Effectiveness of an educational program for clinical educators to promote novice midwives' clinical judgment: A cluster randomized controlled trial.

BACKGROUND: There has been little research on education for clinical educators and particularly on education to promote clinical judgment. Therefore, the purpose of this study was to examine the effectiveness of an educational program for clinical educators to promote the clinical judgment of novice midwives during delivery. METHODS: A cluster randomized controlled trial was conducted in which a facility was considered a cluster. Eleven facilities (44 participants) were randomly assigned to the intervention group with the educational intervention and 10 facilities (33 participants) to the control group without the educational intervention. Inclusion criteria were midwives who had become clinical educators within five years. The educational program consisted of e-learning and a seminar. The primary outcome was educational skills. The secondary outcomes were attitude, knowledge, and satisfaction. Data on the satisfaction was collected only for the intervention group. Intention-to-treat and multi-model analyses using a random intercept model were used to analyze data. St. Luke's International University ethics review committee approved the study (20-A016). RESULTS: No differences in baseline characteristics of participants and facilities were noted. There was no significant difference in educational skills scores at post-test between the intervention and control group (MD 1.88, 95 % CI [-0.55-4.31]). There was no significant difference in attitude scores at post-test between the two groups (MD 2.38, 95 % CI [-0.76, 5.51]). The knowledge scores at post-test were significantly higher in the intervention group (intervention group 2.68 ± 0.26, control group 1.57 ± 0.25; MD 1.10, 95 % CI [0.41-1.80], p = .002). CONCLUSION: The intervention group improved only in knowledge scores, with no effect on educational skills or attitudes compared to the control group. It is necessary to evaluate the effectiveness of the program by conducting long-term follow-up and evaluation.

How children with autism spectrum disorder perceive themselves: A narrative research.

AIM: The purpose of this article is, through a dialog between the child and the author, to clarify how children with autism spectrum disorder (ASD) perceive themselves. METHODS: The qualitative study's participants were nine children with ASD. Their ages were 8-18 years. Data were collected through two sessions of dialog between the child and the author. Data were analyzed through a qualitative inductive approach based on the perspectives of narrative analysis. RESULTS: There were eight categories of how the children perceive themselves. The children talked about themselves as follows. The children with ASD wished to share feelings with others, sensitively read between the lines, and talked about the belief to cherish their friends. They were able to anticipate that repetitive behavior or interest in one thing would end someday. And they then made an effort to deal with problematic matters in social life. CONCLUSION: This article proposes to understand the experience of "increasing alienation" in children with ASD. As a type of support to understand the child, this article proposed a dialog that elicits communication arrangements, specifically a dialog that focuses on forming a profound relationship of being able to share and communicate with each other.

Robust folding of a de novo designed ideal protein even with most of the core mutated to valine.

Protein design provides a stringent test for our understanding of protein folding. We previously described principles for designing ideal protein structures stabilized by consistent local and nonlocal interactions, based on a set of rules relating local backbone structures to tertiary packing motifs. The principles have made possible the design of protein structures having various topologies with high thermal stability. Whereas nonlocal interactions such as tight hydrophobic core packing have traditionally been considered to be crucial for protein folding and stability, the rules proposed by our previous studies suggest the importance of local backbone structures to protein folding. In this study, we investigated the robustness of folding of de novo designed proteins to the reduction of the hydrophobic core, by extensive mutation of large hydrophobic residues (Leu, Ile) to smaller ones (Val) for one of the designs. Surprisingly, even after 10 Leu and Ile residues were mutated to Val, this mutant with the core mostly filled with Val was found to not be in a molten globule state and fold into the same backbone structure as the original design, with high stability. These results indicate the importance of local backbone structures to the folding ability and high thermal stability of designed proteins and suggest a method for engineering thermally stabilized natural proteins.

Abl family tyrosine kinases govern IgG extravasation in the skin in a murine pemphigus model.

