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Background: In carpal tunnel syndrome (CTS), pain and sensory disturbance are the main symptoms, but thumb palmar abduction (TPA) paralysis cannot be ignored as a concurrent symptom. The reliable quantitative measurement of TPA power was not established. The purpose of this study was to report on the reliability of TPA strength measurements by the hand-held dynamometry (HHD) in large samples of CTS and its superiority over other tests, including grip, pinch powers, TPA angles and manual muscle testing, in terms of clinical progress indicators. Methods: We examined the relative and absolute reliabilities of the perioperative TPA strength measured by HHD (HHD-TPA) in 566 participants with CTS and the correlation coefficient between the HHD-TPA and other clinical tests. Results: The reliability of the HHD-TPA was intraclass correlation coefficients: 97% or higher. The Bland-Altman absolute reliability showed a random pattern of bias, and the minimal detectable changes (MDC) of the inter-rater and intra-rater reliabilities indicated 9.0 N and 7.0 N individually. The HHD-TPA showed statistically significant recoveries between perioperative stages; however, the mean difference larger than the MDC was recognised only between the preoperative and 12-month postoperative stages by intra-rater comparison. More individual patients showed recovery of HHD-TPA beyond the MDC when the same examiner continuously measured HHD-TPA than when multiple examiners continuously measured HHD-TPA. Grip strength and pinch strength measurements showed a strong correlation with HHD-TPA and did not show statistically significant improvement during the perioperative period. Conclusions: HHD-TPA is the most reliable method for quantifying muscle strength in the perioperative course of TPA force in CTS. HHD-TPA is a more reliable assessment of CTS motor recovery when measured consistently for each patient by the same hand therapist. Level of Evidence: Level IV (Diagnostic).

Taste receptor type 1 (T1r) proteins are responsible for recognizing nutrient chemicals in foods. In humans, T1r2/T1r3 and T1r1/T1r3 heterodimers serve as the sweet and umami receptors that recognize sugars or amino acids and nucleotides, respectively. T1rs are conserved among vertebrates, and T1r2a/T1r3 from medaka fish is currently the only member for which the structure of the ligand-binding domain (LBD) has been solved. T1r2a/T1r3 is an amino acid receptor that recognizes various l-amino acids in its LBD as observed with other T1rs exhibiting broad substrate specificities. Nevertheless, the range of chemicals that are recognized by T1r2a/T1r3LBD has not been extensively explored. In the present study, the binding of various chemicals to medaka T1r2a/T1r3LBD was analyzed. A binding assay for amino acid derivatives verified the specificity of this protein to l-α-amino acids and the importance of α-amino and carboxy groups for receptor recognition. The results further indicated the significance of the α-hydrogen for recognition as replacing it with a methyl group resulted in a substantially decreased affinity. The binding ability to the protein was not limited to proteinogenic amino acids, but also to non-proteinogenic amino acids, such as metabolic intermediates. Besides l-α-amino acids, no other chemicals showed significant binding to the protein. These results indicate that all of the common structural groups of α-amino acids and their geometry in the l-configuration are recognized by the protein, whereas a wide variety of α-substituents can be accommodated in the ligand binding sites of the LBDs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ishida et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: A simple ambulatory measure of cardiac function could be helpful for monitoring heart failure patients., Objectives: The purpose of this paper was to determine whether a novel pulse waveform analysis using data obtained by our developed multisensor-ambulatory blood pressure monitoring (ABPM) device, the 'Sf/Am' ratio, is associated with echocardiographic left ventricular ejection fraction (LVEF)., Methods: Multisensor-ABPM was conducted twice at baseline in 20 heart failure (HF) patients with HF-reduced LVEF or HF-preserved LVEF (median age 66 years, male 65%) and over a 6- to 12-month follow-up after patient-tailored treatment. We assessed the changes in the pulse waveform index Sf/Am and LVEF that occurred between the baseline and follow-up. The Sf/Am consists of the area of the ejection part in the square forward wave (Sf) and the amplitude of the measured wave (Am). We divided the patients into the recovered (n = 11) and not-recovered (n = 9) groups defined by a ≥10% increase in LVEF., Results: Although the ambulatory BP levels and variabilities did not change in either group, the Sf/Am increased significantly in the recovered group (baseline 21.4 ± 4.5; follow-up, 25.6 ± 3.7, P  = 0.004). The not-recovered group showed no difference between the baseline and follow-up. The follow-up/baseline Sf/Am ratio was significantly associated with the LVEF ratio ( r  = 0.469, P  = 0.037). The Sf/Am was significantly correlated with the LVEF in overall measurements (n = 40, r  = 0.491, P  = 0.001)., Conclusions: These results demonstrated that a novel noninvasive pulse waveform index, the Sf/Am measured by multisensor-ABPM is associated with LVEF. The Sf/Am may be useful for estimating cardiac function., Competing Interests: This study was financially supported in part by A&D Co and by grants from the 10.13039/501100001691Japan Society for the Promotion of Science (JSPS) KAKENHI, nos. JP21K20910 and JP22K16114. Dr Kario has received research funding from Omron Healthcare Co, Fukuda Denshi, and A&D Co. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Single-chain monellin (SCM) is an engineered protein that links the two chains of monellin, a naturally sweet-tasting protein. This protein is an attractive candidate for use as a sugar replacement in food and beverages and has numerous other applications. Therefore, generating SCM mutants with improved stability is an active area of research to broaden the range of its potential applications. In this study, we focused on the Cys41 residue of SCM, which is a single cysteine residue present at a structurally important position. This residue is often substituted with Ser. However, this substitution may destabilize SCM because Cys41 is buried in the hydrophobic core of the protein. Therefore, we designed mutants that substituted Ala, Val, and Leu for this residue, namely C41A, C41V, and C41L. We characterized these three mutants, SCM C41S, and wild type (WT). Differential scanning fluorimetric analysis revealed that substituting Cys41 with Ala or Val increased the thermal stability of SCM, while substitution with Ser or Leu decreased its stability. Determination of the crystal structures of SCM C41A and C41V mutants revealed that the overall structures and main chain structures around the 41st residue of both mutants were almost identical to the WT. On the other hand, the orientations of the amino acid side chains near the 41st residue differed among the SCM variants. Taken together, our results indicate that substituting Cys41 with Ala or Val increases the stability of SCM and provide insight into the structural basis of this improvement., (© 2023. The Author(s).)

Sweet and umami taste receptors recognize chemicals such as sugars and amino acids on their extracellular side and transmit signals into the cytosol of the taste cell. In contrast to ligands that act on the extracellular side of these receptors, little is known regarding the molecules that regulate receptor functions within the cytosol. In this study, we analysed the interaction between sweet and umami taste receptors and calmodulin, a representative Ca2+-dependent cytosolic regulatory protein. High prediction scores for calmodulin binding were observed on the C-terminal cytosolic side of mouse taste receptor type 1 subunit 3 (T1r3), a subunit that is common to both sweet and umami taste receptors. Pull-down assay and surface plasmon resonance analyses showed different affinities of calmodulin to the C-terminal tails of distinct T1r subtypes. Furthermore, we found that T1r3 and T1r2 showed the highest and considerable binding to calmodulin, whereas T1r1 showed weaker binding affinity. Finally, the binding of calmodulin to T1rs was consistently higher in the presence of Ca2+ than in its absence. The results suggested a possibility of the Ca2+-dependent feedback regulation process of sweet and umami taste receptor signaling by calmodulin., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Japanese Biochemical Society.)

