Teleocidin B-4, a PKC Activator, Upregulates Hypoxia-Inducible Factor 1 (HIF-1) Activity by Promoting the Accumulation of HIF-1α Protein via the PKCα/mTORC Signaling Pathway.

Hypoxia-inducible factor 1 (HIF-1) signaling is upregulated in an oxygen-dependent manner under hypoxic conditions. Activation of HIF-1 signaling increases the expression of HIF-1 target genes involved in cell survival, proliferation, and angiogenesis. Therefore, compounds that activate HIF-1 signaling have therapeutic potential in ischemic diseases. Screening for compounds that activate HIF-1 activity identified a microbial metabolite, teleocidin B-4, a PKC activator. Other PKC activators, such as TPA and 10-Me-Aplog-1, also activated HIF-1 activity. PKC activators induced HIF-1α protein accumulation through PKCα/mTORC activation. These results suggest that PKC activators without tumor-promoting activity have potential as therapeutic agents via HIF-1 target gene activation.

Continuous specimen cooling during slicing and thickness measurement contributes to improved accuracy in image analysis of pathologic specimens.

We measured section thickness (ST) after slicing using a film thickness meter and investigated the relationship between ST and the percent area of positive staining using computer-assisted image analysis. METHODS: Sections were prepared from a paraffin-only block and formalin-fixed paraffin-embedded (FFPE) blocks containing fish sausage and human liver specimens. The ST was compared between the sections prepared with cooling using an ice pack (IP) or a continuous cooling device (CCD) paired with a sliding microtome set at an ST of 4 µm. The sections were stained with eosin or aniline blue, and the association between the percent area of positive staining and ST was determined using computer-aided analysis of images captured with a whole slide scanner. RESULTS: The average STs of the paraffin-only block sections measured by four practitioners were 5.01-5.41 and 4.09-4.33 µm in samples prepared using an IP and a CCD, respectively. Therefore, subsequent analyses included sections prepared using the CCD. The ST of the tissue surface was significantly thinner than that of the paraffin surrounding the tissue section. Furthermore, the percent areas of positive staining for eosin and aniline blue were significantly correlated with ST in both the fish sausage and liver sections. The analysis of the ST and percent area of positive staining in 60 sections of the same block, which were categorized into quantiles based on ST, revealed a significant difference in the percent area of positive staining between the thicker and thinner sections. DISCUSSION: Specimen sectioning should be performed with a CCD, ST should be measured before the staining of pathologic specimens prepared for quantitative analysis, and histologic examination should be performed using specimens with uniform ST.

Association of the Stanford Integrated Psychosocial Assessment for Transplant and 1-Year Outcome of Living Kidney Transplantation in Japan.

BACKGROUND: Because most kidney transplantations in Japan are performed on the basis of living donors, after-transplant outcomes should achieve optimum results, overcoming participants' possible reduced adherence. OBJECTIVE: To investigate the association between the Japanese version of the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT-J) and outcomes, 1 year after the patient's living kidney transplant (LKT). METHODS: The prospective cohort study was undertaken at Tokyo Women's Medical University Hospital from January 2020 to July 2021, with a 1-year follow-up period. The SIPAT-J assesses 18 psychosocial risk factors: (1) Patient's Readiness Level and Illness Management (SIPAT A), (2) Social Support System Level of Readiness (SIPAT B), (3) Psychological Stability and Psychopathology (SIPAT C), and (4) Lifestyle and Effect of Substance Use (SIPAT D). The evaluators, a psychiatrist and 3 clinical psychologists, conducted an independent, blinded application of the SIPAT-J using participants' medical records. The study focused on physical composite outcomes, psychiatric outcomes, and nonadherent behaviors. RESULTS: The participants were 173 LKT recipients (median age [interquartile range], 51 [38-59]); 67.1% were male and 67.1% were employed. The median (interquartile range) SIPAT scores were SIPAT A [7 (5-9)], SIPAT B [7 (5-9)], SIPAT C [2 (0-4)], SIPAT D [3 (3-4)], and SIPAT total [20 (16-23)]. The physical composite outcome was 25 (14.5%), psychiatric outcome 9 (5.2%), and nonadherent behavior 17 (9.8%). SIPAT C (odds ratio = 1.34, 95% confidence interval = 1.06-1.72, P = 0.02) was significantly associated with the psychiatric outcome. SIPAT B (odds ratio = 1.49, 95% confidence interval = 1.12-1.98, P = 0.01) and SIPAT total (odds ratio = 1.13, 95% confidence interval = 1.03-1.24, P = 0.01) were significantly associated with nonadherent behaviors. There was no significant association between the SIPAT and physical composite outcomes. CONCLUSION: This study is the first to examine the association between SIPAT and physical and psychiatric outcomes 1 year after LKT, controlling for follow-up periods and factors other than SIPAT. Comprehensive psychosocial assessment before LKT and early identification of factors that may negatively affect transplant success can allow targeted interventions to be implemented and increase the likelihood of favorable recipient outcomes.