The pathway of homeostatic IgG extravasation is not fully understood, in spite of its importance for the maintenance of host immunity, the management of autoantibody-mediated disorders, and the use of antibody-based biologics. Here we show in a murine model of pemphigus, a prototypic cutaneous autoantibody-mediated disorder, that blood-circulating IgG extravasates into the skin in a time- and dose-dependent manner under homeostatic conditions. This IgG extravasation is unaffected by depletion of Fcγ receptors, but is largely attenuated by specific ablation of dynamin-dependent endocytic vesicle formation in blood endothelial cells (BECs). Among dynamin-dependent endocytic vesicles, IgG co-localizes well with caveolae in cultured BECs. An Abl family tyrosine kinase inhibitor imatinib, which reduces caveolae-mediated endocytosis, impairs IgG extravasation in the skin and attenuates the murine pemphigus manifestations. Our study highlights the kinetics of IgG extravasation in vivo, which might be a clue to understand the pathological mechanism of autoantibody-mediated autoimmune disorders.

TAp63 represses transcription of MYCN/NCYM gene and its high levels of expression are associated with favorable outcome in neuroblastoma.

TAp63 is an isoform of p63 gene, a p53 family gene that suppresses tumorigenesis via transcriptional regulation. TAp63 represses transcription of MYC oncogene in glioblastomas; however, its role in another MYC family gene, MYCN, has remained elusive. In this study, we showed that TAp63 repressed transcription of the MYCN gene in human cancer cells. Overexpression of TAp63 in HeLa cells suppressed MYCN expression, whereas knockdown of TAp63 had the opposite effect. By binding to exon 1 of MYCN gene, TAp63 suppressed the promoter activities of MYCN and its cis-antisense gene, NCYM. Other p53 family members, p53 and TAp73, showed lesser ability to suppress MYCN/NCYM promoter activities compared with that of TAp63. All-trans-retinoic acid (ATRA) treatment of MYCN/NCYM-amplified neuroblastoma CHP134 cells induced TAp63 and reduced p53 expressions, accompanied by downregulation of MYCN/NCYM expressions. Meanwhile, TAp63 knockdown inhibited ATRA-induced repression of NCYM gene expression. Blocking the p53 family binding sites by CRISPR-dCas9 system in CHP134 cells induced MYCN/NCYM expression and promoted apoptotic cell death. Expression levels of TAp63 mRNA inversely correlated with those of MYCN/NCYM expression in primary neuroblastomas, which was associated with a favorable prognosis. Collectively, TAp63 repressed MYCN/NCYM bidirectional transcription, contributing to the suppression of neuroblastoma growth.

Structural characterization of the N-terminal kinase-interacting domain of an Hsp90-cochaperone Cdc37 by CD and solution NMR spectroscopy.

Cdc37 is a protein kinase-targeting molecular chaperone, which cooperates with Hsp90 to assist the folding, assembly and maturation of various signaling kinases. It consists of three distinct domains: the N-terminal, middle, and C-terminal domain. While the middle domain is an Hsp90-binding domain, the N-terminal domain is recognized as a kinase-interacting domain. The N-terminal domain contains a well-conserved Ser residue at position 13, and the phosphorylation at this site has been shown to be a prerequisite for the interaction between Cdc37 and signaling kinases. Although the phosphorylation of Ser13 might induce some conformational change in Cdc37 molecule, little is known about the structure of the N-terminal domain of Cdc37. We examined the structural and dynamic properties of several fragment proteins corresponding to the N-terminal region of Cdc37 by circular dichroism and solution NMR spectroscopy. We found that the N-terminal domain of Cdc37 exhibits highly dynamic structure, and it exists in the equilibrium between α-helical and more disordered structures. We also found that phosphorylation at Ser13 did not significantly change the overall structure of N-terminal fragment protein of Cdc37. The results suggested that more complicated mechanisms might be necessary to explain the phosphorylation-activated interaction of Cdc37 with various kinases.

Small Bowel Obstruction Caused by Dried Persimmon.

Dried persimmon is a well-known dried fruit in Asian countries such as Japan, Korea, and China. Small bowel obstruction caused by phytobezoar is a rare but interesting pathogenesis that accounts for 2-4% of all small bowel obstructions. We present the case of an 87-year-old female who suffered from small bowel obstruction caused by ingestion of a huge, dried astringent persimmon. She was initially treated conservatively, but removal by enterotomy was performed after relief failed to be achieved with conservative therapy.

