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The lack of treatment options for congenital (0.1%) and partial (10%) tooth anomalies highlights the need to develop innovative strategies. Over two decades of dedicated research have led to breakthroughs in the treatment of congenital and acquired tooth loss. We revealed that by inactivating USAG-1, congenital tooth agenesis can be successfully ameliorated during early tooth development and that the inactivation promotes late-stage tooth morphogenesis in double knockout mice. Furthermore, Anti- USAG-1 antibody treatment in mice is effective in tooth regeneration and can be a breakthrough in treating tooth anomalies in humans. With approximately 0.1% of the population suffering from congenital tooth agenesis and 10% of children worldwide suffering from partial tooth loss, early diagnosis will improve outcomes and the quality of life of patients. Understanding the role of pathogenic USAG-1 variants, their interacting gene partners, and their protein functions will help develop critical biomarkers. Advances in next-generation sequencing, mass spectrometry, and imaging technologies will assist in developing companion and predictive biomarkers to help identify patients who will benefit from tooth regeneration. more...

Background: Alcohol septal ablation (ASA) is used to treat drug-refractory hypertrophic obstructive cardiomyopathy (HOCM). Intraprocedural echocardiography is essential for identifying the septal area perfused by each septal branch; however, its role in determining the procedural endpoint of ASA remains unclear. This retrospective study aimed to evaluate the impact of intraprocedural echocardiographic findings on clinical outcomes and left ventricular pressure gradient (LVPG) after ASA., Methods: Overall, 120 patients with HOCM who underwent ASA at a single center were divided into two groups based on the presence of optimal ablation. Optimal ablation was defined as the ablated area fully covering the targeted septal myocardium from the point of contact with the onset of the accelerated flow to the basal septum and dense acoustic shadowing accompanying the ablated area. Clinical outcomes and LVPG changes were evaluated using inverse probability of treatment weighting., Results: Significantly more patients showed a New York Heart Association (NYHA) functional class improvement of ≥2 stages or achievement of class I in the optimal ablation group (n = 74) than in the non-optimal ablation group (94 % vs. 62 %; p < 0.001). The optimal ablation group had a significantly greater percentage reduction in LVPG at 1-year after ASA (82 ± 18 % vs. 64 ± 18 %; p = 0.001). Multivariate analyses revealed that optimal ablation was an independent predictor of a NYHA functional class improvement of ≥2 stages or achievement of class I (odds ratio, 11.3; 95 % confidence interval, 3.43-39.1; p < 0.001) and a percentage reduction in LVPG (p = 0.001)., Conclusions: Intraprocedural echocardiographic findings of optimal ablation were associated with favorable clinical outcomes and a significant reduction in LVPG., Competing Interests: Declaration of competing interest None., (Copyright © 2025 Elsevier Ltd. All rights reserved.) more...

Background: Chronic total occlusion (CTO) is a high-risk factor for stent thrombosis, but little is known about the difference in neointimal healing between CTO and non-CTO lesions regarding implanted stents. We investigated factors affecting neointimal healing after stent implantation for CTO and non-CTO lesions using angioscopy., Methods: We retrospectively evaluated 106 stents in 85 consecutive patients between March 2016 and July 2020. Their average age was 68 ± 11 years, and participants (73 male and 12 female) underwent follow-up angiography and angioscopy 1 year after percutaneous coronary intervention (PCI). The stents (n = 106) were divided into three groups according to the lesion status at the previous PCI: CTO (n = 17), acute coronary syndrome (ACS) (n = 35), and stable coronary artery disease without CTO or non-CTO (n = 54)., Results: The neointimal stent coverage grade was significantly lower in the CTO and ACS groups than in the non-CTO group (0.4 ± 0.5, 0.9 ± 0.8, and 1.4 ± 0.8, respectively, p < 0.001). Thrombi were significantly more frequent in CTO and ACS than in non-CTO (71 %, 51 %, and 15 %, respectively, p < 0.001). The yellow grade in CTO was comparable to that in ACS but significantly higher in CTO than in non-CTO (CTO vs. ACS vs. non-CTO 1.5 ± 0.7, 1.4 ± 0.6, and 0.9 ± 0.7, respectively, p = 0.007)., Conclusions: Delayed healing occurs in stents implanted for CTO lesions. Longer dual-antithrombotic therapy may be beneficial., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...

