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Objective: This study aimed to establish an optional newborn screening program for spinal muscular atrophy (SMA-NBS) in Osaka., Methods: A multiplex TaqMan real-time quantitative polymerase chain reaction assay was used to screen for SMA. Dried blood spot samples obtained for the optional NBS program for severe combined immunodeficiency, which covers about 50% of the newborns in Osaka, were used. To obtain informed consent, participating obstetricians provided information about the optional NBS program to all parents by giving leaflets to prospective parents and uploading the information onto the internet. We prepared a workflow so that babies that were diagnosed with SMA through the NBS could be treated immediately., Results: From 1 February 2021 to 30 September 2021, 22,951 newborns were screened for SMA. All of them tested negative for survival motor neuron (SMN)1 deletion, and there were no false-positives. Based on these results, an SMA-NBS program was established in Osaka and included in the optional NBS programs run in Osaka from 1 October 2021. A positive baby was found by screening, diagnosed with SMA (the baby possessed 3 copies of the SMN2 gene and was pre-symptomatic), and treated immediately., Conclusion: The workflow of the Osaka SMA-NBS program was confirmed to be useful for babies with SMA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Primary cilia transduce signals via transmembrane and membrane-associated proteins localized to the ciliary membrane in vertebrate cells. In humans, transmembrane protein 67 (TMEM67), a component of the multiprotein complex functioning as a gatekeeper at the transition zone (TZ) of primary cilia, is mutated in patients suffering from cilia-related pleiotropic diseases, collectively referred to as ciliopathies. The requirement of TMEM67 for the gating function of the TZ that delivers membrane proteins into the ciliary compartment has not been determined. In this study, we established hTERT-RPE1 cells with knockout (KO) of TMEM67 and examined whether cilium formation and TZ gating are affected by its ablation. TMEM67-KO cells displayed impaired ciliogenesis, elongated cilia, perturbed ciliary localization of membrane-associated proteins ARL13B and INPP5E but normal recruitment of TZ proteins CEP290, RPGRIP1L and NPHP5. The exogenous expression of ciliopathy-associated TMEM67 mutants restored ciliary localization of ARL13B and INPP5E but failed to attenuate aberrant cilium elongation in TMEM67-KO cells. Furthermore, we found that TMEM67 localization is not confined to the TZ but extends into the cilium. Our findings indicate that TMEM67 is required not only for ciliogenesis and cilium length regulation but also for the gating function of the TZ independently of RPGRIP1L/CEP290/NPHP5 recruitment to this region. They further suggest that aberrant cilium elongation underlies the pathogenesis of TMEM67-linked ciliopathies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ko Miyoshi reports financial support was provided by the Sakamoto Research Institute of Psychopathology., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Bifidobacteria are widely used as a probiotic for their health-promoting effects. To promote their growth, bifidogenic prebiotics, including human milk oligosaccharides (HMOs), have been added to supplements and infant formula. However, the efficacy of both probiotic and prebiotic interventions is often debated, as clinical responses vary significantly by case. Here, we review clinical studies that aimed to proliferate human-residential Bifidobacterium (HRB) strains in the gut, and we highlight the difference between responders and non-responders to such interventions through an ecological, niche-based perspective and an examination of the prevalence of genes responsible for prebiotic assimilation in HRB genomes. We discuss the criteria necessary to better evaluate the efficacy of probiotic and prebiotic interventions and the recent therapeutic potential shown by synbiotics., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The progression of chronic kidney disease (CKD) increases the risks of cardiovascular morbidity and end-stage kidney disease. Indoxyl sulfate (IS), which is derived from dietary l-tryptophan by the action of bacterial l-tryptophan indole-lyase (TIL) in the gut, serves as a uremic toxin that exacerbates CKD-related kidney disorder. A mouse model previously showed that inhibition of TIL by 2-aza-l-tyrosine effectively reduced the plasma IS level, causing the recovery of renal damage. In this study, we found that (+)-sesamin and related lignans, which occur abundantly in sesame seeds, inhibit intestinal bacteria TILs. Kinetic studies revealed that (+)-sesamin and sesamol competitively inhibited Escherichia coli TIL (EcTIL) with K i values of 7 μM and 14 μM, respectively. These K i values were smaller than that of 2-aza-l-tyrosine (143 μM). Molecular docking simulation of (+)-sesamin- (or sesamol-)binding to EcTIL predicted that these inhibitors potentially bind near the active site of EcTIL, where the cofactor pyridoxal 5'-phosphate is bound, consistent with the kinetic results. (+)-Sesamin is a phytochemical with a long history of consumption and is generally regarded as safe. Hence, dietary supplementation of (+)-sesamin encapsulated in enteric capsules could be a promising mechanism-based strategy to prevent CKD progression. Moreover, the present findings would provide a new structural basis for designing more potent TIL inhibitors for the development of mechanism-based therapeutic drugs to treat CKD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The carbohydrate fraction of mammalian milk is constituted of lactose and oligosaccharides, most of which contain a lactose unit at their reducing ends. Although lactose is the predominant saccharide in the milk of most eutherians, oligosaccharides significantly predominate over lactose in the milk of monotremes and marsupials., Scope of Review: This review describes the most likely process by which lactose and milk oligosaccharides were acquired during the evolution of mammals and the mechanisms by which these saccharides are digested and absorbed by the suckling neonates., Major Conclusions: During the evolution of mammals, c-type lysozyme evolved to α-lactalbumin. This permitted the biosynthesis of lactose by modulating the substrate specificity of β4galactosyltransferase 1, thus enabling the concomitant biosynthesis of milk oligosaccharides