Search

Objective: CT imaging precisely and quantitatively analyzes the kinematics of the carpal bones to evaluate the etiology of related osteoarthritis. Previous studies have investigated the kinematics of the trapeziometacarpal joint using static CT scans of various postures including the pinch position. This study analyzed the in-vivo kinematics of the trapeziometacarpal joint during dynamic pinch motion in young healthy volunteers using four-dimensional CT. Materials and methods: Twelve healthy young volunteers participated in this study. Each participant held the pinch meter between their thumb and index finger and pinched it with maximum force for a period of 6 s. This series of movement was recorded using a four-dimensional CT. The surface data of the trapezium and first metacarpal of all frames were reconstructed, and bone movement at the trapeziometacarpal joint was calculated using sequential three-dimensional registration. The instantaneous pinch force of each frame was measured using a pointer on a pinch meter that was reconstructed from the CT data. Results: The first metacarpal was abducted (15.9 ± 8.3°) and flexed (12.2 ± 7.1°) relative to the trapezium, and significantly translated to the volar (0.8 ± 0.6 mm) and ulnar directions (0.9 ± 0.8 mm) with maximum pinch force. This movement consistently increased with the pinch force. Conclusion: This study successfully employed 4D-CT to precisely demonstrate changes in rotation and translation at the trapeziometacarpal joint during pinch motion for various instantaneous forces. [ABSTRACT FROM AUTHOR]

We aimed to investigate the reliability and validity of sweat lactate threshold (sLT) measurement based on the real-time monitoring of the transition in sweat lactate levels (sLA) under hypoxic exercise. In this cross-sectional study, 20 healthy participants who underwent exercise tests using respiratory gas analysis under hypoxia (fraction of inspired oxygen [FiO2], 15.4 ± 0.8%) in addition to normoxia (FiO2, 20.9%) were included; we simultaneously monitored sLA transition using a wearable lactate sensor. The initial significant elevation in sLA over the baseline was defined as sLT. Under hypoxia, real-time dynamic changes in sLA were successfully visualized, including a rapid, continual rise until volitionary exhaustion and a progressive reduction in the recovery phase. High intra- and inter-evaluator reliability was demonstrated for sLT's repeat determinations (0.782 [0.607–0.898] and 0.933 [0.841–0.973]) as intraclass correlation coefficients [95% confidence interval]. sLT correlated with ventilatory threshold (VT) (r = 0.70, p < 0.01). A strong agreement was found in the Bland–Altman plot (mean difference/mean average time: − 15.5/550.8 s) under hypoxia. Our wearable device enabled continuous and real-time lactate assessment in sweat under hypoxic conditions in healthy participants with high reliability and validity, providing additional information to detect anaerobic thresholds in hypoxic conditions. [ABSTRACT FROM AUTHOR]

Phosphorodiamidate morpholino oligonucleotides (PMOs) are a promising type of antisense oligonucleotides, but their challenging synthesis makes them difficult to access. This research presents an efficient synthetic approach for PMOs using the H-phosphonate approach. The use of phosphonium-type condensing reagents significantly reduced coupling times compared with the current synthetic approach. Furthermore, phosphonium-type condensing reagents facilitated the fragment condensation of PMO, synthesizing up to 8-mer containing all four nucleobases with remarkable coupling efficacy. This is the first report on the convergent synthesis of PMOs. This approach would facilitate the large-scale synthesis of PMOs and accelerate their popularity and accessibility as a next-generation therapy. [ABSTRACT FROM AUTHOR]

Chitosan has various tissue regeneration effects. This study was designed to investigate the nerve regeneration effect of Schwann cell (SC)-encapsulated chitosan-collagen hydrogel nerve conduit (CCN) transplanted into a rat model of sciatic nerve defect. We prepared a CCN consisting of an outer layer of chitosan hydrogel and an inner layer of collagen hydrogel to encapsulate the intended cells. Rats with a 10-mm sciatic nerve defect were treated with SCs encapsulated in CCN (CCN+), CCN without SCs (CCN−), SC-encapsulated silicone tube (silicone+), and autologous nerve transplanting (auto). Behavioral and histological analyses indicated that motor functional recovery, axonal regrowth, and myelination of the CCN+ group were superior to those of the CCN− and silicone+ groups. Meanwhile, the CCN− and silicone+ groups showed no significant differences in the recovery of motor function and nerve histological restoration. In conclusion, SC-encapsulated CCN has a synergistic effect on peripheral nerve regeneration, especially axonal regrowth and remyelination of host SCs. In the early phase after transplantation, SC-encapsulated CCNs have a positive effect on recovery. Therefore, using SC-encapsulated CCNs may be a promising approach for massive peripheral nerve defects. [ABSTRACT FROM AUTHOR]

