Serum Creatinine-Cystatin C Based Screening of Sarcopenia in Community Dwelling Older Adults: A Cross-Sectional Analysis.

OBJECTIVES: To compare the discriminative capabilities for the manifestation of sarcopenia or physical frailty between serum creatinine- and cystatin C-derived indices among community-dwelling older adults. DESIGN: Cross-sectional study. SETTING: Primary Care and Community. PARTICIPANTS: We utilized a subset of data from the Frail Elderly in the Sasayama-Tamba Area (FESTA) study, which was initiated in 2015 to gather comprehensive information on various health-related parameters among community-dwelling older individuals (age ≥65 years). MEASUREMENTS: Five serum creatinine-cystatin C based indices including the Sarcopenia Index, the serum creatinine/cystatin C ratio, the disparity between serum cystatin-C-based and creatinine-based estimated GFR, the total body muscle mass index (TBMM), and the prediction equation for skeletal muscle mass index (pSMI) were employed. Sarcopenia and physical frailty were identified based on the Asian Working Group for Sarcopenia criteria and the revised Japanese version of the Cardiovascular Health Study criteria, respectively. The receiver operating characteristic (ROC) and logistic regression analyses were performed to assess the discriminative abilities of these tools. RESULTS: In the analysis of 954 participants, 52 (5.5%) were identified with sarcopenia and 35 (3.7%) with physical frailty. Regarding sarcopenia discrimination, TBMM and pSMI both exhibited area under the curve (AUC) values exceeding 0.8 for both men and women. Concerning the identification of physical frailty, AUC values ranged from 0.61 to 0.77 for males and 0.50 to 0.69 for females. In the multivariate logistic regression analyses, only TBMM and pSMI consistently displayed associations with sarcopenia, irrespective of sex (P<0.001, respectively). On the other hand, no consistent associations were observed between the indices and physical frailty. CONCLUSIONS: This study provides a robust association of a serum creatinine- and cystatin C-derived indices, especially TBMM and pSMI, with sarcopenia among community-dwelling older adults. Conversely, the application of these indices for the screening of physical frailty has its constraints, necessitating further investigation.

Minisatellite mutation rate variation associated with a flanking DNA sequence polymorphism.

Human minisatellite mutation in the male germline frequently involves complex interallelic gene conversion events restricted to one end of the tandem repeat array. Some alleles at minisatellite MS32 show reduced variability in human populations and are associated with a G to C transversion upstream of the array. Analysis of single sperm demonstrated a frequently profound reduction in mutation rate at alleles carrying the C variant. This mutation suppression acts in cis, but does not affect the ability of an allele to act as sequence donor during gene conversion. This mutation rate polymorphism provides strong evidence for elements near the minisatellite that regulate tandem repeat instability.

Complex gene conversion events in germline mutation at human minisatellites.

Mutation at the human minisatellites MS32, MS205 and MS31A has been investigated by characterizing mutant alleles in pedigrees and in the case of MS32 by direct analysis of mutant molecules in single sperm. Most mutations at all three loci are polar, involving the preferential gain of a few repeat units at one end of the tandem repeat array. Incoming repeats can be derived from the same allele or the homologous chromosome, through they are frequently rearranged during mutation. Lack of exchange of flanking markers suggests the involvement of complex conversion-like events in the generation of mutant alleles. At MS32, high frequency mutation processes in sperm appear to be largely germline specific and to occur at a constant rate irrespective of allele size. Together with mutational polarity, this implies that germline instability is controlled by elements outside the tandem repeat array.

Field test of quantum key distribution in the Tokyo QKD Network.

A secure communication network with quantum key distribution in a metropolitan area is reported. Six different QKD systems are integrated into a mesh-type network. GHz-clocked QKD links enable us to demonstrate the world-first secure TV conferencing over a distance of 45km. The network includes a commercial QKD product for long-term stable operation, and application interface to secure mobile phones. Detection of an eavesdropper, rerouting into a secure path, and key relay via trusted nodes are demonstrated in this network.

Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis.