through the activities of several glycosyltransferases using lactose as an acceptor. In most eutherian mammals the digestion of lactose to glucose and galactose is achieved through the action of intestinal lactase (β-galactosidase), which is located within the small intestinal brush border. This enzyme, however, is absent in neonatal monotremes and macropod marsupials. It has therefore been proposed that in these species the absorption of milk oligosaccharides is achieved by pinocytosis or endocytosis, after which digestion occurs through the actions of several lysosomal acid glycosidases. This process would enable the milk oligosaccharides of monotremes and marsupials to be utilized as a significant energy source for the suckling neonates., General Significance: The evolution and significance of milk oligosaccharides is discussed in relation to the evolution of mammals., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Macrophages play a vital role in the development of atherosclerotic cardiovascular disease. Macrophages are functionally and phenotypically heterogeneous immune cells and commonly exist in two distinct or polarized subsets: pro-inflammatory M1 and anti-inflammatory M2 phenotypes. Previous reports suggest that stimulation of α7 or α4β2 nicotinic acetylcholine receptors (nAChRs) in macrophages leads to an anti-inflammatory response. However, the biological link between nAChR expression on macrophages and the polarization state is unknown. Therefore, we evaluated the relationship between nAChRs and polarized macrophages in peritoneal macrophages and atherosclerotic plaques of apolipoprotein E knockout (ApoE -/- ) mice., Methods: Peritoneal macrophages isolated from mice were polarized into M1 and M2 macrophages, and the uptake of the nAChR-imaging agents, (R)-2-[ 11 C]methylamino-benzoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester ([ 11 C]MeQAA) or 2-[ 18 F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine ([ 18 F]2FA), and 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) was assessed. We also evaluated the accumulation of imaging agents in atherosclerotic plaques of ApoE -/- mice by autoradiography. After an autoradiogram was obtained, the same aortic tissue was used for immunohistochemical staining of CD68, inducible nitric oxide synthase (iNOS), and arginine-1., Results: In an in vitro assay, the uptake of [ 11 C]MeQAA or [ 18 F]2FA was lower in M1 than in M0 and M2 macrophages. In comparison, the uptake of [ 18 F]FDG was higher in M1 macrophages. Ex vivo autoradiography showed that [ 11 C]MeQAA was localized to the extensive plaque area. By contrast, the accumulation of [ 18 F]2FA and [ 18 F]FDG was heterogeneous and found only in some plaques. Moreover, the expression of CD68 and iNOS was higher in [ 18 F]2FA non-uptake than [ 18 F]2FA uptake plaques., Conclusion: Macrophage polarization was related to nAChR expression, and α4β2 nAChR expression was suppressed in the M1 macrophage. These findings suggest that nAChR imaging has the potential to identify the inflammatory status of atherosclerotic plaque., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background & Aims: The number of patients with non-alcoholic steatohepatitis (NASH) is increasing globally. Recently, specific chemokine receptors have garnered interest as therapeutic targets in NASH. This is the first report to examine the role of the C-C chemokine receptor 9 (CCR9)/C-C chemokine receptor ligand 25 (CCL25) axis, and to reveal its therapeutic potential in NASH., Methods: Patients with biopsy-proven non-alcoholic liver disease (NAFLD) were recruited and their serum and hepatic chemokine expression was examined. Furthermore, wild-type (WT) and Ccr9 -/- mice were fed a high-fat high-cholesterol (HFHC) diet for 24 weeks to establish NASH., Results: Serum CCL25, and hepatic CCR9 and CCL25 expression levels were increased in patients with NASH compared to healthy volunteers. Furthermore, Ccr9 -/- mice were protected from HFHC diet-induced NASH progression both serologically and histologically. Flow cytometry and immunohistochemistry analysis showed that CCR9 + CD11b + inflammatory macrophages accumulated in the inflamed livers of HFHC diet-fed mice, while the number was reduced in Ccr9 -/- mice. Consistent with human NASH livers, CCR9 was also expressed on hepatic stellate cells (HSCs) in mice with NASH, while CCR9-deficient HSCs showed less fibrogenic potential in vitro. Administration of a CCR9 antagonist hampered further fibrosis progression in mice with NASH, supporting its potential clinical application. Finally, we showed that CCR9 blockade attenuated the development of NAFLD-related hepatocellular carcinoma in HF diet-fed mice injected with diethylnitrosamine., Conclusions: These results highlight the role of the CCR9/CCL25 axis on macrophage recruitment and fibrosis formation in a murine NASH model, providing new insights into therapeutic strategies for NASH., Lay Summary: Herein, we show that a specific chemokine axis involving a receptor (CCR9) and its ligand (CCL25) contributes to the progression of non-alcoholic steatohepatitis and carcinogenesis in humans and mice. Furthermore, treatment with a CCR9 antagonist ameliorates the development of steatohepatitis and holds promise for the treatment of patients with non-alcoholic steatohepatitis., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: We have developed a surgical glove (SG)-compression therapy and reported that this method significantly reduced the overall occurrence of grade 2 or higher nanoparticle albumin-bound-paclitaxel (nab-PTX)-induced peripheral neuropathy (PN) from 76.1% to 21.4%. In this multicenter single-arm confirmatory study, we investigated the efficacy and safety of SG-compression therapy for the prevention of nab-PTX-induced PN, compared with the incidence of grade 2 or higher PN in published literature as controls., Patients and Methods: Primary breast cancer patients who received 260 mg/m 2 of nab-PTX were eligible for this study. Patients wore two SGs (one size smaller than the tight-fitting size) in each hand for 90 min. PN was evaluated at each treatment cycle using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and the Patient Neurotoxicity Questionnaire (PNQ). The temperature of each fingertip was measured using thermography., Results: Between October 2016 and June 2017, 58 patients were evaluated. The incidence of CTCAE grade 2 or higher PN was as low as 13.8% following SG-compression therapy. A goodness-of-fit test proved that the