaneous indurations, anemia, thrombocytopenia, elevated liver enzymes and hyperferritinemia. Skin biopsy revealed hemophagocytic histiocytes in the adipose tissues. The patient was diagnosed with SLE with cytophagic histiocytic panniculitis (CHP). Treatment with high-dose glucocorticoids and cyclosporine A induced remission of SLE and CHP. CHP is generally a systemic disorder affecting subcutaneous adipose tissues with a high mortality rate. However, based on the present and previously reported cases, we believe that intensive immunosuppression can ameliorate CHP that occurs as a skin manifestation of SLE.

Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis.

Synovial tissue affected by rheumatoid arthritis is characterized by proliferation, which leads to irreversible cartilage and bone destruction. Current and experimental treatments have been aimed mainly at correcting the underlying immune abnormalities, but these treatments often prove ineffective in preventing the invasive destruction. We studied the expression of cyclin-dependent kinase inhibitors in rheumatoid synovial cells as a means of suppressing synovial cell proliferation. Synovial cells derived from hypertrophic synovial tissue readily expressed p16INK4a when they were growth-inhibited. This was not seen in other fibroblasts, including those derived from normal and osteoarthritis-affected synovial tissues. In vivo adenoviral gene therapy with the p16INK4a gene efficiently inhibited the pathology in an animal model of rheumatoid arthritis. Thus, the induction of p16INK4a may provide a new approach to the effective treatment of rheumatoid arthritis.

Beta 1 integrin-mediated interaction with extracellular matrix proteins regulates cytokine gene expression in synovial fluid cells of rheumatoid arthritis patients.

Inflammatory cytokines have been implicated in the pathogenesis of rheumatoid arthritis (RA), whereas the mechanisms for constitutive production of inflammatory cytokines in affected joints are largely unknown. Recently, integrin-mediated interaction with extracellular matrix (ECM) proteins has been demonstrated to play a role in regulating cytokine production in T cells and monocytes. In this study, we investigated the contribution of the beta 1 integrin-mediated interaction with ECM proteins to the persistent cytokine gene expression in RA synovial fluid mononuclear cells (SFMNC). We examined mRNA expression of 14 cytokines in the SFMNC of three RA patients, which were either fresh or cultured overnight in serum-free medium on ECM-coated plates, by polymerase chain reaction with a panel of oligonucleotide primers specific for each cytokine. The persistent expression of various cytokine mRNA found in fresh SFMNC was maintained after overnight culture in serum-free medium on ECM proteins, especially on laminin (LM), but not on serum albumin. This effect of LM was inhibited by an anti-integrin beta 1 chain (CD29) mAb, as well as by an anti-CD3 mAb, indicating an important role of the beta 1 integrin-mediated interaction with ECM proteins in regulating persistent cytokine gene expression in RA SFMNC, and a key role of T cells in regulating inflammatory monokine production.

Disruption of the Bcl6 gene results in an impaired germinal center formation.

The Bcl6 gene has been identified from the chromosomal translocation breakpoint in B cell lymphomas, and its products are expressed highly in germinal center (GC) B cells. To investigate the function of Bcl6 in lymphocytes, we have generated RAG1-deficient mice reconstituted with bone marrow cells from Bcl6-deficient mice (Bcl6(-/-)RM). Lymphogenesis in primary lymphoid tissues of Bcl6(-/-)RM is normal, and Bcl6(-/-)RM produced control levels of primary IgG1 antibodies specific to T cell-dependent antigens. However, GCs were not found in these mice. This defect was mainly due to the abnormalities of B cells. Therefore, Bcl6 is essential for the differentiation of GC B cells.

Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study.