During carcinogenesis of pancreatic islets in transgenic mice, an angiogenic switch activates the quiescent vasculature. Paradoxically, vascular endothelial growth factor (VEGF) and its receptors are expressed constitutively. Nevertheless, a synthetic inhibitor (SU5416) of VEGF signalling impairs angiogenic switching and tumour growth. Two metalloproteinases, MMP-2/gelatinase-A and MMP-9/gelatinase-B, are upregulated in angiogenic lesions. MMP-9 can render normal islets angiogenic, releasing VEGF. MMP inhibitors reduce angiogenic switching, and tumour number and growth, as does genetic ablation of MMP-9. Absence of MMP-2 does not impair induction of angiogenesis, but retards tumour growth, whereas lack of urokinase has no effect. Our results show that MMP-9 is a component of the angiogenic switch.

Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies.

OBJECTIVES: To assess whether smoking is a risk factor for developing rheumatoid arthritis (RA). DESIGN: Meta-analysis. DATA SOURCES: were observational studies that examined the association between smoking history and the risk of developing RA identified through Medline and EMBASE (from 1966 to December 2006), relevant books and a reference search. Two authors independently extracted the following: authors' names, publication year, sample size, participant characteristics, odds ratios (OR) or relative risks, adjustment factors, study design and area where the study was conducted. Data syntheses were based upon random effects model. Summarised syntheses effects were expressed by OR. RESULTS: Sixteen studies were selected from among 433 articles. For men, summary OR for ever, current and past smokers were 1.89 (95% CI 1.56 to 2.28), 1.87 (1.49 to 2.34) and 1.76 (1.33 to 2.31), respectively. For rheumatoid factor-positive (RF+) RA, summary OR for ever, current and past smokers were 3.02 (2.35 to 3.88), 3.91 (2.78 to 5.50) and 2.46 (1.74 to 3.47), respectively. Summary OR for 20 or more pack-years of smoking was 2.31 (1.55 to 3.41). For women, summary OR for ever, current and past smokers were 1.27 (1.12 to 1.44), 1.31 (1.12 to 1.54) and 1.22 (1.06 to 1.40), respectively. For RF+ RA, summary OR for ever, current and past smokers were 1.34 (0.99 to 1.80), 1.29 (0.94 to 1.77) and 1.21 (0.83 to 1.77). Summary OR for 20 or more pack-years of smoking was 1.75 (1.52 to 2.02). CONCLUSION: Smoking is a risk factor for RA, especially RF+ RA men and heavy smokers.

Clinical and laboratory features of Japanese patients with scleroderma and telangiectasia.

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease characterized by sclerotic changes of the skin and internal organs. Telangiectasia is a frequent complication of patients with SSc. OBJECTIVE: To examine the prevalance of telangiectasia in patients with SSc and investigate the clinical and laboratory features of patients with SSc and telangiectasia. METHODS: In total, 211 patients with SSc who fulfilled the diagnostic criteria for SSc of the American College of Rheumatology were examined by laboratory and clinical methods. The average of disease duration time was 7.4 years. RESULTS: Telangiectasia was found in 119 of the 211 patients (56%) with SSc. The prevalence of oesophageal involvement, decreased diffusing capacity for carbon monoxide (DLCO), heart involvement, calcinosis, shortening of the sublingual frenulum, or pitting scars was significantly greater in patients with telangiectasia than in those without telangiectasia. CONCLUSION: Our study suggests that the presence of telangiectasia may be a marker of oesophageal involvement, decreased DLCO, and heart involvement.

Polymorphism in the sorbin and SH3-domain-containing-1 (SORBS1) gene and the risk of brain infarction in the Japanese population: the Fukuoka Stroke Registry and the Hisayama study.