Objectives: Human papillomavirus (HPV) infection drives carcinogenesis in the oropharynx. No standard sampling or HPV detection methods for evaluating oropharyngeal HPV infection exist. The prevalence of oral HPV infection in Japan is unknown., Materials and Methods: We examined 435 healthy Japanese individuals to address whether adding tonsillar washing to oral gargling would improve HPV detection. We compared HPV assessment using GENOSEARCH HPV31 versus nested PCR and direct sequencing. Associations between HPV infection and demographic and behavioral characteristics were examined., Results: Most participants who were HPV-positive based on oral gargles were also HPV-positive based on tonsillar washings: 11 (64.7%) of 17 on nested PCR and 12 (70.6%) of 17 on GENOSEARCH HPV31. Although HPV infection was more prevalent in oral gargles followed by tonsillar washings than in oral gargles alone, the difference was not statistically significant (nested PCR, 4.8% vs. 3.9%, P = 0.46; GENOSEARCH HPV31, 5.3% vs. 3.9%, P = 0.33). The overall agreement between nested PCR and GENOSEARCH HPV31 was 98.6%, with 76.0% positive agreement. The overall prevalence of oral HPV infection in Japan was 5.7% (95% confidence interval, 3.9-8.3%). Men had a significantly higher prevalence of oral HPV infection than women (8.3% vs. 2.6%, P = 0.02). Infection increased with number of lifetime sexual partners (P < 0.001 for trend)., Conclusion: The oropharynx is probably the major source of HPV-infected cells in oral gargles. Oral gargling could be a standard sampling method for evaluating oropharyngeal HPV infection. GENOSEARCH HPV31 could be an option for oral HPV detection., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020. Published by Elsevier Ltd.) more...

A new concept to account for the process of postprandial remnant lipoprotein metabolism is proposed based on the characteristics of lipoprotein particles and their receptors. The characteristics of remnant lipoprotein (RLP) were investigated using an immuno-separation method. The majority of the postprandial lipoproteins increased after fat intake was shown to be VLDL remnants, not chylomicron (CM) remnants, based on the significantly high ratio of apoB100/apoB48 in the RLP and the high degree of similarity in the particle size of the apoB48 and apoB100 carrying lipoproteins, which fluctuate in parallel during a 6 h period after fat intake. The VLDL receptor was discovered as a receptor for TG-rich lipoprotein metabolism and is located in peripheral tissues such as skeletal muscle, adipose tissue, etc., but not in the liver. Postprandial VLDL particles are strongly bound and internalized into cells expressing the VLDL receptor. Ligands that bind to VLDL receptor, such as LPL and Lp(a), present in RLP. The presence of various specific ligands in VLDL remnants may enhance the capacity for binding to the VLDL receptor, which play the role primarily for energy delivery to the peripheral tissues, but is also a causal factor in atherogenic diseases when excessively and/or continuously remained in plasma., (Copyright © 2019 Elsevier B.V. All rights reserved.) more...

We have long thought that remnant lipoproteins (RLP) in the postprandial plasma contain CM remnants (exogenous remnants; RLP-apoB48) and VLDL remnants (endogenous remnants; RLP-apoB100) of different origin, i.e. produced in the intestine and liver, respectively. However, the majority of CM remnants incorporated into liver from the circulation are degraded in liver and may be reused for the remodeling of VLDL. Namely, the most of the apoB48 in CM remnants are smoothly incorporated into the liver after fat intake along with lipids and other apolipoproteins via the LDL receptor and LDL-receptor-related protein (LRP). Subsequently, apoB48 may be reconstituted in VLDL as VLDL apoB48 through an essential physiological pathway similar or the same to that of VLDL apoB100 formation in the liver and secreted into the circulation as VLDL apoB48 to form their remnants. Because those particles are newly reconstituted in liver as a portion of VLDL, we propose that both RLP-apoB100 and RLP-apoB48 are endogenous VLDL remnants produced in liver after fat intake. Also we predict the presence of a new pathway for the formation of VLDL apoB48 along with VLDL apoB100 in liver in humans similar in mice and rats., (Copyright © 2018 Elsevier B.V. All rights reserved.) more...

We have long thought that remnant lipoproteins (RLP) in plasma are significantly increased as the result of disturbed lipoprotein metabolism followed by obesity and insulin resistance. Therefore, it was believed that insulin resistance causes and enhances RLP formation. In contrast, this hypothesis states that RLP induces insulin resistance as the result of obesity associated with the excessive fat intake. The majority of plasma TG increased after fat intake is TG in RLP (RLP-TG) and the majority of postprandial RLP is VLDL remnants, not CM remnants. RLP is newly formed lipoproteins primarily for energy supply against starvation, like blood sugar after carbohydrate intake. Since RLP bearing apoE, LPL and Lp(a) function as ligands for the VLDL receptor, RLP interacts with the VLDL receptor in visceral fat adipocytes and stored as TG similar to excessive blood sugar. However, the excessive VLDL remnants induces obesity and its associated insulin resistance, which plays a major role as the initiator of metabolic domino effects, similar to blood sugar primarily serving as an energy supply to protect against starvation., (Copyright © 2018 Elsevier B.V. All rights reserved.) more...

