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.

Medial meniscus posterior root tear induces pathological posterior extrusion of the meniscus in the knee-flexed position: An open magnetic resonance imaging analysis.

BACKGROUND: A medial meniscus posterior root tear (MMPRT) is defined as an injury to the posterior meniscal insertion on the tibia. In MMPRT, the medial meniscus (MM) hoop function is damaged, and the MM undergoes a medial extrusion into the interior from the superior articular surface of the tibia. However, the details of MM position and movement during knee joint movement are unclear in MMPRT cases. The present study aims to evaluate MM position and movement via magnetic resonance imaging (MRI) examination of the MM posterior extrusion (MMPE) at knee flexion angles of 10° and 90°. We hypothesized that, during knee flexion, the MM will shift to the posterior and the posterior extrusion will increase compared to that when the knee is extended. MATERIALS AND METHODS: Twenty-four patients were diagnosed with symptomatic MMPRT on open MRI examination. Preoperative MMPE, anteroposterior interval (API) of the MM, and MM medial extrusion (MMME) at knee flexion angles of 10° and 90° were measured. RESULTS: For patients with MMPRT, the MMPE increased from -4.77±1.43mm to 3.79±1.17mm (p<0.001) when the knee flexion angle increased from 10° to 90°. Further, flexing the knee from 10° to 90° decreased the API of the MM from 20.19±4.22mm to 16.41±5.14mm (p<0.001). MMME showed no significant change between knee flexion angles of 10° and 90°. DISCUSSION: This study demonstrated that, in cases of MMPRT, the MMPE clearly increases when the knee is flexed to 90°, while MMME does not change. Our results suggest that open MRI examination can be used to evaluate the dynamic position of the posterior MM by scanning the knee as it flexes to 90°. LEVEL OF EVIDENCE: IV: retrospective cohort study.

Medial meniscus extrusion correlates with disease duration of the sudden symptomatic medial meniscus posterior root tear.

INTRODUCTION: Medial meniscus posterior root tear (MMPRT) leads to abnormal biomechanics of the knee by inducing the medial meniscus extrusion (MME). However, a time-dependent increase of the MME is not fully elucidated in patients suffering from the acute MMPRT. The aim of this study was to investigate the relationships among disease duration of the MMPRT and severity of the MME. We hypothesized that MME measurement correlates with disease duration after a sudden onset of the minor traumatic MMPRT during the short-term follow-up period. MATERIALS AND METHODS: Forty-six patients who had an accurate episode of the posteromedial painful popping were investigated. All the patients were diagnosed having a symptomatic MMPRT with magnetic resonance imaging (MRI) examinations. Absolute MME was measured using MRI scans within 12 months after painful popping events. A correlation coefficient between duration from injury to MRI examination and absolute MME was evaluated. RESULTS: Mean absolute MME was 4.5±1.6mm (range, 1.1-8.8mm) on MRI measurements. A good correlation was observed between MME measurement and duration from injury to MRI examination (R2=0.612). The best-fit equation for predicting each value was: MME=0.014×disease duration+3.288mm. DISCUSSION: This study demonstrated that absolute MME increases progressively within the short duration after the onset of symptomatic MMPRT. Our results suggest that preoperative MME assessment may be important in determining disease duration and treatment strategy of the MMPRT. LEVEL OF EVIDENCE: Retrospective cohort study level IV.

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.

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.

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.

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.

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.

Meta-analysis of genome-wide association studies for panic disorder in the Japanese population.

Panic disorder (PD) is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Due to the lack of power in previous association studies, genes that are truly associated with PD might not be detected. In this study, we conducted a genome-wide association study (GWAS) in two independent data sets using the Affymetrix Mapping 500K Array or Genome-Wide Human SNP Array 6.0. We obtained imputed genotypes for each GWAS and performed a meta-analysis of two GWAS data sets (718 cases and 1717 controls). For follow-up, 12 single-nucleotide polymorphisms (SNPs) were tested in 329 cases and 861 controls. Gene ontology enrichment and candidate gene analyses were conducted using the GWAS or meta-analysis results. We also applied the polygenic score analysis to our two GWAS samples to test the hypothesis of polygenic components contributing to PD. Although genome-wide significant SNPs were not detected in either of the GWAS nor the meta-analysis, suggestive associations were observed in several loci such as BDKRB2 (P=1.3 × 10(-5), odds ratio=1.31). Among previous candidate genes, supportive evidence for association of NPY5R with PD was obtained (gene-wise corrected P=6.4 × 10(-4)). Polygenic scores calculated from weakly associated SNPs (P<0.3 and 0.4) in the discovery sample were significantly associated with PD status in the target sample in both directions (sample I to sample II and vice versa) (P<0.05). Our findings suggest that large sets of common variants of small effects collectively account for risk of PD.

Replication and meta-analysis of TMEM132D gene variants in panic disorder.

A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n = 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n = 1038 cases and n = 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations.

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.