BACKGROUND: Tumour necrosis factor (TNF) inhibitors enable tight control of disease activity in patients with rheumatoid arthritis (RA). Discontinuation of TNF inhibitors after acquisition of low disease activity (LDA) is important for safety and economic reasons. OBJECTIVE: To determine whether infliximab might be discontinued after achievement of LDA in patients with RA and to evaluate progression of articular destruction during the discontinuation. METHODS: 114 patients with RA who had received infliximab treatment, and whose Disease Activity Score, including a 28-joint count (DAS28) was <3.2 (LDA) for 24 weeks, were studied. RESULTS: The mean disease duration of the 114 patients was 5.9 years, mean DAS28 5.5 and mean modified total Sharp score (mTSS) 63.3. After maintaining LDA for >24 weeks by infliximab treatment, the drug was discontinued and DAS28 in 102 patients was evaluated at year 1. Fifty-six patients (55%) continued to have DAS28<3.2 and 43% reached DAS<2.6 at 1 year after discontinuing infliximab. For 46 patients remission induction by Remicade in RA (RRR) failed: disease in 29 patients flared within 1 year and DAS28 was >3.2 at year 1 in 17 patients. Yearly progression of mTSS (DeltaTSS) remained <0.5 in 67% and 44% of the RRR-achieved and RRR-failed groups, respectively. The estimated DeltamTSS was 0.3 and 1.6 and Health Assessment Questionnaire-Disability Index was 0.174 and 0.614 in the RRR-achieved and RRR-failed groups, respectively, 1 year after the discontinuation. CONCLUSION: After attaining LDA by infliximab, 56 (55%) of the 102 patients with RA were able to discontinue infliximab for >1 year without progression of radiological articular destruction.

Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study.

OBJECTIVES: To evaluate the safety and efficacy of 5-year, long-term tocilizumab monotherapy for patients with rheumatoid arthritis. METHODS: In an open-label, long-term extension trial following an initial 3-month randomised phase II trial, 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy (8 mg/kg) every 4 weeks. Concomitant therapy with non-steroidal anti-inflammatory drugs and/or oral prednisolone (10 mg daily maximum) was permitted. All patients were evaluated with American College of Rheumatology (ACR) improvement criteria, disease activity score (DAS) in 28 joints, and the European League Against Rheumatism response, as well as for safety issues. RESULTS: 143 patients were enrolled in the open-label, long-term extension trial and 94 (66%) patients had completed 5 years as of March 2007. 32 patients (22%) withdrew from the study due to adverse events and one patient (0.7%) due to unsatisfactory response. 14 patients withdrew because of the patient's request or other reasons. The serious adverse event rate was 27.5 events per 100 patient-years, with 5.7 serious infections per 100 patient-years, based on a total tocilizumab exposure of 612 patient-years. Of the 88 patients receiving corticosteroids at baseline, 78 (88.6%) were able to decrease their corticosteroid dose and 28 (31.8%) discontinued corticosteroids. At 5 years, 79/94 (84.0%), 65/94 (69.1%) and 41/94 (43.6%) of the patients achieved ACR20, ACR50, and ACR70 improvement criteria, respectively. Remission defined as DAS28 less than 2.6 was achieved in 52/94 (55.3%) of the patients. CONCLUSION: In this 5-year extension study, tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile.

A case of polyarteritis nodosa with periurethralaseptic abscesses and testicular lesions.

We describe a 54-year-old man presenting with cutaneous ulcerations, livedo reticularis, numbness of the legs, and skin histological findings compatible with the diagnosis of polyarteritis nodosa (PAN). Initial treatment with 50 mg/day of prednisolone (PSL) was effective. However, the symptoms and signs recurred, and the patient developed multiple periurethral aseptic abscesses, urethra-cutaneous fistula, and testicular lesions after tapering of PSL therapy. The condition improved with PSL and cyclophosphamide administration. Since penile and testicular vasculitis could be associated with PAN, although rarely, we should carefully distinguish such an involvement from infection and malignancy.

Decreased autologous mixed lymphocyte reaction in Sjögren's syndrome.

The autologous mixed lymphocyte reaction (AMLR) measures the response of peripheral blood T cells to antigens present on the surface of non-T cells. The AMLR was studied in 25 patients with Sjögren's syndrome (SS). The AMLR was decreased in 15 of 25 (60%) of patients with SS (5,272 +/- 6,738 cpm vs. 14,396 +/- 10,092 cpm for the normal controls, P < 0.001). The AMLR was decreased in 8 of 15 patients with only glandular disease who were not on any systemic medications. Patients with SS and associated disease had lower responses than patients with SS alone. Two patients with pseudolymphoma had absent response. The decreased AMLR correlated with a decreased response to concanavalin A, suggesting a possible abnormality of a T cell subpopulation. There was no correlation between the decreased AMLR and age, focus score, serum immunoglobulin concentration, the titer of antilymphocyte antibody, or phytohemagglutinin response. In allogeneic MLR, SS non-T cells and macrophages stimulated normal allogeneic T cells less well than normal non-T cells and macrophages, suggesting a possible abnormality in the cells that stimulate in the cells that stimulate in the allogeneic MLR.

Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides.

In this study, we have identified the source of nitric oxide (NO) produced in the human inflammatory joints by analyzing expression of inducible NO synthase. In ex vivo organ cultures, both inflammatory synovium and cartilage from patients with rheumatoid arthritis produced NO. The NO production was suppressed by NG-monomethyl-L-arginine, an inhibitor of NO synthase. The amount of NO produced by the synovium correlated with the proportion of CD14+ cells in the corresponding tissue (r = 0.8, P < 0.05). Immunohistochemical analysis as well as in situ hybridization showed that inducible NO synthase was predominantly expressed in synovial lining cells, endothelial cells, chondrocytes, and to a lesser extent, in infiltrating mononuclear cells and synovial fibroblasts. The synovial lining cells and the infiltrating cells expressing inducible NO synthase were identified where CD14+ cells were located. Together with morphological features, this suggests that they are type A synoviocytes. NO production from freshly isolated synoviocytes and chondrocytes was up-regulated by in vitro stimulation with a combination of IL-TNF-beta, TNF-alpha, and LPS. In summary, the present results suggest that NO is produced primarily by CD14+ synoviocytes, chondrocytes, and endothelial cells in inflammatory joints of arthritides. NO production can be upregulated by cytokines present in inflamed joints. The increased NO production may thus contribute to the pathological features in inflammatory arthritides.

Spontaneous production of an interleukin 1-like factor by cloned rheumatoid synovial cells in long-term culture.

We have cloned adherent synovial cells from rheumatoid synovitis. These can be generally divided into three types, including cells that have the characteristic features of dendritic cells (DCs), macrophagelike cells (MCs) and fibroblastlike cells (FCs), as classified by morphology and immunofluorescent staining. The cloned cells were able to divide and were cultured for up to 11 mo without any significant morphological changes. All the cloned cells were HLA-DR+ after gamma-interferon treatment. Spontaneous production of a factor with interleukin 1 activity by the cloned cells was detected even after long-term culture (the ability, on a per cell basis, being in the following order: DC greater than MC greater than FC). These synovial cells may be important for bony destruction in rheumatoid joints.

Genetic control of T cell receptor BJ gene expression in peripheral lymphocytes of normal and rheumatoid arthritis monozygotic twins.

The amino acids encoded at the junctions of T cell receptor (TCR) V and J genes directly interact with MHC bound peptides. However, the regulation of the human TCRBJ gene repertoire has been difficult to analyze, because of the potentially complex number of BJ gene rearrangements. To overcome this problem, we developed a PCR-ELISA method to study BJ gene expression, and compared peripheral T lymphocytes from 12 pairs of monozygotic twins, including 6 rheumatoid arthritis (RA) discordant pairs, and 5 normals. Analyses of the TCRBV5, 13 and 17 gene families, which have been reported to be increased in RA patients, showed: (a) the three TCRBV transcripts have common features of BJ gene usage; (b) TCR transcripts from each TCRBV family display a distinctive BJ gene profile, which is displayed better by CD4+ than CD8+ lymphocytes; (c) the BJ gene repertoires of monozygotic twins are more similar than those of unrelated individuals; and (d) the inflammation of RA does not induce specific changes in the genetically determined pattern of BJ expression. These results indicate that the frequency of expression particular TCRBV-TCRBJ recombinants in human lymphocytes is controlled genetically, and is maintained despite the presence of a chronic inflammatory disease.

The human immunoglobulin V(H) gene repertoire is genetically controlled and unaltered by chronic autoimmune stimulation.

