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Aim Familial hypercholesterolemia (FH) is an underdiagnosed autosomal dominant genetic disorder characterized by high levels of plasma low-density lipoprotein cholesterol (LDL-C) from birth. This study aimed to assess the genetic identification of FH in children with high LDL-C levels who are identified in a universal pediatric FH screening in Kagawa, Japan. Method In 2018 and 2019, 15,665 children aged 9 or 10 years underwent the universal lipid screening as part of the annual health checkups for the prevention of lifestyle-related diseases in the Kagawa prefecture. After excluding secondary hyper-LDL cholesterolemia at the local medical institutions, 67 children with LDL-C levels of ≥ 140 mg/dL underwent genetic testing to detect FH causative mutations at four designated hospitals. Results The LDL-C levels of 140 and 180 mg/dL in 15,665 children corresponded to the 96.3 and 99.7 percentile values, respectively. Among 67 children who underwent genetic testing, 41 had FH causative mutations (36 in the LDL-receptor, 4 in proprotein convertase subtilisin/kexin type 9, and 1 in apolipoprotein B). The area under the curve of receiver operating characteristic curve predicting the presence of FH causative mutation by LDL-C level was 0.705, and FH causative mutations were found in all children with LDL-C levels of ≥ 250 mg/dL. Conclusion FH causative mutations were confirmed in almost 60% of the referred children, who were identified through the combination of the lipid universal screening as a part of the health checkup system and the exclusion of secondary hyper-LDL cholesterolemia at the local medical institutions.

Cerebral haemodynamics during the immediate transition period in neonates may differ depending on whether delivery is vaginal or by caesarean section. However, these differences have never been confirmed by near-infrared time-resolved spectroscopy (TRS). Therefore, the purpose of this study was to compare cerebral blood volume (CBV) and cerebral haemoglobin oxygen saturation (ScO2) between healthy term neonates by mode of delivery. Subjects were 31 healthy term neonates who did not require resuscitation. Thirteen neonates were delivered vaginally (VD group) and 18 were delivered by elective caesarean section (CS group). Absolute oxyhaemoglobin, deoxyhaemoglobin, and total haemoglobin concentrations were measured continuously by TRS; oxyHb × 100/totalHb (ScO2) (%) and CBV (mL/100 g brain tissue) were also calculated. Measurements were started as soon as possible after birth, obtained from 1 to 2 min after birth, and continued until 15 min after birth. CBV was significantly higher in the VD group than in the CS group in the 4 min after birth but not thereafter. There were no significant between-group differences in ScO2 and SpO2. These findings indicate that there is a difference in cerebral haemodynamic patterns in the first 4 min after delivery between term neonates by mode of delivery when CBV is monitored by TRS.

Background Septic shock is a life-threatening condition and one of the most common causes of acute kidney injury. Polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) is used to reduce endotoxin levels in blood. Here, we report a rare but important case of sepsis-induced acute kidney injury and septic shock, which was successfully treated with PMX-DHP in spite of inappropriate initial antibiotic therapy. Case presentation An 84-year-old man was hospitalized for septic shock and acute kidney injury. Although he was treated with ceftriaxone, he did not recover from hypotension and had reduced urine output. After initiating PMX-DHP on days 3 and 4, his blood pressure was immediately elevated and his white blood cell count and C-reactive protein levels improved. Because ceftriaxone-resistant Escherichia coli was identified in blood culture, we changed his antibiotics to levofloxacin on day 7. He successfully recovered from the septic shock and dialysis was withdrawn. Conclusions Considering the use of inappropriate initial antibiotics, the early induction of PMX-DHP might have been a key determinant of his outcome. PMX-DHP therapy should be considered in septic shock in addition to antibiotic treatment.

Introduction: Familial hypercholesterolemia (FH) is an autosomal hereditary disease found in patients who have elevated low-density lipoprotein cholesterol (LDL-C) levels from birth. Early detection and treatment of FH during childhood potentially reduces the risk of premature cardiovascular events. In Kagawa prefecture, a unique community health system, involving three steps, has been conducted to prevent lifestyle-related diseases for 10-year-old children. This system includes universal lipid screening, selection by pediatricians, and next-generation sequencing (NGS) of FH-related genes in the hospitals. The aim of this study is to investigate whether this system can be effective in detection of FH. Methods: In Kagawa prefecture, the universal lipid screening of children at 10 years of age is performed annually at school, covering over 90% of the target group. After excluding secondary hypercholesterolemia, pediatric clinics introduced children with LDL-C levels >140 mg/dL to four hospitals to perform NGS to detect FH. Results: In 2017, 279 children (3.7%) showed elevated LDL-C >140mg/dL among 7,647 ones who received the screening. We performed NGS for 46 children after excluding secondary hypercholesterolemia by pediatricians (LDL-C 186.0±50.3 mg/dL; M/F 27/19) and 26 children (57%) had FH genetic mutations (23 LDL-R, 3 PCSK9). The children with LDL-C >180mg/dL are recommended to receive statin therapy according to the guideline from the Japanese Atherosclerosis Society (JAS). Children with LDL-C levels ≥180 mg/dL have 74% of positive genetic mutations, and even those with 140-180 mg/dl LDL-C levels have as much as 44%, respectively (Table). Conclusions: The unique community health system in Kagawa can efficiently detect FH of children. Further investigation will be required for the effective prevention of future atherosclerotic cardiovascular diseases.

