Nippon Zoki (Japan)

Background and Objectives: Despite the fact that biologic drugs have transformed inflammatory bowel disease (IBD) treatment, addressing fibrosis-related strictures remains a research gap. This study explored the roles of cytokines, macrophages, and Krüppel-like factors (KLFs), specifically KLF4, in intestinal fibrosis, as well as the interplay of KLF4 with various gut components. Materials and Methods: This study examined macrophage subtypes, their KLF4 expression, and the effects of KLF4 knockdown on macrophage polarization and cytokine expression using THP-1 monocyte models. Co-culture experiments with stromal myofibroblasts and a conditioned medium from macrophage subtype cultures were conducted to study the role of these cells in intestinal fibrosis. Human-induced pluripotent stem cell-derived small intestinal organoids were used to confirm inflammatory and fibrotic responses in the human small intestinal epithelium. Results: Each macrophage subtype exhibited distinct phenotypes and KLF4 expression. Knockdown of KLF4 induced inflammatory cytokine expression in M0, M2a, and M2c cells. M2b exerted anti-fibrotic effects via interleukin (IL)-10. M0 and M2b cells showed a high migratory capacity toward activated stromal myofibroblasts. M0 cells interacting with activated stromal myofibroblasts transformed into inflammatory macrophages, thereby increasing pro-inflammatory cytokine expression. The expression of IL-36α, linked to fibrosis, was upregulated. Conclusions: This study elucidated the role of KLF4 in macrophage polarization and the intricate interactions between macrophages, stromal myofibroblasts, and cytokines in experimental in vitro models of intestinal fibrosis. The obtained results may suggest the mechanism of fibrosis formation in clinical IBD.

Artykuł podejmuje problematykę kreowania wizerunku żydowskich protagonistów w filmach Labirynt kłamstw ( Im Labirynth des Schweigens, 2014, reż. Giulio Ricciarelli) oraz Murer: Anatomia procesu ( Murer: Anatomie des Prozesses, 2018, reż. Christian Frosch). Podstawowym celem badawczym jest tu wskazanie strategii, z jakich korzystają twórcy tych dzieł w procesie kodowania żydowskości. Refleksji poddane zostają także motywy i role przypisywane żydowskim postaciom. Materiał badawczy stanowią współczesne produkcjez Austrii oraz Niemiec. Komparatystyczna analiza umożliwia podjęcie refleksji nad tym, na ile odmienna polityka pamięci i przebieg rozliczeń z nazistowską przeszłości wpływają na filmowe wizerunki Żydów.

Abstract Background Intervertebral disc degeneration, one of the major causes of low-back pain, results from altered biosynthesis/turnover of extracellular matrix in the disc. Previously, we reported that the analgesic drug Neurotropin® (NTP) had an anabolic effect on glycosaminoglycan synthesis in cultured nucleus pulposus (NP) cells via the stimulation of chondroitin sulfate N-acetylgalactosaminyltransferase 1. However, its effect on the aggrecan core protein was not significantly detected, because of the data variance. A microarray analysis suggested that the effect of NTP on aggrecan was correlated with N-acetyltransferase 2 (NAT2), a drug-metabolizing enzyme. Specific NAT2 alleles are known to correlate with rapid, intermediate, and slow acetylation activities and side effects of various drugs. We investigated the association between the efficacy of NTP on aggrecan expression and the NAT2 genotype in cell donors. Methods NP cells were isolated from intervertebral disc tissues donated by 31 Japanese patients (28–68 years) who underwent discectomy. NTP was added to the primary cell cultures and its effect on the aggrecan mRNA was analyzed using real-time quantitative PCR. To assess acetylator status, genotyping was performed based on the inferred NAT2 haplotypes of five common single-nucleotide polymorphisms using allele-specific PCR. Results The phenotype frequencies of NAT2 in the patients were 0%, 42.0%, and 58.0% for slow, intermediate, and rapid acetylators, respectively. The proportions of responders to NTP treatment (aggrecan upregulation, ≥1.1-fold) in the intermediate and rapid acetylators were 76.9% and 38.9%, respectively. The odds ratio of the comparison of the intermediate acetylator status between responders and nonresponders was 5.2 (95% CI, 1.06–26.0, P = 0.036), and regarding the 19 male patients, this was 14.0 (95% CI, 1.54–127.2, P = 0.012). In the females, the effect was not correlated with NAT2 phenotype, but was negatively correlated with age (r = − 0.773, P = 0.006). Conclusions An intermediate acetylator status significantly favored the efficacy of NTP treatment to enhance aggrecan production in NP cells. In males, this tendency was detected with higher significance. Sex and age were also implicated in NTP efficacy. This study provides evidence of the association between NAT2 variants and the efficacy of NTP treatment.