overall incidence of 13.8% grade 2 or higher PN in this study was comparable to the hypothesis-predicted value (13%). No adverse events, including compression intolerance or skin disorders caused by use of SG, were observed. SG-compression therapy significantly reduced the temperature of each fingertip by 1.3°C-2.3 °C compared to pre-chemotherapy level., Conclusions: This study suggested the safety and efficacy of SG-compression therapy for the amelioration of CIPN., Clinical Trial Number: UMIN 000024836., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The primary cilia are known as biosensors that transduce signals through the ciliary membrane proteins in vertebrate cells. The ciliary membrane contains transmembrane proteins and membrane-associated proteins. Tubby-like protein 3 (TULP3), a member of the tubby family, has been shown to interact with the intraflagellar transport-A complex (IFT-A) and to be involved in the ciliary localization of transmembrane proteins, although its role in the ciliary entry of membrane-associated proteins has remained unclear. Here, to determine whether TULP3 is required for the localization of ciliary membrane-associated proteins, we generated and analyzed TULP3-knockout (KO) hTERT RPE-1 (RPE1) cells. Immunofluorescence analysis demonstrated that ciliary formation was downregulated in TULP3-KO cells and that membrane-associated proteins, ADP-ribosylation factor-like 13B (ARL13B) and inositol polyphosphate-5-phosphatase E (INPP5E), failed to localize to primary cilia in TULP3-KO cells. These defects in the localization of ARL13B and INPP5E in TULP3-KO cells were rescued by the exogenous expression of wild-type TULP3, but not that of mutant TULP3 lacking the ability to bind IFT-A. In addition, the expression of TUB protein, another member of the tubby family whose endogenous expression is absent in RPE1 cells, also rescued the defective ciliary localization of ARL13B and INPP5E in TULP3-KO cells, suggesting that there is functional redundancy between TULP3 and TUB. Our findings indicate that TULP3 participates in ciliogenesis, and targets membrane-associated proteins to primary cilia via binding to IFT-A., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Catabolism of the branched-chain amino acids (BCAAs: leucine, isoleucine, and valine) is regulated by the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which in turn is regulated by phosphorylation catalyzed by BCKDH kinase (BDK). Thiamine pyrophosphate (TPP) is required as a coenzyme for the E1 component of the BCKDH complex and can also bring about activation of the complex by inhibiting BDK. The present study shows that free Ca 2+ in the physiological range greatly increases the sensitivity of BDK to inhibition by TPP (IC 50 of 2.5 μM in the presence of 1 μM free Ca 2+ ). This novel mechanism may be responsible for the stimulation of BCAA oxidation by conditions that increase mitochondrial free Ca 2+ levels, e.g. in skeletal muscle during exercise., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: A new 23S ribosomal RNA genes-targeted in situ hybridization (ISH) probe to detect global bacterial genomic DNA (59 species from 35 genera; referred to as the GB probe) phagocytized in leukocytes was recently developed. This method provided early and direct evidence of bacterial infection with high sensitivity and specificity in spontaneous bacterial peritonitis ascites. However, the utility of this method in febrile neutropenia (FN) is unknown., Methods: We prospectively evaluated the utility of the ISH approach using the GB probe and previously reported probes in patients with neutropenia and fever undergoing chemotherapy at our institution between June 2011 and July 2013. Blood samples for culture analysis and ISH tests were collected simultaneously at the onset of fever; the latter were performed repeatedly., Results: Fifty febrile episodes were evaluated. In 24 episodes of fever of unknown origin and 15 episodes of local infection (all negative for blood cultures), ISH tests identified causal bacteria in 21% and 13% of cases, respectively, at the onset of fever. In seven sepsis cases (all positive for blood culture), positive ISH test results at fever onset were achieved in 71%; for two patients with neutrophil counts of 0/μl and 171/μl, respectively, negative results were obtained., Conclusions: This new ISH approach could prove useful for early detection of bacteria in patients with neutropenia and blood culture-negative, with fever of unknown etiology after chemotherapy. Using this method in combination with blood culture, even in cases with extremely low neutrophil counts, might contribute to better management of FN., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Whether presepsin (soluble CD14-subtype) is better than other markers including procalcitonin (PCT), has not been adequately investigated in febrile neutropenia (FN)., Methods: We prospectively examined the utility of presepsin in FN in Cohort 1 (C1) and 2 (C2), between November 2010 and February 2012, and between November 2013 and January 2014, respectively. The purpose of this study was to investigate 1) the relative value of serum presepsin over serum PCT in C1, and 2) the relative value of plasma presepsin as compared with serum PCT, C-reactive protein, interleukin-6 and interleukin-8 with frequent, repeated sampling in C2., Results: Seventy-nine FN episodes (C1, 75; C2, 4) were evaluable. In C1, when compared with control values, presepsin was significantly higher at onset of FN (P = 0.004), while PCT was not significantly higher (P = 0.54). The median value of serum presepsin within 72 h of onset of FN in subjects with fever of unknown origin, local infection, bacteremia and septic shock was 680 (reference 314) pg/ml, 763, 782 and 1359, respectively. In C2, the mean levels of plasma presepsin from onset of FN to 72 h were classified as negative in the two patients with no suspected site of infection, and those of the remaining two patients with clinically probable infections were positive (175, 131, 346 and 329 pg/ml, respectively). In contrast, the other markers did not discriminate between this two groups., Conclusions: In FN, presepsin may be an earlier and more sensitive indicator of bacterial infection than PCT., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The use of granular steelmaking slag as a substitute for natural sand in the construction of tidal flats was investigated. Using an intertidal flat simulator, we evaluated dephosphorization slag mixed