Salt taste sensation is multifaceted: NaCl at low or high concentrations is preferably or aversively perceived through distinct pathways. Cl - is thought to participate in taste sensation through an unknown mechanism. Here, we describe Cl - ion binding and the response of taste receptor type 1 (T1r), a receptor family composing sweet/umami receptors. The T1r2a/T1r3 heterodimer from the medaka fish, currently the sole T1r amenable to structural analyses, exhibited a specific Cl - binding in the vicinity of the amino-acid-binding site in the ligand-binding domain (LBD) of T1r3, which is likely conserved across species, including human T1r3. The Cl - binding induced a conformational change in T1r2a/T1r3LBD at sub- to low-mM concentrations, similar to canonical taste substances. Furthermore, oral Cl - application to mice increased impulse frequencies of taste nerves connected to T1r-expressing taste cells and promoted their behavioral preferences attenuated by a T1r-specific blocker or T1r3 knock-out. These results suggest that the Cl - evokes taste sensations by binding to T1r, thereby serving as another preferred salt taste pathway at a low concentration., Competing Interests: NA, KY, YT, CI, NY, RM, AY No competing interests declared, (© 2023, Atsumi, Yasumatsu et al.)

Chondromodulin (Cnmd) is a glycoprotein known to stimulate chondrocyte growth. We examined in this study the expression and functional role of Cnmd during distraction osteogenesis that is modulated by mechanical forces. The right tibiae of the mice were separated by osteotomy and subjected to slow progressive distraction using an external fixator. In situ hybridization and immunohistochemical analyses of the lengthened segment revealed that Cnmd mRNA and its protein in wild-type mice were localized in the cartilage callus, which was initially generated in the lag phase and was lengthened gradually during the distraction phase. In Cnmd null (Cnmd-/-) mice, less cartilage callus was observed, and the distraction gap was filled by fibrous tissues. Additionally, radiological and histological investigations demonstrated delayed bone consolidation and remodeling of the lengthened segment in Cnmd-/- mice. Eventually, Cnmd deficiency caused a one-week delay in the peak expression of VEGF, MMP2, and MMP9 genes and the subsequent angiogenesis and osteoclastogenesis. We conclude that Cnmd is necessary for cartilage callus distraction., Competing Interests: The authors have that no competing interests exist., (Copyright: © 2023 Yukata et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

DNA methyltransferases (DNMTs) catalyze methylation at the C5 position of cytosine with S-adenosyl-L-methionine. Methylation regulates gene expression, serving a variety of physiological and pathophysiological roles. The chemical mechanisms regulating DNMT enzymatic activity, however, are not fully elucidated. Here, we show that protein S-nitrosylation of a cysteine residue in DNMT3B attenuates DNMT3B enzymatic activity and consequent aberrant upregulation of gene expression. These genes include Cyclin D2 (Ccnd2), which is required for neoplastic cell proliferation in some tumor types. In cell-based and in vivo cancer models, only DNMT3B enzymatic activity, and not DNMT1 or DNMT3A, affects Ccnd2 expression. Using structure-based virtual screening, we discovered chemical compounds that specifically inhibit S-nitrosylation without directly affecting DNMT3B enzymatic activity. The lead compound, designated DBIC, inhibits S-nitrosylation of DNMT3B at low concentrations (IC 50  ≤ 100 nM). Treatment with DBIC prevents nitric oxide (NO)-induced conversion of human colonic adenoma to adenocarcinoma in vitro. Additionally, in vivo treatment with DBIC strongly attenuates tumor development in a mouse model of carcinogenesis triggered by inflammation-induced generation of NO. Our results demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by NO, and DBIC protects against tumor formation by preventing aberrant S-nitrosylation of DNMT3B., (© 2023. The Author(s).)

An accelerating aging society and rise in serious illnesses has led to an increase in deaths and made the demand for palliative care even greater. An integrated review was conducted to identify the impact of interprofessional education (IPE) on palliative/end of life (EOL) care for unlicensed health care students with a multidisciplinary approach. The databases searched included MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Education Resources Information Center (ERIC), PsycINFO, and the Cochrane Library's CENTRAL. Fifteen studies were included. Participants' disciplines included medicine, nursing, pharmacy, physical therapy, occupational therapy, social work, chaplain, public health and psychology. Nine were pre-post design and others were post course evaluations. One research study was an interventional trial with a comparative group. The selected studies included a variety of teaching strategies such as simulation or role play, clinical experience, case study, and TOSCE training. The importance of an interprofessional approach to palliative/EOL care has been highlighted, and our review suggests that combined IPE and palliative/EOL interventions can potentially impact palliative/EOL patient outcomes. More studies are needed to clarify the effectiveness of interprofessional palliative/EOL educational interventions including facilitators, learning outcomes, variable methods or teaching strategy, and the level of students.

We evaluated the accuracy of a 24-hr ambulatory blood pressure monitoring (ABPM) device with a new irregular heartbeat (IHB) algorithm for detecting atrial fibrillation (AF) during each BP measurement. Ninety patients with a history of elevated BP and some type of arrhythmia (mean age 63.2 ± 10.3 years; 94% with hypertension; 81% with previously diagnosed AF) simultaneously underwent evaluation by 24-hr ABPM with the IHB algorithm and 24-hr Holter electrocardiography (ECG). Among the 3,347 valid readings, 843 readings were considered to indicate an IHB. Among these IHB readings, 195 readings were found to have an AF rhythm by 24-hr Holter ECG. The IHB algorithm showed 100% sensitivity and 79.4% specificity for accurately detecting AF rhythm. An IHB was detected in 12.1% of the measurements during normal rhythm, 48.8% of those during atrial premature complex, and 54.4% of those during ventricular premature complex. The percentage of IHBs detected during normal rhythm was higher in the daytime than at nighttime (16.3% vs. 4.5%, respectively), suggesting that daytime physical activity sometimes induces a false detection of IHBs. The optimal IHB parameters for suggesting potential AF were (1) an IHB burden defined as a percentage of IHB-positive readings in total valid BP measurements >22.5% (84.6% sensitivity, 85.1% specificity; AUC 0.906, p < 0.0001) and (2) 2.5 or more consecutive IHBs during 24-hr ABPM (84.6% sensitivity, 83.0% specificity; AUC 0.881, p < 0.0001). The novel 24-hr ABPM device with the IHB algorithm assessed herein could contribute to the future comprehensive management of hypertensive patients, with the main goal of preventing cerebrovascular events., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: Radiofrequency ablation (RFA) is an effective treatment for early-stage hepatocellular carcinoma (HCC). Although RFA is a relatively safe technique compared with surgery, several complications have been reported to be following/accompanying this treatment. Delayed diaphragmatic hernia caused by RFA is rare; however, the best surgical approach for its treatment is uncertain. We present a case of laparoscopic repair of diaphragmatic hernia due to RFA., Case Summary: An 80-year-old woman with segment VIII HCC was treated twice in 5 years with RFA; 28 mo after the second RFA, the patient complained of right hypochondriac pain. Computed tomography revealed that the small intestine was incarcerated in the right thorax. The patient was diagnosed with diaphragmatic hernia and underwent laparoscopic repair by non-absorbable running sutures. The patient's postoperative course was favorable, and the patient was discharged on postoperative day 12. The diaphragmatic hernia has not recurred 24 mo after surgery., Conclusion: Laparoscopic treatment of iatrogenic diaphragmatic hernia is effective and minimally invasive., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Non-polyadenylated mRNAs of replication-dependent histones (RDHs) are synthesized by RNA polymerase II (Pol II) at histone locus bodies (HLBs). HLBs frequently associate with Cajal bodies (CBs), in which 3'-end processing factors for RDH genes are enriched; however, this association's role in transcription termination of RDH genes remains unclear. Here, we show that Pol II pauses immediately upstream of transcript end sites of RDH genes and Mediator plays a role in this Pol II pausing through CBs' association with HLBs. Disruption of the Mediator docking site for Little elongation complex (LEC)-Cap binding complex (CBC)-Negative elongation factor (NELF), components of CBs, interferes with CBs' association with HLBs and 3' Pol II pausing, resulting in increased aberrant unprocessed RDH gene transcripts. Our findings suggest Mediator's involvement in CBs' association with HLBs to facilitate 3' Pol II pausing and subsequent 3'-end processing of RDH genes by supplying 3'-end processing factors., (© 2022. The Author(s).)