BACKGROUND AND PURPOSE: Sorbin and SH3-domain-containing-1 (SORBS1) is an important adaptor protein in insulin-signalling pathway, and its genetic polymorphism may regulate the activity of insulin resistance. We investigated the association between the SORBS1 T228A polymorphism and ischaemic stroke. METHODS: Genotyping was achieved by a rapid-cycle PCR and melting curve analysis using fluorescent probes in 1049 incident cases of ischaemic stroke and 1049 age- and sex-matched control subjects recruited from the Hisayama study. RESULTS: The allele distributions of the SORBS1 T228A polymorphism were similar amongst cases and controls. The multivariate-adjusted odds ratio (OR) of the AA genotype for ischaemic stroke was 2.897 (95% CI, 0.907-8.018) compared with the TT genotype. In terms of stroke subtype, there was a trend toward a difference in the AA genotypes for lacunar infarction, compared with the TT genotype (OR = 8.740, P = 0.0510), and combined TT and TA genotypes (OR = 8.768, P = 0.0505). The other polymorphisms genotyped were not associated with any subtypes of ischaemic stroke. T228A polymorphism of SORBS1 was not associated with the prevalence of diabetes. CONCLUSIONS: The AA genotype of SORBS1 T228A polymorphism may play a role in lacunar infarction in the Japanese population.

Serum 5-S-cysteinyldopa levels in patients with psoriasis undergoing narrowband ultraviolet B phototherapy.

BACKGROUND: Ultraviolet (UV) B radiation from sunlight can result in tanning or burning of the skin. Narrowband UVB (NB-UVB), a relatively new light source that is not yet widely available, is effective for treating generalized psoriasis without the use of psoralens. AIMS: The melanin-related metabolite 5-S-cysteinyldopa (5-S-CD), which reflects pheomelanin production, has been used as a biological marker of melanoma progression, but there are no studies available on therapeutic UVB effects on serum 5-S-CD of human subjects. In the present study, we measured the time course of changes in serum levels of 5-S-CD in patients with psoriasis undergoing NB-UVB phototherapy. METHODS: In total, 11 Japanese patients with generalized psoriasis vulgaris received NB-UVB treatment five times per week, at an initial dose of 0.1 J/cm(2). The dose was increased by 10-20% per treatment for > 20 treatments. Serum samples were taken before and 3, 7, 10, 14 and 28 days after phototherapy. RESULTS: After 4 weeks of NB-UVB treatment, 9 of 11 patients were in remission, confirming the effectiveness of NB-UVB for treating Japanese patients with psoriasis. Two patients withdrew before day 28 because of other complications. Mean level of 5-S-CD in serum was significantly increased on day 7, 10 14 and 28 compared with the level before phototherapy and it peaked on day 10. CONCLUSIONS: Serum 5-S-CD levels were significantly increased by therapeutic UVB exposure. Sustained levels of 5-S-CD in serum appear to reflect the degree of skin injury during NB-UVB phototherapy.

Overproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopic dermatitis-like lesions.

We have examined the expression of chemokines and their receptors in the atopic dermatitis-like (AD-like) lesions of NC/Nga mice. Such lesions develop when the mice are kept in conventional conditions, but not when they are kept isolated from specific pathogens. The thymus- and activation-regulated chemokine TARC is unexpectedly highly expressed in the basal epidermis of 14-week-old mice with lesions, whereas it is not expressed in the skin without lesions. Production of TARC by keratinocytes was confirmed by culturing murine keratinocytic cell line cells (PAM212) with TNF-alpha, IFN-gamma, or IL-1beta. Expression of another Th2 chemokine, macrophage-derived chemokine (MDC), was observed in the skin from mice kept in both conventional and pathogen-free conditions, but expression of MDC was increased severalfold in the skin with lesions. The cellular origin of MDC was identified to be dermal dendritic cells. Infiltration of the skin by IL-4-producing T cells and mast cells, and the increase of CCR4 mRNA in the skin, coincided with the development of AD lesions. These observations indicate that TARC and MDC actively participate in the pathogenesis of AD-like lesions in NC/Nga mice and that these Th2 chemokines could be novel targets for intervention therapy of AD in humans.

Increased serum levels of a proliferation-inducing ligand in patients with bullous pemphigoid.