with 8% by dry weight of dredged sediment (DPS+DS) as a basal medium for the growth of benthic macro- and microalgae in comparison with silica sand mixed with 8% dredged sediment (SS+DS). Species compositions of macro- and microalgae were distinctly different between DPS+DS and SS+DS. The mean dry weight of macroalgae on DPS+DS was three orders of magnitude higher than that on SS+DS. Sediment shear strength and pH were higher in DPS+DS than in SS+DS or in the sediment of natural tidal flats. These results suggest that DPS contributes to changing the sediment environment, thereby changing the algal composition compared to the composition on natural tidal flats., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We describe the novel substrate specificities of two independently evolved lacto-N-biosidases (LnbX and LnbB) towards the sugar chains of globo- and ganglio-series glycosphingolipids. LnbX, a non-classified member of the glycoside hydrolase family, isolated from Bifidobacterium longum subsp. longum, was shown to liberate galacto-N-biose (GNB: Galβ1-3GalNAc) and 2'-fucosyl GNB (a type-4 trisaccharide) from Gb5 pentasaccharide and globo H hexasaccharide, respectively. LnbB, a member of the glycoside hydrolase family 20 isolated from Bifidobacterium bifidum, was shown to release GNB from Gb5 and GA1 oligosaccharides. This is the first report describing enzymatic release of β-linked GNB from natural substrates. These unique activities may play a role in modulating the microbial composition in the gut ecosystem, and may serve as new tools for elucidating the functions of sugar chains of glycosphingolipids., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The perioperative risk of non-cardiac surgery (NCS) in the patients on antiplatelet therapy after percutaneous coronary intervention (PCI) remains unclear., Methods: This study was a retrospective and single center study. Between January 2008 and December 2011, 198 patients who had already received PCI underwent NCS in our hospital. Among them, 63 patients underwent surgery on dual antiplatelet therapy (DAPT group) and 88 patients on single antiplatelet therapy (SAPT group). We compared bleeding events and cardiovascular events during perioperative period between the two groups., Results: There was no stent thrombosis in either group. The bleeding events in the DAPT group were significantly higher than that in the SAPT group (9.5% vs 2.3%, p=0.049). There was no difference in events between with or without heparin-bridge in the SAPT group., Conclusions: The frequency of bleeding events was higher in the DAPT group. Both bleeding and cardiovascular events with aspirin alone were low in our study. It may be safe to undergo NCS with SAPT after PCI., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objective: Elderly hypertensive patients are characterized by blood pressure (BP) variability, impaired autonomic function, and vascular endothelial dysfunction and stiffness. However, the mechanisms causing these conditions are unclear. The present study examined the effect of angiotensin receptor blockers (ARBs) on aged spontaneously hypertensive rats (SHR)., Methods: We surgically implanted telemetry devices in SHR and WKY at the age of 15 weeks (Young) and 80 weeks (Aged). Aged SHR were orally administered either olmesartan or valsartan once daily at 19:00 h (at the beginning of the dark period (active phase)) for 4 weeks to examine the effects on BP variability, impaired autonomic function, and vascular senescence., Results: Aging and hypertension in SHR additively caused the following: increased low frequency (LF) power of systolic BP, a decreased spontaneous baroreceptor reflex gain (sBRG), increased BP variability, increased urinary norepinephrine excretion, increased vascular senescence-related beta-galactosidase positive cells and oxidative stress. Treatment with olmesartan or valsartan significantly ameliorated these changes in aged SHR. However, olmesartan ameliorated these changes in aged SHR better than valsartan. The reductions in BP caused by olmesartan in aged SHR were sustained longer than reductions by valsartan. This result indicates longer-lasting inhibition of the AT1 receptor by olmesartan than by valsartan., Conclusion: ARBs ameliorated autonomic dysfunction, BP variability, and vascular senescence in aged SHR. Olmesartan ameliorated the aging-related disorders better than valsartan and was associated with longer-lasting AT1 receptor inhibition by olmesartan. Thus, the magnitude of improvement of these aging-related abnormalities differs for ARBs., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To investigate radiographic criteria for scapholunate instability (SLI) in the setting of distal radius fracture (DRF) confirmed by arthroscopy., Methods: Eighty-eight wrists with DRF treated by open reduction and internal fixation and assessed for SLI arthroscopically were evaluated. The scapholunate distance (SLD) was measured by preoperative posteroanterior wrist radiography and computed tomography (CT). SLD on radiographs was measured as the distance between the scaphoid cortex and the lunate cortex at the center of the scapholunate joint. SLDs were measured at the volar end (A1), center (A2), and dorsal end (A3) of the scapholunate joint on the central CT axial slice; and at the proximal end (C1), center (C2), and distal end (C3) of the scapholunate joint on the central CT coronal slice. Wrists were divided into three groups by arthroscopic assessments: stable (normal, Geissler grade 1 or 2), G3 (Geissler grade 3), and G4 (Geissler grade 4). SLD measurements on radiographs and CTs (A1-C3) were compared among the three groups. Receiver-operating characteristic (ROC) curve analyses were performed to evaluate the abilities of SLD measurements on radiographs and CTs to identify SLI in wrists with DRF. Interobserver and intraobserver reliabilities of SLD measurements on radiographs and CTs were analyzed by intraclass correlation coefficients (ICCs)., Results: SLDs of C3 differed significantly among the G3 and G4 groups, and among the stable and G4 groups. The area under the curve on ROC curve analysis was 0.855 for the SLD of C3, which was larger than that for SLD on radiographs. For C3, the intraobserver ICC was 0.832 and interobserver ICC was 0.73., Conclusions: SLD at the distal end of the scapholunate joint on the central coronal CT slice was the most appropriate measurement for discrimination of Geissler grade 4 SLI in wrists with DRF., Level of Evidence: Level 2.