The factors controlling immunoglobulin (Ig) gene repertoire formation are poorly understood. Studies on monozygotic twins have helped discern the contributions of genetic versus environmental factors on expressed traits. In the present experiments, we applied a novel anchored PCR-ELISA system to compare the heavy chain V gene (V(H)) subgroup repertoires of mu and gamma expressing B lymphocytes from ten pairs of adult monozygotic twins, including eight pairs who are concordant or discordant for rheumatoid arthritis. The results disclosed that the relative expression of each Ig V(H) gene subgroup is not precisely proportional to its relative genomic size. The monozygotic twins had more similar IgM V(H) gene repertoires than did unrelated subjects. Moreover, monozygotic twins who are discordant for RA also use highly similar IgM V(H) gene-subgroup repertoires. Finally, the V(H) gene repertoire remained stable over time. Collectively, these data reveal that genetic factors predominantly control V(H) gene repertoire formation.

Fine epitope mapping of the human SS-B/La protein. Identification of a distinct autoepitope homologous to a viral gag polyprotein.

To analyze the autoepitopes on the SS-B/La protein, a cDNA covering the entire region coding the protein was isolated from a human cDNA library. The cDNA was subcloned into an expression plasmid vector, pEX, to express its protein product as a fusion protein with cro-beta-galactosidase in Escherichia coli. A recombinant pEX plasmid expressing three-fourths of the protein (amino acid 112-408) was also constructed. The antigenicities of these recombinant proteins were confirmed with a patient's serum. Their various deletion mutants were produced with exonuclease III treatment from the 3' ends of the cDNAs without changing the proper translational frame. Immunoblot analysis and enzyme-linked immunosorbent assay were used to evaluate the reactivities of the recombinant proteins with patients' sera to determine the autoepitopes. A narrow segment (amino acid 88-101) and the region where several epitopes were located (amino acid 283-338) on the SS-B/La protein were universally recognized by all the sera with anti-SS-B/La antibodies examined. An additional epitope region (amino acid 179-220) was recognized by some patients' sera. Computer analysis revealed that the most distinct autoepitope, amino acid 88-101, had a striking homology to a retroviral gag polyprotein. These findings indicate that exogenous or endogenous retroviruses may play a role in initiation of the anti-SS-B/La autoimmunity.

Identification of negative regulatory regions within the first exon and intron of the BCL6 gene.

Chromosomal translocations involving BCL6 gene are frequent in human B-cell lymphomas. Chromosomal breaks preferentially occur within a 3-kb region containing the first exon and intron. Recent reports have revealed that internal deletions or point mutations also are common in this region, suggesting that structural alteration of this region may be a crucial event in the development of lymphomas. In this study, we identified two regions in the BCL6 gene that negatively regulate BCL6 expression. One region, ES, is located within the first exon between nucleotides +472 and +543, and a second region, IS, is located between +783 and + 918 of the first intron. A consensus nucleotide sequence for the binding of the BCL6 protein itself was found within the ES region. An electrophoretic mobility shift assay and a co-transfection experiment using a BCL6 expression vector showed that transcription of the BCL6 gene was negatively regulated by the BCL6 gene product. The IS region which is included in the regions commonly deleted in B-cell lymphomas had a silencer activity. Structural alterations of these two regions may play roles in the deregulated expression of the BCL6 gene in B-cell lymphomas.

Signaling through the antigen receptor of B lymphocytes activates a p53-independent pathway of c-Myc-induced apoptosis.

Deregulated expression of c-Myc has been shown to induce or enhance apoptosis in various different cell types. c-Myc requires p53 for apoptosis in some but not all the cell types, indicating heterogeneous mechanisms for c-Myc-induced apoptosis. In B lymphoma line WEHI-231, stable expression of c-Myc has been demonstrated to protect cells from BCR-mediated apoptosis. However, stable expression of c-Myc carrying pro-apoptotic functions may generate variant cells resistant to apoptosis. By utilizing an inducible system for c-Myc, we demonstrated here that deregulated expression of c-Myc induced apoptosis of WEHI-231 by itself, indicating that c-Myc induces apoptosis in WEHI-231 as is the case for other cell types. When transactivation of p53 was inactivated, WEHI-231 cells overexpressing c-Myc no longer underwent apoptosis in the absence of other stimuli, but showed markedly enhanced apoptosis in the presence of BCR ligation. These results indicate that deregulated c-Myc expression enhances apoptosis by a p53-independent pathway in the presence of BCR signaling but requires p53 for apoptosis in the absence of BCR crosslinking in WEHI-231. BCR ligation may thus activate a p53-independent pathway of c-Myc-induced apoptosis.