BACKGROUND: B cells have been demonstrated to have critical roles in developing autoimmune bullous diseases. Recently identified tumor necrosis factor-like molecules, B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) are essential molecules for B cell development, survival, and proliferation. Although the functions of APRIL have not been fully evaluated, recent studies suggest that circulating levels of APRIL are increased in various autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. OBJECTIVES: To determine serum APRIL levels in patients with pemphigus vulgaris (PV) and bullous pemphigoid (BP), and compare those with clinical findings and laboratory findings. PATIENTS/METHODS: Sera from 15 PV patients, 43 BP patients, and 15 normal controls were subjected to ELISA assays to measure serum APRIL, BAFF, Dsg3, and BP180 levels. RESULTS AND CONCLUSIONS: Circulating APRIL levels were significantly elevated in BP patients but not in PV patients, and correlated with serum BAFF levels. Our study revealed that serum APRIL levels tended to be increased in the quite early stage of disease. In conclusion, circulating APRIL levels may be a useful marker for early activation of autoimmune diathesis, and furthermore, an effective therapeutic target molecule in patients with BP.

NAD(P)H oxidase p22phox C242T polymorphism and ischemic stroke in Japan: the Fukuoka Stroke Registry and the Hisayama study.

The C242T polymorphism of p22phox, a component of NAD(P)H oxidase, may have an impact on cardiovascular diseases; however, the association between this polymorphism and brain infarction is not fully understood. Here, we investigate the relationship between the C242T polymorphism and brain infarction in Japan. We recruited 1055 patients with brain infarction and 1055 control subjects. A chi-squared test revealed that the T-allele frequency was lower in patients with cardioembolic infarction (5.6%) than in control subjects (11.0%, P < 0.001); however, allele frequencies in patients with lacunar and atherothrombotic infarction (11.2%) were not significantly different from those in control subjects (11.0%). A multivariate-adjusted conditional logistic regression analysis also revealed no association between CT + TT genotype, and lacunar and atherothrombotic infarction (odds ratio = 0.97, 95% confidence interval: 0.72-1.32). To investigate the functional effects of the C242T polymorphism, we examined superoxide production in COS-7 cells cotransfected with Nox4 and p22phox of each genotype. The superoxide-producing activity in those cells expressing p22phox with the T allele was not significantly different from that in cells expressing p22phox with the C allele. The present results suggest that the p22phox C242T polymorphism may have a protective effect against cardioembolic infarction, but is not related to lacunar and atherothrombotic infarction in Japan.

Adult-onset acute tubulointerstitial nephritis and uveitis with Fanconi syndrome. Case report and review of the literature.

We report a case of tubulointerstitial nephritis and uveitis (TINU syndrome) with full type Fanconi syndrome. A 32-year-old woman presented with fatigue, anorexia and weight loss. Laboratory findings showed anemia, polyclonal hypergammaglobulinemia and moderate renal dysfunction. Tubular function abnormalities were normoglycemic glucosuria, panaminoaciduria, phosphaturia and kaliuresis leading to hypokalemia. Renal tubular acidosis and hypouricemia were also evident. Serum antistreptolysin O titer was high. Ocular symptoms (bilateral anterior uveitis) emerged soon after admission. Renal biopsy showed diffuse tubulointerstitial infiltration by lymphocytes and plasma cells without granuloma. Treatment with systemic steroids was given and renal function, and ocular symptom returned to normal with 3 months. Although tubular abnormalities involving TINU syndrome has already been reported, the disease associated with full type Fanconi syndrome has rarely been seen, and systemic steroid may be beneficial in reducing the development of tubulointerstitial injury.

Increased serum levels of circulating CD40 ligand in patients with bullous pemphigoid: preliminary results.