Achondroplasia, the most common skeletal dysplasia, is characterized by a variety of medical, functional and psychosocial challenges across the lifespan. The condition is caused by a common, recurring, gain-of-function mutation in FGFR3, the gene that encodes fibroblast growth factor receptor 3. This mutation leads to impaired endochondral ossification of the human skeleton. The clinical and radiographic hallmarks of achondroplasia make accurate diagnosis possible in most patients. However, marked variability exists in the clinical care pathways and protocols practised by clinicians who manage children and adults with this condition. A group of 55 international experts from 16 countries and 5 continents have developed consensus statements and recommendations that aim to capture the key challenges and optimal management of achondroplasia across each major life stage and sub-specialty area, using a modified Delphi process. The primary purpose of this first International Consensus Statement is to facilitate the improvement and standardization of care for children and adults with achondroplasia worldwide in order to optimize their clinical outcomes and quality of life., (© 2021. Springer Nature Limited.)

Purpose: Achondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported., Methods: After completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 μg/kg/day., Results: In children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected., Conclusion: Vosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years., (© 2021. The Author(s).)

Somatic mutations in mitochondrial DNA may provide a new avenue for cancer therapy due to their associations to a number of cancers and a tendency of homoplasmicity. In consideration of mitochondrial features and its relatively small genome size, a nucleotide-based targeting approach is a considerably more promising option. To explore the efficacy of short linear N-methylpyrrole-N-methylimidazole polyamide (PI polyamide), we synthesized a five-ring short PI polyamide that provided sequence-specific homing for the A3243G mitochondrial mutation upon conjugation with triphenylphosphonium cation (TPP). This PI polyamide-TPP was able to induce cytotoxicity in HeLamtA3243G cybrid cells, while preserving preferential binding for oligonucleotides containing the A3243G motif from melting temperature assays. The PI polyamide-TPP also localized in the mitochondria in HeLamtA3243G cells and induced mitochondrial reactive oxygen species production, mitophagy and apoptosis in a mutation-specific fashion compared to the wild-type HeLamtHeLa cybrids; normal human dermal fibroblasts were also relatively unaffected to suggest discriminating selectivity for the mutant mitochondria, offering a novel outlook for cancer therapy via mitochondrial homing of short linear PIP-TPPs., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Distraction osteogenesis is a widely used surgical technique to treat bone deformity and shortening. Several biological treatments have been studied to enhance bone formation during distraction osteogenesis in animals. However, role of osteoactivin in the osseous tissues during distraction osteogenesis remains poorly understood. In this animal experimental study, we investigated the spatiotemporal expression of osteoactivin by immunohistochemistry and real-time PCR using a mouse model for tibial lengthening. Furthermore, to address the role of osteoactivin in bone lengthening, we subjected the osteoactivin-transgenic mice to distraction osteogenesis model. During the lag phase, the fibroblast-like cells (possible progenitors of the osteoblasts or chondrocytes), which mainly express osteoactivin, were infiltrated into the osteotomy site. Osteoactivin was ubiquitously expressed in the lengthened segment during the distraction and consolidation phases. Consistent with the immunohistochemical analysis, the levels of the osteoactivin transcripts in the tibias were significantly increased throughout the distraction osteogenesis process. The bone mineral content in the osteoactivin-transgenic mice calculated using peripheral quantitative computed tomography was also significantly increased at the remodeling zone. The histomorphometric analysis revealed that newly formed callus resorption in the remodeling zone was significantly reduced but bone formation was not altered in the osteoactivin-transgenic mice. We conclude that osteoactivin functions as an inhibitor of callus resorption during the consolidation phase of distraction osteogenesis., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Synthetic binding proteins that have the ability to bind with molecules can be generated using various protein domains as non-antibody scaffolds. These designer proteins have been used widely in research studies, as their properties overcome the disadvantages of using antibodies. Here, we describe the first application of a phage display to generate synthetic binding proteins using a sweet protein, monellin, as a non-antibody scaffold. Single-chain monellin (scMonellin), in which two polypeptide chains of natural monellin are connected by a short linker, has two loops on one side of the molecule. We constructed phage display libraries of scMonellin, in which the amino acid sequence of the two loops is diversified. To validate the performance of these libraries, we sorted them against the folding mutant of the green fluorescent protein variant (GFPuv) and yeast small ubiquitin-related modifier. We successfully obtained scMonellin variants exhibiting moderate but significant affinities for these target proteins. Crystal structures of one of the GFPuv-binding variants in complex with GFPuv revealed that the two diversified loops were involved in target recognition. scMonellin, therefore, represents a promising non-antibody scaffold in the design and generation of synthetic binding proteins. We termed the scMonellin-derived synthetic binding proteins 'SWEEPins'., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