Key component of inflammasome, NLRC4, was identified in the lesional epidermis of psoriatic patients.

Inflammasomes are multimolecular complexes that control the inflammatory response. The function of inflammasomes in the pathogenesis of psoriasis is still unclear. To clarify the relationship between inflammasomes and the pathophysiology of psoriasis, and in particular, to identify molecules interacting with caspase-1, a crucial component of inflammasomes, scale extracts obtained from patients with psoriasis were immunoprecipitated with anti-caspase-1 antibody and analyzed by liquid chromatography coupled with electrospray tandem mass spectrometry (LC-MS/MS). The expression of the inflammasome component was assessed by immunohistochemical analysis and an in vitro assay. We identified several candidates for caspase-1-interacting proteins from the psoriatic scale extracts by immunoprecipitation and LC-MS/MS. Nucleotide-binding oligomerization domain-containing protein-like receptor family CARD domain-containing protein 4 (NLRC4) was the only inflammasome component among the candidates; thus, the protein is considered to be a key factor of inflammasomes in psoriasis. No inflammasome component was found in the extracts of atopic dermatitis or normal skin by LC-MS/MS. Immunohistochemical analysis demonstrated upregulation of NLRC4 in the lesional epidermis of some psoriatic patients whereas weak expression of NLRC4 was detected in the normal and non-lesional epidermis. The mRNA expression of the NLRC4 gene increased in keratinocytes at confluency, 48 h after air exposure and after the addition of 1.5 mmol/L calcium chloride. Our findings suggest that NLRC4 may be involved in the exacerbation or modification of psoriatic lesions.

Low Seroprevalence of Severe Fever with Thrombocytopenia Syndrome Virus Antibodies in Individuals Living in an Endemic Area in Japan.

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infection with a high mortality rate. It is caused by the SFTS virus (SFTSV) and is endemic in some areas in western Japan, including the Kagoshima prefecture. In the present study, healthy individuals living in this prefecture were examined to assess for anti-SFTSV seroprevalence. An initial study was performed using the serum samples collected from a total of 646 individuals living in Kagoshima. At the same time, a questionnaire was used to collect information (such as occupation and a history of tick bite). Enzyme-linked immunosorbent assay and indirect immunofluorescence assay were used for the screening. Finally, the seroprevalence of anti-SFTSV antibodies was confirmed using a neutralization assay. Only 2 (0.3%) out of 646 study participants were positive for anti-SFTSV antibodies. No significant difference was observed between individuals who are at a high or low risk of tick bite in terms of seropositivity. Next, a total of 1,000 serum samples collected from general blood donors by the Japanese Red Cross Kyushu Block Blood Center were tested. None of these samples tested positive for anti-SFTSV antibodies. These results suggest a low seroprevalence of anti-SFTSV antibodies in healthy individuals living in an endemic area in Japan.

Obscure Gastrointestinal Bleeding Due to a Small Intestinal Gastrointestinal Stromal Tumor in a Young Adult.

The source of most cases of gastrointestinal bleeding is the upper gastrointestinal tract. Since bleeding from the small intestine is very rare and difficult to diagnose, time is required to identify the source. Among small intestine bleeds, vascular abnormalities account for 70-80%, followed by small intestine tumors that account for 5-10%. The reported peak age of the onset of small intestinal tumors is about 50 years. Furthermore, rare small bowel tumors account for only 1-2% of all gastrointestinal tumors. We describe a 29-year-old man who presented with obscure anemia due to gastrointestinal bleeding and underwent laparotomy. Surgical findings revealed a well-circumscribed lesion measuring 45 × 40 mm in the jejunum that initially appeared similar to diverticulosis with an abscess. However, the postoperative pathological diagnosis was a gastrointestinal stromal tumor with extramural growth.

Identification of an S100A8 Receptor Neuroplastin-ß and its Heterodimer Formation with EMMPRIN.