Aim: To report on sleep hypercapnia in Becker muscular dystrophy (BMD) at earlier stages than ever recognized., Subjects and Methods: This retrospective study examined nocturnal hypercapnia in six young Becker muscular dystrophy (BMD) patients with deletions of one or more exons of DMD gene. Clinical information, consecutive data on forced vital capacity (FVC%), forced expiratory volume in one second (FEV1%), peak expiratory flow (PEF%), peak cough flow (PCF), average PCO 2 in all-night monitoring, and left ventricular ejection fraction (LVEF) were reviewed., Results: In five BMD patients, including three who were still ambulant, nocturnal average PCO 2 was elevated to >45 mmHg at 12-31 years of age. Noninvasive positive pressure ventilation was initiated in four patients. Gradual declines in FVC% and PEF% were evident in one BMD patient with exon 3-7 deletion, whereas these functions did not change in the remaining BMD patients. PCF, FEV1%, and LVEF were less informative for the assessment of respiratory function in this patient series., Conclusion: Sleep hypercapnia was present in certain BMD patients, which was unexpected from the routine pulmonary function tests. Individualized assessment of nocturnal PCO 2 , partly based on the deletion types, should be further explored in the clinical practice of BMD patients., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.) more...

Background: The relationship between the effects of diet and exercise intervention and the body weight associated with the serum lipoprotein lipase (LPL), hepatic triglyceride lipase (HTGL) and glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 (GPIHBP1) concentrations has not been elucidated., Methods: Sixty-six overweight/obese middle aged women were assigned to the diet and exercise intervention for 4months. They were divided into 2 groups followed by the body mass index (BMI) decreased >3% (n=41) and <3% (n=25). Serum lipids, lipoproteins and the LPL, HTGL, GPIHBP1 concentrations were determined., Results: The cases in which the BMI decreased >3% exhibited significant improvement of diagnostic markers compared with the cases with <3% decrease after the intervention. The LPL concentration did not significantly change, but GPIHBP1 increased significantly after the intervention. The increased GPIHBP1 was significantly associated with decreased body weight. Multiple regression analysis indicated a strong association between GPIHBP1 and percentage of body fat., Conclusions: The diet and exercise intervention significantly increased the serum GPIHBP1 concentration in association with a decrease in body weight and percentage of body fat. These results suggest that GPIHBP1 is a better marker for body weight decrease than LPL., (Copyright © 2017 Elsevier B.V. All rights reserved.) more...

Background: Williams syndrome (WS) is known for its uneven cognitive abilities, especially the difficulty in visuo-spatial cognition, though there are some inter-individual phenotypic differences. It has been proposed that the difficulty in visuo-spatial cognition of WS patients can be attributed to a haploinsufficiency of some genes located on the deleted region in 7q11.23, based on an examination of atypical deletions identified in WS patients with atypical cognitive deficits. According to this hypothesis, the inter-individual differences in visuo-spatial cognitive ability arise from variations in deletion., Methods: We investigated whether there were inter-individual differences in the visuo-spatial constructive abilities of five unrelated WS patients with the typical deletion on chromosome 7q11.23 that includes the candidate genes contributing visuo-spatial difficulty in WS patients. We used tests with three-dimensional factors such as Benton's three-dimensional block construction test, which are considered to be more sensitive than those with only two-dimensional factors., Results: There were diverse inter-individual differences in the visuo-spatial constructive abilities among the present participants who shared the same typical genomic deletion of WS. One of the participants showed almost equivalent performances to typically developing adults in those tests., Conclusion: In the present study, we found a wide range of cognitive abilities in visuo-spatial construction even among the patients with a common deletion pattern of WS. The findings suggest that attributing differences in the phenotypes entirely to genetic factors such as an atypical deletion may not be always correct., (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.) more...

Background: Previous large population studies reported that non-fasting plasma triglyceride (TG) reflect a higher risk for cardiovascular disease than TG in the fasting plasma. This is suggestive of the presence of higher concentration of remnant lipoproteins (RLP) in postprandial plasma., Methods: TG and RLP-TG together with other lipids, lipoproteins and lipoprotein lipase (LPL) in both fasting and postprandial plasma were determined in generally healthy volunteers and in patients with coronary artery disease (CAD) after consuming a fat load or a more typical moderate meal., Results: RLP-TG/TG ratio (concentration) and RLP-TG/RLP-C ratio (particle size) were significantly increased in the postprandial plasma of both healthy controls and CAD patients compared with those in fasting plasma. LPL/RLP-TG ratio demonstrated the interaction correlation between RLP concentration and LPL activity The increased RLP-TG after fat consumption contributed to approximately 90% of the increased plasma TG, while approximately 60% after a typical meal. Plasma LPL in postprandial plasma was not significantly altered after either type of meal., Conclusions: Concentrations of RLP-TG found in the TG along with its particle size are significantly increased in postprandial plasma compared with fasting plasma. Therefore, non-fasting TG determination better reflects the presence of higher RLP concentrations in plasma., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.) more...