An online survey on differences in knowledge and stigma about epilepsy among the Tokyo metropolitan area and non-urban areas in Japan, a post-hoc study.

PURPOSE: Extant research elucidating the domains of knowledge and bias on epilepsy has consistently underscored a deficiency in cognizance and an inclination toward bias within non-urban areas. Investigations into geographical disparities concerning epilepsy awareness and prejudice within the Japanese context remain conspicuously absent. To address this lacuna in the literature, we undertook a post-hoc analysis to elucidate the discernible regional differentials in epilepsy awareness and the associated stigma. METHODS: From July to August 2021, we conducted an internet questionnaire survey for 310 people with epilepsy (PWE) and 213 ordinary people without epilepsy who registered on the database of the Japanese Research Company. We inquired PWE to answer the Epilepsy Self-Stigma Scale (ESSS), the Rosenberg Self-Esteem Scale (RSES), and the Epilepsy Knowledge Scale (EKS). We inquired to answer ordinary people without epilepsy EKS. We analyzed residential addresses separately for Greater Tokyo and non-urban areas by comparing the degree of knowledge of people with epilepsy and people without epilepsy. RESULTS: The average knowledge of people with and without epilepsy in the Greater Tokyo area was 39.60 and 28.43 points, although in non-urban areas (nine regions from all over Japan except for the Greater Tokyo, Tokai region, and Kinki region), the knowledge averages were 38.44 and 28.66 points of 100. In addition, self-stigma was highest in the Greater Tokyo area: 22.99 and in non-urban areas: 22.77. An two-way ANOVA with knowledge as the dependent variable and epilepsy diagnosis status and region (Greater Tokyo area/non-urban areas) as the independent variables revealed no interaction between diagnosis and region (F(1,346) = 1.48, η2 = 0.003). Knowledge was significantly higher in PWE than in people without epilepsy, but we could not identify any significant difference between ESSS (t = 0.24, d = 0.03) and RSES (t = 1.16, d = 0.16) in the Greater Tokyo/non-urban areas. CONCLUSIONS: We obtained specific information about regional differences in the level of knowledge and stigma about epilepsy in Japan. Because Japan underwent educational reforms after World War II and more than 90% of the population received equally advanced education, the results found no regional differences in knowledge and stigma about epilepsy. We believe collecting information about the respondents' birth and upbringing environment and conducting a thorough investigation is necessary in the future.

One-day psychosocial education program for people with epilepsy: A continuation study of the "Epi-school".

Psychosocial education programs for people with epilepsy (PWE) can improve epilepsy knowledge and quality of life (QOL), whereas the availability of these programs is limited in Japan compared to other developed countries. This study evaluated the feasibility and effectiveness of a one-day group psychosocial education program named the "one-day Epi-school" for PWE and their relatives. The previous program (Epi-school) required consistent participation in three sessions, resulting in problems with program continuation rates, with 45.5% of PWE completing the program. Therefore, the "one-day Epi-school" was designed to provide information about epilepsy and address psychosocial issues related to coexisting epilepsy symptoms, such as self-stigma and self-esteem, while allowing participants to accomplish these programs within a single day. The study recruited a sample of 32 PWE and their relatives from a psychiatric clinic. They completed assessments of knowledge, self-stigma, self-esteem, and quality of life before and after the program. The results exhibited a significant increase in epilepsy knowledge after the intervention for PWE and their relatives. However, we could not identify other significant changes. The participation completion rate was 100%. The post-participation questionnaire proved beneficial to interact with other PWE. The study suggests that a single intervention, e.g., the one-day Epi-school, may be insufficient for enhancing other factors, yet it can be an adequate opportunity for learning and interacting. It is also necessary to implement future studies with larger sample sizes, a control group, and prolonged follow-up periods for the program's value and validity.

Family functioning before kidney transplantation from living-related donors: Perspectives of donors and recipients in Japan.