BackgroundHepatocellular carcinoma (HCC) may lead to extrahepatic metastasis (EHM). Most patients with EHM had either intrahepatic stage III or IVA tumor at the site of metastases. Herein, we present the case of a fairly rare 1.5-cm small-diameter HCC with right adrenal gland tumor having an inferior vena cava (IVC) tumor thrombus.Case presentationA 75-year-old man had a 1.5-cm hepatocellular carcinoma (HCC) in segment 8 of the liver and a 3.0-cm right adrenal gland tumor with inferior vena cava (IVC) tumor thrombus. He underwent partial hepatectomy, right adrenalectomy, and IVC tumor thrombectomy. Tumor resection was successful, but the tumor progressed rapidly, and the patient died 8 months after the operation. Immunohistochemical staining revealed that both HCC cells and adrenal tumor cells were positive for HCC markers Glypican-3 and alpha-fetoprotein. In terms of adrenal carcinoma markers vimentin and Melan-A, vimentin was negative in the HCC and adrenal tumor, and Melan-A was negative in the HCC. In adrenal tumor, slight positivity of Melan-A was observed, but the intensity of staining was clearly weak compared with that in normal adrenal glands. CD133, one of the stem cell markers, was positive in both HCC and adrenal tumor cells. Next-generation amplicon sequencing analyses were performed using DNA derived from the HCC, adrenal tumor, and normal liver tissue. After exome data analyses for representative HCC-related genes as TERT, CTNNB1, TP53, and ARID2, TP53 mutation (exon3: c.G351 T: p.R117S) was found in both HCC cells and adrenal tumor cells. Conversely, no significant mutations in other genes were observed. These pathological findings and sequencing results showed that the adrenal tumor might be an adrenal metastasis of HCC in spite of small primary tumor size.ConclusionsThis case suggests that the right adrenal tumor was a metastasis of HCC. Immunohistochemical staining and gene mutation analyses using NGS are very useful in differentiating the tumor origin.

PurposeTo define the median endometrial thickness (ET) in office gynecology is thought to be important for clinical practice. However, there are few reports about ET that have included the general female population on a large scale. The median ET was determined prospectively in premenopausal women who attended office gynecology for cervical cancer screening.MethodsIn total, 849 women were enrolled. The median ET was determined by using transvaginal ultrasound and the relationships between the ET and various clinical factors were analyzed.ResultsThe participants' median age was 38.5 years. The median ET was 8.6 mm (90% and 95% quantiles: 13.8 and 15.8 mm). The ET was not related to their age, symptoms, obstetric history, geographical location, or risk factors for endometrial cancer. In the women with a menstrual cycle length of 28–30 days, the ET was 7 mm on days 1–6, but it increased from 5.4 mm immediately after menstruation (day 7 or 8) to 9.2 mm on days 13–14. Subsequently, the ET increased further to 11.1 mm on day 18.ConclusionIn all the women, the upper limit of the ET was 13.8 mm and 15.8 mm in the 90% and 95% quantile, respectively, in office gynecology.

Introduction: Respiratory care for pediatric out-of-hospital cardiac arrest (OHCA) may play an important role due to the asphyxial nature of the majority of pediatric OHCA events. Hypothesis: We assessed the hypothesis that prehospital advanced airway management (endotracheal intubation or supraglottic airway device) is associated with an increased chance of favorable outcomes compared with basic airway management (bag-valve-mask ventilation) after pediatric OHCA. Methods: This was a nationwide, population-based, propensity score-matched study of pediatric OHCA in Japan from January 1, 2011, to December 31, 2012, based on data from the All-Japan Utstein Registry. We included pediatric patients aged < 18 years. Infants (≤ 1 year old) were excluded. The primary outcome was a favorable neurological state one month after OHCA defined as a Glasgow-Pittsburgh cerebral performance category (CPC) score of 1-2 (corresponding to a Pediatric CPC score of 1-3). The secondary outcomes included a neurologically favorable survival with a CPC score of 1 (corresponding to a Pediatric CPC score of 1), one-month survival, and prehospital return of spontaneous circulation (ROSC). Results: A total of 2,157 patients were included in the final cohort; 365 received advanced airway management and 1,792 received basic airway management. Among 2,157 patients, 213 (9.9%) survived with a favorable neurological status one month after OHCA. There were no significant differences in neurologically favorable survival between the advanced airway management group and the basic airway management group after adjusting for potential confounders: propensity score matching, OR 0.74 (95%CI 0.35-1.59), and multivariable logistic regression modeling, OR 0.55 (95% CI 0.24-1.14). Similar findings were observed for the secondary outcomes. In subgroup analyses (including the non-cardiac [mainly asphyxial] etiology group), there were no subgroups in which advanced airway management was associated with neurologically favorable survival. Conclusions: In conclusion, advanced airway management was not associated with an increased chance of neurologically favorable survival, one-month survival, or prehospital ROSC compared to basic airway management after pediatric OHCA.