The large, secreted glycoprotein reelin regulates embryonic brain development as well as adult brain functions. Although reelin binds to its receptors via its central part, the N-terminal region directs multimer formation and is critical for efficient signal transduction. In fact, the inhibitory antibody CR-50 interacts with the N-terminal region and prevents higher-order multimerization and signalling. Reelin is a multidomain protein in which the central part is composed of eight characteristic repeats, named reelin repeats, each of which is further divided by insertion of a epidermal growth factor (EGF) module into two subrepeats. In contrast, the N-terminal region shows unique 'irregular' domain architecture since it comprises three consecutive subrepeats without the intervening EGF module. Here, we determined the crystal structure of the murine reelin fragment named RX-R1 including the irregular region and the first reelin repeat at 2.0-Å resolution. The overall structure of RX-R1 has a branched Y-shaped form. Interestingly, two incomplete subrepeats cooperatively form one entire subrepeat structure, though an additional subrepeat is inserted between them. We further reveal that Arg335 of RX-R1 is crucial for binding CR-50. A possible self-association mechanism via the N-terminal region is proposed based on our results., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Mitochondrial DNA (mtDNA) mutations occur frequently in cancer cells, and some of them are often homoplasmic. Targeting such mtDNA mutations could be a new method for killing cancer cells with minimal impact on normal cells. Pyrrole-imidazole polyamides (PIPs) are cell-permeable minor groove binders that show sequence-specific binding to double-stranded DNA and inhibit the transcription of target genes. PIP conjugated with the lipophilic triphenylphosphonium (TPP) cation can be delivered to mitochondria without uptake into the nucleus. Here, we investigated the feasibility of the use of PIP-TPP to target a mtDNA mutation in order to kill cancer cells that harbor the mutation. We synthesized hairpin-type PIP-TPP targeting the A3243G mutation and examined its effects on the survival of HeLa cybrid cells with or without the mutation (HeLamtA3243G cells or HeLamtHeLa cells, respectively). A surface plasmon resonance assay demonstrated that PIP-TPP showed approximately 60-fold higher binding affinity for the mutant G-containing synthetic double-stranded DNA than for the wild-type A-containing DNA. When added to cells, it localized in mitochondria and induced mitochondrial reactive oxygen species production, extensive mitophagy, and apoptosis in HeLamtA3243G cells, while only slightly exerting these effects in HeLamtHeLa cells. These results suggest that PIP-TPPs targeting mtDNA mutations could be potential chemotherapeutic drugs to treat cancers without severe adverse effects., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The authors evaluated the diagnostic accuracy of a new algorithm for detecting atrial fibrillation (AF) using a home blood pressure (BP) monitor. Three serial BP values were measured in 205 subjects with sinus rhythm and 75 subjects with AF confirmed by electrocardiogram. Irregular pulse peak (IPP) 15 was defined as follows: |interval of pulse peak - the average of the interval of the pulse peak| ≥ the average of the interval of the pulse peak × 15%. Irregular heartbeat (IHB) was defined as follows: beats of IPP ≥ total pulse × 20%. The sensitivities of IPP15 for diagnosing AF defined as two or three IHBs of three readings were 1.0 and 0.99, and the corresponding specificities were 0.97 and 0.99, respectively. The algorithm using two or more IHBs of three readings in the setting of IPP15 had the highest diagnostic accuracy for AF., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings., Methods: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 μg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11., Findings: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred., Interpretation: Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be., Funding: BioMarin Pharmaceutical., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: The specific morphology and differences between patients with cervical spondylotic myelopathy (CSM) and those with normal spines remain unclear. This study aimed to evaluate and determine the features of cervical spine morphology on reconstructive CT., Methods: We investigated that axial reconstructive CT scans of the cervical spine at C3 to C7 were obtained from 309 individuals (97 CSM patients and 212 controls). Those of the optimal pedicle diameter were selected, and the following parameters were measured: (a) sagittal diameter of the spinal canal (b) transverse diameter of the spinal canal, (c) pedicle width, (d) lateral mass thickness, (e) transverse diameter of the foramen, (f) sagittal diameter of the vertebral body, and (g) transverse diameter of the vertebral body. The following ratios were calculated using these values: the sagittal-transverse ratio and the canal-body ratio., Results: Most parameters differed significantly between the sexes in both groups. The parameters without the mean sagittal diameter of the spinal canal were significantly larger in men than in women. However, the mean sagittal diameter of the spinal canal did not differ significantly between the sexes in CSM patients. The sagittal-transverse ratio and canal-body ratio were significantly smaller in the CSM patients at all levels. According to relative operating characteristic curves of the sagittal diameter of the spinal canal, sagittal-transverse ratio, and canal-body ratio, the sensitivity from C3 to C7 in both sexes was > 60% at the threshold. In men, the specificity from C3 to C7 was also >60% at the threshold., Conclusions: The morphometry of the sagittal diameter of the spinal canal, sagittal-transverse ratio, and canal-body ratio on axial reconstructive CT images appears useful for distinguishing cervical spinal canal stenosis involving myelopathy., Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest., (Copyright © 2021 by The Japanese Society for Spine Surgery and Related Research.)

Advances in modern genomics have allowed researchers to apply phylogenetic analyses on a genome-wide scale. While large volumes of genomic data can be generated cheaply and quickly, data missingness is a non-trivial and somewhat expected problem. Since the available information is often incomplete for a given set of genetic loci and individual organisms, a large proportion of trees that depict the evolutionary history of a single genetic locus, called gene trees, fail to contain all individuals. Data incompleteness causes difficulties in data collection, information extraction, and gene tree inference. Furthermore, identifying outlying gene trees, which can represent horizontal gene transfers, gene duplications, or hybridizations, is difficult when data is missing from the gene trees. The typical approach is to remove all individuals with missing data from the gene trees, and focus the analysis on individuals whose information is fully available - a huge loss of information. In this work, we propose and design an optimization-based imputation approach to infer the missing distances between leaves in a set of gene trees via a mixed integer non-linear programming model. We also present a new research pipeline, imPhy, that can (i) simulate a set of gene trees with leaves randomly missing in each tree, (ii) impute the missing pairwise distances in each gene tree, (iii) reconstruct the gene trees using the Neighbor Joining (NJ) and Unweighted Pair Group Method with Arithmetic Mean (UPGMA) methods, and (iv) analyze and report the efficiency of the reconstruction. To impute the missing leaves, we employ our newly proposed non-linear programming framework, and demonstrate its capability in reconstructing gene trees with incomplete information in both simulated and empirical datasets. In the empirical datasets apicomplexa and lungfish, our imputation has very small normalized mean square errors, even in the extreme case where 50 percent of the individuals in each gene tree are missing. Data, software, and user manuals can be found at https://github.com/yasuiniko/imPhy.

BACKGROUND The diagnosis of early non-convulsant status epilepticus (NCSE) can be challenging and can overlap with other critical conditions. Two patients with Alzheimer's disease are reported with clinically suspected NCSE presenting in the emergency setting who were diagnosed using arterial spin-labeling magnetic resonance imaging (ASL-MRI) sequences. CASE REPORT In Case 1, a 69-year-old woman with mild Alzheimer's disease and diabetes presented with acute worsening of cognitive status and fluctuating level of consciousness. In Case 2, a 70-year-old man with mild cognitive impairment due to Alzheimer's disease and hypertension presented with acute loss of consciousness and left hemiparesis, without evidence of hypoglycemia or a hypertensive crisis. In both cases, ASL-MRI perfusion images showed focal cerebral hyperperfusion in the posterior cingulate and parietal associative cortex, which involved neurodegenerative areas associated with epilepsy in early Alzheimer's disease. In both cases, the patients developed generalized tonic-clonic epileptic seizures that lasted for 5 minutes or more, which indicated the emergence of status epilepticus that developed from the initial presentation of NCSE. In both cases, electroencephalogram (EEG) findings confirmed that the seizures were controlled by intravenous administration of antiepileptic drugs. Both patients discharged home from the hospital without recurrence of seizures, between 10-12 days after the onset of symptoms. CONCLUSIONS These two cases have demonstrated that ASL-MRI is feasible as an emergency diagnostic tool in clinically suspected NCSE in patients with Alzheimer's disease.