INTRODUCTION: In Japan, approximately 90% of kidney transplantations involve living donors who are relatives. Selection of a living donor from potential family member donors could affect the entire family. However, reports focusing on preliving-related kidney transplant (LRKT) family functioning are lacking. Family functioning comprises ways that family members communicate and cooperate with each other. The Family Assessment Device (FAD) was used to measure family functioning from the perspective of donors and recipients just prior to LRKT. METHOD: A total of 122 donor-recipient pairs (244 participants in total) who planned to have LRKT were recruited consecutively from July 2020 to July 2021 and included in the analysis. RESULTS: There was no significant difference in FAD scores between donors and recipients, with approximately 20% of both groups reporting poor family functioning. Differences in family functioning according to types of relatives were shown in recipients. The rate of poor family functioning was significantly lower in the spouse group than in the parent-to-child group (recipient: 6.6%, 29.3%; donor: 8.2%, 34.1%, respectively). However, agreement regarding good or poor family functioning assessment was high in the parent-to-child pairs and low in the spouse pairs. DISCUSSION: Most LRKT donors and recipients reported good family functioning; however, some perceived poor family functioning. Evaluations by donors did not always align with that of recipients, especially among spouse pairs. It is important to treat them as independent entities. Preoperative assessment to connect them with appropriate support can enhance recovery after LRKT. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Characterization of the stanford integrated psychosocial assessment for transplant for heart, liver, and kidney transplant candidates in Japan.

BACKGROUND: The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a comprehensive psychosocial assessment proven useful for predicting the outcomes of organ transplantation that is expected to be useful in Japan. However, the characteristics of organ-specific SIPAT scores for organ transplant recipient candidates in Japan are unclear and, to date, the SIPAT has not been properly utilized in clinical practice. The purpose of this study was to present basic data that can be used to establish the relation between SIPAT scores and post-transplantation psychosocial outcomes as well as organ-specific outcomes. METHODS: This study included 167 transplant recipient candidates (25 heart, 71 liver, and 71 kidney) who completed a semi-structured interview based on the Japanese version of SIPAT (SIPAT-J) prior to transplantation. The differences between organs in terms of SIPAT scores and differences in SIPAT scores based on demographic data were comparatively analyzed. RESULTS: The total SIPAT scores were higher for liver recipient candidates than for heart recipient candidates (P = .019). Regarding the subscales, SIPAT B (social support system) scores were higher for liver and kidney recipient candidates than for heart recipient candidates (P = .021), whereas SIPAT C (psychological stability and psychopathology) scores were higher for liver recipient candidates than for kidney recipient candidates (P = .002). Recipient candidates with a history of psychiatric treatment and those who were unemployed had higher SIPAT scores, regardless of the transplant organ, than recipient candidates without a history of psychiatric treatment and those who were employed (P < .001, P = .016, respectively). CONCLUSIONS: There were notable differences in the total SIPAT-J and subscale scores among the liver, heart, and kidney recipient candidates. Each organ was associated with specific psychosocial issues that should be addressed before transplantation. Interventions such as information provision and patient education based on SIPAT assessment results for each organ may improve recipient post-transplant outcomes.

Decreased lamin A and B1 expression results in nuclear enlargement in serous ovarian carcinoma, whereas lamin A-expressing tumor cells metastasize to lymph nodes.

BACKGROUND: Lamins, located beneath the nuclear membrane, are involved in maintaining nuclear stiffness and morphology. The nuclei of tumor cells are enlarged in serous carcinoma, a histologic subtype of ovarian cancer that is notable for its poor prognosis. The present study investigated the association of lamin A, B1, and B2 expression with nuclear morphology and metastatic route in serous ovarian carcinoma. METHODS: We performed immunohistochemistry for lamins A, B1, and B2 using specimens of patients who underwent surgery for serous ovarian carcinoma in Gunma University Hospital between 2009 and 2020. Following staining, the specimens were scanned using a whole-slide scanner and processed using computer-assisted image analysis. RESULTS: The positivity rates for lamins A and B1 as well as the rank sum of the positivity rates for lamins A, B1, and B2 were negatively correlated with the mean and standard deviation of the nuclear area. Interestingly, the positivity rate for lamin A was significantly higher in metastatic lesions than in primary tumors in cases with lymph node metastasis. DISCUSSION: Previous studies indicated that decreased lamin A led to nuclear enlargement and deformation and that lamin B1 was required to maintain the meshworks of lamins A and B2 to maintain nuclear morphology. The present study findings suggest that decreased lamin A and B1 expression might lead to nuclear enlargement and deformation and raise the possibility that tumor cells maintaining or not losing lamin A expression might metastasize to lymph nodes.

Phosphotungstic Acid-treated Picrosirius Red Staining Improves Whole-slide Quantitative Analysis of Collagen in Histological Specimens.

