Dispersive and dissipative coupling in a micromechanical resonator embedded with a nanomechanical resonator.

A micromechanical resonator embedded with a nanomechanical resonator is developed whose dynamics can be captured by the coupled-Van der Pol-Duffing equations. Activating the nanomechanical resonator can dispersively shift the micromechanical resonance by more than 100 times its bandwidth and concurrently increase its energy dissipation rate to the point where it can even be deactivated. The coupled-Van der Pol-Duffing equations also suggest the possibility of self-oscillations. In the limit of strong excitation for the nanomechanical resonator, the dissipation in the micromechanical resonator can not only be reduced, resulting in a quality factor of >3× 10(6), it can even be eliminated entirely resulting in the micromechanical resonator spontaneously vibrating.

Diagnosis and molecular basis of mitochondrial respiratory chain disorders: exome sequencing for disease gene identification.

Mitochondrial disorders have the highest incidence among congenital metabolic diseases, and are thought to occur at a rate of 1 in 5000 births. About 25% of the diseases diagnosed as mitochondrial disorders in the field of pediatrics have mitochondrial DNA abnormalities, while the rest occur due to defects in genes encoded in the nucleus. The most important function of the mitochondria is biosynthesis of ATP. Mitochondrial disorders are nearly synonymous with mitochondrial respiratory chain disorder, as respiratory chain complexes serve a central role in ATP biosynthesis. By next-generation sequencing of the exome, we analyzed 104 patients with mitochondrial respiratory chain disorders. The results of analysis to date were 18 patients with novel variants in genes previously reported to be disease-causing, and 27 patients with mutations in genes suggested to be associated in some way with mitochondria, and it is likely that they are new disease-causing genes in mitochondrial disorders. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.

Overexpression of CXCR4 on circulating B cells in patients with active systemic lupus erythematosus.

OBJECTIVES: To evaluate the roles of circulating B cells in the pathogenic process of systemic lupus erythematosus (SLE) by measuring the expression of chemokines and their receptors. METHODS: Peripheral-blood mononuclear cells were obtained from 17 active, 21 inactive SLE patients, and 13 healthy controls. The expression of CXCR4, CXCR5, and CCR7 on CD19+ B cells was determined by flow cytometry, serum concentration of CXCL12 was measured by enzyme-linked immunosorbent assay, and the chemotactic responsiveness of B cells toward CXCL12 was evaluated. B or plasma cells expressing CXCR4 in renal biopsy specimens were detected using immnofluorescent staining. RESULTS: Flow cytometric analysis revealed that expression level of CXCR4 on circulating B cells was significantly higher in patients with active disease than in those with inactive disease or controls. Serum CXCL12 concentration was not different between these groups. In addition, the migratory ability of B cells toward CXCL12 was enhanced in active SLE patients. Finally, CXCR4-expressing B cells were more frequently observed in the renal biopsy specimens of lupus nephritis. CONCLUSIONS: Up-regulated CXCR4 expression on circulating B cells in active SLE may enhance their chemotactic response toward CXCL12, which may promote infiltration of these cells into inflamed renal tissue and contribute to the development of SLE.

Clinical efficacy and treatment persistence of monthly minodronate for osteoporotic patients unsatisfied with, and shifted from, daily or weekly bisphosphonates: the BP-MUSASHI study.

UNLABELLED: This multi-center, prospective, open-label, observational study evaluated the effects of once-monthly minodronate (50 mg) on treatment persistence, bone turnover markers, bone mineral density, low back pain, and upper gastrointestinal symptoms in outpatients with osteoporosis previously treated with daily or weekly bisphosphonate products. INTRODUCTION: The purposes of this study were to investigate the effects of once-monthly oral minodronate (MIN 50 mg) on bone turnover markers and bone mineral density, low back pain, and upper gastrointestinal symptoms, as well as preference for and treatment persistence of MIN 50 mg among Japanese osteoporosis patients currently treated with daily or weekly bisphosphonates. METHODS: Study patients were allocated based on their preference to either the Switch group (patients willing to switch over to MIN 50 mg) or the Continue group (patients wanting to continue their current therapies). Patients' treatment persistence and satisfaction levels with the therapies were assessed using a self-administered questionnaire. The study endpoints were serum TRACP-5b, serum P1NP, bone mineral density, upper gastrointestinal symptoms, and low back pain. RESULTS: In total, 264 and 133 patients were allocated into the Switch and Continue groups, respectively. Approximately, 65 % of patients were willing to switch to MIN 50 mg, with the predominant reason being "less frequent dosing more convenient." Treatment persistence was significantly higher in the Switch group (MIN 50 mg) than the Continue group. Almost all patients with abnormal bone metabolism markers demonstrated normalization after switchover. MIN 50 mg alleviated low back pain and upper gastrointestinal symptoms induced by prior bisphosphonate use. CONCLUSIONS: MIN 50 mg alleviates low back pain, reduces bone turnover markers and increases bone density, and induces fewer upper gastrointestinal symptoms after switchover from prior bisphosphonate products, and therefore, it may provide patients with a more convenient treatment option and enhance long-term treatment persistence.