Introduction: Familial hypercholesterolemia (FH) is an autosomal hereditary disease found in patients who have elevated low-density lipoprotein cholesterol (LDL-C) from birth. Early detection and treatment of FH during childhood potentially reduces the risk of premature cardiovascular events. In Kagawa prefecture, a unique community health system, involving three steps, has been conducted to prevent lifestyle-related diseases for 10-year-old children. This system includes universal lipid screening, selection by pediatricians, and next-generation sequencing (NGS) of FH-related genes in hospitals. The aim of this study is to compare 3 international guidelines to detect pediatric FH with this unique community health system in Kagawa. Methods: In Kagawa prefecture, the universal lipid screening of approximately 8,000 children at 10 years of age is performed annually, covering over 90% of the target group. After excluding secondary hypercholesterolemia, pediatric clinics introduced children with LDL-C >140mg/dL to 4 designated hospitals to perform NGS. We applied the guidelines of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), and the Japanese Atherosclerosis Society (JAS) to children who received NGS in the unique community health system in Kagawa. Results: We performed NGS for 46 children from January 2018 to February 2020 (LDL-C 186.0±50.3 mg/dL; Male/F 27/19) and 26 (57%) had FH genetic mutations (23 LDL-R and 3 PCSK9 mutations). Seventeen children met FH criteria for DLCN (35%), 10 for Simon Broome (22%), and 11 for JAS (24%), respectively. The combination of NGS and either of the 3 guidelines increased the number of children diagnosed as FH up to 31 (67%). Conclusion: International guidelines detected only half of pediatric FH who were diagnosed by the unique community health system in Kagawa. Further investigation will be required to build an effective universal screening system for pediatric FH.

Background: Therapeutic hypothermia (TH) is a standard therapy for neonatal hypoxic-ischaemic encephalopathy. One potential additional therapy is the free radical scavenger edaravone (EV; 3-methyl-1-phenyl-2-pyrazolin-5-one). Objectives and Methods: This study aimed to compare the neuroprotective effects of edaravone plus therapeutic hypothermia (TH + EV) with those of TH alone after a hypoxic-ischaemic insult in the newborn piglet. Anaesthetized piglets were subjected to 40 min of hypoxia (3–5% inspired oxygen), and cerebral ischaemia was assessed using cerebral blood volume. Body temperature was maintained at 39.0 ± 0.5°C in the normothermia group (NT, n = 8) and at 33.5 ± 0.5°C (24 h after the insult) in the TH (n = 7) and TH + EV (3 mg/kg intravenous every 12 h for 3 days after the insult; n = 6) groups under mechanical ventilation. Results: Five days after the insult, the mean (standard deviation) neurological scores were 10.9 (5.7) in the NT group, 17.0 (0.4) in the TH group (p = 0.025 vs. NT), and 15.0 (3.9) in the TH + EV group. The histopathological score of the TH + EV group showed no significant improvement compared with that of the other groups. Conclusion: TH + EV had no additive neuroprotective effects after hypoxia-ischaemia in neurological and histopathological assessments.

Hypothermia (HT) improves the outcome of neonatal hypoxic-ischemic encephalopathy. Here, we investigated changes during HT in cortical electrical activity using amplitude-integrated electroencephalography (aEEG) and in cerebral blood volume (CBV) and cerebral hemoglobin oxygen saturation using near-infrared time-resolved spectroscopy (TRS) and compared the results with those obtained during normothermia (NT) after a hypoxic-ischemic (HI) insult in a piglet model of asphyxia. We previously reported that a greater increase in CBV can indicate greater pressure-passive cerebral perfusion due to more severe brain injury and correlates with prolonged neural suppression during NT. We hypothesized that when energy metabolism is suppressed during HT, the cerebral hemodynamics of brains with severe injury would be suppressed to a greater extent, resulting in a greater decrease in CBV during HT that would correlate with prolonged neural suppression after insult.Twenty-six piglets were divided into four groups: control with NT (C-NT, n = 3), control with HT (C-HT, n = 3), HI insult with NT (HI-NT, n = 10), and HI insult with HT (HI-HT, n = 10). TRS and aEEG were performed in all groups until 24 h after the insult. Piglets in the HI-HT group were maintained in a hypothermic state for 24 h after the insult.There was a positive linear correlation between changes in CBV at 1, 3, 6, and 12 h after the insult and low-amplitude aEEG (5 µV) duration after insult in the HI-NT group, but a negative linear correlation between these two parameters at 6 and 12 h after the insult in the HI-HT group. The aEEG background score and low-amplitude EEG duration after the insult did not differ between these two groups.A longer low-amplitude EEG duration after insult was associated with a greater CBV decrease during HT in the HI-HT group, suggesting that brains with more severe neural suppression could be more prone to HT-induced suppression of cerebral metabolism and circulation.

Loop-mediated isothermal amplification (LAMP) rapidly amplifies DNA under isothermal conditions. The aim of this study was to detect Candida albicans and compare the positivity rate in the LAMP reaction with that of conventional methods for oral exfoliative cytology (EC) samples. Sixty-eight EC samples from 53 patients were subjected to LAMP analysis. These patients had been clinically diagnosed with leukoplakia, squamous cell carcinoma, oral lichen planus (OLP), stomatitis, oral candidiasis, and other malignancies. LAMP reactions were defined as positive when the sample turbidity exceeded 0.1 (arbitrary unit). Periodic acid-Schiff (PAS) staining and microbial culture were also performed to detect Candida species in EC samples. The LAMP reaction detected C. albicans in 42.6% of EC samples. Candida species were detected in 32.4% of the same samples by culturing and in 29.4% of samples by PAS staining. C. albicans DNA was detected most frequently in samples from OLP patients. We conclude that, in comparison to conventional methods for detection of C. albicans, the LAMP method is highly sensitive and time-saving, and does not require expensive equipment or diagnostic technology. It may therefore be useful for on-site screening of C. albicans at dental clinics.

