Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with possible complication of thrombotic microangiopathy.

This case study illustrates a 63-year-old Japanese woman who presented with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis. She was administered a therapeutic regimen consisting of corticosteroids, tacrolimus, and cyclophosphamide. However, after a month of treatment, symptoms of confusion and depressive tendencies emerged, followed by the manifestation of hematuria, thrombocytopenia, and fragmented erythrocytes. A disintegrin-like and metalloprotease with thrombospondin type 1 motifs 13 activity was 45%. Thrombotic microangiopathy was contemplated, yet a definitive diagnosis remained elusive. She died 2 months after admission. Although the occurrence of thrombotic microangiopathy in patients with dermatomyositis is rare, the prognosis is poor, emphasizing the importance of prompt diagnosis and treatment.

A large-scale genomically predicted protein mass database enables rapid and broad-spectrum identification of bacterial and archaeal isolates by mass spectrometry.

MALDI-TOF MS-based microbial identification relies on reference spectral libraries, which limits the screening of diverse isolates, including uncultured lineages. We present a new strategy for broad-spectrum identification of bacterial and archaeal isolates by MALDI-TOF MS using a large-scale database of protein masses predicted from nearly 200,000 publicly available genomes. We verify the ability of the database to identify microorganisms at the species level and below, achieving correct identification for > 90% of measured spectra. We further demonstrate its utility by identifying uncultured strains from mouse feces with metagenomics, allowing the identification of new strains by customizing the database with metagenome-assembled genomes.

Assessing prognostic factors correlating with response to nintedanib for connective tissue disease-associated interstitial lung disease: A real-world single-center study.

OBJECTIVE: For patients with connective tissue disease-associated interstitial lung disease (CTD-ILD), early medical intervention would be desirable. This study analyzed the real-world, single-center use of nintedanib for CTD-ILD patients. METHODS: Patients with CTD who received nintedanib from January 2020 to July 2022 were enrolled. Medical records review and stratified analyses of the collected data were conducted. RESULTS: Reduction in the percentage of predicted forced vital capacity (%FVC) was seen in the elderly group (>70 years; P = .210), males (P = .027), the late group who started nintedanib >80 months after confirmation of an ILD disease activity (P = .03), the severe %DLco (diffusing capacity for carbon monoxide as a percentage of predicted) group (<40%; P = .20), the group who had extensive pulmonary fibrosis at the beginning of nintedanib (pulmonary fibrosis score >35%), and the low-dose group (nintedanib 50-100 mg/d; P = .40). %FVC did not decrease by >5% in the young group (<55 years), the early group who started nintedanib within 10 months after confirmation of an ILD disease activity, and the group whose pulmonary fibrosis score at the beginning of nintedanib was <35%. CONCLUSION: It is important to diagnose ILD early and start antifibrotic drugs with proper timing for cases in need. It is better to start nintedanib early, especially for patients at risk (>70 years old, male, <40% DLco, and >35% areas of pulmonary fibrosis).

Therapeutic angiogenesis for patients with no-option critical limb ischemia by adipose-derived regenerative cells: TACT-ADRC multicenter trial.

BACKGROUND: Patients with critical limb ischemia (CLI) still have a high rate of lower limb amputation, which is associated with not only a decrease in quality of life but also poor life prognosis. Implantation of adipose-derived regenerative cells (ADRCs) has an angiogenic potential for patients with limb ischemia. OBJECTIVES: We investigated safety, feasibility, and efficacy of therapeutic angiogenesis by cell transplantation (TACT) of ADRCs for those patients in multicenter clinical trial in Japan. METHODS: The TACT-ADRC multicenter trial is a prospective, interventional, open-labeled study. Patients with CLI (Fontaine class III-IV) who have no other option for standard revascularization therapy were enrolled in this study. Thirty-four target ischemic limbs of 29 patients were received freshly isolated autologous ADRCs implantation. RESULTS: The overall survival rate at a post-operative period and at 6 months follow-up was 100% at any time points. As a primary endpoint for efficacy evaluation, 32 limbs out of 34 (94.1%) were free from major amputation for 6 months. Numerical rating scale (from 6 to 1) as QOL score, ulcer size (from 317 mm2 at to 109 mm2), and 6-min walking distance (from 255 to 369 m) improved in 90.6%, 83.3%, and 72.2% patients, respectively. CONCLUSIONS: Implantation of autologous ADRCs could be safe and effective for the achievement of therapeutic angiogenesis in the multicenter settings, as a result in no major adverse event, optimal survival rate, and limb salvage for patients with no-conventional option against critical limb ischemia. TRN: jRCTb040190118; Date: Nov. 24th, 2015.