BACKGROUND: Autoimmune bullous diseases are characterized by autoantibodies against specific adhesion molecules of the skin and/or mucous membrane. While these autoantibodies are known to play a primary role in the disease manifestation, it remains unknown how disease-specific autoreactive B cells and autoantibodies are induced. Recent studies have indicated the importance of the CD40 and CD40 ligand (CD40L) receptor-ligand pair in the immunopathogenesis of autoimmune diseases. CD40L circulates in soluble form, and some reports suggest that serum soluble CD40L (sCD40L) levels are increased in various autoimmune diseases. OBJECTIVES: To determine serum sCD40L levels in patients with pemphigus vulgaris (PV) and bullous pemphigoid (BP), and to determine their correlation with clinical findings and laboratory findings. PATIENTS AND METHODS: Sera from 10 PV patients, 35 BP patients and 12 normal controls were subjected to ELISA assays to measure serum levels of sCD40L, anti-desmoglein-3 antibody and anti-BP180 antibody. RESULTS AND CONCLUSIONS: Circulating sCD40L levels were significantly elevated in BP patients, but not in PV patients. Serum sCD40L levels increased in the early stage of disease onset and recurrence in BP patients. In conclusion, circulating sCD40L levels may be a useful marker for early activation of autoimmune diathesis and, furthermore, an effective therapeutic target in patients with BP.

Clinical significance of serum matrix metalloproteinase-13 levels in patients with localized scleroderma.

OBJECTIVES: To investigate the clinical significance of serum matrix metalloproteinase-13 (MMP-13) levels in patients with localized scleroderma (LSc). METHODS: Serum MMP-13 levels were determined by using a peptide substrate cleavage assay in 10 patients with generalized morphea, 10 with linear scleroderma, 10 with morphea, and 10 normal controls. RESULTS: The serum MMP-13 levels in patients with LSc were lower than those in normal controls, but there was no significant difference (64.9 +/- 19.9 versus 73.2 +/- 11.5, p = 0.058). Serum MMP-13 levels in patients with generalized morphea were significantly lower than those in normal controls (54.0 +/- 18.7 versus 73.2 +/- 11.5 ng/ml; p < 0.01). Serum levels of MMP-13 were comparable among normal controls, the patients with linear scleroderma, and those with morphea. The prevalence of muscle involvement was significantly greater in the LSc patients with decreased MMP-13 levels compared with those with normal MMP-13 levels (50% versus 8%, p < 0.05). Serum MMP-13 levels were significantly inversely correlated with the number of linear lesions (r = 0.366, p < 0.05) and the number of involved body areas (r = 0.552, p < 0.005) in patients with LSc, while there was no significant correlation between serum MMP-13 levels and the number of plaque lesions. Furthermore, there was significant inverse correlation between serum MMP-13 levels and the number of involved body areas in patients with generalized morphea (r = 0.631, p < 0.05). CONCLUSION: The serum MMP-13 levels may reflect the disease severity in patients with LSc, especially generalized morphea, the severest form of this disorder.

[Surgical treatment for clinical stage II and III small cell lung cancer patients].

To evaluate a surgical resection in multidisciplinary treatment for clinical stage (c-stage) II and III small cell lung cancer (SCLC) patients, we examined the postoperative prognosis concerning in 18 patients who underwent complete surgical resection. Five-year survival rate of 8 c-stage II and 10 c-stage III patients showed 62.5% and 46.7%, respectively. Of these, 7 patients underwent preoperative induction chemotherapy resulting in down-staging to c-stage 0-I, and their survival rate at 5 years after sugery was as good as 68.6%. However, in 4 (57.1%) of 7 patients, tumor cells proved to be alive by pathological assessment of lymph nodes. As a consequence, it was suggested that surgery for c-stage II and III SCLC patients is a meaningful treatment considering their prognoses. In particular, even though the patients show a favorable response of preoperative chemotherapy, to completely eliminate remnant tumor cells, a surgical resection may be necessary.

ZFP521 contributes to pre-B-cell lymphomagenesis through modulation of the pre-B-cell receptor signaling pathway.