The aim of this study was to use near-infrared time-resolved spectroscopy (TRS) to determine the absolute values of cerebral blood volume (CBV) and cerebral hemoglobin oxygen saturation (ScO2) during the immediate transition period in term neonates and the changes in optical properties such as the differential pathlength factor (DPF) and reduced scattering coefficient (&mu, s&rsquo, ). CBV and ScO2 were measured using TRS during the first 15 min after birth by vaginal delivery in term neonates who did not need resuscitation. Within 2&ndash, 3 min after birth, CBV showed various changes such as increases or decreases, followed by a gradual decrease until 15 min and then stability (mean (SD) mL/100 g brain: 2 min, 3.09 (0.74), 3 min, 3.01 (0.77), 5 min, 2.69 (0.77), 10 min, 2.40 (0.61), 15 min, 2.08 (0.47)). ScO2 showed a gradual increase, then kept increasing or became a stable reading. The DPF and &mu, values (mean (SD) at 762, 800, and 836 nm) were stable during the first 15 min after birth (DPF: 4.47 (0.38), 4.41 (0.32), and 4.06 (0.28)/cm, &mu, 6.54 (0.67), 5.82 (0.84), and 5.43 (0.95)/cm). Accordingly, we proved that TRS can stably measure cerebral hemodynamics, despite the dramatic physiological changes occurring at this time in the labor room.

Background Direct-reacting bilirubin concentrations measured using vanadate chemical oxidation method do not exactly match the conjugated bilirubin concentration. One of the causes is the effect of bilirubin photoisomers. However, the quantitative evaluation of the effects of these photoisomers has not been sufficiently conducted. In particular, the influence of bilirubin configurational isomers on direct bilirubin is the most critical factor. Methods Sixteen residual serum samples were used. For quantitative analysis based on the change in direct bilirubin and bilirubin configurational isomer, samples were irradiated via blue light-emitting diodes to suppress the production of bilirubin structural isomers. Total bilirubin and direct bilirubin concentrations were measured using the vanadate chemical oxidation method. Concentrations of 4Z,15Z-bilirubin IXα and its photoisomers were measured using high-performance liquid chromatography. The sum of 4Z,15E-bilirubin IXα and 4E,15Z-bilirubin IXα was notated as bilirubin configurational isomer, and the differences between the measured values of the irradiated and non-irradiated samples were calculated and notated as ΔDB and ΔBCI. Results In non-irradiated and irradiated samples, total bilirubin and direct bilirubin concentrations were 10.73 mg/dL with significant a decrease to 10.60 mg/dL and 0.69 mg/dL with a significant increase to 0.78 mg/dL, while bilirubin configurational isomer values were 1.00 mg/dL and 1.52 mg/dL, respectively. The linear regression equation revealed a significant positive correlation of Y = 0.187X−0.006 between ΔDB (Y) and ΔBCI (X). Conclusion Applying the vanadate chemical oxidation method affected approximately 19% of the bilirubin configurational isomer concentration for direct bilirubin. Extreme caution is necessary when interpreting the measured values of samples indicative of unconjugated hyperbilirubinaemia.

There have been a number of recent reports on the occurrence of autoimmune conditions after autologous hematopoietic stem cell transplantation. We describe a rare case of Evans syndrome (ES) that developed in a 16-year-old patient >1 year after autologous peripheral blood stem cell transplantation for recurrent Hodgkin lymphoma. ES is a rare and frequently refractory condition. No therapy for the condition has been established, and it can often be fatal. In the present case, i.v. cyclosporine A injection was significantly effective against the ES, which has not recurred.

Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor that diminishes tissue destruction during inflammation. A recent report revealed high levels of SLPI expression in the oral carcinoma cell. In addition, overexpression of SLPI up-regulates metastasis in lung carcinoma cells. On the other hand, matrix metalloproteinases (MMPs) are proteinases that participate in extracellular matrix degradation. SLPI and MMPs are involved as accelerators of the tumor invasion process; however, their exact roles are not fully understood. Understanding the mechanism of tumor invasion requires models that take the effect of microenvironmental factors into account. In one such in vitro model, different carcinoma cells have been shown to invade myoma tissue in highly distinct patterns. We have used this myoma model, as it provides a more natural stroma-like environment, to investigate the role of SLPI in tumor invasion. Our results indicate that the model provides a relevant matrix for tumor invasion studies, and that SLPI is important for the invasion of oral carcinoma Ca9-22 cells in conjunction with MMPs. Furthermore, using bioinformatics analysis, we have identified candidates as key molecules involved in SLPI-mediated tumor invasion.

Background The effects of eicosapentaenoic acid (EPA) on coronary artery disease have been previously reported; however, those of the addition of EPA to strong statins on coronary plaque components and local inflammatory cytokines are not known. Methods and results A total of 95 patients who had been treated with strong statin for at least 6 months were randomized into 2 groups: an EPA group (additional treatment with EPA at 1,800 mg/day, n=48) or a control group (no additional treatment, n=47), for 6 months. The tissue characteristics of target coronary plaque in each patient were analyzed using IB-IVUS before and after treatment. We also measured plasma levels of inflammatory cytokines sampled in the coronary sinus (CS) and peripheral vein.A significant reduction in lipid volume (18.5 ± 1.3 to 15.0 ± 1.5 mm(3), P=0.007) and a significant increase in fibrous volume (22.9 ± 0.8 to 25.6 ± 1.1 mm(3), P=0.01) were observed in IB-IVUS image analyses in the EPA group, but no significant changes in the plaque components in the control group. CS levels of pentraxin 3 and monocyte chemoattractant protein-1 were lower after than before treatment with EPA (3.3 ± 2.1 to 2.6 ± 1.2 ng/ml, 120.4 ± 26.2 to 110.2 ± 26.8 pg/ml, P=0.015 and P=0.008, respectively); however, there were no significant changes in those inflammatory cytokines between pre- and post-treatment in the control group. Conclusions The addition of EPA was associated with reduced lipid volume in coronary plaques and decreased inflammatory cytokines.