Background: Previous reports have shown that lipoprotein lipase (LPL) activity significantly increases in the postprandial plasma associated with the increase of TG-rich lipoproteins. Therefore, we have reexamined those relationships using newly developed LPL assay with the different kinds of food intake., Methods: Standard meal (n=81), 50g of fat (n=54), 75g of glucose (n=25) and cookie (25g fat and 75g carbohydrate fat) (n=28) were administered in generally healthy volunteers. Plasma LPL, HTGL and TC, TG, LDL-C, HDL-C, RLP-C and RLP-TG were determined at subsequent withdrawal after the food intake., Results: Plasma TG, RLP-C and RLP-TG were significantly increased at 8PM (2h after dinner of standard meal) compared with 8AM before breakfast within the same day. Also those parameters were significantly increased in 2-6h after fat load. However, the concentrations and activities of LPL and HTGL did not significantly increase in association with an increase in the TG and remnant lipoproteins. Also LPL concentration did not significantly increase after glucose and "cookie test" within 4h., Conclusion: No significant increase of LPL activity was found at CM and VLDL overload after different kinds of food intake when reexamined by newly developed assay for LPL activity and concentration., (Copyright © 2016 Elsevier B.V. All rights reserved.) more...

Objective: There is no clinical evidence that supports the benefit of integrative medicine, defined as combination therapy of oriental and western medicine, on obesity-related hypertension. This study evaluates the efficacy of Bofu-tsusho-san (BOF), an oriental herbal medicine, on the ambulatory blood pressure (BP) profile in hypertensive patients with obesity., Methods: The study design was a multicenter, randomized, open-label, parallel-group controlled trial in 107 hypertensive patients with obesity. Participants were randomly assigned to receive either the conventional control therapy or BOF add-on therapy. In both groups antihypertensive therapy was aimed at achieving the target clinic BP. The primary outcome was change in the ambulatory BP profile from baseline to 24 weeks after randomization., Results: Daytime systolic BP variability, an important parameter of ambulatory BP profile, was decreased in the BOF group, and the difference in the changes in daytime systolic BP variability was significant between the BOF and control group (Control vs BOF; the change from baseline in daytime systolic BP variability, 1.0±3.3 vs -1.0±3.3%; p=0.006)., Conclusion: The BOF add-on therapy effectively improved the ambulatory BP variability. This is the first report suggesting that an integrative medicine approach may exert favorable effects on obesity-related hypertension compared with conventional pharmaceutical treatment., Clinical Trial Registration: UMIN000003878., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.) more...

Background: Serum small dense LDL-cholesterol (sdLDL-C) levels in healthy controls and the cases with diabetes (T2DM) and metabolic syndrome (MetS) with or without a fatty liver in a large, typical Japanese population was determined., Methods: The plasma lipids and lipoproteins, including sdLDL-C by homogeneous assay, were determined in controls, MetS and T2DM patients (n=5255). The cases with MetS and preliminary MetS (pre-MetS) as well as T2DM and preliminary T2DM (pre-DM) were selected based on the Japanese criteria for MetS and T2DM. Fatty liver was diagnosed using the ultrasonography., Results: The 75th percentile values for sdLDL-C were 27.5mg/dl for men and 23.3mg/dl for women and increased with age. The concentrations of sdLDL-C and sdLDL-C/LDL-C were significantly higher in pre-MetS and pre-T2DM patients than healthy controls as well as in MetS and T2DM patients. Significantly higher sdLDL-C was found in cases with a fatty liver than without a fatty liver in all five groups., Conclusions: Significantly elevated sdLDL-C levels were found in pre-MetS, MetS and pre-T2DM, T2DM patients compared to the healthy controls. Fatty liver significantly enhanced serum sdLDL-C levels and the multiple regression analyses ascertained that fatty liver was an independent determinant for sdLDL-C., (Copyright © 2014. Published by Elsevier B.V.) more...

Although muscular dystrophy patients often have feeding difficulty and need long-term enteral nutrition, only a few reports have described gastrostomy feeding in these patients. This study was designed to evaluate the efficacy and tolerance of gastrostomy feeding in patients with muscular dystrophy. We performed a retrospective, multicenter study on 144 patients with muscular dystrophy who received gastrostomy feeding between 2007 and 2009 in 25 neuromuscular centers in Japan. There were 77 Duchenne muscular dystrophy (median age at gastrostomy placement 26 years, range 13-47 years), 40 myotonic dystrophy (median age 54.5 years, range 13-70 years), 11 Fukuyama congenital muscular dystrophy (median age 22 years, range 13-29 years), 5 limb girdle muscular dystrophy (median age 62 years, range 43-78 years), and 5 facioscapulohumeral muscular dystrophy (median age 52 years, range 28-67 years) patients. Many benefits including amelioration of malnutrition, swallowing difficulty and respiratory status were observed after the introduction of gastrostomy feeding. Especially in patients with Duchenne muscular dystrophy, mean body weight significantly increased after gastrostomy placement. Although most complications, which are commonly observed in other populations, were tolerable, respiratory failure and peritonitis were important concerns. These findings suggest that gastrostomy placement at an appropriate time is advisable in patients with muscular dystrophy., (Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.) more...