ZFP521 was previously identified as a putative gene involved in induction of B-cell lymphomagenesis. However, the contribution of ZFP521 to lymphomagenesis has not been confirmed. In this study, we sought to elucidate the role of ZFP521 in B-cell lymphomagenesis. To this end, we used a retroviral insertion method to show that ZFP521 was a target of mutagenesis in pre-B-lymphoblastic lymphoma cells. The pre-B-cell receptor (pre-BCR) signaling molecules BLNK, BTK and BANK1 were positively regulated by the ZFP521 gene, leading to enhancement of the pre-BCR signaling pathway. In addition, c-myc and c-jun were upregulated following activation of ZFP521. Stimulation of pre-BCR signaling using anti-Vpreb antibodies caused aberrant upregulation of c-myc and c-jun and of Ccnd3, which encodes cyclin D3, thereby inducing the growth of pre-B cells. Stimulation with Vpreb affected the growth of pre-B cells, and addition of interleukin (IL)-7 receptor exerted competitive effects on pre-B-cell growth. Knockdown of BTK and BANK1, targets of ZFP521, suppressed the effects of Vpreb stimulation on cell growth. Furthermore, in human lymphoblastic lymphoma, analogous to pre-B-cell lymphoma in mice, the expression of ZNF521, the homolog of ZFP521 in humans, was upregulated. In conclusion, our data showed that the ZFP521 gene comprehensively induced pre-B-cell lymphomagenesis by modulating the pre-B-cell receptor signaling pathway.

Coronary angioplasty ameliorates hypoperfusion-induced endothelial dysfunction in patients with stable angina pectoris.

OBJECTIVES: This study sought to investigate the effect of coronary angioplasty on chronic hypoperfusion-induced endothelial dysfunction in patients with coronary heart disease. BACKGROUND: The endothelium is an important component for organ flow regulation. Ischemia with or without reperfusion is known to cause endothelial dysfunction. We tested the hypothesis that chronic hypoperfusion impairs endothelial function in the angiographically normal coronary artery segment distal to stenosis and that the impairment by chronic hypoperfusion is reduced by coronary angioplasty. METHODS: In 13 patients with stable angina pectoris, substance P (10, 30 and 100 pmol) and nitroglycerin (200 micrograms) were sequentially infused into the coronary artery in a cumulative manner on the day after coronary angioplasty. In 10 of these patients, vascular responses to these agents were again investigated 3 months after angioplasty. Changes in vascular diameter were evaluated in vessels located proximal and distal to the target lesion, both of which were angiographically normal, by performing computer-assisted quantitative coronary angiography. In five patients, the transstenotic pressure gradient was also measured with a pressure sensor-mounted guide wire before angioplasty. RESULTS: On the day after angioplasty, the magnitude of dilation by substance P in distal segments was significantly less than that in proximal segments and inversely correlated with the transstenotic pressure gradient (p < 0.05) and lesion stenosis (p < 0.05). There was no difference in nitroglycerin-induced vasodilation between the two vessel segment groups. Three months later, the impaired response to substance P in the distal segment was restored to normal. CONCLUSIONS: We conclude that chronic hypoperfusion impairs endothelium-dependent dilation of coronary artery distal to critical stenosis in patients with ischemic heart disease and that coronary angioplasty ameliorates the endothelial dysfunction within 3 months.

Functional CD40 ligand is expressed on epidermal Langerhans cells.

Epidermal Langerhans cells (LC) are bone-marrow-derived major histocompatibility complex (MHC) class II antigen-expressing antigen-presenting cells (APC) that comprise 1-3% of total epidermal cells (EC). LC express high levels of MHC class II antigen and augment costimulatory molecules such as B7-1, B7-2 during culture. In a previous report, using purified murine LC, we showed that freshly prepared LC (fLC) do not express CD40, whereas cLC express CD40. Tumor necrosis factor alpha (TNF-alpha) enhanced CD40 expression on LC during culture. We examined the expression of CD40L on LC and found that both fLC and cLC expressed mRNA for CD40L. FACS analysis revealed that cLC cultured for 36 h expressed CD40L but fLC did not. When we examined the cytoplasmic CD40L, however, both fLC and cLC expressed cytoplasmic CD40L. TNF-alpha, which up-regulated CD40 expression on LC during culture, did not modulate CD40L. Co-culture of purified LC ith anti-CD40L markedly inhibited the up-regulation of B7-1 expression on LC and caused partial inhibition of B7-2 expression during culture. These results indicate that CD40L is expressed on cLC, and that CD40L on LC modulates the expression of costimulatory molecules such as B7-1 and B7-2 on LC.