Background: Although increasing evidence suggests that epicardial adipose tissue volume (EATV) is associated with atrial fibrillation (AF), it is controversial whether there is a dose-response relationship of increasing EATV along the continuum of AF. We evaluated the effect of the EATV on the prevalence of paroxysmal AF (PAF) and persistent AF (PeAF) and the relationships with cardiac structure and functional remodeling. Methods and Results: Subjects who underwent multidetector computed tomography (MDCT) coronary angiography because of symptoms suggestive of coronary artery disease were divided into sinus rhythm (SR) (n=112), PAF (n=133), and PeAF (n=71) groups. The EATV index (EATV/body surface area, mL/m2) was strongly associated with the prevalence of PAF and PeAF on the model adjusted for known AF risk factors. The effect of the EATV index on the prevalence of PeAF, but not on that of PAF, was modified by the left atrial (LA) dimension, suggesting that extension of the LA dimension is related to EATV expansion in PeAF. The cutoff value of the EATV index for the prevalence was higher in PeAF than in PAF (64 vs. 55 mL/m2, P

Background: Compared with global cardiac adiposity, the local accumulation of fat surrounding coronary arteries might have a more direct impact on coronary artery disease (CAD). Here, we compared the local epicardial adipose tissue (EAT) thickness and global cardiac adiposity volumes for predicting CAD. Methods and Results: A total of 197 consecutive subjects underwent 320-slice multi-detector computed tomography coronary angiography and were segregated into CAD (≥1 coronary artery branch stenosis ≥50%) and non-CAD groups. EAT thickness was measured at the right coronary artery (EATRCA), the left anterior descending artery (EATLAD), and the left circumflex artery (EATLCX). Although EATRCA and EATLCX were similar between the 2 groups, EATLAD was larger in the CAD group than in the non-CAD group (5.45±2.16 mm vs. 6.86±2.19 mm, P

Loop-mediated isothermal amplification (LAMP) rapidly amplifies DNA under isothermal conditions. The aim of this study was to detect Candida albicans and compare the positivity rate in the LAMP reaction with that of conventional methods for oral exfoliative cytology (EC) samples. Sixty-eight EC samples from 53 patients were subjected to LAMP analysis. These patients had been clinically diagnosed with leukoplakia, squamous cell carcinoma, oral lichen planus (OLP), stomatitis, oral candidiasis, and other malignancies. LAMP reactions were defined as positive when the sample turbidity exceeded 0.1 (arbitrary unit). Periodic acid-Schiff (PAS) staining and microbial culture were also performed to detect Candida species in EC samples. The LAMP reaction detected C. albicans in 42.6% of EC samples. Candida species were detected in 32.4% of the same samples by culturing and in 29.4% of samples by PAS staining. C. albicans DNA was detected most frequently in samples from OLP patients. We conclude that, in comparison to conventional methods for detection of C. albicans, the LAMP method is highly sensitive and time-saving, and does not require expensive equipment or diagnostic technology. It may therefore be useful for on-site screening of C. albicans at dental clinics.

The promotion of adipose tissue inflammation by lifestyle-related diseases such as obesity and diabetes accelerates atherogenesis; however, the underlying mechanisms remain incompletely understood. Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome contributes to chronic inflammation in adipose tissue. Here, we investigated the link between NLRP3 expression in subcutaneous adipose tissue (SAT) and the severity of coronary atherosclerosis.SAT was obtained from 72 patients who underwent heart device implantation and coronary angiography. Expression of NLRP3 inflammasome-related molecules (NLRP3, IL-1β and IL-18) in SAT were evaluated by quantitative RT-PCR. Laboratory markers related to lifestyle-related diseases were measured. Patients with obesity, dyslipidemia (P0.05, respectively), diabetes or hyperuricemia (P0.01, respectively) had significantly higher expression of NLRP3. Multivariate analysis demonstrated that body mass index and serum level of uric acid were predictors of NLRP3 expression in SAT. The expression of NLRP3 in SAT correlated negatively with serum adiponectin level (r = -0.23, P0.05). Patients with coronary artery disease showed higher NLRP3 expression than patients without significant stenosis (P0.01). Furthermore, the expression of NLRP3 in SAT correlated positively with the severity of coronary atherosclerosis as determined by Gensini score (r = 0.47, P0.0001) or SYNTAX score (r = 0.55, P0.0001). Multiple regression analysis revealed that the expression of NLRP3 in SAT remains as an independent predictors for the severity of coronary atherosclerosis.The expression of NLRP3 in SAT, which is affected by lifestyle-related diseases, is associated with the severity of coronary atherosclerosis. Our results suggest that NLRP3 inflammasome in SAT may have a role in atherogenesis.

Polymeric immunoglobulin receptor (pIgR) plays an important role in mucosal immune systems. Secretory immunoglobulin A, composed of secretory component of pIgR and a dimeric form of immunoglobulin A, is secreted on mucosal surfaces and serves as a biological defense factor. pIgR gene expression is reportedly induced by activation of the transcription factor nuclear factor (NF)-κB. On the other hand, secretory leukocyte protease inhibitor (SLPI) is a glycoprotein that functions as a serine protease inhibitor. In alveolar epithelial cells, SLPI increases the level of IκBβ, which indicates that it is an inhibitor of NF-κB at the protein level. Taken together, SLPI may regulate pIgR expression; however, the specific mechanism by which this occurs is unclear. Therefore, the aim of this study was to elucidatethe influence of SLPI on pIgR expression.SLPI and pIgR localized in goblet cells and ciliated epithelial cells of the gastrointestinal tract, respectively. No cells were detected in which SLPI and pIgR were co-expressed. In addition, recombinant human SLPI stimulation of an epithelial cell line (HT-29) decreased the pIgR expression. The pIgR expression was also higher in SLPI-deficient Ca9-22 cells than in wild-type Ca9-22 cells. Furthermore, a luciferase assay using a NF-κB reporter plasmid and real-time RT-PCR analysis indicated that when SLPI was present, the transcriptional activity of NF-κB protein was suppressed, which was accompanied by anincrease in the protein, but not the mRNA,expression of IκBβ. These results demonstrate that SLPI down-regulates pIgR expression through the NF-κB signaling pathway by inhibiting degradation of IκBβ protein.

