Predictors of the Response to Tolvaptan Therapy and Its Effect on Prognosis in Cirrhotic Patients with Ascites

Aims: The vasopressin V2 receptor antagonist, tolvaptan, has been reported to be effective in cirrhotic patients with ascites. Here, we evaluated predictors of the response to tolvaptan. Methods: A total of 97 patients with cirrhosis (60 males; median age, 63 years) who had been treated for ascites with oral tolvaptan were enrolled. Tolvaptan efficacy was defined as urine volume increase of ≥500 mL or a urine volume ≥2000 mL/day on the day following treatment. Normalization of the serum sodium (Na) level after 1 week of treatment and the posttreatment survival rate was analyzed. Results: Tolvaptan therapy resulted in effective urination in 67% of patients. A multivariate analysis revealed that the blood urea nitrogen/creatinine (BUN/Cr) ratio and urinary Na/potassium (Na/K) ratio were predictive of the tolvaptan response (p <0.05). The serum Na level was 135 (121–145) mEq/L, and normal levels were recovered in 50.0% of the patients with an initial Na level of <135 mEq/L. The posttreatment survival rate was significantly higher in patients who responded to tolvaptan therapy (p <0.05). Conclusions: The combination of the initial BUN/Cr and urine Na/K ratios and a normalized serum Na level after 1 week was predictive of a favorable outcome to tolvaptan therapy

The Hayabusa Spacecraft Asteroid Multi-Band Imaging Camera: AMICA

The Hayabusa Spacecraft Asteroid Multiband Imaging Camera (AMICA) has acquired more than 1400 multispectral and high-resolution images of its target asteroid, 25143 Itokawa, since late August 2005. In this paper, we summarize the design and performance of AMICA. In addition, we describe the calibration methods, assumptions, and models, based on measurements. Major calibration steps include corrections for linearity and modeling and subtraction of bias, dark current, read-out smear, and pixel-to-pixel responsivity variations. AMICA v-band data were calibrated to radiance using in-flight stellar observations. The other band data were calibrated to reflectance by comparing them to ground-based observations to avoid the uncertainty of the solar irradiation in those bands. We found that the AMICA signal was linear with respect to the input signal to an accuracy of << 1% when the signal level was < 3800 DN. We verified that the absolute radiance calibration of the AMICA v-band (0.55 micron) was accurate to 4% or less, the accuracy of the disk-integrated spectra with respect to the AMICA v-band was about 1%, and the pixel-to-pixel responsivity (flatfield) variation was 3% or less. The uncertainty in background zero-level was 5 DN. From wide-band observations of star clusters, we found that the AMICA optics have an effective focal length of 120.80 \pm 0.03 mm, yielding a field-of-view (FOV) of 5.83 deg x 5.69 deg. The resulting geometric distortion model was accurate to within a third of a pixel. We demonstrated an image-restoration technique using the point-spread functions of stars, and confirmed that the technique functions well in all loss-less images. An artifact not corrected by this calibration is scattered light associated with bright disks in the FOV.Comment: 107 pages, 22 figures, 9 tables. will appear in Icaru

Protein–protein interaction analysis by C-terminally specific fluorescence labeling and fluorescence cross-correlation spectroscopy

Here, we describe novel puromycin derivatives conjugated with iminobiotin and a fluorescent dye that can be linked covalently to the C-terminus of full-length proteins during cell-free translation. The iminobiotin-labeled proteins can be highly purified by affinity purification with streptavidin beads. We confirmed that the purified fluorescence-labeled proteins are useful for quantitative protein–protein interaction analysis based on fluorescence cross-correlation spectroscopy (FCCS). The apparent dissociation constants of model protein pairs such as proto-oncogenes c-Fos/c-Jun and archetypes of the family of Ca2+-modulated calmodulin/related binding proteins were in accordance with the reported values. Further, detailed analysis of the interactions of the components of polycomb group complex, Bmi1, M33, Ring1A and RYBP, was successfully conducted by means of interaction assay for all combinatorial pairs. The results indicate that FCCS analysis with puromycin-based labeling and purification of proteins is effective and convenient for in vitro protein–protein interaction assay, and the method should contribute to a better understanding of protein functions by using the resource of available nucleotide sequences

Genetic Polymorphisms of the Human PNPLA3 Gene Are Strongly Associated with Severity of Non-Alcoholic Fatty Liver Disease in Japanese

Nonalcoholic fatty liver disease (NAFLD) includes a broad range of liver pathologies from simple steatosis to cirrhosis and fibrosis, in which a subtype accompanying hepatocyte degeneration and fibrosis is classified as nonalcoholic steatohepatitis (NASH). NASH accounts for approximately 10-30% of NAFLD and causes a higher frequency of liver-related death, and its progression of NASH has been considered to be complex involving multiple genetic factors interacting with the environment and lifestyle.To identify genetic factors related to NAFLD in the Japanese, we performed a genome-wide association study recruiting 529 histologically diagnosed NAFLD patients and 932 population controls. A significant association was observed for a cluster of SNPs in PNPLA3 on chromosome 22q13 with the strongest p-value of 1.4 × 10(-10) (OR = 1.66, 95%CI: 1.43-1.94) for rs738409. Rs738409 also showed the strongest association (p = 3.6 × 10(-6)) with the histological classifications proposed by Matteoni and colleagues based on the degree of inflammation, ballooning degeneration, fibrosis and Mallory-Denk body. In addition, there were marked differences in rs738409 genotype distributions between type4 subgroup corresponding to NASH and the other three subgroups (p = 4.8 × 10(-6), OR = 1.96, 95%CI: 1.47-2.62). Moreover, a subgroup analysis of NAFLD patients against controls showed a significant association of rs738409 with type4 (p = 1.7 × 10(-16), OR = 2.18, 95%CI: 1.81-2.63) whereas no association was obtained for type1 to type3 (p = 0.41). Rs738409 also showed strong associations with three clinical traits related to the prognosis of NAFLD, namely, levels of hyaluronic acid (p = 4.6 × 10(-4)), HbA1c (p = 0.0011) and iron deposition in the liver (p = 5.6 × 10(-4)).With these results we clearly demonstrated that Matteoni type4 NAFLD is both a genetically and clinically different subset from the other spectrums of the disease and that the PNPLA3 gene is strongly associated with the progression of NASH in Japanese population

長崎県における退院促進支援事業(一学生が経験した事例を通じて)

我が国の精神医療において長期入院および社会的入院が長年の問題点であった。精神科病院における在院日数は減少してきてはいるもののその速度は緩やかである。大阪府において2000年度から「社会的入院解消研究事業」2002年度から「精神障害者地域生活移行支援研究事業」が開始され、2003年度から国の事業として「精神障害者退院促進支援事業」が行われている。長崎県では2003年10月より開始され初年度は13名が参加し2名が退院、1名が支援中に死亡、8名が入院中で支援継続という結果であった。支援内容は外出支援が最も多かった。本研究では継続的に面接を行った。その結果利用者のニーズを細かく十分に把握し支援を進めること、退院だけでなく地域に生活の場を確立することが重要であることがわかった

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

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