We previously reported a positive feedback loop between S100A8/A9 and proinflammatory cytokines mediated by extracellular matrix metalloproteinase inducer, an S100A9 receptor. Here, we identify neuroplastin-ß as an unreported S100A8 receptor. Neuroplastin-ß and extracellular matrix metalloproteinase inducer form homodimers and a heterodimer, and they are co-localized on the surface of cultured normal human keratinocytes. Knockdown of both receptors suppressed cell proliferation and proinflammatory cytokine induction. Upon stimulation with S100A8, neuroplastin-ß recruited GRB2 and activated extracellular signal-regulated kinase, resulting in keratinocyte proliferation. Keratinocyte proliferation in response to inflammatory stimuli was accelerated in involucrin promoter-driven S100A8 transgenic mice. Further, S100A8 and S100A9 were strongly up-regulated and co-localized in lesional skin of atopic dermatitis patients. Our results indicate that neuroplastin-ß and extracellular matrix metalloproteinase inducer form a functional heterodimeric receptor for S100A8/A9 heterodimer, followed by recruitment of specific adaptor molecules GRB2 and TRAF2, and this signaling pathway is involved in activation of both keratinocyte proliferation and skin inflammation in atopic skin. Suppression of this pathway might have potential for treatment of skin diseases associated with chronic inflammation such as atopic dermatitis.

Developing the "Skippu-Mama" program for mothers of children with autism spectrum disorder.

The "Skippu-Mama" peer support program was developed to improve quality of life and reduce parental stress in mothers of children with autism spectrum disorders. The program was designed to improve these variables by refreshing and healing participants' minds and bodies. Twenty-four mothers of 26 children diagnosed with ASD in Japan were included in the study and completed measures of quality of life and parental stress before, during, and after participation in the Skippu-Mama program. Our results demonstrated that time was a significant main effect. Further, multiple comparisons with Bonferroni corrections indicated a significant increase in World Health Organization Quality of Life 26 scores three months into the program and at its conclusion six months after commencement. Overall, the Skippu-Mama program improved the quality of life of mothers of children with ASD, and we believe that the intervention's focus on both individual and family variables may be especially effective in this population.

An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway.

In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of newly transcribed RNA and pri/pre-miRNA in IFN-activated macrophages, we identify a new post-transcriptional viral defense mechanism mediated by miR-342-5p. On the basis of ChIP and site-directed promoter mutagenesis experiments, we find the synthesis of miR-342-5p is coupled to the antiviral IFN response via the IFN-induced transcription factor, IRF1. Strikingly, we find miR-342-5p targets mevalonate-sterol biosynthesis using a multihit mechanism suppressing the pathway at different functional levels: transcriptionally via SREBF2, post-transcriptionally via miR-33, and enzymatically via IDI1 and SC4MOL. Mass spectrometry-based lipidomics and enzymatic assays demonstrate the targeting mechanisms reduce intermediate sterol pathway metabolites and total cholesterol in macrophages. These results reveal a previously unrecognized mechanism by which IFN regulates the sterol pathway. The sterol pathway is known to be an integral part of the macrophage IFN antiviral response, and we show that miR-342-5p exerts broad antiviral effects against multiple, unrelated pathogenic viruses such Cytomegalovirus and Influenza A (H1N1). Metabolic rescue experiments confirm the specificity of these effects and demonstrate that unrelated viruses have differential mevalonate and sterol pathway requirements for their replication. This study, therefore, advances the general concept of broad antiviral defense through multihit targeting of a single host pathway.

Visualization of RelB expression and activation at the single-cell level during dendritic cell maturation in Relb-Venus knock-in mice.