Background: The effective energy density (ED) diet model for customized meal plans has not been adequately explored, and the specific differences in appetite sensation among age groups remain unclear., Design: A randomized, crossover study was conducted in 2010 to examine the effects of lunches with different dietary EDs on sensory properties across age groups., Participants/setting: In this experiment, 276 healthy Japanese subjects aged 22 to 59 years consumed packed lunches over six sessions. Using the control meal (150 g cooked rice, sautéed beef menu containing 40 g raw beef, and 240 g vegetable) as a reference, a high-meat/low-rice meal, a low-vegetable meal, a medium-fat/low-vegetable meal, a high-fat meal, and a high-fat/low-vegetable meal were served as modified test meals with varying macronutrient distribution and ED., Main Outcome Measures: Subjective levels of fullness and satisfaction were assessed over time by visual analogue scale ratings., Statistical Analyses Performed: Data were analyzed using analysis of variance with body mass index as a covariate followed by Bonferroni post hoc tests., Results: Meals with high vegetable content resulted in greater fullness and satisfaction than meals with low vegetable content, regardless of the diner's age. Particularly among the 500-kcal low-ED meals, a high-meat meal resulted in greater fullness and satisfaction than a medium-fat/low-vegetable meal among participants aged 30 to 40 years. Postprandial fullness was significantly higher with control meal than with high-meat meal among participants aged 40 to 50 years., Conclusions: This study indicated that high vegetable content in the low-ED diet model provided sufficient fullness and satisfaction despite the low energy content and increased rice content is more effective for satiety than increased meat content for Japanese adults aged around 40 years., (Copyright © 2013 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Aim: The aim of this study was to assess the diagnostic performance of fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in combination with ultrasonography-guided fine needle aspiration cytology (US-guided FNAC) for the preoperative diagnosis of axillary lymph node (ALN) metastases in patients with breast cancer., Materials and Methods: A total of 318 patients with breast cancer were recruited retrospectively. Some of the cases that underwent neoadjuvant chemotherapy (NAC) were included. The sensitivity and specificity of FDG-PET/CT were calculated. We assessed the relationship between the combined results for US-guided FNAC with FDG-PET/CT and the pathological ALN status., Results: A total of 271 patients underwent FDG-PET/CT. Of these patients, 41 underwent US-guided FNAC. The sensitivity and the specificity of FDG-PET/CT for the cases without NAC were 18.5%, 97.1%, respectively. The sensitivity in cases with NAC was 68.2%. As a whole, the sensitivity was 40.8%. ALN metastasis was detected using US-guided FNAC in a case with a negative FDG uptake in the ALN. The T stage was T2 in the case and the FDG uptake at the primary site was poor., Conclusion: FDG-PET/CT has a good specificity for ALN metastasis, although its sensitivity is limited, especially in early-stage cases. In cases with a negative FDG uptake in the ALN, US-guided FNAC may play a role in the detection of lymph node metastasis when the primary tumor size is large and the FDG uptake in the primary tumor is low., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: A persistent articular gap and a step-off of ≥1 mm after a distal radial fracture (DRF) may lead to post-traumatic arthritis of the radiocarpal joint. This study aims to arthroscopically assess the reduction in the articular surface in patients requiring volar locked-plate fixation for DRF via fluoroscopy-guided open reduction and internal fixation (ORIF)., Methods: Seventy consecutive patients with DRF were prospectively enrolled. Posteroanterior and lateral radiographs and axial, coronal, and sagittal computed tomography (CT) scans were obtained before ORIF for DRF. The widest articular gap (pregap) and step-off (prestep-off) at the radiocarpal joint surface of the distal radius were measured on all radiographs and CT images. Total predisplacement was defined as the sum of all pregaps and prestep-offs. The DRF was reduced under fluoroscopic guidance, and a volar locked-plate was applied after fluoroscopic ORIF. The residual maximum articular gap and step-off (postgap and poststep-off) were measured arthroscopically with a calibrated probe. Total incongruity was defined as the sum of postgap and poststep-off. The receiver operating characteristic curve was applied within the pregaps, prestep-offs and total incongruity in order to identify the cutoff values of pregap and prestep-off beyond which total incongruity would exceed 1 mm., Results: Of the 70 patients, 40 had a postgap of ≥1 mm, and 15 had a poststep-off of ≥1 mm. All pregap and prestep-off cutoff values were judged to be unsuitable as the screening criteria for arthroscopic reduction of DRF because of their low sensitivity and specificity. The cutoff value obtained from total predisplacement was 7.85 mm, and its sensitivity and specificity were 90 and 70 %, respectively., Conclusions: Since the cutoff value of 7.85 mm derived from total predisplacement is a good indicator of post-ORIF residual total incongruity of ≥1 mm, it is also a good indicator of the need for arthroscopic reduction.

