Intra-Day Variation of Urinary Nuclear Matrix Protein 22

Nuclear Matrix Protein 22 (NMP22), a urinary tumor marker for urothelial cancers, is directly released into the urine from the nucleus after cell death, Accordingly, values of NMP22 do not requlre adjustment using other substances such as urinary creatinine. On the other hand, its values might vary according to urine concentration. This study investigated the intra-day variation in the urinary level of NMP22. NMP22 and urinary creatinine were measured in a 24-hour urine sample and 4 spot urine samples obtained from 20 inpatients (10 with bladder cancer, and 10 with non-urothelial cancer or benign tumors). The spot urine samples were collected at 6 a.m., 10 a.m., 2p.m. and 9 p.m. There were no significant differences in NMP22 values between the 24-hour and spot samples in all patients. Out of 10 bladder cancer patients, 6 had positive 24-hour samples. Among these 6 patients, only 3 had 4 positive spot samples (>12.O U/ml): one had 3 positive samples, and 2 had one positive sample. Among the controls, only one patient with renal cancer had a positive 24-hour sample. Only 3 controls, 2 With prostatic cancer and one with renal cancer, had a single positive spot sample. The highest margin between the maximum and minimum levels in the 4 spot samples was 237.8 U/ml in the bladder cancer patients and 16.6 U/ml in the controIs. When the ratios of NMP22 and urinary creatinine values for the 24-hour to spot samples were calculated in each patient, a significant correlation was observed between the ratios of NMP22 and urinary creatinine (r=0.575, p<0.001). The urinary level of NMP22 shows intra-day variation and might be affected by the extent of the concentration of urine samples. The measurement results must be judged with this in mind, especially when judging the results around the cut-off value

Maackiain Suppresses H1R and IL-4 Gene Transcriptions

Kujin contains antiallergic compounds that inhibit upregulation of histamine H1 receptor (H1R) and interleukin (IL)‐4 gene expression. However, the underlying mechanism remains unknown. We sought to identify a Kujin‐derived antiallergic compound and investigate its mechanism of action. The H1R and IL‐4 mRNA levels were determined by real‐time quantitative RT‐PCR. To investigate the effects of maackiain in vivo, toluene‐2,4‐diisocyanate (TDI)‐sensitized rats were used as a nasal hypersensitivity animal model. We identified (−)‐maackiain as the responsible component. Synthetic maackiain showed stereoselectivity for the suppression of IL‐4 gene expression but not for H1R gene expression, suggesting distinct target proteins for transcriptional signaling. (−)‐Maackiain inhibited of PKCδ translocation to the Golgi and phosphorylation of Tyr311 on PKCδ, which led to the suppression of H1R gene transcription. However, (−)‐maackiain did not show any antioxidant activity or inhibition of PKCδ enzymatic activity per se. Pretreatment with maackiain alleviated nasal symptoms and suppressed TDI‐induced upregulations of H1R and IL‐4 gene expressions in TDI‐sensitized rats. These data suggest that (−)‐maackiain is a novel antiallergic compound that alleviates nasal symptoms in TDI‐sensitized allergy model rats through the inhibition of H1R and IL‐4 gene expression. The molecular mechanism underlying its suppressive effect for H1R gene expression is mediated by the inhibition of PKCδ activation

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Moisture content estimation of green softwood logs of three species based on measurements of flexural vibration

Abstract The moisture contents of sugi (Cryptomeria japonica), todomatsu (Abies sachalinensis) and hinoki (Chamaecyparis obtusa) logs were estimated using a method of moisture content estimation proposed in our previous study. In the course of estimation, it was revealed that the regression line of the correlation between specific dynamic Young’s modulus (E/ρ) and tangent loss (tan δ) of green wood was different from that of moisture-conditioned wood and showed species dependency, both of which are not previously reported. Regression lines at the fiber saturation point (FSP) were constructed for each species by measuring E/ρ and tan δ from the flexural vibration of green small specimens and correcting the E/ρ values at their own moisture contents into E/ρ values at the FSP. The correlation of green wood in this study was different from that reported in previous studies of moisture-conditioned wood near the FSP. The correlations of sugi and hinoki were similar, whereas those of sugi and todomatsu were different despite no previous report of species dependency in air-dried wood. The moisture contents 86 logs (not those used to prepare small specimens) were estimated using regression lines of each species. The standard deviation of the difference between the estimated moisture content and the measured moisture content was 15.7%. A systematic error of 25.9% in moisture content was attributed to the different methods of specimen support used for small specimens and logs

The formation of spiro-bridged dimers of cycloctane-1,2-dicarbonyl compounds via domino aldol-cycloalkylation

Starting from the corresponding 8-membered cyclic 1,2-diones, spiro-bridged cyclic dimers were prepared in moderate to good yields via barium oxide/hydroxide mediated coupling, followed by in situ methylation with dimethyl sulfate