The transcription factor complex LMO2/TAL1 regulates branching and endothelial cell migration in sprouting angiogenesis.

The transcription factor complex, consisting of LMO2, TAL1 or LYL1, and GATA2, plays an important role in capillary sprouting by regulating VEGFR2, DLL4, and angiopoietin 2 in tip cells. Overexpression of the basic helix-loop-helix transcription factor LYL1 in transgenic mice results in shortened tails. This phenotype is associated with vessel hyperbranching and a relative paucity of straight vessels due to DLL4 downregulation in tip cells by forming aberrant complex consisting of LMO2 and LYL1. Knockdown of LMO2 or TAL1 inhibits capillary sprouting in spheroid-based angiogenesis assays, which is associated with decreased angiopoietin 2 secretion. In the same assay using mixed TAL1- and LYL1-expressing endothelial cells, TAL1 was found to be primarily located in tip cells, while LYL1-expressing cells tended to occupy the stalk position in sprouts by upregulating VEGFR1 than TAL1. Thus, the interaction between LMO2 and TAL1 in tip cells plays a key role in angiogenic switch of sprouting angiogenesis.

East Asian variant aldehyde dehydrogenase type 2 genotype exacerbates ischemia/reperfusion injury with ST-elevation myocardial infarction in men: possible sex differences.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies toxic aldehydes generated during ischemia/reperfusion (I/R) injury in ST-elevation myocardial infarction (STEMI). The deficient variant ALDH2 genotype (ALDH2*2) is prevalent among East Asians. Whether ALDH2*2 exacerbates I/R injury of in patients with STEMI is not known. The study subjects comprised 218 Japanese patients with STEMI (158 men and 60 women, mean age 67.9 ± 11.9) who underwent successful percutaneous coronary intervention. Of these, 120 (55.0%) were the carriers of variant ALDH2*2 and 98 (45.0%) those of wild ALDH2*1/*1 on genotyping. There were no differences in clinical characteristics between the ALDH2*2 and ALDH2*1/*1 group except lower alcohol habit (14.2% vs 46.3%, P < 0.001) in the ALDH2*2 group. The peak plasma levels of creatine phosphokinase myocardial binding (CKMB), a marker of myocardial injury, however, were significantly higher in the patients with ALDH2*2 than in those with ALDH2*1/*1 [a median 275.0 (175.8-407.5) vs 177.5 (126.9-344.3) U/L, P = 0.001] among men but not among women (P = 0.811). There was a significant interaction between men (male sex) and ALDH2*2 for I/R injury (χ2 = 4.425, P = 0.040). The variant ALDH2*2 was associated with more severe I/R injury than the wild ALDH2*1/*1 in STEMI patients in men with possible sex differences.

Premature Acute Myocardial Infarction in a Young Patient With Sitosterolemia.

Sitosterolemia is a rare, inherited, autosomal recessive disorder of lipid metabolism characterized by increased levels of plant sterols, such as sitosterol and campesterol, xanthomas, and accelerated atherosclerosis. In a 15-year-old boy exhibiting ST-elevation acute myocardial infarction, lipid panels, including plant sterol, and genetic testing for the ATP-binding cassette sub-family G member 5 (ABCG5) gene mutation, confirmed the diagnosis of sitosterolemia. A comprehensive lipid panel and genetic testing should be considered in patients with premature coronary artery disease to prevent disease progression through dietary and pharmacologic interventions specific to sitosterolemia.