Background: Profound changes in gene expression can result from abnormalities in the concentrations of sequence-specific transcription factors like specificity protein 1 (Sp1). Specificity protein 1 binding sites have been reported in the promoter regions of several genes implicated in autism. We hypothesize that dysfunction of Sp1 could affect the expression of multiple autism candidate genes, contributing to the heterogeneity of autism., Methods: We assessed any alterations in the expression of Sp1 and that of autism candidate genes in the postmortem brain (anterior cingulate gyrus [ACG], motor cortex, and thalamus) of autism patients (n = 8) compared with healthy control subjects (n = 13). Alterations in the expression of candidate genes upon Sp1/DNA binding inhibition with mithramycin and Sp1 silencing by RNAi were studied in SK-N-SH neuronal cells., Results: We observed elevated expression of Sp1 in ACG of autism patients (p = .010). We also observed altered expression of several autism candidate genes. GABRB3, RELN, and HTR2A showed reduced expression, whereas CD38, ITGB3, MAOA, MECP2, OXTR, and PTEN showed elevated expression in autism. In SK-N-SH cells, OXTR, PTEN, and RELN showed reduced expression upon Sp1/DNA binding inhibition and Sp1 silencing. The RNA integrity number was not available for any of the samples., Conclusions: Transcription factor Sp1 is dysfunctional in the ACG of autistic brain. Consequently, the expression of potential autism candidate genes regulated by Sp1, especially OXTR and PTEN, could be affected. The diverse downstream pathways mediated by the Sp1-regulated genes, along with the environmental and intracellular signal-related regulation of Sp1, could explain the complex phenotypes associated with autism.

Escherichia coli contains two thioredoxins, Trx1 and Trx2, and a thioredoxin-like protein, YbbN, that displays both redox and chaperone properties. Since three out of the six proteins of the YbbN interactome (Butland et al., 2005) are components of DNA polymerase 3 holoenzyme (i.e. the β-clamp DnaN, the θ subunit HolE and the δ' subunit HolB), we investigated whether the ybbN mutant presents DNA replication defects. We found that this mutant incorporates (3)H-thymidine at higher rates than the parental strain and displays overinitiation, hypermutator and filamentation phenotypes with the occurrence of anucleated cells. Moreover, YbbN functions as a bona fide chaperone in the refolding of the urea-unfolded β-clamp. These results suggest that the DNA replication and cell division defects of the ybbN mutant might best be explained by chaperone functions of YbbN in the biogenesis of DNA polymerase 3 holoenzyme., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: The effects of theta burst stimulation (TBS) have been extensively investigated in primary motor cortex, where it leads to long-lasting LTP/LTD-like effects on synaptic plasticity. This study aimed to extend these observations to sensory cortex., Methods: Fourteen healthy subjects participated in the study. Conditioning 600-pulse intermittent TBS (iTBS) and continuous TBS (cTBS) were delivered to left somatosensory cortex (S1) with an intensity of 80% active motor threshold. Somatosensory evoked potentials (SEPs) were evoked by median nerve electrical stimulation at right wrist. High frequency oscillations (HFOs) were obtained by digital filtering of original SEPs and divided into early and late subcomponents, relative to N20(peak) latency., Results: Repeated-measures ANOVA showed that iTBS facilitated N20(onset)-N20(peak) at 15min and N20(peak)-P25 at 15 and 30min after conditioning, whereas cTBS did not. iTBS left the early and late HFOs unchanged. Conversely, cTBS facilitated the early HFOs, whereas it inhibited the late HFOs at 15min after conditioning., Conclusions: S1-iTBS facilitated SEPs without changes in HFOs whereas cTBS modulated early and late HFOs without changes in SEPs., Significance: S1-TBS produces lasting changes in the excitability of intracortical circuits generating SEPs and HFOs differentially through mechanisms of LTP/LTD-like synaptic plasticity., (Copyright © 2010 International Federation of Clinical Neurophysiology. All rights reserved.)

Background: The purpose of this study was to assess articular surface reduction arthroscopically after volar locked-plate fixation of distal radius fractures (DRFs) via fluoroscopyguided open reduction/internal fixation. We also aimed to develop preoperative radiographic criteria to help assist in determining which DRFs may need arthroscopic evaluation., Methods: A total of 31 consecutive patients with DRF were prospectively enrolled. Posteroanterior (PA) and lateral radiographs as well as axial, coronal, and sagittal CT scans were obtained just after attempted reduction of the DRF. The widest articular displacement at the radiocarpal joint surface of the distal radius (preopD) was then measured using a digital radiography imaging system. The DRF was reduced under fluoroscopy, and a volar locked plate was applied. The degree of residual articular displacement was then measured arthroscopically, and the maximum displacement (postopD) was measured with a calibrated probe., Results: Of the 31 patients, 7 had an arthroscopically assessed maximum postopD of > or = 2 mm after internal fixation. The correlation coefficients between each preopD and postopD of all radiographs and CTs were statistically significant. The cutoff values were 0.5 mm for PA radiographs, 2.10 mm for lateral radiographs, 2.15 mm for axial CT scans, 3.15 mm for coronal CT scans, and 1.20 mm for sagittal CT scans. All cutoff values for PA and lateral radiographs and for axial, coronal, and sagittal CT scans were unsuitable as screening criteria for arthroscopic reduction of DRF because of their low sensitivities and specificities. The cutoff value of the new preopD (the sum of the preopDs determined by lateral radiography and coronal CT scan) was 5.80 mm, and its sensitivity and specificity were 100% and 83.3%, respectively., Conclusions: Because a new preopD cutoff value of 5.80 mm is a good indicator for residual articular displacement after internal fixation of >2 mm, it is also a good indicator for the need for arthroscopic evaluation after internal fixation.