RelB is activated by the non-canonical NF-κB pathway, which is crucial for immunity by establishing lymphoid organogenesis and B-cell and dendritic cell (DC) maturation. To elucidate the mechanism of the RelB-mediated immune cell maturation, a precise understanding of the relationship between cell maturation and RelB expression and activation at the single-cell level is required. Therefore, we generated knock-in mice expressing a fusion protein between RelB and fluorescent protein (RelB-Venus) from the Relb locus. The Relb(Venus/Venus) mice developed without any abnormalities observed in the Relb(-/-) mice, allowing us to monitor RelB-Venus expression and nuclear localization as RelB expression and activation. Relb(Venus/Venus) DC analyses revealed that DCs consist of RelB(-), RelB(low) and RelB(high) populations. The RelB(high) population, which included mature DCs with projections, displayed RelB nuclear localization, whereas RelB in the RelB(low) population was in the cytoplasm. Although both the RelB(low) and RelB(-) populations barely showed projections, MHC II and co-stimulatory molecule expression were higher in the RelB(low) than in the RelB(-) splenic conventional DCs. Taken together, our results identify the RelB(low) population as a possible novel intermediate maturation stage of cDCs and the Relb(Venus/Venus) mice as a useful tool to analyse the dynamic regulation of the non-canonical NF-κB pathway.

Age is no longer a limit: two cases of hepatectomy in patients over 90 years old.

Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. The age of patients affected by HCC is considered to be increasing, and several studies have reported significantly higher rates of morbidity and mortality after hepatectomy for HCC in elderly patients. However, other studies have reported that the short- and long-term outcomes of surgery for HCC in elderly patients are similar to those in younger patients. Whether the indications for hepatic resection in elderly patients resemble those in younger patients has thus been questioned. We describe two cases of patients over 90 years old who underwent major hepatectomy for HCC, representing the oldest patients in the world to have done so.

Successfully treated intra-abdominal abscess caused by fish bone with perforation of ascending colon: a case report.

Ingestion of a foreign body is not uncommon, but rarely results in perforation of the gastrointestinal tract. The most common sites of perforation are reportedly the narrowest parts of the bowel, and perforation of the right side of the colon is rare. We report herein the case of a 69-year-old man who presented with an 8-week history of right upper abdominal pain. Laboratory data revealed inflammation at the first hospital visit. Computed tomography revealed a hypodense lesion containing a hyperdense foreign body in the abdomen. Intra-abdominal abscess caused by foreign body perforation was diagnosed. After administering antibiotics for 2 weeks, surgery was performed. Symptoms had resulted from perforation of the ascending colon by a fish bone.

Identification of a gene, FMP21, whose expression levels are involved in thermotolerance in Saccharomyces cerevisiae.

Elucidation of the mechanism of high temperature tolerance in yeasts is important for the molecular breeding of high temperature-tolerant yeasts that can be used in bioethanol production. We identified genes whose expression is correlated with the degree of thermotolerance in Saccharomyces cerevisiae by DNA microarray analysis. Gene expression profiles of three S. cerevisiae strains showing different levels of thermotolerance were compared, and we chose three of them as candidate genes. Among these genes, FMP21 was investigated as a thermotolerance-related gene in S. cerevisiae by comparing the growth at high temperature with the gene expression in eight strains. The expression ratio of FMP21 at 37°C was correlated with the doubling time ratio at a coefficient of determination of 0.787. The potential involvement of the Fmp21 in the thermotolerance of yeasts was evaluated. The FMP21 deletion variant showed a decreased respiratory growth rate and increased thermosensitivity. Furthermore, the overexpression of FMP21 improved thermotolerance in yeasts. In conclusion, the function of Fmp21 is important for thermotolerance in yeasts.

Tubulopapillary adenoma of the gallbladder accompanied by bile duct tumor thrombus.

Intraductal papillary mucinous neoplasm of the bile duct (IPNB) is recognized as a precancerous lesion; however, both its pathogenesis and progression remain unclear. We present here a case of IPNB arising from the gallbladder accompanied by bile duct tumor thrombus in a 79-year-old female. The resected specimen revealed a tubulopapillary adenoma with no malignant cells. This case suggests that even in the absence of malignant cells, these tumors can behave as malignant tumors requiring aggressive treatment. Even if no malignant cells are present, intraepithelial neoplasms occurring in the ampullopancreatobiliary tract can behave as malignant tumors.

Up-regulation of the ATP-binding cassette transporter A1 inhibits hepatitis C virus infection.