Background: Remnant-like lipoprotein particles (RLP) have been measured by cholesterol as RLP-C for CHD risk assessment in the fasting plasma. However, RLP-triglyceride (TG) is a better marker of the characteristics of remnant lipoproteins in the postprandial plasma, especially in plasma with TG concentrations <150 mg/dl., Method: The RLP-TG and RLP-C concentrations in subjects undergoing a health check-up and in volunteers receiving an oral fat load were determined in the fasting and postprandial plasma. TC, TG, HDL-C, LDL-C, apoB 100, apoB48, RLP apoB-100 and RLP apoB48 were also determined., Results: When fasting TG concentrations were <150 mg/dl, the 95th percentile of RLP-TG was 20mg/dl and the RLP-C 7.5 mg/dl in healthy subjects. The prevalence of RLP-TG and RLP-C above the cut-off values with a TG concentration <150 mg/dl was significantly higher in the metabolic syndrome cases than in the controls. RLP-TG increased significantly in plasma to >20mg/dl after an oral fat load in cases with TG concentrations >80 mg/dl. Further, RLP apoB100, but not RLP apoB48 was highly correlated with the increase of TG in the postprandial plasma., Conclusion: RLP-TG and RLP-C were increased significantly above the cut-off values in the postprandial plasma in healthy volunteers from a TG concentration >80 mg/dl. RLP apoB100, but not RLP apoB48, increased significantly when the plasma TG increased after an oral fat load despite the increase of plasma apoB48. The results show that the major lipoproteins which were increased in postprandial plasma were VLDL remnants, not CM remnants., (Copyright © 2012 Elsevier B.V. All rights reserved.) more...

Background: Skeletal muscle metabolism is a major determinant of resting energy expenditure (REE). Although the severe muscle loss that characterizes Duchenne muscular dystrophy (DMD) may alter REE, this has not been extensively investigated., Methods: We studied REE in 77 patients with DMD ranging in age from 10 to 37 years using a portable indirect calorimeter, together with several clinical parameters (age, height, body weight (BW), body mass index (BMI), vital capacity (VC), creatine kinase, creatinine, albumin, cholinesterase, prealbumin), and assessed their influence on REE. In addition, in 12 patients maintaining a stable body weight, the ratio of energy intake to REE was calculated and defined as an alternative index for the physical activity level (aPAL)., Results: REE (kcal/day, mean±SD) in DMD patients was 1123 (10-11 years), 1186±188 (12-14 years), 1146±214 (15-17 years), 1006±136 (18-29 years) and 1023±97 (≥30 years), each of these values being significantly lower than the corresponding control (p<0.0001). VC (p<0.001) was the parameter most strongly associated with REE, followed by BMI (p<0.01) and BW (p<0.05). The calculated aPAL values were 1.61 (10-11 years), 1.19 (12-14 years), 1.16 (15-17 years), and 1.57 (18-29 years)., Conclusion: The REE in DMD patients was significantly lower than the normal value in every age group, and strongly associated with VC. Both the low REE and PAL values during the early teens, resulting in a low energy requirement, might be related to the obesity that frequently occurs in this age group. In contrast, the high PAL value in the late stage of the disease, possibly due to the presence of respiratory failure, may lead to a high energy requirement, and thus become one of the risk factors for development of malnutrition., (Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.) more...

Since Zilversmit first proposed postprandial lipemia as the most common risk of cardiovascular disease, chylomicrons (CM) and CM remnants have been thought to be the major lipoproteins which are increased in the postprandial hyperlipidemia. However, it has been shown over the last two decades that the major increase in the postprandial lipoproteins after food intake occurs in the very low density lipoprotein (VLDL) remnants (apoB-100 particles), not CM or CM remnants (apoB-48 particles). This finding was obtained using the following three analytical methods; isolation of remnant-like lipoprotein particles (RLP) with specific antibodies, separation and detection of lipoprotein subclasses by gel permeation HPLC and determination of apoB-48 in fractionated lipoproteins by a specific ELISA. The amount of the apoB-48 particles in the postprandial RLP is significantly less than the apoB-100 particles, and the particle sizes of apoB-48 and apoB-100 in RLP are very similar when analyzed by HPLC. Moreover, CM or CM remnants having a large amount of TG were not found in the postprandial RLP. Therefore, the major portion of the TG which is increased in the postprandial state is composed of VLDL remnants, which have been recognized as a significant risk for cardiovascular disease., (Copyright © 2011 Elsevier B.V. All rights reserved.) more...