We tried to prevent nonspecific nuclear staining (NS-NS) of picrosirius red (PSR) staining by treating the specimens with one of the heteropoly acids phosphotungstic acid (PTA). We analyzed a total of 35 cases of non-cancerous liver tissue for fibrosis and NS-NS under PSR-alone, phosphomolybdic acid (PMA)-pretreated PSR (PMA + PSR), or PTA-pretreated PSR (PTA + PSR) condition. In addition, we analyzed the photosensitivity of PMA or PTA single stain specimens. PTA + PSR significantly suppressed NS-NS compared with PSR. The color of the specimens did not change into blue by 30 times the exposure to whole slide scanner (WSS) light. The PTA + PSR condition showed the highest correlation with the Ishak score (pathological evaluation of liver fibrosis) compared with other conditions. Furthermore, Sirius Red-positive percentage (SRP%) in PSR was increased in the NS-NS observed cases. SRP% in PMA + PSR was significantly affected by WSS light exposure time. Moreover, the deposition of non-polarized PSR-stained substances (NP-PSR+S) clinging to the collagen fibers potentially explains why SRP% seemed bigger under PSR than PTA + PSR. Our protocol enabled us to analyze the whole slide image of PSR staining by high magnification, which would contribute to the accurate analysis of collagen amount in the tissue sections.

Internet survey on knowledge and perceptions of epilepsy among the general public in Japan.

Objective: To improve the life quality of people with epilepsy, it is necessary to provide comprehensive epilepsy care and disseminate accurate information related to epilepsy to the public. In Japan, reports of traffic accidents involving people with epilepsy started to draw attention in the media in 2011. Ever since that, the association between the image of epilepsy from the general public, "Epilepsy," and "Danger," was more robust in 2013. Since 2017, no previous surveys have examined the perceptions and knowledge of epilepsy among the public in Japan. As an essential source of information for epilepsy care, we conducted a nationwide Internet-based survey to elucidate the current state of knowledge and perceptions of epilepsy among the public without epilepsy in Japan. Methods: We conducted an online survey from July 29 to August 2, 2021, with 213 respondents (115 male, 97 female, and one unidentified; mean age: 50.52 ± 12.34 years) registered with an online survey service in Japan. In this survey, we first questioned whether or not a respondent had epilepsy, and then those with epilepsy were excluded from participation. We collected basic demographic information, administered the Epilepsy Knowledge Scale (18 items), and asked the open-ended response question, "What kind of disease do you think epilepsy is? If you do not know, please describe epilepsy in your words." We adopted quantitative text analysis using KH Coder3 and co-occurrence network analysis to examine the connections between words. Results: Among the respondents, 92% have heard of epilepsy, and 26.8% have observed an epileptic seizure before the survey. The knowledge scale yields an average score of 27.96 ± 21.3 (out of 100), with the question with the highest percentage of correct responses being "People with epilepsy are just as capable as other people" at 51.64%. The question with the lowest percentage of correct responses was "If the person with epilepsy only has seizures during sleep, the person can have a driver's license," at 9.85%. The average number of Japanese characters responding to open-ended text questions was 10.45 ± 8.87 characters (including Kanji, Hiragana, and Katakana). We found that the word "froth" appeared more frequently with experience of observing a seizure, and the words "occur" and "brain" appeared more frequently with higher knowledge of epilepsy. Furthermore, comparing the sources of information from what they learned about epilepsy, the words "seizure," "faint," and "consciousness" appeared more frequently in school, with family and friends, and in newspapers and television, respectively. Conclusion: We identified the level of knowledge and perceptions of epilepsy among the general public in Japan in 2021. By analyzing the qualitative aspects of open-ended text responses, we gathered information that might be useful for informing the public of future efforts to provide accurate information related to epilepsy.

Negative correlation between the nuclear size and nuclear Lamina component Lamin A in intraductal papillary mucinous neoplasms of the pancreas.