Background Uremic toxin has emerged as an important determinant of cardiovascular risk. The aim of this study was to examine the relationship between serum uremic toxin and coronary plaque composition on integrated backscatter intravascular ultrasound (IB-IVUS). Methods and results IB-IVUS was performed in 47 patients with planned treatment for angina pectoris. Non-culprit intermediate plaque analyzed in this study had to be >5 mm apart from the intervention site. 3-D IB-IVUS analysis was performed to determine percent lipid volume (LV) and fibrous volume (FV). We also measured serum uremic toxins (indoxyl sulfate [IS], asymmetric dimethylarginine [ADMA], and p-cresol [PC]). Glomerular filtration rate correlated with IS (r=-0.329, P=0.04), but did not correlate with ADMA or PC. Percent LV correlated with IS (r=0.365, P=0.02), but did not correlate with ADMA or PC. Percent FV also correlated with IS (r=-0.356, P=0.03), but did not correlate with ADMA or PC. On multivariate regression, only IS was associated with percent LV (r=0.359, P=0.04) and percent FV (r=-0.305, P=0.04) independently of potentially confounding coronary risk factors. Conclusions Among the uremic toxins, serum IS might be a novel useful biomarker to detect and monitor lipid-rich coronary plaque on IB imaging.

Several studies have shown that various chemokines are more highly expressed in atherosclerotic plaques than in normal vessel walls. In the present study, we investigated the relationship between coronary atherosclerosis and noteworthy chemokines, including interferon-inducible protein of 10 kD (IP-10); monocyte chemoattractant protein 1 (MCP-1); regulated on activation, normal T-cell expressed and secreted (RANTES); and high-sensitivity C-reactive protein (hsCRP), an established marker of atherosclerotic disease. We studied 28 patients who underwent coronary angiography because of suspected coronary artery disease (CAD). CAD was defined as stenosis of more than 50% of the vessel diameter on coronary angiograms. Blood samples were obtained both from the aorta and the coronary sinus (CS) just before coronary angiography. Relative to CAD (-) patients, those who were CAD (+) tended to have higher plasma concentrations of IP-10 in the aorta, as well as significantly higher transcoronary concentration gradients of circulating IP-10. There were no significant differences between the two groups in aortic plasma concentrations or transcoronary concentration gradients of MCP-1, RANTES, and hsCRP. Furthermore, both the aortic plasma concentrations and transcoronary concentration gradients of IP-10 correlated with the Gensini score (r = 0.58 and r = 0.63, respectively, P < 0.01), while the plasma MCP-1, RANTES, and serum hsCRP concentrations did not. This study suggests that IP-10 is a good surrogate marker of coronary atherosclerosis.

An 8-year-old Japanese girl was admitted with an ovarian yolk sac tumor. Regarding birth history, the patient had been delivered by cesarean section at 25 weeks of gestation with a birthweight of 711g. She had required neonatal intensive care including oxygenation, various medications, and tests. After surgery and chemotherapy, there was no recurrence for 2 years, at the time of writing. Yolk sac tumor, which is a malignant germ cell tumor, is rare in children. Although the cause and risk factors are unclear, it has been reported that malignant germ cell tumors in childhood have been associated with pathophysiology at birth. Given that premature infants are more likely to survive due to advances in perinatal care, it is expected that such cases will increase in the near future. We suggest that children born prematurely require careful follow up.

Regular health checkups for mothers of patients with Duchenne muscular dystrophy have been performed at National Hospital Organization Tokushima Hospital since 1994. Among 43 mothers participated in this study, 28 dystrophinopathy carriers were identified. Skeletal and cardiac muscle functions of these subjects were examined. High serum creatine kinase was found in 23 subjects (82.1%). Obvious muscle weakness was present in 5 (17.8%) and had progressed from 1994 to 2015. Cardiomyopathy was observed in 15 subjects (60.0%), including dilated cardiomyopathy-like damage that was more common in the left ventricular (LV) posterior wall. Late gadolinium enhancement on cardiac MRI was found in 5 of 6 subjects, suggesting fibrotic cardiac muscle. In speckle tracking echocardiography performed seven years later, global longitudinal strain was decreased in these subjects, indicating LV myocardial contractile abnormality. These results suggest that female dystrophinopathy carriers should receive regular checkups for detection and treatment of cardiomyopathy, even if they have no cardiac symptoms.

Background Natriuretic peptides have been proposed as biomarkers of cardiovascular disease, especially heart failure. Brain natriuretic peptide (BNP) has also been shown to be upregulated at the transcriptional and translational levels by pro-inflammatory cytokines in cardiac myocytes. Although we often measure plasma BNP levels in cancer patients, it remains unknown whether cancer-related inflammation affects the plasma BNP levels. We investigated the relationship between the BNP and human cancers. Methods We retrospectively studied 2,923 patients in whom the plasma BNP levels and serum C-reactive protein (CRP) were measured and echocardiography was performed. Patients with clinically evident heart failure (NYHA II or higher), heart disease requiring medical treatment or surgery, renal dysfunction, and inflammatory disease were excluded. There were 234 patients in the final analysis. Blood sampling was performed before surgery and chemotherapy. In addition, we evaluated the relationship between the inflammation and plasma BNP levels in mouse models of colon cancer. Results Of the 234 patients, 80 were diagnosed with cancer. Both the plasma BNP and serum CRP levels were significantly higher in cancer patients than those without. There were no significant differences in the echocardiographic parameters. There was a significant positive correlation between the plasma BNP and serum CRP levels in cancer patients (r = 0.360, P