Association of a single nucleotide polymorphism in the SH2D1A intronic region with systemic lupus erythematosus.

SH2D1A, also known as signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), is an adaptor protein. Recently, it was reported that SAP deficient mice were protected from systemic lupus erythematosus (SLE). In this study, we postulated SH2D1A gene to be a candidate susceptibility gene for SLE and analyzed its association with SLE. A case-control association study was conducted on 5 tag single nucleotide polymorphisms (SNPs) in SH2D1A region in 506 Japanese female SLE patients and 330 healthy female controls. The luciferase assay was performed to determine the functional role of the SNP associated with SLE. One SNP in the intron 2, rs2049995, showed association with SLE (p=0.0110, odds ratio (OR) 1.97, 95% confidence interval (CI) 1.16-3.34, under the dominant model). The association of rs2049995 seemed to be stronger in the subset with the age of onset less than 20 years (p=0.0067, OR 2.65, 95% CI 1.28-5.46). Functional evaluation of rs2049995 showed that reporter gene activity was increased 1.9-fold for the susceptible allele compared with the resistant allele. An intronic SNP of SH2D1A is associated with SLE.

A genetic linkage map of the Syrian hamster and localization of cardiomyopathy locus on chromosome 9qa2.1-b1 using RLGS spot-mapping.

The Syrian cardiomyopathic hamster (BIO14.6) has an inherited form of progressive myocardial necrosis and congestive heart failure. Although widely studied as an animal model for human hypertrophic cardiomyopathy, further genetic analysis has been limited by a scarcity of DNA markers. Until now, only six autosomal linkage groups have been described and the number of polymorphic loci was extremely limited. In this study, we applied the restriction landmark genome scanning (RLGS) spot-mapping method to construct a genetic map of the Syrian hamster (Mesocricetus auratus) using 72 back-cross progeny. Although the polymorphic rate is very low (3-7%) between the strains, 531 polymorphic spots/loci were mapped, showing the power of this approach and reasonable applicability to other organisms lacking a well-defined genetic map. Further, the spot markers which flank the cardiomyopathy (cm) locus were cloned to determine the chromosomal location of cm by fluorescent in situ hybridization (FISH) analysis, resulting in the assignment of the locus to the centromeric region of hamster chromosome 9qa2.1-b1. Several candidate genes responsible for hypertrophic cardiomyopathy in humans have been excluded.

Identification of an imprinted U2af binding protein related sequence on mouse chromosome 11 using the RLGS method.

A new imprinted gene has been discovered in mice using the technique of restriction landmark genomic scanning (RLGS) with methylation sensitive enzymes. Eight out of 3,100 strain-specific NotI and BssHII spots were identified as imprinted in reciprocal F1 hybrids. Subsequently, we isolated a genomic clone for one locus on proximal chromosome 11 near the Glns locus, an imprinted region in uniparental disomic mice, and its corresponding cDNA clone. Expression of this transcript from the paternal allele was established using RT-PCR of reciprocal F1-hybrid mice. The amino-acid sequence deduced from the cDNA showed significant homology to the U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit.

Identification of Grf1 on mouse chromosome 9 as an imprinted gene by RLGS-M.

Normal mammalian development requires a diploid combination of both haploid parental genomes. Uniparental disomy for certain segments of specific chromosomes results in aberrant development or prenatal lethality, indicating that the parental genomes have undergone modifications during gametogenesis. These modifications result in parent-of-origin specific expression for some genes, a phenomenon called genomic imprinting. Recent work with DNA methyltransferase deficient mice showed that differential methylation is the probable basis of the imprinted character of several genes. Screening for endogenous imprinted loci using restriction landmark genomic scanning with methylation sensitive enzymes (RLGS-M) identified eight imprinted RLGS (Irigs) candidate loci. Molecular analysis of the genomic region of one of the loci (Irigs2) resulted in the discovery of the paternally imprinted U2afbp-rs gene within a previously identified imprinted region on mouse chromosome 11 (refs 5, 7). This paper describes the characterisation of a novel imprinted RLGS-M locus, Irigs3, on mouse chromosome 9 (ref. 6). Within this locus we identified the Grf1 (also called Cdc25Mm) gene, which is homologous to the RAS-specific guanine nucleotide exchange factor gene, CDC25, in Saccharomyces cerevisiae. Grf1 is located about 30 kb downstream of the methylation imprinted site, identified by RLGS-M, and shows paternal allele specific expression in mouse brain, stomach and heart. Our results indicate that imprinting may have a role in regulating mitogenic signal transduction pathways during growth and development.