Taste receptor type 1 (T1r) is responsible for the perception of essential nutrients, such as sugars and amino acids, and evoking sweet and umami (savory) taste sensations. T1r receptors recognize many of the taste substances at their extracellular ligand-binding domains (LBDs). In order to detect a wide array of taste substances in the environment, T1r receptors often possess broad ligand specificities. However, the entire ranges of chemical spaces and their binding characteristics to any T1rLBDs have not been extensively analyzed. In this study, we exploited the differential scanning fluorimetry (DSF) to medaka T1r2a/T1r3LBD, a current sole T1rLBD heterodimer amenable for recombinant preparation, and analyzed their thermal stabilization by adding various amino acids. The assay showed that the agonist amino acids induced thermal stabilization and shifted the melting temperatures (Tm) of the protein. An agreement between the DSF results and the previous biophysical assay was observed, suggesting that DSF can detect ligand binding at the orthosteric-binding site in T1r2a/T1r3LBD. The assay further demonstrated that most of the tested l-amino acids, but no d-amino acid, induced Tm shifts of T1r2a/T1r3LBD, indicating the broad l-amino acid specificities of the proteins probably with several different manners of recognition. The Tm shifts by each amino acid also showed a fair correlation with the responses exhibited by the full-length receptor, verifying the broad amino-acid binding profiles at the orthosteric site in LBD observed by DSF., Competing Interests: The authors have declared that no competing interests exist.

Background: Fluid therapy guided by cardiac output measurements is of particular importance for adequate cerebral perfusion and oxygenation in neurosurgical patients. We examined the usefulness of a noninvasive electrical velocimetry (EV) device based on the thoracic bioimpedance method for perioperative hemodynamic monitoring in patients after aneurysmal subarachnoid hemorrhage., Patients and Methods: In total, 18 patients who underwent surgical clipping or endovascular coiling for ruptured aneurysms were examined prospectively. Simultaneous cardiac index (CI) measurements obtained with EV (CIEV) and reference transpulmonary thermodilution (CITPTD) were compared. A total of 223 pairs of data were collected., Results: A significant correlation was found between CIEV and CITPTD (r=0.86; P<0.001). Bland and Altman analysis revealed a bias between CIEV and CITPTD of -0.06 L/min/m, with limits of agreement of ±1.14 L/min/m and a percentage error of 33%. Although the percentage error for overall data was higher than the acceptable limit of 30%, subgroup analysis during the postoperative phase showed better agreement (23% vs. 42% during the intraprocedure phase). Four-quadrant plot and polar plot analyses showed fair-to-poor trending abilities (concordance rate of 90% to 91%, angular bias of +17 degrees, radial limits of agreement between ±37 and ±40 degrees, and polar concordance rate of 72% to 75%), including the subgroup analysis., Conclusions: Absolute CI values obtained from EV and TPTD are not interchangeable with TPTD for perioperative use in subarachnoid hemorrhage patients. However, considering the moderate levels of agreement with marginal trending ability during the early postoperative phase, this user-friendly device can provide an attractive monitoring option during neurocritical care.

We evaluated the diagnostic value of atrial fibrillation (AF) measured by a wrist-type pulse wave monitor in this case-control study. Six serial pulse wave values (three in the left and three in the right wrist) were measured using a wrist-type monitor in 29 AF patients and 30 subjects with sinus rhythm. We defined "monitor AF in irregular pulse peak (IPP) 15/20/25" as follows: (a) IPP: |interval of pulse peak - the average of the interval of the pulse peak| ≥ the average of the interval of the pulse peak × 15/20/25%; (b) irregular heartbeat (IHB): beats of IPP ≥ total pulse × 20%; and (c) monitor AF: ≥4 IHBs of the six pulse wave measurements. In IPP 15, the sensitivity and specificity were 0.97 and 1.00, respectively. Pulse wave analysis by a wrist-type monitor was shown to have high sensitivity and specificity for the diagnosis of AF., (©2019 Wiley Periodicals, Inc.)

Green fluorescent protein (GFP) is amenable to recombinant expression in various kinds of cells and is widely used in life science research. We found that the recombinant expression of GFPuv, a commonly-used mutant of GFP, in E. coli produced two distinct molecular species as judged by in-gel fluorescence SDS-PAGE. These molecular species, namely form I and II, could be separately purified by anion-exchange chromatography without any remarkable differences in the fluorescence spectra. Mass spectrometric analyses revealed that the molecular mass of form I is almost the same as the calculated value, while that of form II is approximately 1 Da larger than that of form I. Further mass spectrometric top-down sequencing pinpointed the modification in GFPuv form II, where the ε-amino group of the C-terminal Lys238 residue is converted into the hydroxyl group. No equivalent modification was observed in the native GFP in jellyfish Aequorea victoria, suggesting that this modification is not physiologically relevant. Crystal structure analysis of the two species verified the structural identity of the backbone and the vicinity of the chromophore. The modification found in this study may also be generated in other GFP variants as well as in other recombinant expression systems.

Pharmaceutical agents currently approved for the treatment of multiple sclerosis reduce relapse rates, but do not reverse or prevent neurodegeneration nor initiate myelin repair. The highly selective estrogen receptor (ER) β ligand chloroindazole (IndCl) shows particular promise promoting both remyelination while reducing inflammatory cytokines in the central nervous system of mice with experimental autoimmune encephalomyelitis. To optimize these benefits, we developed and screened seven novel IndCl analogues for their efficacy in promoting primary oligodendrocyte (OL) progenitor cell survival, proliferation, and differentiation in vitro by immunohistochemistry. Two analogues, IndCl-o-chloro and IndCl-o-methyl, induced proliferation and differentiation equivalent to IndCl and were selected for subsequent in vivo evaluation for their impact on clinical disease course, white matter pathology, and inflammation. Both compounds ameliorated disease severity, increased mature OLs, and improved overall myelination in the corpus callosum and white matter tracts of the spinal cord. These effects were accompanied by reduced production of the OL toxic molecules interferon-γ and chemokine (C-X-C motif) ligand, CXCL10 by splenocytes with no discernable effect on central nervous system-infiltrating leukocyte numbers, while IndCl-o-methyl also reduced peripheral interleukin (IL)-17. In addition, expression of the chemokine CXCL1, which is associated with developmental oligodendrogenesis, was upregulated by IndCl and both analogues. Furthermore, callosal compound action potential recordings from analogue-treated mice demonstrated a larger N1 component amplitude compared to vehicle, suggesting more functionally myelinated fibers. Thus, the o-Methyl and o-Chloro IndCl analogues represent a class of ERβ ligands that offer significant remyelination and neuroprotection as well as modulation of the immune system; hence, they appear appropriate to consider further for therapeutic development in multiple sclerosis and other demyelinating diseases.

Antibody-drug conjugate (ADC) is a class of targeted cancer therapies that combine the advantages of monoclonal antibody (mAb)'s specific targeting and chemotherapy's potent cytotoxicity. The therapeutic effect of ADC is significantly affected by its bioproduction process. This study aims to develop an effective ADC production process using anti-HER2 mAb-drug as a model therapeutic. First, a high titer (>2 g/L) of mAb was produced by Chinese hamster ovary cells from fed-batch cell culture. Both live-cell confocal microscopy imaging and flow cytometry analysis demonstrated that the produced mAb and ADC had strong and specific binding to HER2+ cell line BT474. Second, various conjugation conditions of mAb and drug, including linker selection, ratio of drug and mAb, and conjugation approaches, were investigated to improve the production yield and product quality. Finally, the ADC structure and biological quality were evaluated by SDS-PAGE and anti-breast cancer toxicity study, respectively. The ADC with integral molecular structure and high cytotoxicity (IC50 of 1.95 nM) was produced using the optimized production process. The robust bioproduction process could guide the development of ADC-based biopharmaceuticals., Competing Interests: The authors have declared that no competing interests exist.