La sitostérolémie est une maladie génétique rare à transmission autosomique récessive touchant le métabolisme des lipides, qui est caractérisée par une augmentation des taux de stérols végétaux comme le sitostérol et le campestérol, la présence de xanthomes et une athérosclérose accélérée. Chez un garçon âgé de 15 ans ayant subi un infarctus aigu du myocarde avec élévation du segment ST, le diagnostic de sitostérolémie a été confirmé par un bilan lipidique comprenant un dosage des stérols d'origine végétale et un test génétique de dépistage de la mutation du gène ABCG5 (ATP-binding cassette sub-family G member 5). Un bilan lipidique exhaustif et un test génétique doivent être envisagés chez les patients présentant une coronaropathie prématurée afin de prévenir la progression de la maladie grâce à des interventions d'ordre tant diététique que pharmacologique propres à la sitostérolémie.

Identification of biogenic amines involved in photoperiod-dependent caste-fate determination during the adult stage in a temperate paper wasp.

In the temperate paper wasp Polistes jokahamae, caste is influenced by photoperiod during the adult stage, but the mechanisms underlying the caste-fate determination system have been unclear. We measured the brain levels of monoamines and related substances in females kept isolated for two weeks under different photoperiods. Except for in the first-emerging group, the females developed ovaries under long-day conditions, whereas they stored lipids under short-day conditions. The levels of tyramine in the brain were significantly higher under long-day than under short-day conditions and positively correlated with maximum oocyte lengths. These results suggest that tyramine was produced in response to long daylength during the adult stage and associated with ovarian development, which is the principal characteristic of reproductive workers. There was also a significant positive correlation between dopamine levels in the brain and maximum oocyte length, independent of photoperiod, suggesting that dopamine is involved in reproductive function with tyramine resulting in the induction of reproductive workers. Meanwhile, higher levels of tryptophan in the brain were found in short-day conditions and positively correlated with lipid stores. However, serotonin synthesized from tryptophan and N-acetylserotonin were not associated with lipid stores without photoperiodic responses, suggesting that tryptophan is involved in the physiological changes toward gyne under short daylength, independently of serotonin signaling. In conclusion, tyramine and tryptophan are candidates for mediating photoperiod-dependent caste-fate determination in P. jokahamae: the former is involved in generating the worker caste while the latter is involved in generating the gyne caste.

Feasibility of simultaneous 99mTc-tetrofosmin and 123I-BMIPP dual-tracer imaging with cadmium-zinc-telluride detectors in patients undergoing primary coronary intervention for acute myocardial infarction.

BACKGROUND: Simultaneous dual-tracer imaging using isotopes with close photo-peaks may benefit from improved properties of cadmium-zinc-telluride (CZT)-based scanners. METHODS: Thirty patients having undergone primary percutaneous coronary intervention for acute myocardial infarction underwent single-(99mTc-tetrofosmin (TF) or 123I-BMIPP first) followed by simultaneous 99mTc-TF /123I-BMIPP dual-tracer imaging using a Discovery NM/CT 670 CZT. The values for the quantitative gated-SPECT (QGS) and the quantitative perfusion SPECT (QPS) were assessed. RESULTS: The intra-class correlation (ICC) coefficients between the single- and dual-tracer imaging were high in all the QGS and QPS data (Summed motion score: 0.95, summed thickening score: 0.94, ejection fraction: 0.98, SRS for 99mTc-TF: 0.97/ for 123I-BMIPP: 0.95). Wall motion, wall thickening and rest scores per coronary-territory-based regions were also comparable between the single- and dual imaging (ICC coefficient > 0.91). The interrater concordance in the visual analysis for the infarction and perfusion-metabolism mismatch was significant for the global and regional left ventricle (P < 0.001). CONCLUSION: The quantitative/semi-quantitative values for global and regional left-ventricular function, perfusion, and fatty acid metabolism were closely comparable between the dual-tracer imaging and the single-tracer mode. These data suggests the feasibility of the novel CZT-based scanner for the simultaneous 99mTc-TF /123I-BMIPP dual-tracer acquisitions in clinical settings.

Relationship between Soluble (pro)Renin Receptor and Renin Activity in Patients with Severe Heart Failure.