Objective: Nocturnal hypertension is a risk factor of cardiovascular disease, especially in on-treatment patients. We developed an information and communications technology (ICT)-based home blood pressure (BP) monitoring device that automatically measures BP during sleep (Nocturnal HBPM). Angiotensin receptor blocker (ARB)/diuretic combination therapy (ADI) showed synergistic ability to decrease BP. ARB/calcium channel blocker combination therapy (ACC) showed an additive ability to decrease BP. To prospectively assess these therapies’ effects on nocturnal hypertension using Nocturnal HBPM, we conducted the NOCTURNE study, the first comparing the efficacy/safety of antihypertensive medication on nocturnal BP levels assessed by an ICT-based home BP device. Design and Method: Japanese patients with uncontrolled nocturnal hypertension medicated by irbesartan 100 mg/day with nocturnal home BP > 120/70 mmHg (55.8% male, mean age 63 yrs) were randomly assigned to 8-week oral irbesartan 100 mg + trichlormethiazide 1 mg (ADI, n = 209) or irbesartan 100 mg + amlodipine 5 mg treatment (ACC, n = 207). Primary endpoint: a change in nocturnal systolic BP as measured by Nocturnal HBPM at the end of follow-up vs. the baseline during the run-in. Results: The SBP/DBP mean ± SD of baseline nocturnal home BP and office BP were 128.5 ± 13.8/79.3 ± 8.4 mmHg and 145.9 ± 19.3/89.6 ± 12.6 mmHg, respectively. Randomization was successfully conducted without difference in age, sex, BMI, prevalence of diabetes, and serum NT-proBNP level. The study ends at the last follow-up on July 20, 2016. Conclusions: Our findings will help identify appropriate antihypertensive treatment for hypertensive patients with disrupted circadian BP rhythm.

Purpose: Several studies have reported gender difference in presentation, management and outcome in patients with acute myocardial infarction (AMI). In this study, we focused the impact of age on gender difference in mortality after AMI. Methods: Between July 2012 and March 2014, 3283 patients were admitted to the 28 hospitals participating to the J-MINUET group within 48 hours after the onset of AMI. AMI was diagnosed by universal definition (type 1 or type 2). Patients were divided into 5 strata according to their age: those with age <55 years, 55-64 years, 65-74 years, 75-84 years and ≥85 years. Results: There were 813 women (24.8%). Women were significantly older than men (74.5±11.8 years vs 66.6±12.3 years, P<0.001). Women had longer time from onset to admission, more NSTEMI, atypical symptom other than chest pain, Killip class ≥2, CKD and type 2 MI. They also had less diabetes and current smoking habits. Although most of the patients received urgent angiography (93.1%), it was less frequent in women (90.4% vs 94.0%, P<0.001). Among patients who underwent primary PCI (85.1%), achievement of final TIMI-3 flow was similar (91.2% vs 92.0%, P=0.53). In-hospital mortality was significantly higher in women than men (9.6% vs 5.5%, P<0.001). When patients were stratified according to their age, there was a liner increase in the prevalence of women as age advanced: 10.6% in <55 years, 15.1% in 55-64 years, 19.8% in 65-74 years, 35.6% in 75-84 years and 53.6% in ≥85 years (P<0.001). There was no significant gender difference in mortality in each stratum (Figure). Multivariate analysis showed that women was no more an independent predictor of death after adjusting age (OR 1.29, 95%CI 0.95-1.75, P=0.10), or age and other variables (OR 1.19, 95%CI 0.79-1.76, P=0.40). Conclusions: Women had higher in-hospital mortality than men after AMI even in the contemporary troponin era. However, their high mortality was mostly explained by their advanced age.

Background: Hyperglycemia is recognized as a common occurrence associated with a high risk of poor outcome in ischemic stroke patients. However, little is known about the association between elevated glucose level, growth of infarct volume, and neurological deterioration in ischemic stroke patients without diabetes. The present study aimed to clarify this issue in acute ischemic stroke patients with arterial occlusion. Methods: We studied 375 acute ischemic stroke patients with arterial occlusion within 24 h of onset. Diabetes was diagnosed in patients with known history of diabetes or HbA1c value ≥6.5%. Infarct volume was measured on admission and at follow-up within 48 h using diffusion-weighted imaging. Neurological deterioration was defined as an increase of ≥4 points increase in National Institutes of Health Stroke Scale score within seven days of stroke onset. We examined the relationship between glucose level on admission, infarct volume growth, and neurological deterioration in three categories (all patients, non-diabetes, and diabetes) using multivariate modeling. Regression models included admission glucose level and other potentially predictive variables (NIHSS score on admission, initial infarct volume, arterial recanalization, hemorrhagic infarction, and ICA occlusion). Results: Diabetes was present in 104 patients (27.7%). Multivariate regression analysis showed that elevated glucose level was independently associated with infarct volume growth in all patients (P=0.034) and non-diabetes (P=0.002), but not in diabetes (P=0.871). Moreover, elevated glucose level was independently associated with neurological deterioration in all patients (odds ratio [OR], 1.010; 95% confidence interval [CI], 1.004-1.017; P=0.002) and non-diabetes (OR, 1.014; 95%CI, 1.002-1.026; P=0.022), but not diabetes (OR, 1.006; 95%CI, 0.998-1.014; P=0.151). Conclusions: Glucose level appears to influence infarct volume growth and neurological deterioration, particularly in non-diabetic patients with ischemic stroke.