Long-term follow-up of patients with adhesive capsulitis (AC) reveals that approximately half of them suffer from a limited range of shoulder motion, particularly external and/or internal rotation. We report the surgical technique and short-term clinical outcomes of ultrasound-guided release of the thickened coracohumeral (CH) ligament in 8 patients (9 shoulders) with AC. Passive external rotation with the arm by the side significantly increased from an average of 18° preoperatively to 47° immediately after CH ligament release. VAS and ASES scores were improved at 3months follow-up in all 9 shoulders, and maintained at 6months follow-up in 6 shoulders. No procedure-related adverse events developed over the 6-month follow-up period. Ultrasound-guided release for thickened CH ligament is a reliable and effective minimally invasive surgery for persistent limited external rotation due to AC of the shoulder., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Case: Non-convulsive status epilepticus (NCSE) is among the differential diagnoses of decreased consciousness, but often presents a diagnostic challenge. A 65-year-old woman was admitted to our emergency department with bradylalia. No abnormal finding was detected by computed tomography or magnetic resonance imaging. Subsequently, acquired arterial spin-labeling images showed hyperperfusion in the right hemisphere., Outcome: After the examination, the patient began experiencing left hemifacial seizures, which were relieved by diazepam; however, she was still agitated. Ictal confusion due to NCSE was suspected. Electroencephalography revealed periodic, generalized epileptiform activities with brief seizures of facial muscles by intermittent photic stimulation. Another supportive case of NCSE detected by arterial spin-labeling from a 56-year-old right-handed man has also been presented., Conclusion: Arterial spin-labeling magnetic resonance perfusion imaging provides valuable information regarding cerebral perfusion status in NCSE patients in emergency/acute settings.

Hyperparathyroidism, which is increased parathyroid hormone (PTH) levels in the blood, could cause delayed or non-union of bone fractures. But, no study has yet demonstrated the effects of excess continuous PTH exposure, such as that seen in hyperparathyroidism, for fracture healing. Continuous human PTH 1-34 (teriparatide) infusion using an osmotic pump was performed for stabilized tibial fractures in eight-week-old male mice to determine the relative bone healing process compared with saline treatment. Radiographs and micro-computed tomography showed delayed but increased calcified callus formation in the continuous PTH 1-34 infusion group compared with the controls. Histology and quantitative histomorphometry confirmed that continuous PTH 1-34 treatment significantly increased the bone callus area at a later time point after fracture, since delayed endochondral ossification occurred. Gene expression analyses showed that PTH 1-34 resulted in sustained Col2a1 and reduced Col10a1 expression, consistent with delayed maturation of the cartilage tissue during fracture healing. In contrast, continuous PTH 1-34 infusion stimulated the expression of both Bglap and Acp5 through the healing process, in accordance with bone callus formation and remodeling. Mechanical testing showed that continuously administered PTH 1-34 increased the maximum load on Day 21 compared with control mice. We concluded that continuous PTH 1-34 infusion resulted in a delayed fracture healing process due to delayed callus cell maturation but ultimately increased biomechanical properties.

Estrogen receptor β (ERβ) ligands promote remyelination in mouse models of multiple sclerosis. Recent work using experimental autoimmune encephalomyelitis (EAE) has shown that ERβ ligands induce axon remyelination, but impact peripheral inflammation to varying degrees. To identify if ERβ ligands initiate a common immune mechanism in remyelination, central and peripheral immunity and pathology in mice given ERβ ligands at peak EAE were assessed. All ERβ ligands induced differential expression of cytokines and chemokines, but increased levels of CXCL1 in the periphery and in astrocytes. Oligodendrocyte CXCR2 binds CXCL1 and has been implicated in normal myelination. In addition, despite extensive immune cell accumulation in the CNS, all ERβ ligands promoted extensive remyelination in mice at peak EAE. This finding highlights a component of the mechanism by which ERβ ligands mediate remyelination. Hence, interplay between the immune system and central nervous system may be responsible for the remyelinating effects of ERβ ligands. Our findings of potential neuroprotective benefits arising from the presence of CXCL1 could have implications for improved therapies for multiple sclerosis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

We herein report the case of a 65-year-old man who presented with an anaplastic carcinoma of the pancreas, producing granulocyte colony-stimulating factor (G-CSF). The patient's laboratory data showed an increase in his serum CA19-9 levels 1 year after he had undergone surgery for transverse colon cancer. Computed tomography (CT) showed a mass in the pancreatic head. Following a diagnosis of primary or metastatic pancreatic cancer, we performed the pancreatoduodenectomy. The postoperative course was uneventful. However, on postoperative day 28, he suffered a disturbance of consciousness and demonstrated hypercalcemia with elevated serum levels of parathyroid hormone-related protein (PTHrP). CT revealed multiple liver metastases and massive ascites. His serum Ca level decreased temporarily, and he subsequently died 58 days after the pancreatoduodenectomy. A pathological examination revealed pleomorphic-type anaplastic carcinoma of the pancreas. Immunohistochemical staining showed the tumor cells to be positive for G-CSF. To the best of our knowledge, there have been no reports of G-CSF-producing anaplastic carcinoma of the pancreas associated with humoral hypercalcemia of malignancy.

We herein report a 75-year-old woman who presented with an intraductal papillary mucinous carcinoma(IPMC)who was treated with surgical resection 4 years after the initial diagnosis was made. She previously underwent a high anterior resection of the rectum for rectal cancer at 71 years of age. Preoperative CT revealed a multilocular cystic mass measuring 6 cm in size in the body of the pancreas, which was considered benign. We followed up the intraductal papillary mucinous neoplasm(IPMN) by using annual CT imaging for 4 years. CT revealed a gradual increase in the size of the mass and the development of an intramural nodule in the IPMN. Endoscopic retrograde pancreatography revealed dilatations of the main pancreatic duct communicating with the multilocular cystic lesion. The cytology of the pancreatic juice demonstrated class III b. We therefore diagnosed the patient as having IPMC and performed total pancreatectomy. The postoperative course was uneventful without any recurrence. To our knowledge, only few reports have described the natural history of IPMNs. This resected case of IPMC is rare on the basis of our observation of the natural history of an IPMN using long-term imaging studies.