The (pro)renin receptor ((P)RR), which evokes renin activity with prorenin, is secreted extracellularly as soluble (P)RR (s(P)RR) and may participate in tissue renin-angiotensin system (RAS) activity in severe heart failure (HF) patients. The aim of this study was to determine whether s(P)RR is an adequate marker in severe HF patients treated with RAS inhibitors, beta-blockers, and tolvaptan. We enrolled 11 patients with severe HF between May 2013 and June 2014. First of all, furosemide of all patients was changed to tolvaptan with hydrochlorothiazide and then the treatment had been changed according to the patient's condition. After 1, 3, 6, and 12 months, the variance of s(P)RR, plasma renin activity (PRA), plasma renin concentration (PRC), brain natriuretic peptide (BNP) and their association was investigated. Furosemide was restarted in five patients and two patients suffered cardiac death. PRA/PRC and s(P)RR were unchanged (PRA: 10.7 ± 13.9 to 12.8 ± 8.5 ng/mL/h; PRC: 347.1 ± 577.5 to 148.3 ± 123.8 pg/mL; s(P)RR: 28.2 ± 19.3 to 33.4 ± 22.4 ng/mL) and had no significant correlations (PRA and s(P)RR: p = 0.36; PRC and s(P)RR: p = 0.35). There was a significant positive correlation with a high correlation coefficient (CC) between PRA and PRC (p < 0.0001, CC = 0.76), and a negative correlation with weak CC between BNP and s(P)RR (p = 0.01, CC = -0.45). In conclusion, s(P)RR was always high and had no correlations with disease state and PRA/PRC in severe HF patients.

Rationale and Design of Therapeutic Angiogenesis by Cell Transplantation Using Adipose-Derived Regenerative Cells in Patients With Critical Limb Ischemia　- TACT-ADRC Multicenter Trial.

Background: Despite the growing knowledge regarding optimal treatments for critical limb ischemia (CLI), there are still a considerable number of patients who have to undergo major limb amputation. Intramuscular injection of autologous adipose-derived regenerative cells (ADRCs) in these patients has shown therapeutic potential in improving tissue ischemia, in both preclinical and initial pilot studies. Here, we present a clinical protocol for ADRCs use in a multicenter trial. Methods and Results: The TACT-ADRC multicenter trial is a prospective, interventional, single-arm, open-labeled study at 8 hospitals in Japan, investigating the safety and feasibility of intramuscular injections of ADRCs and testing the hypothesis that this treatment promotes neovascularization and improves major amputation-free survival rates in patients with CLI who have no other treatment option. 40 patients with CLI will be enrolled and followed up from November 2015 to November 2020. Freshly isolated autologous ADRCs will be injected into the target ischemic limbs. Survival rate, adverse events, major limb amputation, ulcer size, 6-min walking distance, numerical rating scale, ankle-brachial pressure index, skin perfusion pressure and digital subtraction angiography will be evaluated at baseline and during 6 months' follow-up. Conclusions: This trial will demonstrate whether implantation of autologous ADRCs is a safe and effective method for therapeutic angiogenesis, resulting in an improvement in major amputation-free survival rates in patients with CLI.

Effects of long- and short-term experiences on stress during identification works of dead bodies: Rapid stress level measurement using voice.

OBJECTIVE: The mental health issues of personnel dealing with the deceased at times of disasters is a problem and techniques are needed that allow for real-time, easy-to-use stress checks. We have studied techniques for measuring mental state using voice analysis which has the benefit of being non-invasive, easy-to-use, and can be performed in real-time. For this study, we used voice measurement to determine the stress experienced during body identification training workshops for dentists. We studied whether or not stress levels were affected by having previous experience with body identification either in actual disaster settings or during training. DESIGN: Since participants training using actual dead bodies in particular are expected to suffer higher stress exposure, we also assessed their mental state pre- and post-training using actual dead bodies. RESULTS: The results confirmed marked differences in the mental state between before and after training in participants without any actual experience, between participants who engaged in training using manikins before actual dead bodies and participants who did not. CONCLUSIONS: These results suggest that, in body identification training, the level of stress when coming into contact with dead bodies varies depending on participants' experience and the training sequence. Moreover, it is believed that voice-based stress assessment can be conducted in the limited time during training sessions and that it can be usefully implemented in actual disaster response settings.