Background: Causes of left atrial (LA) enlargement and its gender difference in patients with normal left ventricular (LV) systolic function have not been clarified. We investigated the factors contributing to LA enlargement in patients with normal LV systolic function, addressing its gender difference., Methods: We enrolled 380 patients (175 males and 205 females; mean age: 63 + or - 15 years) with LV ejection fraction > or = 50% who underwent Doppler echocardiography and blood tests at the same time as echocardiography. Patients with arrhythmias, significant valvular heart disease, and LV asynergy were excluded. The LA volume was measured by Simpson's method from apical 2- and 4-chamber views, and LA volume index (LAVI) was calculated as LA volume/body surface area. All patients, male and female were assigned to a group with a low or a high LAVI based on the median LAVI value, respectively., Results: Age, female gender, hypertension, diabetes, hemoglobin concentration, LV mass index, Doppler parameters of LA contraction, and the ratio of mitral early diastolic velocity to early diastolic velocity of the mitral annulus (E/E') were significantly associated with a high LAVI in all patients. Multivariate analysis showed that LV mass index [odds ratio (OR) 1.05, 95% confidence interval (CI) 1.03-1.06, P<0.0001], hemoglobin concentration (OR 0.76, 95% CI 0.64-0.90, P<0.01), and female gender (OR 1.92, 95% CI 1.12-3.30, P<0.05) independently contributed to a high LAVI in all patients. In addition, LV mass index and hemoglobin concentration independently contributed to a high LAVI in both genders despite the absence of overt LV hypertrophy or anemia., Conclusion: Increased LV wall thickness and decreased hemoglobin concentration might contribute to LA enlargement in patients with normal LV systolic function irrespective of gender., (Copyright 2009 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Introduction: The efficacy of high-dose (1250 mg/d) gefitinib for the treatment of leptomeningeal metastasis in a patient with lung cancer harboring a mutation in the epidermal growth factor receptor (EGFR) gene was previously reported. We speculate that erlotinib, instead of high dose of gefitinib, may be also effective for the treatment of central nervous system (CNS) lesions, as trough serum concentration of erlotinib is nine times higher than that of gefitinib., Patients and Methods: Patients with lung cancer in whom CNS lesions developed after an initial good response to gefitinib for extra CNS lesions were enrolled in the study. Tumor response, performance status, neurologic symptoms, and survival were retrospectively evaluated., Results: All seven patients had EGFR mutations in their primary tumors except one patient. The median interval between gefitinib withdrawal and erlotinib administration was 5 days. Three patients showed partial response, three had stable disease, and one had progressive disease. Performance status and symptoms improved in five patients. The overall survival from the initiation of erlotinib treatment ranged from 15 to 530 days (median, 88 days)., Conclusions: Erlotinib was a reasonable option for the treatment of CNS diseases that appeared after a good initial response of extra CNS disease to gefitinib.

A number of reports have provided genetic evidence for an association between the DTNBP1 gene (coding dysbindin) and schizophrenia. In addition, sandy mice, which harbor a deletion in the DTNBP1 gene and lack dysbindin, display behavioral abnormalities suggestive of an association with schizophrenia. However, the mechanism by which the loss of dysbindin induces schizophrenia-like behaviors remains unclear. Here, we report that small interfering RNA-mediated knockdown of dysbindin resulted in the aberrant organization of actin cytoskeleton in SH-SY5Y cells. Furthermore, we show that morphological abnormalities of the actin cytoskeleton were similarly observed in growth cones of cultured hippocampal neurons derived from sandy mice. Moreover, we report a significant correlation between dysbindin expression level and the phosphorylation level of c-Jun N-terminal kinase (JNK), which is implicated in the regulation of cytoskeletal organization. These findings suggest that dysbindin plays a key role in coordinating JNK signaling and actin cytoskeleton required for neural development.

Disrupted-In-Schizophrenia 1 (DISC1) was identified as a novel gene disrupted by a (1;11)(q42.1;q14.3) translocation segregating with schizophrenia, bipolar disorder and other major mental illnesses in a Scottish family. We previously identified 446-533 amino acids of DISC1 as the kendrin-binding region by means of a directed yeast two-hybrid interaction assay and showed that the DISC1-kendrin interaction is indispensable for the centrosomal localization of DISC1. In this study, to confirm the DISC1-kendrin interaction, we examined the interaction between deletion mutants of DISC1 and kendrin. Then, we demonstrated that the carboxy-terminus of DISC1 is indispensable for the interaction with kendrin. Furthermore, the immunocytochemistry revealed that the carboxy-terminus of DISC1 is also required for the centrosomal targeting of DISC1. Overexpression of the DISC1-binding region of kendrin or the DISC1 deletion mutant lacking the kendrin-binding region impairs the microtubule organization. These findings suggest that the DISC1-kendrin interaction plays a key role in the microtubule dynamics.