Importance: Elevated lipoprotein(a) levels are a risk factor for aortic stenosis (AS). However, a large-scale replication of associations between LPA variants and AS, their interactions with risk factors, and the effect of multiple risk alleles is not well established., Objective: To replicate the association between LPA variants with AS and identify subgroups who are at higher risk of developing AS., Design, Setting, and Participants: This case-control study of AS included 44 703 individuals (3469 cases) 55 years or older who were enrolled in the Genetic Epidemiology Research on Aging cohort and who were members of the Kaiser Permanente Northern California health care delivery system. The study leveraged the linkage of administrative health data, electronic medical records, genotypes, and self-reported questionnaire data. The 3469 AS cases were diagnosed between January 1996 and December 2015. Individuals with congential valvular heart disease were excluded., Exposures: Two single-nucleotide polymorphisms in the LPA locus, rs10455872 and rs3798220, that are known to associate with circulating plasma lipoprotein(a) levels and an LPA risk score., Main Outcomes and Measures: Aortic stenosis or aortic valve replacement., Results: The 44 703 participants were of European ancestry,of whom 22 019 (49.3%) were men. The mean (SD) age for the control group was 69.3 (8.3) years and the mean (SD) age for AS cases was 74.6 (8.5) years. Both LPA variants were associated with AS, with a per risk allele odds ratio of 1.34 (95% CI, 1.23-1.47; P = 1.7 × 10-10) for rs10455872 and 1.31 (95% CI, 1.09-1.58; P = 3.6 × 10-3) for rs3798220 after adjusting for age, age2, and sex. The results remained significant after adjusting for risk factors. The estimates were similar for an LPA risk score. Individuals with 2 risk alleles had a 2-fold or greater odds of AS compared with individuals with no risk alleles (for rs10455872, homozygous odds ratio, 2.05; 95% CI, 1.37-3.07; P = 5.3 × 10-4; for rs3798220, homozygous odds ratio, 3.74; 95% CI, 1.03-13.62; P = .05; and for compound heterygotes, odds ratio, 2.00; 95% CI, 1.17-3.44; P = .01). For rs10455872, the odds ratio for AS was greatest in individuals aged 55 to 64 years and declined with age (interaction P = .03). Each rs10455872 risk allele was also associated with AS that was diagnosed 0.71 years earlier (95% CI, -1.42 to 0; P = .05)., Conclusions and Relevance: We provide a large-scale confirmation of the association between 2 LPA variants and AS, reaching genome-wide significance. In addition, individuals with 2 risk alleles have 2-fold or greater odds of developing AS. Age may modify these associations and identify subgroups who are at greater risk of developing AS.

Introduction: Perforation of the abdominal esophagus caused by nasogastric tube (NGT) intubation has been rarely reported in adults., Presentation of Case: A 73-year-old man was admitted to our hospital with pneumonia. He had been bedridden long-term and had previously undergone a gastrectomy for gastric ulcer. Since admission was prolonged, and he required enteral feeding because of his inability to swallow, a NGT was inserted blindly. The next day, he had a high fever and abdominal pain. Abdominal computed tomography scan revealed that the tube was inserted through the wall of the abdominal esophagus into the abdominal cavity. In the emergency surgery, we sutured the perforated site of abdominal esophagus and patched it with lesser omentum. The postoperative course was good., Discussion: Abdominal esophageal perforation due to NGT insertion is very rare. The cause of perforation was suggested to be an abnormal deformity created by adhesion due to previous distal gastrectomy and long-term bedridden status. A chest X-ray usually is performed to confirm the position of the NGT tube. In this case, a frontal radiographic view apparently showed the NGT placed in the stomach., Conclusion: When NGT is inserted to such patients, frontal and lateral radiographic views or fluoroscopic guidance should be obtained., (Copyright © 2018. Published by Elsevier Ltd.)

We have developed a multisensor home and ambulatory blood pressure (BP) monitoring system for monitoring 24-h central and brachial BP variability concurrent with physical activity (PA), temperature, and atmospheric pressure. The new BP monitoring system utilizes our recently developed biological and environmental signal monitoring Information Communication Technology/Internet of Things system, which can simultaneously monitor the environment (temperature, illumination, etc.) of different rooms in a house (entryway, bedroom, living room, bathing room, and toilet), and a wrist-type high-sensitivity actigraph for identifying the location of patients. By collecting both data on BP and environmental parameters, the system can assess the brachial and central hemodynamic BP reactivity profiles of patients, such as actisensitivity (BP change with PA), thermosensitivity (with temperature), and atmospheric sensitivity (with atmospheric pressure). We used this new system to monitor ambulatory BP variability in outpatients with one or more cardiovascular disease (CVD) risk factors both in summer and winter. Actisensitivity (the slope of the regression line of ambulatory BP against the log-physical activity) was higher in winter than summer. By multi-level analysis using the parameters monitored by this system, we estimated the ambulatory BPs under different conditions. The individual time-series big data collected by this system will contribute to anticipation medicine for CVD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background Boron neutron capture therapy (BNCT) is a molecular radiation therapy approach based on the 10 B (n, α) 7 Li nuclear reaction in cancer cells. In BNCT, delivery of 10 B in the form of 4-borono-phenylalanine conjugated with fructose (BPA-fr) to the cancer cells is important. The PET tracer 4-borono-2-18F-fluoro-phenylalanine (FBPA) has been used to predict the accumulation of BPA-fr before BNCT. Purpose To determine the biodistribution and dosimetric parameters in 18F-BPA PET/CT studies. Material and Methods Human biokinetic data were obtained during clinical 18F-BPA PET studies between February and June 2015 at one institution. Nine consecutive patients were studied prospectively. The internal radiation dose was calculated on the basis of radioactivity data from blood, urine, and normal tissue of the heart, liver, spleen, kidney, and other parts of the body at each time point using OLINDA/EXM1.1 program. We compared our calculations with published 18F-FDG data. Results Adult patients (3 men, 3 women; age range, 28-68 years) had significantly smaller absorbed doses than pediatric patients (3 patients; age range, 5-12 years) ( P = 0.003). The mean effective dose was 57% lower in adult patients compared with pediatric patients. Mean effective doses for 18F-BPA were 25% lower than those for 18F-FDG presented in International Commission of Radiation Protection (ICRP) publication 106. Conclusion We found significant differences in organ absorbed doses for 18F-BPA against those for 18F-FDG presented in ICRP publication 106. Mean effective doses for 18F-BPA were smaller than those for 18F-FDG in the publication by 0.5-38% (mean difference, 25%).

The objective of this work was to evaluate the biological effect of the secondary effluent (SE) of a wastewater treatment plant and reclaimed water treated via ultrafiltration (UF) followed by either reverse osmosis (RO) membrane filtration or nanofiltration (NF) to be used for environmental use by comparing the results of algal growth inhibition tests of concentrated samples of the SE and permeates of RO and NF with those of six rivers in southern Okinawa Island. Although the SE water had no adverse effects on the growth of the algae Pseudokirchneriella subcapitata, it could lead to water quality degradation of rivers in terms of its toxic unit value, whereas the use of RO and NF permeates would not lead to such degradation. The recharge of rivers, into which domestic wastewater and livestock effluents might be discharged in southern Okinawa Island, with reclaimed water subjected to advanced treatment could dilute the concentrations of chemicals that cause biological effects and improve the water quality of the rivers, based on the results of the bioassay using P. subcapitata. Comparing the results of bioassays of reclaimed water with those of the ambient water at a site might be effective in assessing the water quality of reclaimed water for environmental use at the site.