Background: Serum concentration of remnant-like lipoprotein particles (RLP) have been measured by cholesterol as RLP-C for clinical diagnostic purpose. However, the measurement of TG in RLP and the ratio of RLP-TG/total TG has not been well established., Method: Highly sensitive triglyceride assay reagent (TG-EX) was used for RLP-TG assay and compared with the previously used TG reagent (Determiner LTGII). Sera in health check-up populations, cardiovascular disease, diabetes and oral fat load cases were used for the evaluation of the new RLP-TG assay. Serum TC, TG, HDL-C, LDL-C and RLP-C concentrations were also determined in above cases., Results: The detection limit of new RLP-TG using TG-EX was 2.0mg/dl. The within-run imprecision (n=10) was CV=3.0% (RLP-TG: 4.1 mg ± 0.7 mg/dl), CV = 1.4% (RLP-TG: 42.0 ± 0.6 mg/dl) and CV=0.5% (RLP-TG: 100.6 ± 0.6 mg/dl). Cut-off value (75 percentile) of RLP-TG determined in the fasting Japanese population was 13.1mg/dl in men and 9.9 mg/dl in women. In patients with metabolic syndrome, cardiovascular disease and diabetes, RLP-TG levels were significantly higher than those in normal control subjects. RLP-TG levels increased significantly after an oral fat load and the ratio of RLP-TG/total TG increased > 3-fold compared to the ratio in the fasting state. Approximately 80% of TG increased after an oral fat load was TG derived from remnant lipoproteins., Conclusion: Normal range of plasma RLP-TG in the fasting Japanese population was first determined using a highly sensitive TG assay reagent. RLP-TG was shown to be higher in cases with metabolic syndrome, cardiovascular disease, etc and a better marker than RLP-C for the measurement of postprandial remnant lipoproteins, together with total TG for RLP-TG/total TG ratio., (Copyright © 2010 Elsevier B.V. All rights reserved.) more...

Background: An easy and specific enzyme-linked immunoassay (ELISA) for the determination of metallothionein-1 (MT-1) and 2 (MT-2) simultaneously in serum and other biological specimens in humans and experimental animals has not been developed yet., Methods: We developed a competitive ELISA, a specific polyclonal antibody against rat MT-2. The epitope mapping of the antibody was conducted using MTs in mouse, rat, rabbit, human and the fragment peptides of human MT-2. MT1/2 and MT-3 knock-out mice and cadmium treated mice were used for the evaluation of the ELISA. Pretreatment method of serum was examined to deplete blocking factors for this assay., Results: The antibody used for this ELISA had the same cross-reactivity with MT in humans and experimental animals. NH2 terminal peptide of MT with acetylated methionine was proved to be the epitope of this antibody. The reactivity of this ELISA system with liver, kidney and brain in MT1/2 knock-out mice was significantly low, but was normal in MT-3 knock-out mouse. The lowest detection limit of this ELISA was 0.6 ng/ml and the added MT-1 was fully recovered from serum. The mean MT concentration in our preliminary study was 23+/-4.6 ng/ml in human serum. Cadmium treatment to mice induced significantly higher amount of MT in serum, liver, kidney and spleen as reported previously by different established methods., Conclusion: The proposed competitive ELISA is an easy and specific method for practical use, determining total MT-1 and -2 simultaneously in serum and other biological specimens of human and experimental animals., (Copyright 2010 Elsevier B.V. All rights reserved.) more...

Morphology and function (secretion of thyroid hormone) of human thyroid tissues from Graves' disease patients are well maintained in C57BL/6J-scid mice. Serum level of thyroid hormone was reduced by fission neutrons from the nuclear reactor UTR-KINKI, and changes in thyroid hormone by fission neutrons were bigger than those by low LET radiations, X-rays and (137)Cs gamma-rays, suggesting high relative biological effectiveness (RBE; 6.5) of fission neutrons. Microarray analyses revealed that about 3% of genes showed more than 4-fold change in gene expression in the unexposed thyroid tissues against surgically resected thyroid tissues from the same patient, probably due to the difficult oxygen and nutrient supply shortly after transplantation. Dose-dependent changes in gene expression against unexposed concurrent controls were observed with increasing doses of fission neutrons (0.2-0.6Gy) and (137)Cs gamma-rays (1.0-3.0Gy) and showed high RBE (4.2). Furthermore, there were some specific genes which showed more than 4-fold change in gene expression in all the thyroid tissues exposed to higher doses of radiation, especially neutrons (0.4 and 0.6Gy), but none at lower doses (0.2Gy of neutrons and 1.0 and 2.0Gy of gamma-rays). These genes related to degeneration, regeneration, apoptosis, and transcription, respond specifically and very sensitively to neutron injury in human thyroid tissues. This is the first experimental report that fission neutrons can induce some morphological and functional disorders in human tissues, showing high RBE against gamma-ray exposure. These results are useful to evaluate the risks of fission neutrons and cosmic rays to humans., (Copyright © 2010 Elsevier B.V. All rights reserved.) more...