Poor oral health and hygiene are increasingly recognized as major risk factors for pneumonia among the elderly. To identify modifiable oral health–related risk factors, we prospectively investigated associations between a constellation of oral health behaviors and incident pneumonia in the community-living very elderly (i.e., 85 years of age or older). At baseline, 524 randomly selected seniors (228 men and 296 women; mean age, 87.8 years) were examined for oral health status and oral hygiene behaviors as well as medical assessment, including blood chemistry analysis, and followed up annually until first hospitalization for or death from pneumonia. During a 3-year follow-up period, 48 events associated with pneumonia (20 deaths and 28 acute hospitalizations) were identified. Among 453 denture wearers, 186 (40.8%) who wore their dentures during sleep were at higher risk for pneumonia than those who removed their dentures at night (log rank P = 0.021). In a multivariate Cox model, both perceived swallowing difficulties and overnight denture wearing were independently associated with an approximately 2.3-fold higher risk of the incidence of pneumonia (for perceived swallowing difficulties, hazard ratio [HR], 2.31; and 95% confidence interval [CI], 1.11–4.82; and for denture wearing during sleep, HR, 2.38; and 95% CI, 1.25–4.56), which was comparable with the HR attributable to cognitive impairment (HR, 2.15; 95% CI, 1.06–4.34), history of stroke (HR, 2.46; 95% CI, 1.13–5.35), and respiratory disease (HR, 2.25; 95% CI, 1.20–4.23). In addition, those who wore dentures during sleep were more likely to have tongue and denture plaque, gum inflammation, positive culture for Candida albicans, and higher levels of circulating interleukin-6 as compared with their counterparts. This study provided empirical evidence that denture wearing during sleep is associated not only with oral inflammatory and microbial burden but also with incident pneumonia, suggesting potential implications of oral hygiene programs for pneumonia prevention in the community.

Rates of morbidity and mortality from cardiovascular disease are high in patients with rheumatoid arthritis (RA); however, the mechanisms and biomarkers that reflect coronary plaque vulnerability have not yet been established. We present a case of acute coronary syndrome (ACS) presumably caused by exacerbation of chronic inflammation of RA, in which an abrupt increase in serum triglyceride was seen on the day of onset of ACS but not during effort angina. This case suggests that RA patients with an abrupt increase in triglyceride need intensive care including anti-platelet and statin therapy for the prevention of coronary plaque rupture.

Objective: This study was undertaken to explore the efficacy and safety of Citrus sudachi peel for metabolic risk factors in obese male and female adults.Background: Citrus sudachi Hort. ex Shirai (Rutaceae), called “sudachi”, is a small, round, green citrus fruit that is mainly cultivated in Tokushima Prefecture in Japan. Our group reported that Citrus sudachi peel powder improved glucose tolerance and dyslipidemia in Zucher-fatty rats and reduced hyperglycemia and hypertriglyceridemia in GK diabetic rats.Materials and Methods: We conducted a randomized, double-blind, placebo-controlled trial in 40 participants with abdominal obesity and metabolic risk factors including hypertension, impaired glucose tolerance and elevated triglyceride levels. Participants were randomized to receive either tablets that contained 1.3 g dried Citrus sudachi peel powder or placebo tablets for 12 weeks. The sudachi peel group included 14 males and 5 females with a mean age of 54.5 years, and the placebo group included 18 males and 2 females with a mean age of 51.9 years. Results: Physical status including body weight, waist circumference and blood pressure and laboratory markers including metabolic parameters were not different at any observation point between the two groups. However, among participants with serum triglyceride levels of more than 120 mg/dl, body weight, waist circumference and serum triglyceride levels were significantly decreased at several observation points after the start of treatment in the sudachi peel group but not in the placebo group. No serious adverse events were observed in the sudachi peel group. Conclusions: Citrus sudachi peel has the potential effect to safely improve abdominal obesity and lower serum levels of TG in obese individuals with hypertriglyceridemia. A large-scale randomized, double-blind clinical study targeting subjects with both abdominal obesity and high TG levels is needed to confirm the metabolic effects of Citrus sudachi peel.Trial registration: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000002682. Accession number of the Ethics Committee for Clinical Trials of Food in Tokushima University Hospital is F5.Key words: health functional food, anti-obesity, triglyceride

ObjectivesThis study sought to introduce and confirm the efficacy of pre-load stress echocardiography with leg-positive pressure (LPP) for improving risk stratification of patients with mild stable heart failure.BackgroundHeart failure patients with mild symptoms and a poor prognosis should be identified and treated aggressively to improve clinical outcome.MethodsWe performed transthoracic echocardiography with LPP in 202 patients with chronic cardiac disease. Twenty-two of these patients also underwent cardiac catheterization, and left ventricular pressure was measured during LPP along with simultaneous Doppler recordings. Patients were classified into 3 groups on the basis of their left ventricular (LV) diastolic dysfunction as assessed by transmitral flow velocity: restrictive or pseudonormal (PN) at rest, impaired relaxation (IR) at rest and during LPP (stable IR), and IR at rest and PN during LPP (unstable IR). Clinical outcome was compared among these groups.ResultsThe LPP increased LV end-diastolic pressure from 15.8 ± 4.7 mm Hg to 20.5 ± 5.0 mm Hg in the unstable IR group and from 10.5 ± 2.6 mm Hg to 14.7 ± 3.8 mm Hg in the stable IR group (both p < 0.001). During an average follow-up of 548 ± 407 days, 5 patients had cardiac death, 37 had acute heart failure, 4 had an acute myocardial infarction, and 7 had a stroke. The all-cause cardiac event rate in unstable IR was higher than in stable IR (p < 0.001), and was similar in the PN group (p = 0.81). Event-free survival was significantly lower in unstable IR than in stable IR (p = 0.003). In a Cox proportional hazards model, unstable IR was an independent predictor of all-cause cardiac events (hazard ratio: 8.0; p