Apolipoprotein E receptor 2 (ApoER2) is a close homologue of low-density lipoprotein receptor (LDLR) that mediates the endocytosis of ligands, including LDL particles. LDLR family members have been presumed to explore a large conformational space to capture ligands in the extended conformation at the cell surface. Ligands are subsequently released through a pH-titrated structural transition to a self-docked, contracted-closed conformation. In addition to lipoprotein uptake, ApoER2 is implicated in signal transduction during brain development through capture of the extracellular protein reelin. From crystallographic analysis, we determine that the full-length ApoER2 ectodomain adopts an intermediate contracted-open conformation when complexed with the signaling-competent reelin fragment, and we identify a previously unappreciated auxiliary low-affinity binding interface. Based on mutational analyses, we propose that the pH shift during endocytosis weakens the affinity of the auxiliary interface and destabilizes the ligand-receptor complex. Furthermore, this study elucidates that the contracted-open conformation of ligand-bound ApoER2 at neutral pH resembles the contracted-closed conformation of ligand-unbound LDLR at acidic pH in a manner suggestive of being primed for ligand release even prior to internalization., (© 2017 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

The taste receptor type 1 (T1r) family perceives 'palatable' tastes. These receptors function as T1r2-T1r3 and T1r1-T1r3 heterodimers to recognize a wide array of sweet and umami (savory) tastes in sugars and amino acids. Nonetheless, it is unclear how diverse tastes are recognized by so few receptors. Here we present crystal structures of the extracellular ligand-binding domains (LBDs), the taste recognition regions of the fish T1r2-T1r3 heterodimer, bound to different amino acids. The ligand-binding pocket in T1r2LBD is rich in aromatic residues, spacious and accommodates hydrated percepts. Biophysical studies show that this binding site is characterized by a broad yet discriminating chemical recognition, contributing for the particular trait of taste perception. In contrast, the analogous pocket in T1r3LBD is occupied by a rather loosely bound amino acid, suggesting that the T1r3 has an auxiliary role. Overall, we provide a structural basis for understanding the chemical perception of taste receptors.

Introduction: Giant inguinal hernia is unusual, and duodenal rupture accompanying it is particularly very rare and significantly hard to manage surgically., Presentation of Case: An 81-year-old man was admitted to our institution with upper abdominal pain. He had tenderness of the upper mid abdomen and a bilateral large inguinal hernia but he did not have pain in the inguinal-scrotal area. Computed tomography (CT) showed slight dilatation of the small bowel and stomach. There were no remarkable signs of incarceration of the inguinal hernia. Therefore, he was admitted to the internal ward. On the second day in hospital, he suddenly went into shock. CT revealed that there was free air and ascites in the inguinal hernia and therefore an emergency operation was performed. The tranverse colon, ascending colon, and ileum were incarcerated, and perfolation of the cecum was found. We also detected duodenal rupture at the inferior duodenal angle. We resected the terminal ileal (almost 90cm) and ileocecal area, followed by side-to-side anastomosis of duodenum and jejunum. We only repaired the peritoneum at the internal hernia ring. After the operation, despite intensive-care therapy, this patient passed away on the 18th postoperative day., Discussion: The mesocolon and third portion of the duodenum were strongly pulled down into giant inguinal hernia, probably causing the rupture of the inferior duodenal angle., Conclusion: Giant inguinal hernia possibly provokes duodenal rupture and therefore should definitively be repaired if feasible., (Copyright © 2017. Published by Elsevier Ltd.)

Plexins are type I membrane proteins that function as receptors for semaphorins. All of the known plexins contain a large globular domain, termed the sema domain, in the N-terminal extracellular region, which interacts with semaphorins during signal transduction. Here, we describe procedures for protein production and purification that we utilized in the crystallographic study of the mouse Plexin A2 (mPlxnA2) extracellular fragment, including the sema domain. A mutant mammalian cell line, HEK293S GnTI - , was used as an expression host for the production of a crystallizable-quality mPlxnA2 fragment, which contains several N-glycosylation sites and disulfide bonds.

Connective tissues such as tendon, ligament and cartilage are mostly composed of extracellular matrix (ECM). These tissues are insoluble, mainly due to the highly cross-linked ECM proteins such as collagens. Difficulties obtaining suitable samples for mass spectrometric analysis render the application of modern proteomic technologies difficult. Complete solubilization of them would not only elucidate protein composition of normal tissues but also reveal pathophysiology of pathological tissues. Here we report complete solubilization of human Achilles tendon and yellow ligament, which is achieved by chemical digestion combined with successive protease treatment including elastase. The digestion mixture was subjected to liquid chromatography-mass spectrometry. The low specificity of elastase was overcome by accurate mass analysis achieved using FT-ICR-MS. In addition to the detailed proteome of both tissues, we also quantitatively determine the major protein composition of samples, by measuring peak area of some characteristic peptides detected in tissue samples and in purified proteins. As a result, differences between human Achilles tendon and yellow ligament were elucidated at molecular level.

When ultrafiltration (UF) membrane processes that are able to effectively reduce viruses are installed in a waste water reclamation system, the security of sanitation safety for water-borne diseases is essential. It is important to understand the behaviour of enteric viruses such as Adenovirus, Rotavirus and Norovirus (NV), the detection rate of which is relatively high in sewage. This study focused on the UF membrane process for the reclaimed water treatment process, and investigated the removal performance in NV type GI and GII in the UF membrane process by performing coagulation and sedimentation as the pre-treatment process in a pilot-plant by considering the concentration fluctuation of the influent. The removal ratio of GI and GII by the UF membrane process alone was 3.3 ± 0.7 Log in GI and 3.6 ± 1.0 Log in GII, and no clear difference in the removal ratio by NV species type was observed. The removal ratio of NV GII was increased by about 0.6 Log on average (4.2 ± 1.1 Log) compared with the UF membrane process only when the coagulation and sedimentation process were conducted as pre-treatment. However, there was no significant difference in the removal of NV GI by conducting the coagulation and sedimentation process.

Background: Obesity is a known risk factor for complications after digestive surgery. Body mass index (BMI) is commonly used as an index of obesity but does not always reflect the degree of obesity. Although some studies have shown that high visceral fat area (VFA) is associated with poor outcomes in digestive surgery, few have examined the relationship between VFA and total gastrectomy. In this study, we demonstrated that VFA is more useful than BMI in predicting complications after total gastrectomy., Methods: Seventy-five patients who underwent total gastrectomy for gastric cancer were enrolled in this study; they were divided into two groups: a high-VFA group (n = 26, ≥100 cm(2)) and a low-VFA group (n = 49, <100 cm(2)). We retrospectively evaluated the preoperative characteristics and surgical outcomes of all patients and examined postoperative complications within 30 days of surgery (including cardiac complications, pneumonia, ileus, anastomotic leakage, pancreatic fistula, incisional surgical site infection [SSI], abdominal abscess, and hemorrhage)., Results: The incidence of anastomotic leakage (p = 0.03) and incisional SSI (p = 0.001) were higher in the high-VFA group than in the low-VFA group. No significant differences were observed in the other factors. We used univariate analysis to identify risk factors for anastomotic leakage and incisional SSI. Age and VFA were risk factors for anastomotic leakage, and BMI and VFA were risk factors for incisional SSI. A multivariate analysis including these factors found that only VFA was a predictor of anastomotic leakage (hazard ratio [HR] 4.62; 95 % confidence interval [CI] 1.02-21.02; p = 0.048) and incisional SSI (HR 4.32; 95 % CI 1.18-15.80; p = 0.027]., Conclusions: High VFA is more useful than BMI in predicting anastomotic leakage and SSI after total gastrectomy. Therefore, we should consider the VFA value during surgery.