Objective: Previous studies have shown increases in ambulatory short-term blood pressure (BP) variability to be related to cardiovascular disease. In this study, we examined whether an angiotensin II type 1 receptor blocker losartan would improve ambulatory short-term BP variability in hypertensive patients on hemodialysis., Methods: Forty hypertensive patients on hemodialysis therapy were randomly assigned to the losartan treatment group (n=20) or the control treatment group (n=20). At baseline and 6 and 12 months after the treatment, 24-h ambulatory BP monitoring was performed. Echocardiography and measurements of brachial-ankle pulse wave velocity (baPWV) and biochemical parameters were also performed before and after therapy., Results: After 6- and 12-months of treatment, nighttime short-term BP variability, assessed on the basis of the coefficient of variation of ambulatory BP, was significantly decreased in the losartan group, but remained unchanged in the control group. Compared with the control group, losartan significantly decreased left ventricular mass index (LVMI), baPWV, and the plasma levels of brain natriuretic peptide and advanced glycation end products (AGE). Furthermore, multiple regression analysis showed significant correlations between changes in LVMI and changes in nighttime short-term BP variability, as well as between changes in LVMI and changes in the plasma levels of AGE., Conclusion: These results suggest that losartan is beneficial for the suppression of pathological cardiovascular remodeling though its inhibitory effect on ambulatory short-term BP variability during nighttime. more...

Background: Rapid and accurate methods for screening are necessary for the diagnosis of acute cardiovascular diseases (ACVD), including acute coronary syndrome (ACS), pulmonary thromboembolism, and acute aortic dissection. In this study, the utility of rapid D-dimer measurement for the screening of ACVD was evaluated., Methods and Results: Consecutive 279 emergent patients in whom ACVD was suspected or not ruled out were enrolled. The median D-dimer concentration of ACVD group (1.10 μg/ml) was significantly higher than that in the non-ACVD group (0.69 μg/ml, p<0.05). Sensitivity, specificity, positive predictive value, and negative predictive value of D-dimer (with cut-off level of 0.75 μg/ml) for the discrimination of ACVD from non-ACVD was 75%, 55%, 38%, and 85%, respectively. In ACVD group, the level of D-dimer in the large vessel disease subgroup was significantly higher than that in the ACS subgroup (6.99 μg/ml and 0.89 μg/ml, respectively; p<0.05). The well-balanced cut-off point for discriminating the two subgroups was D-dimer level of 5.0 μg/ml. D-dimer (with cut-off level of 0.75 μg/ml) showed significantly higher positive test rate for the detection of ACS in very early phase (within 2 h from the onset) compared with troponin T (p<0.05)., Conclusions: Rapid measurement of D-dimer is useful for the screening of ACVD in the emergency setting. more...

Hypoxia-ischemia is a common cause of neonatal brain injuries. Nitric oxide (NO) is upregulated in the brain after hypoxia-ischemia and generally believed to exert a paradoxical effect on neurons, neurodestruction and neuroprotection, but it has not been demonstrated that NO is actually neuroprotective in neonatal hypoxic-ischemic encephalopathy. We evaluated the effect of intracerebroventricular administration of nipradilol (3,4-dihydro-8-(2-hydroxy-3-isopropylamino)-propoxy-3-nitroxy-2H-1-benzopyran), a potent NO donor, at various concentrations (0.1 muM to 1 mM in 5 mul PBS/brain) to neonatal rats with hypoxic-ischemic treatment. The extent of the infarct area in the brain was significantly reduced by injection of the 1 muM nipradilol solution. However, denitro-nipradilol (3,4-dihydro-8-(2-hydroxy-3-isopropylamino)-propoxy-3-hydroxy-2H-1-benzopyran), that does not release NO, did not show the neuroprotective effect, suggesting that NO released from nipradilol exerts a neuroprotective effect on neonatal neurons. more...

A 54-year-old man was admitted to our hospital for evaluation of chest pain occurring at rest in the morning. ST segment depression was observed during a treadmill exercise test. Coronary angiography identified spontaneous spasm of the proximal right coronary artery, and right coronary obstruction was improved from 90% to about 50% stenosis after intracoronary administration of nitroglycerin. Myocardial iodine-123 beta-methyl-p-iodophenyl-pentadecanoic acid uptake was absent, but thallium-201 uptake during single photon emission computed tomography was normal, and neither platelet nor monocyte expression of the CD36 molecule was observed, indicating type I CD36 deficiency. High blood pressure, elevated plasma triglyceride and fasting plasma glucose levels, and low high-density lipoprotein values suggested metabolic syndrome. The final diagnosis was type I CD 36 deficiency associated with metabolic syndrome and vasospastic angina. more...

Neuroglycan C (NGC) is a transmembrane chondroitin sulfate proteoglycan expressed predominantly in the brain that possesses an EGF-like extracellular domain. The goal of the present study was to determine whether NGC may activate ErbB tyrosine kinases. A recombinant human NGC extracellular domain induced tyrosine phosphorylation of ErbB2 and ErbB3 as well as cell growth of the human breast tumor cell lines, T47D and MDA-MB-453. In vitro pull-down assay revealed that NGC could directly bind to a recombinant ErbB3-immunoglobulin Fc fusion protein (ErbB3-Fc) but not to ErbB1-Fc, ErbB2-Fc or ErbB4-Fc. A newly established anti-ErbB3 neutralizing monoclonal antibody (#5C3) almost completely blocked NGC-induced ErbB activation in MDA-MB-453 cells. Taken together, these data indicate that NGC is an active growth factor and a direct ligand for ErbB3 and that NGC transactivates ErbB2. Thus, NGC should be classified as the sixth member (neuregulin-6) of the neuregulin family. more...