Hepatitis C virus (HCV) establishes infection using host lipid metabolism pathways that are thus considered potential targets for indirect anti-HCV strategies. HCV enters the cell via clathrin-dependent endocytosis, interacting with several receptors, and virus-cell fusion, which depends on acidic pH and the integrity of cholesterol-rich domains of the hepatocyte membrane. The ATP-binding Cassette Transporter A1 (ABCA1) mediates cholesterol efflux from hepatocytes to extracellular Apolipoprotein A1 and moves cholesterol within cell membranes. Furthermore, it generates high-density lipoprotein (HDL) particles. HDL protects against arteriosclerosis and cardiovascular disease. We show that the up-regulation of ABCA1 gene expression and its cholesterol efflux function in Huh7.5 hepatoma cells, using the liver X receptor (LXR) agonist GW3965, impairs HCV infection and decreases levels of virus produced. ABCA1-stimulation inhibited HCV cell entry, acting on virus-host cell fusion, but had no impact on virus attachment, replication, or assembly/secretion. It did not affect infectivity or properties of virus particles produced. Silencing of the ABCA1 gene and reduction of the specific cholesterol efflux function counteracted the inhibitory effect of the GW3965 on HCV infection, providing evidence for a key role of ABCA1 in this process. Impaired virus-cell entry correlated with the reorganisation of cholesterol-rich membrane microdomains (lipid rafts). The inhibitory effect could be reversed by an exogenous cholesterol supply, indicating that restriction of HCV infection was induced by changes of cholesterol content/distribution in membrane regions essential for virus-cell fusion. Stimulation of ABCA1 expression by GW3965 inhibited HCV infection of both human primary hepatocytes and isolated human liver slices. This study reveals that pharmacological stimulation of the ABCA1-dependent cholesterol efflux pathway disrupts membrane cholesterol homeostasis, leading to the inhibition of virus-cell fusion and thus HCV cell entry. Therefore besides other beneficial roles, ABCA1 might represent a potential target for HCV therapy.

NCYM, a Cis-antisense gene of MYCN, encodes a de novo evolved protein that inhibits GSK3ß resulting in the stabilization of MYCN in human neuroblastomas.

The rearrangement of pre-existing genes has long been thought of as the major mode of new gene generation. Recently, de novo gene birth from non-genic DNA was found to be an alternative mechanism to generate novel protein-coding genes. However, its functional role in human disease remains largely unknown. Here we show that NCYM, a cis-antisense gene of the MYCN oncogene, initially thought to be a large non-coding RNA, encodes a de novo evolved protein regulating the pathogenesis of human cancers, particularly neuroblastoma. The NCYM gene is evolutionally conserved only in the taxonomic group containing humans and chimpanzees. In primary human neuroblastomas, NCYM is 100% co-amplified and co-expressed with MYCN, and NCYM mRNA expression is associated with poor clinical outcome. MYCN directly transactivates both NCYM and MYCN mRNA, whereas NCYM stabilizes MYCN protein by inhibiting the activity of GSK3ß, a kinase that promotes MYCN degradation. In contrast to MYCN transgenic mice, neuroblastomas in MYCN/NCYM double transgenic mice were frequently accompanied by distant metastases, behavior reminiscent of human neuroblastomas with MYCN amplification. The NCYM protein also interacts with GSK3ß, thereby stabilizing the MYCN protein in the tumors of the MYCN/NCYM double transgenic mice. Thus, these results suggest that GSK3ß inhibition by NCYM stabilizes the MYCN protein both in vitro and in vivo. Furthermore, the survival of MYCN transgenic mice bearing neuroblastoma was improved by treatment with NVP-BEZ235, a dual PI3K/mTOR inhibitor shown to destabilize MYCN via GSK3ß activation. In contrast, tumors caused in MYCN/NCYM double transgenic mice showed chemo-resistance to the drug. Collectively, our results show that NCYM is the first de novo evolved protein known to act as an oncopromoting factor in human cancer, and suggest that de novo evolved proteins may functionally characterize human disease.