Circulating anti-double-stranded DNA antibody-secreting cells in patients with systemic lupus erythematosus: a novel biomarker for disease activity.

Antibodies against double-stranded DNA (dsDNA) are widely used to diagnose systemic lupus erythematosus (SLE) and evaluate its activity in patients. This study was undertaken to examine the clinical utility of circulating anti-dsDNA antibody-secreting cells for evaluating SLE patients. Anti-dsDNA antibody-secreting cells quantified using an enzyme-linked immunospot assay were detected in the spleen, bone marrow and peripheral blood from MRL/lpr but not in control BALB/c mice. Circulating anti-dsDNA antibody-secreting cells were detected in 29 (22%) of 130 patients with SLE, but in none of 49 with non-SLE connective-tissue disease or 18 healthy controls. The presence of circulating anti-dsDNA antibody-secreting cells was associated with persistent proteinuria, high SLE disease activity index and systemic lupus activity measures, and a high serum anti-dsDNA antibody titre measured with an enzyme-linked immunosorbent assay. The positive predictive value for active disease was 48% for circulating anti-dsDNA antibody-secreting cells versus 17% for serum anti-dsDNA antibodies. A prospective cohort of patients with circulating anti-dsDNA antibodies and inactive SLE showed that the cumulative disease flare-free rate was significantly lower in patients with than without circulating anti-dsDNA antibody-secreting cells (p < 0.001). Circulating anti-dsDNA antibody-secreting cells are a useful biomarker for assessing disease activity in SLE patients.

Remimazolam anaphylaxis confirmed by serum tryptase elevation and skin test.

Anaphylactic reactions during the induction of general anaesthesia are rare. Anaesthetists should determine the pathogenesis of anaphylaxis in order to establish appropriate treatment and prevent recurrence. Very little clinical information has been published to date about anaphylaxis induced by the recently launched drug remimazolam. A 78-year-old man, scheduled for elective surgery for colon cancer, became profoundly hypotensive and hypoxic shortly following the induction of general anaesthesia with remimazolam, remifentanil and rocuronium. His physiological derangement was successfully managed with adrenaline, vasopressors and intravenous fluid resuscitation. His serum tryptase level was significantly elevated and an intradermal test with diluted remimazolam revealed a positive reaction, confirming the diagnosis of anaphylaxis. We believe this is the first case report of remimazolam-induced anaphylactic shock diagnosed with a serum tryptase elevation and positive skin test.

Multiparameter evaluation of acrylamide HEMA alternative monomers in 2-step adhesives.

OBJECTIVE: As frequently added to adhesives, the mono-functional monomer 2-hydroxyethyl methacrylate (HEMA) acts as co-solvent and improves surface wetting. Nevertheless, HEMA promotes watersorption and hydrolysis at adhesive interfaces, affecting bond durability to dentin. This study investigated if two acrylamide co-monomer alternatives could replace HEMA in experimental adhesive-resin formulations as part of 3/2-step universal adhesives applied, respectively, in etch-and-rinse (E&R) and self-etch (SE) bonding modes. METHODS: Upon priming dentin with the 10-MDP-based Clearfil SE Bond 2' primer ('C-SE2p'; Kuraray Noritake), three experimental adhesive resins, consisting of 50 wt.% Bis-GMA, 15 wt.% TEGDMA, and either 35 wt.% diethyl acrylamide ('DEAA'), hydroxyethyl acrylamide ('HEAA') or HEMA ('HEMA+'), were applied. The control HEMA-free adhesive resin contained 60 wt.% Bis-GMA and 40 wt.% TEGDMA ('HEMA-'). All adhesives were evaluated for 'immediate' and 'aged' micro-tensile bond strength (µTBS) to dentin upon, respectively, 1-week (1w) and 6-month (6m) water storage, TEM adhesive-dentin interfacial interaction, 24-h and 6m three-point bending, contact-angle wetting, viscosity and watersorption. RESULTS: Linear mixed-effects model statistics revealed significantly better bonding performance of the adhesives applied in E&R than SE mode, except for DEAA_1w, with the highest µTBSs recorded for DEAA and HEMA- applied in SE mode. In E&R mode, aging did not significantly reduce DEAA's µTBS. Best wetting on primed dentin was recorded for HEMA+, significantly better than DEAA, further HEAA and HEMA-, these directly related to their viscosity. HEAA absorbed significantly more water than all other adhesive-resin formulations. HEMA->DEAA>HEAA>HEMA+ was the significant order for 6m bending strength. CONCLUSIONS: The acrylamide co-monomer DEAA could replace HEMA, while HEAA not.