Background: Augmentation index (AI) has been used as a clinical index of arterial stiffness and has been reported to be an independent predictor of cardiovascular events, but some investigators have reported that AI is not a useful marker to identify coronary artery disease (CAD) in elderly patients. The majority of CAD patients are elderly people, therefore the aim of this study was to examine whether AI is a useful marker to identify the risk of CAD. Methods and Results: A total of 120 patients (69±10 years of age; 83 male) who underwent cardiac catheterization for suspected CAD were enrolled. Invasive central blood pressure (BP) was measured using a fluid-filled catheter. Non-invasive AI was calculated by the SphygmoCor (AtCor Medical) system at the end of catheterization. Subjects consisted of 99 patients with CAD and 21 patients without CAD. There was no significant difference in AI between the CAD and the non-CAD groups (24±10 vs. 24±14%). Non-invasive systolic central BP was lower than the invasive systolic central BP (115±18 vs. 130±23 mmHg, P

A 70-year-old woman with dyspnea on exertion was admitted to our hospital. She had a history of apical hypertrophic cardiomyopathy (HCM) and repeated hospitalization for heart failure. Results of physical examination were normal except for leg edema. Echocardiography showed apical HCM with preserved LV systolic function (LVEF=70%). Although dyspnea on exertion and leg edema improved rapidly with the use of diuretics, her symptoms soon worsened when daily activity was started again. In order to examine the effect of preload on hemodynamics, we performed a lower limb positive pressure test by compressing both legs using a household air leg massager. Echocardiography showed increases in mitral E velocity, E/A ratio and pulmonary venous D flow as well as decrease in stroke volume during the lower limb positive pressure test. Simultaneously-recorded pressure study also showed elevated LVEDP and increased v wave of pulmonary capillary wedge pressure. These results suggested that even a small increase in preload led to elevation of LVEDP and symptomatic worsening due to severe diastolic heart failure in the present case. The lower limb positive pressure test may be useful for assessing the effect of preload on hemodynamics in patients with diastolic heart failure.

Excess parathyroid hormone (PTH), known as primary hyperparathyroidism (pHPT), results in hypercalcemia and bone loss. Recent studies have shown that PTH is associated with the occurrence of hypertension in Western countries; however, controversy remains regarding high serum levels of PTH and calcium as risk factors for hypertension in Japanese patients. We retrospectively enrolled 114 consecutive Japanese patients who visited our hospital for examination and treatment of hypercalcemia and/or hypertension with serum calcium levels ≥ 9.8 mg/dL. To estimate the prevalence of hypertension, the patients were categorized according to calcium levels into hypercalcemic (10.2-13.4 mg/dL) and normocalcemic (9.8-10.1 mg/dL) groups, which were further categorized into high PTH (50-440 pg/mL) and low PTH (8-49 pg/mL) groups. The prevalence of hypertension was higher in patients with hypercalcemia than in patients with normocalcemia in both the high and low PTH groups. The prevalence of hypertension was higher in patients with high serum PTH levels than in patients with low serum PTH levels in both the hypercalcemic and normocalcemic groups. Logistic multiple regression analysis determined that serum calcium (P < 0.05) and PTH (P < 0.01) levels were positive contributors to hypertension. In conclusion, high serum levels of PTH and calcium are risk factors for hypertension in Japanese patients.

Purpose : The purpose of this study was to evaluate the physiological uptake pattern of 18F-FDG in the left ventricular myocardium of patients under preparation for tumor FDG-PET. Patients and Methods : We enrolled 188 patients without cardiac disease. The accumulation patterns were classified as either ‘none’, ‘diffuse’, ‘focal’ or ‘focal on diffuse’. When a focal uptake was only observed on the basal wall, then the patterns were classified as having either a ‘ring’, ‘over half’ or ‘spot’ uptake. Results : The frequencies of the myocardial FDG uptake patterns were as follows : none, n=52 (27.7%) ; diffuse, n= 63 (33.5%) ; focal on diffuse, n=40 (21.3%) and focal, n=33 (17.6%). The age, blood glucose level, weight and dose of FDG did not differ significantly for each pattern. The focal and focal on diffuse patterns were seen in 73 patients, and 65 patients had a focal uptake only on the basal wall ; ring uptake in 29 patients, over half in 20 and spot uptake in 16 patients. Conclusions : The physiological myocardial uptake showed several patterns. Focal uptake was often seen in patients with cardiac disease, but it did not always indicate an abnormal finding when the accumulation was only on the basal wall.

Measurement of the cross-sectional area (CSA) of the right ventricular outflow tract (RVOT) has been required to calculate stroke volume, especially for estimation of the pulmonary blood flow/systemic blood flow ratio. Current guidelines of the American Society of Echocardiography state that the CSA

Increasing evidence indicates that inflammation contributes to the pathogenesis of atrial fibrillation (AF). Pentraxin 3 (PTX3) is produced abundantly in local inflammatory lesions while C-reactive protein (CRP) is produced mainly in the liver. In this study, we investigated whether a local level of PTX3 might be a sensitive marker for the local inflammation of AF. Blood from the periphery and left atrial appendage (LAA) was sampled from 23 patients with AF undergoing pulmonary vein isolation, and from 10 control subjects with Wolff–Parkinson–White syndrome. We measured peripheral and LAA plasma concentrations of CRP, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and PTX3. Plasma PTX3 concentrations in both locations were higher in patients with AF than in control subjects. PTX3 concentrations were significantly higher in the LAA than the periphery in patients with AF (3.7 ± 1.4 vs 3.3 ± 1.2 ng/ml, P < 0.01), but not in control subjects (2.4 ± 0.5 vs 2.4 ± 0.5 ng/ml, not significant). Patients and controls showed no significant differences in CRP, IL-6, or TNF-α concentrations between the periphery and LAA. Interestingly, there was a significant positive correlation between LAA plasma concentrations of PTX3 and left atrial volume (r = 0.55, P < 0.01). These data demonstrate that Local PTX3 production in the left atrium might reflect the local inflammation of AF.