Background: The nuclear laminar protein Lamin A and inner nuclear membrane protein Emerin plays important role in sustaining nuclear structure. However, They have not investigated the significance of these proteins for development of pancreatic intraductal papillary mucinous neoplasm (IPMN). Methods: We examined pancreatic IPMN specimens for nuclear morphology and nuclear protein expression pattern of Lamin A and Emerin. Forty-two IPMN specimens were included, with 30 classified as intraductal papillary mucinous adenoma (IPMA) and 12 as intraductal papillary mucinous carcinoma (IPMC). Results: Classification according to histological subtype revealed that 26 specimens were of the gastric subtype (1 IPMC case), 8 were pancreatobiliary (6 IPMC cases), 6 were intestinal (3 IPMC cases), and 2 were oncocytic (all cases were IPMC). The frequency of IPMN subtypes in this study seemed to agree with those in previous reports. We analyzed Feulgen staining sections for nuclear morphological analysis using computer-assisted image analysis. Nuclear area and perimeter were significantly larger in IPMC than in IPMA. Finally, we examined the positive ratios of Lamin A and Emerin in immunohistochemical staining sections by image analysis. We found a negative correlation between the nuclear size and Lamin A-positive ratio, which was significantly lower in IPMC than that in IPMA. However, no significant correlation was observed between nuclear size and Emerin expression was observed, and no differences were found in the Emerin-positive ratio between IPMA and IPMC. Conclusion: Our results suggest that a decreased Lamin A positive ratio induces nuclear enlargement in adenomas, which thereby induce promotion to carcinomas. Furthermore, Lamin A expression can be a reliable biomarker for distinguishing between IPMC and IPMA.

A study of factors influencing self-stigma in people with epilepsy: A nationwide online questionnaire survey in Japan.

OBJECTIVE: Epilepsy carries a significant stigma. While there is some evidence that self-stigma accompanies a lack of knowledge about epilepsy, there are no studies in Japan. This study aimed to determine factors contributing to self-stigma in Japan. METHODS: We conducted an online questionnaire survey. Three hundred and ten patients completed the questionnaire (mean age of 47.8 ± 11.9) in contrast to the total registered users on the questionnaire site as 28 315 from Jul 29 to Aug 2, 2021. We asked about demographic variables, satisfaction with treatment, limitations in life, support status, seizure frequency, the Epilepsy Self-Stigma Scale (ESSS), the Rosenberg Self-Esteem Scale (RSES), and the Epilepsy Knowledge Scale (EKS). We conducted the statistical analysis on self-stigma, self-esteem, knowledge of epilepsy, and seizure frequency associations by Spearman's rank correlation. RESULTS: The mean value of the EKS was 40.19 ± 18.75, the ESSS was 17.69 ± 6.25, and the RSES was 26.02 ± 6.13. We identified a significant moderate negative correlation between self-esteem and self-stigma (P < .001, ρ = -.423), a significant weak positive correlation between self-esteem and knowledge (P = .005, ρ = .177), and a significant weak negative correlation between seizure frequency and self-stigma (P < .001, ρ = -.162). Of the 186 respondents who were working or studying, 91 (49%) participants had experienced any discrimination due to epilepsy. The use of psychosocial support, that is, participating in epilepsy self-help groups and educational programs, was 5.8%. SIGNIFICANCE: There was no correlation between the strength of self-stigma and the knowledge, while there was a positive correlation between self-esteem and knowledge (P = .005, ρ = .177). There was a negative and weak correlation between seizure frequency and self-stigma (p < .001, ρ = -.162). These results suggest that sufficient knowledge may improve the self-esteem and thus reduce the self-stigma. In addition, short-term treatment for seizure control is insufficient to reduce self-stigma. The dissemination for people to enable sufficient epilepsy knowledge and positive perceptions of epilepsy by increasing self-efficacy throughout a lifetime may reduce self-stigma.

Association between psychotropic prescriptions and the total amount of psychotropics ingested during an intentional overdose: A single-center retrospective study.

AIM: To investigate the association between psychotropic prescriptions and the total amount of psychotropics ingested during a subsequent intentional overdose and to examine factors related to the number of psychotropic prescriptions. METHODS: The initial sample comprised 69 patients who were admitted to the emergency department of a general hospital in Japan following an intentional overdose via psychotropic medications. We performed retrospective hierarchical multiple regression analysis with the total amount of psychotropics ingested at the overdose as a dependent variable and factors related to deliberate self-harm or overdose identified in previous studies as independent variables. We compared two models, one that did not (Step 1) and one that did (Step 2) include the number of different prescribed psychotropic medications as an independent variable in the analysis. RESULTS: Forty-seven patients were eligible for the analysis. The number of different prescribed psychotropic medications was associated with the total amount of psychotropics ingested at the overdose in Step 2 (ß = 0.40, P = .01). There was a trend toward an association between the past number of deliberate self-harm events and the total amount of psychotropics ingested at the overdose in Step 1 (ß = 0.30, P = .05), but this trend was weakened in Step 2 (ß = 0.15, P = .33). CONCLUSION: The number of different prescribed psychotropics appeared to influence the risk of subsequent intentional overdose through increasing the total amount of psychotropics ingested. Cumulative psychotropic prescriptions, particularly those delivered after deliberate self-harm, might be indirectly related to this risk.