The effects of glycosaminoglycans (GAG) on cell-to-substratum adhesion and neurite elongation were examined in primary cultures of fetal rat hippocampal neurons using tissue culture dishes coated with GAGs coupled to dipalmitoylphosphatidylethanolamine (PE), a novel probe for biological functions of GAGs. Both chondroitin sulfate conjugate to PE (CS-PE) and hyaluronic acid conjugate to PE (HA-PE) promoted neurite elongation from neurons in a dose-dependent manner when immobilized onto polylysine-coated dishes at various concentrations up to 1.0 microg/ml. The coating of CS-PE or HA-PE at a concentration higher than 1.0 microg/ml resulted in failure of neurite extension and adhesion of neurons to the substrata. In contrast, heparin conjugate to PE (HP-PE) did not exert any effects on neurite elongation or on cell attachment at these concentrations. These findings suggest that GAGs serve as a modulator for neurite elongation during neuronal network formation in the developing central nervous system. more...

Aggrecan family proteoglycans, phosphacan/RPTPzeta/beta, and neuroglycan C (NGC) are the major classes of chondroitin sulfate proteoglycan in the developing mammalian brain. A multidomain is a common structural feature of these proteoglycans which can interact with various molecules including growth factors, cell adhesion molecules, and extracellular matrix molecules. Individual proteoglycans are distributed in the developing brain in a distinct temporal and spatial pattern, suggesting that they are involved in distinct phases of the brain development through multiple molecular interactions. This review mainly summarizes recent studies on the involvement of these three classes of proteoglycan in cell-cell and cell-substratum interactions during the brain development. Their expressions and proposed functional roles in injured brains are also mentioned. In addition, this review briefly covers potential functions of other neural chondroitin sulfate proteoglycans such as decorin, testican, NG2 proteoglycan, and amyloid precursor protein (APP) in developing and injured brains., (Copyright 2000 Academic Press.) more...

Neuroglycan C (NGC) is a 150 kDa transmembrane chondroitin sulfate proteoglycan with a 120 kDa core glycoprotein that was originally isolated from the developing rat brain. A rabbit antiserum, raised against a recombinant polypeptide representing a protein of the rat NGC core protein, recognized an NGC homolog in homogenates of brains of various vertebrates including humans. Because of the possible involvement of this proteoglycan in the etiology of a human neuronal disease, we cloned a complete coding sequence from a human brain cDNA library using a rat NGC cDNA as a probe. The predicted protein contains 539 amino acids and shows 86% homology with the rat counterpart. The domain structure characteristic of rat NGC was completely conserved in human NGC, which consisted of an N-terminal signal sequence, a chondroitin sulfate-attachment domain, an acidic amino acid cluster, an EGF-like domain, a transmembrane domain and a cytoplasmic tail. Northern blot analysis revealed that a single transcript of 2.4 kb was detectable in the brain, but not in other human tissues. By fluorescence in situ hybridization (FISH) analysis, the human NGC gene was assigned to the chromosomal 3p21.3 band, where the Sotos syndrome has been mapped. Involvement of the NGC gene in the etiology of the Sotos syndrome remains to be examined. more...

Horizontal root fractures of both maxillary central incisors were diagnosed radiographically; neither responded to electric pulp testing nor to cold testing. The pulp of the right incisor was necrotic, whereas the pulpal status of the left incisor was uncertain. Pulpal blood flow of the teeth was measured with laser Doppler flowmetry. The blood flow of the left central incisor was 4.0. Eight months after the injury, a local anesthetic with a vasoconstrictor was administered to confirm pulp vitality. The blood flow of the tooth was decreased to 51% of the preanesthesia value after the local anesthesia. At 19 months after the injury, it responded to both the electric pulp test and cold test. Laser Doppler flowmetry is a noninvasive method of evaluating the blood flow status in human teeth, and it may provide a clinically reliable method of assessing pulpal vitality. more...

Receptor molecules for basic fibroblast growth factor (bFGF) were isolated from rat brain by a novel and rapid procedure and characterized. Purification was performed by wheatgerm agglutinin (WGA) gel affinity chromatography in combination with bFGF gel affinity chromatography, utilizing a novel elution method involving heparin. The eluted proteins were active in binding bFGF and were separated as two bands with respective molecular masses of 140 kDa and 110 kDa on SDS-PAGE. More than half of this bFGF-binding activity was lost after 16 h at 4 degrees C. Thus, bFGF receptors were purified as labile glycoconjugates. more...