Anisotropic ultimate strength and microscopic fracture patterns during tensile testing in the dentin-enamel junction region.

The dentin-enamel junction (DEJ), which is the interface between the outer tooth enamel and the underlying dentin, has unique biomechanical properties that allow the two different materials to function together without fracture. The aim of this study was to investigate the anisotropic ultimate tensile strength of the DEJ. Twenty dumbbell-shaped samples were prepared from 10 extracted human molar teeth for tensile strength testing. The maximum tensile forces at fracture were measured in the direction parallel (10 samples) and perpendicular (10 samples) to the DEJ. The mean tensile strength of the samples was significantly higher under parallel forces (30.9±3.3 MPa) than under perpendicular forces (20.6±4.8 MPa; p<0.05). Our findings confirm the structural anisotropy of the DEJ.

Classification of Cutibacterium acnes at phylotype level by MALDI-MS proteotyping.

Cutibacterium acnes is a major commensal human skin bacteria. It is a producer of propionic acids that maintain skin acidic pH to inhibit the growth of pathogens. On the other hand, it is also associated with diseases such as acne vulgaris and sarcoidosis. C. acnes strains have been classified into six phylotypes using DNA-based approaches. Because several characteristic features of C. acnes vary according to the phylotype, the development of a practical method to identify these phylotypes is needed. For rapid identification of phylotypes for C. acnes strains, a matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) fingerprinting technique has been applied; however, some phylotypes have not been discriminated. We developed a high-throughput protein purification method to detect biomarker proteins by ultrafiltration. MALDI-MS proteotyping using profiling of identified biomarker peaks was applied for the classification of 24 strains of C. acnes, and these were successfully classified into the correct phylotypes. This is a promising method that allows the discrimination of C. acnes phylotypes independent of a DNA-based approach.

Addition of S-1 to radiotherapy for treatment of T2N0 glottic cancer: Results of the multiple-center retrospective cohort study in Japan with a propensity score analysis.

OBJECTIVES: This multicenter retrospective cohort study aimed to evaluate the significance of adding S-1 to radiotherapy (RT) for the treatment of T2N0 glottic cancer using a propensity score matched analysis in Japan. MATERIALS AND METHODS: This study was conducted on 287 patients with T2N0 glottic cancer who were treated with definitive RT or chemoradiotherapy with S-1 (S-1 RT) between April 2007 and March 2017. Propensity score matched analysis was performed to ensure the well-balanced characteristics of the groups of patients who received RT alone and S-1 RT. Overall, progression-free and laryngectomy-free survivals and local control and laryngeal preservation rates were compared. RESULTS: Fifty-four pairs of patients were selected after performing propensity score matched analysis. Clinical characteristics were well-balanced between the two groups. The overall survival of patients in the S-1 RT group was significantly better than those in the RT alone group (P = 0.008). The progression-free and laryngectomy-free survivals of patients in the S-1 RT group were also better than those in the RT alone group; however, the differences were not significant. In contrast, patients in the S-1 RT group had slightly lower local control and laryngeal preservation rates compared with those in the RT alone group. The incidence of dermatitis in the S-1 RT group was significantly higher than that in the RT alone group in the matched population (P = 0.013). CONCLUSIONS: The addition of S-1 to RT for the treatment of T2N0 glottic cancer was not associated with better local control and laryngeal preservation rates in this study.

Improved MALDI-MS method for the highly sensitive and reproducible detection of biomarker peaks for the proteotyping of Salmonella serotypes.