Purpose: Prostate cancer (PC) treatment causes sexual dysfunction (SD) and alters fertility, male identity, and intimate relationships with partners. In Japan, little attention has been paid to the importance of providing care for SD associated with PC treatment. This study is aimed at clarifying the care needs of Japanese men regarding SD associated with PC treatment. Methods: One-to-one semi-structured interviews were conducted with 44 PC patients to identify their care needs. Data were analyzed using thematic analysis. Results: Four core categories emerged from the analysis. (1) "Need for empathy from medical staff regarding fear of SD": patients had difficulty confiding in others about their sexual problems, and medical staff involvement in their SD issues was lacking. (2) "Need for information that provides an accurate understanding of SD and coping strategies before deciding on treatment": lack of information about SD in daily life and difficulty understanding information from medical institutions, caused men to regret their treatment. (3) "Need for professional care for individuals and couples affected by SD": men faced loss of intimacy because of their partners' unwillingness to understand their SD issues or tolerate non-sexual relationships. (4) "Need for an environment that facilitates interaction among men to resolve SD issues": men felt lonely and wanted to interact with other patients about their SD concerns. Conclusion: These findings may help form care strategies tailored to these needs and applicable to other societies with strong traditional gender norms. [ABSTRACT FROM AUTHOR]

Purpose: Hospital-based palliative care teams (HPCTs) are widespread internationally, but multicenter studies about their effectiveness, using patient-reported outcomes (PROs), are limited to Australia and a few other countries. We conducted a multicenter, prospective observational study in Japan to explore the effectiveness of the HPCTs using PROs. Methods: Nationwide, eight hospitals participated in the study. We included newly referred patients for one month in 2021 and followed them for one month. We asked the patients to complete the Integrated Palliative Care Outcome Scale or the Edmonton Symptom Assessment System as PROs at the time of the intervention, three days later, and weekly after the intervention. Results: A total of 318 participants were enrolled, of whom 86% were patients with cancer, 56% were undergoing cancer treatment, and 20% received the Best Supportive Care. After one week, the following 12 symptoms showed more than a 60% improvement from severe to moderate or less: vomiting (100%), shortness of breath (86%), nausea (83%), practical problems (80%), drowsiness (76%), pain (72%), poor sharing of feelings with family or friends (72%), weakness (71%), constipation (69%), not feeling at peace (64%), lack of information (63%), and sore or dry mouth (61%). Symptoms with improvement from severe/moderate to mild or less were vomiting (71%) and practical problems (68%). Conclusion: This multicenter study showed that HPCTs effectively improved symptoms in several severe conditions, as assessed by PROs. This study also demonstrated the difficulty of relieving symptoms in patients in palliative care and the need for improved care. [ABSTRACT FROM AUTHOR]

A simple, non-invasive algorithm for maximal lactate steady state (MLSS) assessment has not been developed. We examined whether MLSS can be estimated from the sweat lactate threshold (sLT) using a novel sweat lactate sensor for healthy adults, with consideration of their exercise habits. Fifteen adults representing diverse fitness levels were recruited. Participants with/without exercise habits were defined as trained/untrained, respectively. Constant-load testing for 30 min at 110%, 115%, 120%, and 125% of sLT intensity was performed to determine MLSS. The tissue oxygenation index (TOI) of the thigh was also monitored. MLSS was not fully estimated from sLT, with 110%, 115%, 120%, and 125% of sLT in one, four, three, and seven participants, respectively. The MLSS based on sLT was higher in the trained group as compared to the untrained group. A total of 80% of trained participants had an MLSS of 120% or higher, while 75% of untrained participants had an MLSS of 115% or lower based on sLT. Furthermore, compared to untrained participants, trained participants continued constant-load exercise even if their TOI decreased below the resting baseline (P < 0.01). MLSS was successfully estimated using sLT, with 120% or more in trained participants and 115% or less in untrained participants. This suggests that trained individuals can continue exercising despite decreases in oxygen saturation in lower extremity skeletal muscles. [ABSTRACT FROM AUTHOR]