Gastrin and ghrelin are secreted from G cells and X/A-like cells in the stomach, respectively, and respective hormones stimulate gastric acid secretion by acting through histamine and the vagus nerve. In this study, we examined the relationship between gastrin, ghrelin and gastric acid secretion in rats. Intravenous (iv) administration of 3 and 10 nmol of gastrin induced transient increases of ghrelin levels within 10 min in a dose-dependent manner. Double immunostaining for ghrelin and gastrin receptor revealed that a proportion of ghrelin cells possess gastrin receptors. Although (iv) administration of gastrin or ghrelin induced significant gastric acid secretion, simultaneous treatment with both hormones resulted in a synergistic, rather than additive, increase of gastric acid secretion. This synergistic increase was not observed in vagotomized rats. These results suggest that gastrin may directly stimulate ghrelin release from the stomach, and that both hormones may increase gastric acid secretion synergistically.

Inhalation of hydrogen (H(2)) gas has been demonstrated to limit the infarct volume of brain and liver by reducing ischemia-reperfusion injury in rodents. When translated into clinical practice, this therapy must be most frequently applied in the treatment of patients with acute myocardial infarction, since angioplastic recanalization of infarct-related occluded coronary artery is routinely performed. Therefore, we investigate whether H(2) gas confers cardioprotection against ischemia-reperfusion injury in rats. In isolated perfused hearts, H(2) gas enhances the recovery of left ventricular function following anoxia-reoxygenation. Inhaled H(2) gas is rapidly transported and can reach 'at risk' ischemic myocardium before coronary blood flow of the occluded infarct-related artery is reestablished. Inhalation of H(2) gas at incombustible levels during ischemia and reperfusion reduces infarct size without altering hemodynamic parameters, thereby preventing deleterious left ventricular remodeling. Thus, inhalation of H(2) gas is promising strategy to alleviate ischemia-reperfusion injury coincident with recanalization of coronary artery.

Background: DISC1 has been suggested as a causative gene for psychoses in a large Scottish kindred. PCNT2 has recently been identified as an interacting partner of DISC1. In this study, we investigated the role of PCNT2 in bipolar disorder, by gene expression analysis and genetic association study., Methods: By TaqMan real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), we examined the messenger RNA (mRNA) levels of PCNT2 in the postmortem prefrontal cortex of bipolar disorder (n = 34), schizophrenia (n = 31), and control subjects (n = 32), obtained from Stanley Array Collection. We also compared the mRNA levels of PCNT2 in the peripheral blood lymphocytes of bipolar disorder (n = 21), schizophrenia (n = 21), depression (n = 33), and control subjects (n = 57). For the association study, 23 single nucleotide polymorphisms (SNPs) were analyzed in 285 bipolar disorder patients and 287 age-and gender-matched control subjects, all of Japanese origin. The genotypes were determined by TaqMan assay., Results: Significantly higher expression of PCNT2 was observed in the brain samples of bipolar group, compared with the control (p = .001) and schizophrenia (p = .018) groups. In the peripheral blood lymphocytes also, a significantly higher expression of PCNT2 was observed in the bipolar group, compared with the control subjects (p = .043). However, none of the SNPs analyzed in our study showed a significant association with bipolar disorder; a weak tendency toward association was observed for two intronic SNPs., Conclusions: Our findings suggest that elevated levels of PCNT2 might be implicated in the pathophysiology of bipolar disorder.

CLP36 belongs to the ALP subfamily of PDZ-LIM proteins and has a PDZ domain at its N-terminal and a LIM domain at its C-terminal. It has been shown that CLP36 is localized to stress fibers through interaction with alpha-actinin, but its function is still unclear. To investigate the role of CLP36 in stress fibers, we suppressed CLP36 expression in BeWo cells by RNAi and examined the phenotypic changes. CLP36-knockdown resulted in cell spreading and the loss of stress fibers and focal adhesions. These changes were reversed by addition of exogenous CLP36, but not by addition of mutant forms of CLP36 that lacked the PDZ or LIM domain. These findings indicate that CLP36 plays a critical role in stress fiber formation and the assembly of focal adhesions in BeWo cells. In addition, the PDZ and LIM domains are both essential for CLP36 to function.

Objective: To study the modulation of somatosensory evoked potentials (SEP) using transcranial magnetic intermittent theta burst stimulation (iTBS) over human primary motor (M1) and sensory (S1) cortices., Methods: Eleven healthy subjects participated in the study. Median nerve SEP were elicited by electrical stimulation at the right wrist before and after 600-pulse iTBS over M1 or S1 of the left hemispheres at the intensity of 80% active motor threshold., Results: iTBS over S1 facilitated the N20o-N20p, N20p-P25 and P25-N33 amplitudes significantly and the maximal effect appeared 15 min after the stimulation. The facilitating effect was observed when the initial phase of the current in the brain was directed antero-medially, whereas the facilitation did not appear when the inverted coil direction was applied. On the other hand, no changes were observed after iTBS over M1. The latencies of the measured onsets and peaks were not affected through the experiments., Conclusions: iTBS over S1 has the facilitating effect on the central somatosensory pathway, and the position and direction of the coil are the determinant factors of the effects., Significance: iTBS can be useful technique to induce synaptic plasticity in human central somatosensory pathway.