The rapid identification and classification of pathogenic microorganisms, including Salmonella enterica, is important for the surveillance and prevention of foodborne diseases. Matrix-assisted laser desorption\ionization time-of-flight mass spectrometry (MALDI-TOFMS) has been shown to be an effective tool for the rapid identification of microorganisms. In a previous report, a mass database consisting of 12 biomarker proteins, S8, L15, L17, L21, L25, S7, superoxide dismutase (SodA), peptidylprolyl cis-trans isomerase C, Gns, YibT, YaiA, and YciF, was introduced for the serotyping of S. enterica via MALDI-MS (Applied Microbiology and Biotechnology, 2017, 101, 8557-8569). However, the reproducibility of peak detection of biomarkers such as SodA at m\z 23 000 was poor. We report here an optimized MALDI-MS method for detecting these biomarkers with high sensitivity and reproducibility. The issue was solved by controlling the bacterial concentration at 1 × 10 to 1 × 102 MFU (3 × 106 to 3 × 107 CFU\µL, as calculated from the MFU), using the colony suspension supernatant obtained by centrifugation, and using matrix additives such as methylenediphosphonic acid and N-decyl-ß-D-maltopyranoside. We propose that the method including the above steps is one of the best for detecting biomarkers with high sensitivity and reproducibility.

Molecular identification of biwa trout (Oncorhynchus masou rhodurus) using PCR-RFLP method.

Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was used to identify meat from biwa trout (Oncorhynchus masou rhodurus), amago trout (Oncorhynchus masou ishikawae), yamame trout (Oncorhynchus masou masou), and rainbow trout (Oncorhynchus mykiss). PCR amplification was conducted using primers flanking conserved regions of NADH dehydrogenase subunits 4 and 5 (ND4-ND5) (2848 bp) and ND1 (1091 bp) genes of mitochondrial DNA following restriction digestion with the enzyme HaeIII. Although the segments of ND4-ND5 and ND1 genes showed intraspecies variation, the generation of DNA fragments larger than 300 bp and 160 bp following cleavage by HaeIII of ND4-ND5 and ND1, respectively, was efficient to differentiate the four species. Furthermore, this method was successful in species identification even when using PCR-amplified products obtained from thermally processed biwa trout samples. This sensitive technique can be utilized to reveal commercial fraud, where biwa trout is adulterated with meat from cheaper counterparts.

Shortened acquisition time in simultaneous 99mTc-tetrofosmin and 123I-ß-methyl-p-iodophenyl pentadecanoic acid dual-tracer imaging with cadmium-zinc-telluride detectors in patients undergoing primary coronary intervention for acute myocardial infarction.

OBJECTIVE: The use of cadmium-zinc-telluride-based scanners may increase the clinical feasibility of simultaneous dual-isotope imaging. In the current study, we sought to investigate a potential acquisition time in simultaneous Tc-tetrofosmin/I-ß-methyl-p-iodophenyl pentadecanoic acid dual-isotope imaging using a Discovery NM/CT 670 cadmium-zinc-telluride. METHODS: Simultaneous Tc-tetrofosmin/I-ß-methyl-p-iodophenyl pentadecanoic acid dual-isotope imaging was performed in 29 patients who had undergone primary percutaneous coronary intervention for acute myocardial infarction. Referenced images with an acquisition time of 65 s/view (16.25 min) were reframed to produce images with acquisition times of 33, 16, and 8 s/view. The values for the quantitative-gated single-photon emission computed tomography (SPECT) and the quantitative perfusion SPECT were compared. RESULTS: The quantitative-gated SPECT values for images with 33, 16, and 8 s/views showed good consistency with those for 65 s/view (the lower 95% confidence intervals for the intraclass correlation were ≥0.80). The quantitative perfusion SPECT values for Tc-tetrofosmin images with 33, 16, and 8 s/views also showed good consistency with those for 65 s/view; however, the quantitative perfusion SPECT values for I-ß-methyl-p-iodophenyl pentadecanoic acid images with an acquisition time of 8 s/view were not consistent with the reference acquisition time of 65 s/view. CONCLUSIONS: The quantitative-gated SPECT and quantitative perfusion SPECT values obtained from images with shorter acquisition times correlated with the values obtained from images with a reference acquisition time of 65 s/view; however, tracer-specific predisposition should be considered. These findings suggest that it is possible to reduce acquisition time when performing simultaneous Tc-tetrofosmin/I-ß-methyl-p-iodophenyl pentadecanoic acid dual-tracer imaging with the novel cadmium-zinc-telluride scanner.