Psychosocial Assessment of Transplant Candidates: Inter-rater Reliability and Concurrent Validity of the Japanese Version of the Stanford Integrated Psychosocial Assessment for Transplantation.

BACKGROUND: The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a comprehensive instrument developed to provide a standardized, objective, and evidence-based psychosocial evaluation of the main pretransplant psychosocial risk factors that may influence transplant outcomes. OBJECTIVE: Because established assessment procedures or standardized tools designed to perform pre-solid organ transplant psychosocial evaluation are currently unavailable in Japan, the present study aimed to develop and preliminarily validate the Japanese version of the SIPAT. METHODS: First, the Japanese version of the SIPAT was developed using standard forward-back-translation procedures. Then, the Japanese versions of the SIPAT and the Japanese version of Psychosocial Assessment of Candidates for Transplant were retrospectively and blindly applied to 107 transplant cases by 4 independent raters. RESULTS: The interrater reliability of the scores obtained with the Japanese version of the SIPAT was excellent (Pearson's correlation coefficient = 0.86). The concurrent validity of the SIPAT to the Psychosocial Assessment of Candidates for Transplant for each examiner was substantial (Spearman's rank correlation coefficient = -0.66). CONCLUSION: These findings suggest that the Japanese version of the SIPAT is a promising and reliable instrument. Further research is required to test the predictive validity of the Japanese version of the SIPAT.

Role of Lamin A and emerin in maintaining nuclear morphology in different subtypes of ovarian epithelial cancer.

The nuclear lamina protein, Lamin A and inner nuclear membrane protein, emerin participate in maintaining nuclear morphology. However, their correlations with the nuclear shape in the four representative ovarian epithelial cancer subtypes, high-grade serous carcinoma (HGSCa), clear cell carcinoma (CCCa), endometrioid carcinoma (EMCa) and mucinous carcinoma (MUCa), remains unclear. The present study aimed to investigate the association between nuclear morphology and nuclear membrane protein expression in four histological subtypes of ovarian epithelial cancer. A total of 140 surgically resected ovarian cancer specimens were subjected to Feulgen staining to evaluate nuclear morphology, and immunohistochemistry analysis to assess Lamin A and emerin expression. The histological images were analyzed via computer-assisted image analysis (CAIA). The results demonstrated that the mean nuclear area of EMCa was significantly smaller compared with CCCa (P=0.0009). The standard deviation of the mean nuclear area was used to assess nuclear size variation, and the results indicated that EMCa lesions were significantly smaller than CCCa lesions (P=0.0006). Regarding the correlation between the Lamin A-positive rate and nuclear morphological factors, positive correlations were observed with nuclear area in CCCa and EMCa (R=0.2855 and R=0.2858, respectively) and nuclear perimeter in CCCa, EMCa and MUCa (R=0.2409, R=0.4054 and R=0.2370, respectively); however, a negative correlation with nuclear shape factor was observed in HGSCa and EMCa (R=-0.2079 and R=-0.3707, respectively). With regards to the correlation between emerin positivity and nuclear morphological factors, positive correlations were observed with nuclear shape factor in HGSCa (R=0.2673) and nuclear area in CCCa (R=0.3310). It is well-known that HGSCa and CCCa have conspicuous nuclear size variation, and EMCa has small nuclei without strong atypia. These findings were verified in the present study via CAIA. Taken together, the results of the present study suggest that Lamin A strongly contributes to the maintenance of nuclear morphology in ovarian epithelial cancer compared with emerin, although their contributions differ based on tumor subtype.

Quasi-cluster randomized trial of a six-month low-intensity group-based resistance exercise for hemodialysis patients on depression and cognitive function: a 12-month follow-up.