Background— Hypoandrogenemia is associated with an increased risk of ischemic diseases. Because actions of androgens are exerted through androgen receptor (AR) activation, we studied hind-limb ischemia in AR knockout mice to elucidate the role of AR in response to ischemia. Methods and Results— Both male and female AR knockout mice exhibited impaired blood flow recovery, more cellular apoptosis, and a higher incidence of autoamputation after ischemia. In ex vivo and in vivo angiogenesis studies, AR-deficient vascular endothelial cells showed reduced angiogenic capability. In ischemic limbs of AR knockout mice, reductions in the phosphorylation of the Akt protein kinase and endothelial nitric oxide synthase were observed despite a robust increase in hypoxia-inducible factor 1α and vascular endothelial cell growth factor ( VEGF ) gene expression. In in vitro studies, siRNA-mediated ablation of AR in vascular endothelial cells blunted VEGF-stimulated phosphorylation of Akt and endothelial nitric oxide synthase. Immunoprecipitation experiments documented an association between AR and kinase insert domain protein receptor that promoted the recruitment of downstream signaling components. Conclusions— These results document a physiological role of AR in sex-independent angiogenic potency and provide evidence of novel cross-talk between the androgen/AR signaling and VEGF/kinase insert domain protein receptor signaling pathways.

Vagal nerve stimulation has been postulated to confer an antifibrillatory effect. We studied whether ghrelin administration would exert an antiarrhythmic effect via modulation of autonomic nerve activity in rats after acute myocardial ischemia (MI). Male Sprague-Dawley rats were exposed to 30 min of ischemia following ligation of the left coronary artery. Animals were then randomized to receive either ghrelin (n = 26) or saline (n = 26) during the period of coronary ligation. Power spectral analysis of heart-rate variability revealed that the administration of ghrelin increased the high-frequency (HF) power and decreased the low-frequency (LF)/HF ratio. Ventricular tachyarrhythmias were less frequent in rats after MI who received ghrelin in comparison with rats that received saline. Immunoblotting and immunohistochemistry revealed that rats given saline alone during MI exhibited a marked reduction in phosphorylated connexin-43 within the left ventricle, whereas those that received ghrelin displayed only minor reductions in comparison with sham-operated rats. These effects of ghrelin were diminished by the coadministration of atropine or the blockade of vagal afferents. These data demonstrate that the beneficial effect of ghrelin might be mediated by modulation of cardiac autonomic nerve activity.

The renin-angiotensin-aldosterone system (RAAS) and arginine vasopressin (AVP) regulate body fluids. Although conventional diuretics have been used for treating heart failure, they activate RAAS and exacerbate renal function. Tolvaptan, a newly developed vasopressin-2 receptor antagonist, elicits aquaresis and improves volume overload in heart failure patients, however, the predictors of tolvaptan effectiveness and the influence on the RAAS and renal function according to tolvaptan therapy are not established. We evaluated 26 chronic heart failure patients receiving therapy with 15 mg/day tolvaptan and examined their laboratory and urinary data before and after tolvaptan therapy. A response to tolvaptan was defined as a body weight decrease by more than 2 kg in a week and a urine volume increase by 500 mL/ day compared with that before tolvaptan administration. Body weight, urine volume, and brain natriuretic peptide levels significantly improved (P < 0.05), without any worsening of renal function represented by serum creatinine, sodium, and potassium. Moreover, no significant changes were observed in the plasma renin activity and plasma aldosterone concentration (PAC). In the responder group, urine osmolality before tolvaptan administration was significantly higher (P < 0.05) but declined significantly after tolvaptan administration (P < 0.05). The AVP/PAC ratio before administration was positively correlated with the efficacy of tolvaptan. Tolvaptan treatment could prevent RAAS activation in chronic heart failure patients. Moreover, monitoring the AVP/PAC ratio may be useful in predicting the tolvaptan response.

Porphyromonas gingivalis is important in the development of marginal periodontitis. However, the precise role and localization of P. gingivalis in chronic periapical periodontitis remain unclear. Thus, methods that can detect P. gingivalis in formalin-fixed and paraffin-embedded (FFPE) tissue samples are needed. We assessed a technique combining loop-mediated isothermal amplification (LAMP) with PCR (PCR-LAMP) for detection of P. gingivalis, using 110 FFPE tissue samples of chronic apical periodontitis. PCR-LAMP specifically detected P. gingivalis with high sensitivity in FFPE tissue samples, and the sensitivity of the technique was higher than that of PCR or LAMP alone. The results of immunohistochemistry (IHC) confirmed the specificity of PCR-LAMP. IHC showed that P. gingivalis was localized in a granular layer of chronic apical periodontitis, a region that correlated with the localization of macrophages. This is the first study to describe the localization of P. gingivalis in human periapical periodontitis. In conclusion, PCR-LAMP was an effective tool for detecting P. gingivalis in periapical periodontitis. In addition, IHC results improve our understanding of the role of P. gingivalis in the progression of periapical periodontitis. (J Oral Sci 58, 163-169, 2016).