Meta-analysis of 32 genome-wide linkage studies of schizophrenia.

A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

Psychotic-like experiences are associated with suicidal feelings and deliberate self-harm behaviors in adolescents aged 12-15 years.

OBJECTIVE: Psychotic disorders are a significant risk factor for suicide, especially among young people. Psychotic-like experiences (PLEs) in the general population may share an etiological background with psychotic disorders. Therefore, the present study examined the association between PLEs and risk of suicide in a community sample of adolescents. METHOD: Psychotic-like experiences, suicidal feelings, and self-harm behaviors were studied using a self-report questionnaire administered to 5073 Japanese adolescents. Depression and anxiety were evaluated using the 12-item General Health Questionnaire (GHQ). RESULTS: The presence of PLEs was significantly associated with suicidal feelings (OR = 3.1, 95% CI = 2.2-4.5) and deliberate self-harm behaviors (OR = 3.1, 95% CI = 2.0-4.8) after controlling for the effects of age, gender, GHQ-12 score, victimization, and substance use. Suicidal feelings and behaviors were more prevalent in subjects with a greater number of PLEs. CONCLUSION: Psychotic-like experiences may increase the risk of suicidal problems among adolescents.

Single nucleotide polymorphism of interleukin-1beta associated with Helicobacter pylori infection in immune thrombocytopenic purpura.

To examine the role of genetic factors in development of immune thrombocytopenic purpura (ITP) in association with Helicobacter pylori infection, gene polymorphisms within the loci for human leukocyte antigen class II, interleukin (IL)-1beta (-511), tumor necrosis factor-beta (+252), immunoglobulin (Ig)G1 heavy chain (+643), and Igkappa light chain (+573) were determined in 164 adults with ITP and 75 healthy controls. Of these gene polymorphisms, the IL-1beta (-511) T allele was less frequently detected in H. pylori-infected than in H. pylori-uninfected (58% vs 81%, P = 0.01, odds ratio = 0.31) ITP patients diagnosed before age 50. These findings suggest that a single nucleotide polymorphism within the IL-1beta (-511) may affect susceptibility to early-onset ITP associated with H. pylori infection.

[Aortitis syndrome with repeated restenoses of a drug eluting stent].

The patient was a 49-year-old female who developed acute myocardial infarction of the right coronary artery in August 2005. In a short period of time, the patient had restenosis repeatedly after percutaneous coronary intervention (PCI). Restenosis could not be prevented even with a drug eluting stent (DES), and thus, off-pump coronary artery bypass grafting (OPCAB) was performed. The diagnosis of aortitis syndrome was made due to protracted postoperative inflammation. Aortitis syndrome was determined to be the main cause of repeated restenosis. This case was a middle-aged female who had restenosis in a short period of time, and aortitis syndrome should have been included in the differential diagnosis. Although some positive results have been reported on DES placement for coronary lesions of aortitis syndrome, DES was completely ineffective in our patient. Further studies with more patients are necessary to examine the effectiveness of DES.

[Anomalous origin of the right coronary artery from the ascending aorta].

The patient was a 77-year-old man. In June 2008, he underwent off-pump coronary artery bypass (OPCAB) for unstable angina Intraoperative epiaortic echo showed an anomalous origin of theright coronary artery from the ascending aorta 4 cm above the sinotubular junction (STJ). The right coronary artery traveled through the planned proximal anastomotic site of the saphenous vein graft (SVG). If diagnosis of the anomalous origin of the right coronary artery had not been made, there would have been a high likelihood that the right coronary artery could have been injured. Thus, the usefulness of epiaortic echo was reaffirmed. An anomalous origin of the coronary artery is a rare congenital anomaly and its incidence is approximately 1%. An anomalous origin of the right coronary artery is very rare from the ascending aorta 4 cm above the STJ and only a few cases have been reported. An anomalous origin of the coronary artery can cause serious complications affecting the prognosis after open heart surgery. Thus, such an anomalous origin needs to be considered in preoperative evaluation.

The timing of face selectivity and attentional modulation in visual processing.