OBJECTIVE: This study aimed to examine the effects of a six-month group-based low-intensity resistance exercise program on depression and the cognitive function of hemodialysis patients. METHOD: We conducted a quasi-cluster randomized, open-label controlled study from October 2017 to December 2018. Forty-two patients undergoing hemodialysis completed the trial over six months; half participated in the resistance exercise group (n = 21, mean = 74.90 years of age, SD = 2.23, 66.67% female) and the other half were in a stretching control group (n = 21, mean = 72.57 years of age, SD = 2.26, 28.57% female). Depressive symptoms and cognitive function were the primary outcome measures. Behavioral and psychological problems associated with cognitive decline (NPI-Q), subjective insomnia, and exercise self-efficacy were secondary outcomes. Outcomes were measured at baseline, three-month (mid-intervention), six-month (end of intervention), and 12-month (six months after intervention) follow-ups. Linear mixed model analyses were used to determine short-term (immediately after intervention) and long-term (six months after intervention) effects. RESULTS: In depression, cognitive function, and the NPI-Q, there were no significant effects. In subjective insomnia, a short-term group-by-time interaction in the intervention group compared to the control group was found (ES = .43). However, the effect had disappeared by the 12-month follow-up. In exercise self-efficacy, short- and long-term group-by-time interactions were found. A significant short-term increase in the resistance exercise and a significant decrease in the stretching control was observed (ES = -.83). However, the effect was weakened in the long term (ES = -.38). CONCLUSION: The results showed that low-intensity group resistance exercise would reduce subjective insomnia and improve exercise self-efficacy, but the effect was not maintained by six months after the program.Trial registration: This study was registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN000029372). Trial registration: UMIN Japan identifier: UMIN000029372.

Design, synthesis, and target identification of new hypoxia-inducible factor 1 (HIF-1) inhibitors containing 1-alkyl-1H-pyrazole-3-carboxamide moiety.

Hypoxia-inducible factor 1 (HIF-1) is a promising drug target for cancer chemotherapy. In our screening program aimed at identifying new HIF-1 inhibitors by using a hypoxia-responsive luciferase reporter gene assay, KUSC-5001 containing the 1-alkyl-1H-pyrazole-3-carboxamide moiety was found as a potential hit molecule. During an extensive structure-activity relationship (SAR) study, we developed a more effective HIF-1 inhibitor KUSC-5037 (IC50 = 1.2 µM). Under hypoxic conditions, KUSC-5037 suppressed the HIF-1α (a regulatory subunit of HIF-1) mRNA, causing decreases in the gene expression of HIF-1 target genes such as carbonic anhydrase 9 (CA9) and vascular endothelial growth factor (VEGF) genes. Furthermore, by applying our fluorescent and bifunctional probes, ATP5B, a catalytic ß subunit of mitochondrial FoF1-ATP synthase, was identified as a target protein of KUSC-5037. These results indicate that the derivatives of KUSC-5037 containing the 1-alkyl-1H-pyrazole-3-carboxamide moiety are promising lead molecules for the inhibition of HIF-1 signaling via FoF1-ATP synthase suppression.

Computer-assisted image analysis of cytological specimens clarify the correlation between nuclear size and intranuclear cytoplasmic inclusions regardless of BRAFV600E mutation in papillary thyroid carcinoma.

OBJECTIVE: The morphological features of nuclei in cytological and histological specimens were compared and examined for the presence of BRAFV600E mutation and the appearance rate of intranuclear cytoplasmic inclusions (NI). METHODS: BRAFV600E mutation was identified using a mutation-specific antibody (clone; VE1) in 103 thyroid papillary carcinoma cases at Gunma University Hospital. The nuclear area, perimeter, and roundness of the corresponding cytological specimens and haematoxylin and eosin-stained specimens were analysed using image analysis software, and the appearance rate of NI was calculated and compared. RESULTS: BRAFV600E mutation was detected in 71 (69%) cases. The appearance rate of NI was significantly higher in the BRAFV600E mutation-positive group in cytological and histological specimens (P = .0070 and .0184, respectively). Significant differences were observed between the BRAFV600E mutation-negative and -positive groups in the average nuclear area and average nuclear perimeter in cytological specimens (P = .0137 and .0152, respectively). In addition, nuclear enlargement was correlated with the appearance rate of NI regardless of the presence of BRAFV600E mutation in cytological specimens. In the BRAFV600E mutation-negative group, the nuclear area and perimeter were significantly smaller in the lymph node metastasis-positive cases (P = .0182 and .0260, respectively). CONCLUSION: This study found that the appearance rate of NI was positively correlated with the nuclear area and perimeter and negatively correlated with nuclear roundness in cytological specimens. Furthermore, these results were observed regardless of the existence of BRAFV600E mutation. These results have never been previously reported and clearly demonstrate the usefulness of cytological specimens in computer-assisted image analysis.

Pilot trial of "Epi-school" group psychosocial education program for patients with epilepsy and their relatives in Japan.

INTRODUCTION: In epilepsy treatment, it is important for patients with epilepsy (PWE) to have accurate knowledge of epilepsy and to actively engage in treatment. In Japan, there are a few facilities for implementing learning programs for PWE, and their long-term usefulness has not been established. We conducted a pilot group psychosocial education program for PWE and their relatives in Japan. METHODS: Participants were PWE and their relatives who were 18 years old or older, were able to consent to participate in the study, and who were visiting the outpatient clinic of Saitama Medical Center from September 2019 to March 2020. As an intervention, we created a psychosocial educational program called "Epi-school" for PWE and their relatives, consisting of three sessions. Outcomes included patients' quality of life (QOL) measured with the epilepsy-31-P (QOLIE-31P), Rosenberg self-esteem scale (RSES), Stigma scale for chronic neurological disease (SSCI-8), and Epilepsy knowledge scale, before and after Epi-school. In addition, in a free-form questionnaire, we collected the impressions of patients and their relatives regarding the experience of participating in a group psychosocial education program. RESULTS: We examined 11 patients (two males, nine females) and 12 relatives (four males, eight females) who participated in Epi-school during the target period. The analyses revealed that only the scales measuring knowledge about epilepsy in the effect index showed significant increases in both patients and relatives after the program compared with before the program (patients: F [1,5.30] = 13.65, P < .05; relatives: F [1,4] = 17.50, P < .05). Moreover, a large effect size (d = 0.85) was obtained in patients, and a large effect size (d = 1.03) was obtained in relatives. In the open-ended questionnaire after participating in Epi-school, respondents reported changes in the psychological state of patients in the "learning epilepsy knowledge and coping methods", including changes in "acquired knowledge of illness" and "acquisition of coping with psychological aspects". Furthermore, it reports of "discovery/surprise", "thanks to medical staff", "interaction with other patients/relatives", and "new anxiety". In addition, "positive thoughts on treatment", "hopes for the future", "expectations for interaction with medical staff", "expectations for interaction with colleagues with the same disease", and "coming out of epilepsy" were reported. Regarding the psychological state of relatives after participating in Epi-school, it revealed "thanks to medical staff", "interactions with other patients/relatives", and "awareness of and remarks about other patients' statements". The results also revealed responses including "positive thoughts about treatment", "expectations of medical care", and "expectations of the community". DISCUSSION: The results confirmed that Epi-school led to improved knowledge, and psychological changes, including improved QOL and positive acceptance of epilepsy. Participants' awareness about epilepsy appeared to improve through encounters with other participants' attitudes toward epilepsy, possibly changing via the ways participants interacted. It is important to promote understanding of epilepsy, enhance the effects of treatment, and reduce psychosocial restrictions. CONCLUSIONS: Epi-school may be useful as part of epilepsy treatment to improve the QOL of PWE by making it easier for patients and their relatives to develop acceptance of living with epilepsy. The main limitation in the current study was the small sample size and the lack of a control group. In future studies, we plan to further investigate the usefulness of psychosocial education programs in Japan, including Epi-school, by increasing the sample size, including a control comparison, and collecting more comprehensive data. We hope that the current findings will encourage the provision of appropriate medical insurance funding for patient learning programs in Japan.

Macrophages in Giemsa-stained cerebrospinal fluid specimens predict carcinomatous meningitis.

Carcinomatous meningitis is a condition in which tumor cells spread to the subarachnoid space. Leukocyte counting and typing of cerebrospinal fluid (CSF) cell components are performed manually or using flow cytometry. However, a detailed analysis of these variables using cytological specimens has not yet been reported. The present study analyzed cytological specimens using Giemsa staining and whole slide imaging with computer-assisted image analysis (CAIA) to clarify the characteristics of the leukocyte population in CSF, especially in carcinomatous meningitis. Manual evaluation was performed using 280 Giemsa-stained cytological CSF specimens. For 49 samples, CAIA was used for the whole area of Papanicolaou (Pap) staining, and Giemsa-stained specimens of the same samples were imaged using a virtual slide scanner. The nuclear morphology of the leukocytes was assessed, and the total leukocyte and leukocyte subset (lymphocytes, neutrophils and macrophages) counts were evaluated. Then, the number and percentage of each leukocyte subset population were evaluated. The total leukocyte count was significantly higher in Giemsa-stained specimens compared with in Pap-stained specimens. The percentage of macrophages was significantly higher in samples from patients with non-hematological tumors compared with in samples from patients without tumors, which was confirmed by manual evaluation of the specimens. In addition, the cut-off value of the percentage of macrophages that could discriminate between the tumor history negative cases and cytologically tumor positive cases was determined, revealing that a higher proportion of macrophages reflected the existence of atypical/malignant epithelial tumor cells in CSF samples. Thus, atypical cell screening and analysis of the background characteristics of the leukocyte population should be the focus of cytological specimen screening, especially not to miss carcinomatous meningitis.