Despite the complete imprint of a visual scene on the retina, the brain selects particular items for further processing. However, there is considerable debate about when and where the first attentional effects take hold in the cortex. We examined the timing of face specificity and attentional influences in the primary/secondary visual cortex (V1/V2) and in the fusiform gyrus (FG) in two experiments using magnetoencephalography (MEG). In experiment 1, using a passive viewing task, we identified three components in response to "Face," "Hand," and "Shoe" stimuli bilaterally in the FG: M(FG)100, M(FG)170, and M(FG)200-all showing a stronger preference for faces. The timing of these three activations of the FG is consistent with earlier studies claiming distinct stages of processing of visual stimuli in the first 300 ms. In experiment 2, subjects performed a gender-discrimination task on either faces or hands, drawing attention to only one of the two object categories. In addition to the previously identified three components in FG, here we found object-selective attentional enhancement first appearing in V1/V2 at around 170 ms, and then in FG at around 200 ms, i.e. concurrent with the third component. No attentional effects were evident on the first or second magnetoencephalography components. These findings may indicate that the visual input for an object is first encoded and matched to an attended "cue" object held in mind. When the attended and encoded objects match, a third stage involving attentive processing is enhanced.

Overexpression of RegIV in peritoneal dissemination of gastric cancer and its potential as A novel marker for the detection of peritoneal micrometastasis.

BACKGROUND: Regenerating gene type IV (RegIV) is a candidate marker for cancer and inflammatory bowel disease. In this study, its potential as a novel marker for the detection of gastric cancer peritoneal micrometastases was examined. PATIENTS AND METHODS: RegIV mRNA levels in the peritoneal washes of 95 gastric cancer patients and 22 with benign disease were quantified by real-time RT-PCR. To examine whether expression of RegIV enhance tumorigenicity or not, thirty two mice were injected intraperitoneally or subcutaneously with RegIV transfectants of TMK-1 cells, parental TMK-1 cells, or neomycin control transfectants. RESULTS: RegIV expression was markedly higher in patients with peritoneal metastases compared to those without. The level of RegIV mRNA in gastric cancer patients was related to the extent of wall penetration. A cut-off value for RegIV-positive expression was based on an analysis of negative control patients with benign disease, and gastric cancer patients above the cut-off value constituted the micrometastasis (MM+) group. Based on this criteria, 3 out of 43 T1 or T2 cases were MM+ (93% specificity). Among 15 patients with peritoneal dissemination (7 out of 15 cases were positive by cytology), 14 cases were positive for RegIV expression (93% sensitivity), while analysis of carcinoembryonic antigen (CEA) mRNA failed to detect micrometastases in 4 cases (73% sensitivity). Combined analysis of CEA and RegIV improved the accuracy of diagnosis to 100%. The prognosis of RegIV-positive cases was significantly worse than that of RegIV-negative cases. Multivariate analysis using the Cox proportional hazards model suggested that RegIV may be an independent prognostic factor. Stable expression of RegIV significantly enhanced peritoneal metastasis in an animal model of gastric cancer. CONCLUSION: These findings suggest that RegIV mRNA expression has the potential to serve as a novel marker for detecting peritoneal dissemination in gastric cancer.

Antioxidant biofactor, a processed grain food, inhibits iron nitrilotriacetate-induced renal tumorigenesis, hyperproliferative response, and oxidative damage.

We have evaluated the effect of dietary antioxidant, antioxidant biofactor (a processed grain food), on iron nitrilotriacetate-induced renal tumorigenesis, hyperproliferative response, and oxidative damage. In tumorigenesis studies, iron nitrilotriacetate alone treatment resulted in a development of 75% renal cell tumor incidence, whereas, in the group of animals fed with antioxidant biofactor diet and treated with iron nitrilotriacetate, only 43% of renal cell tumor incidence was observed. In oxidative damage studies, the decrease in the level of renal glutathione and antioxidant enzymes induced by iron nitrilotriacetate was significantly reversed by antioxidant biofactor diet pretreatment in a dose-dependent manner (18-71% recovery, P < 0.05). Antioxidant biofactor diet pretreatment also resulted in a dose-dependent inhibition (35-49% inhibition, P < 0.05) of iron nitrilotriacetate-induced lipid peroxidation as measured by thiobarbituric acid reactive substances formation in renal tissues. Similarly, in hyperproliferation studies, antioxidant biofactor diet pretreatment showed a strong inhibition of iron nitrilotriacetate-induced renal ornithine decarboxylase activity (18-54% inhibition, P < 0.05). In addition, antioxidant biofactor fed diet pretreatment also protected the kidney tissues against observed histopathological alterations. From this data, it can be concluded that antioxidant biofactor diet can abrogate the toxic and tumor promoting effects of iron nitrilotriacetate and can serve as a potent chemopreventive agent to suppress oxidant-induced tissue injury and tumorigenesis.