Introduction: In women, the female athlete triad, marked by low energy availability, functional hypothalamic amenorrhea and osteoporosis, is a recognized risk for stress fractures. Stress injuries also occur in men, but by contrast risks and mechanisms underlying them are less characterized. Materials and methods: 5 week-old wild-type male mice were fed ad libitum (ad) or subjected to 60% food restriction (FR) for five weeks. In both groups, some mice were allowed access to an exercise wheel in cages to allow voluntary wheel running (ex) and/or treated with active vitamin D analogues. Mice were sacrificed and analyzed at 10 weeks of age. Result: Male FR mice exhibited significantly reduced testicle weight, serum testosterone levels and bone mass. Such bone losses in FR male mice were enhanced by exercise. Histological analysis revealed that both bone-resorbing and -forming activities were significantly reduced in FR or FR plus exercise (FR + ex) mice, mimicking a state of low bone turnover. Significantly reduced bone mass in FR or FR + ex male mice was significantly rescued by treatment with active vitamin D analogues, with significant restoration of osteoblastic activities. Serum levels of insulin-like growth factor I (IGF-I), which is critical for bone remodeling, were significantly lower in FR versus control male mice. Conclusions: Low energy availability puts men at risk for stress injuries as well, and low energy availability is upstream of gonadal dysfunction and osteoporosis in males. Active vitamin D analogues could serve as therapeutic or preventive options for stress injuries in men. [ABSTRACT FROM AUTHOR]

Purpose: Cancer of unknown primary site (CUP) is an aggressive disease with poor prognosis. As research on the experiences of CUP patients and their families is scarce, this study aimed to compare the family caregiver-perceived burden of CUP with that of common cancers (lung, colon, and stomach cancers). The association between family caregiver-perceived burden and CUP patients' quality of life (QOL) at end-of-life and family depression, respectively, was also explored.Methods: This was a pre-planned secondary analysis of nationwide cross-sectional survey data from the bereaved family caregivers of patients with cancer who died at 286 institutions. The major measurements were the eight-item family caregiver-perceived Burden scale (comprising specialist access, uncertainty, and prolonged diagnosis), Good Death Inventory, and Patient Health Questionnaire 9.Results: Of 27,591 survey responses, we analyzed 97 and 717 responses from family caregivers of patients with CUP and common cancer, respectively. The families of CUP patients scored significantly higher on all three burden subscales than those of common cancer patients (effect sizes: specialist access subscale, 0.3; uncertainty subscale, 0.66; and prolonged diagnosis subscale, 0.69; adjusted P < 0.01). Greater family burden was significantly associated with lower patient QOL and higher family depression. Burden was significantly associated with being a spouse, second opinion consultation, and diagnosis period of > 1 month.Conclusion: The family caregivers of CUP patients experience poor specialist access, greater uncertainty, and a prolonged diagnosis. They should be cared for from the initial stages to establish access to specialists, obtain an early diagnosis, and reduce uncertainty. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the experiences of Japanese men with sexual dysfunction associated with various prostate cancer treatments. Methods: We included 38 Japanese men who underwent the following initial treatments for prostate cancer: radical prostatectomy (n = 10), external beam radiotherapy (n = 12), brachytherapy (n = 5), and androgen deprivation therapy (n = 11). Semi-structured interviews were conducted regarding sexual dysfunction associated with prostate cancer treatment. Data were analyzed using a content analysis method. To obtain a unique experience for each treatment, we confirmed and organized the treatment method from which the code that constituted each category was derived. The category reliability was calculated based on Scott's formula for the matching rate of the classification by three qualitative researchers. The criterion for good reliability was set at 70%. Results: Japanese men with sexual dysfunction associated with prostate cancer treatments experienced the following: a desire to maintain sexual function and conflict in decision-making concerning the initial treatment for prostate cancer; a loss of values related to sexual dysfunction; an uncertainty regarding the consequences of sexual dysfunction; a sense of calm with fewer adverse effects of sexual dysfunction at the early treatment stage; an effort to accept sexual dysfunction; and management of their changed body at the later treatment stages. The concordance rates for the categories were 70% and 78%. Additionally, there were glimpses of experiences common to all treatments and trends in treatment-specific experiences. Conclusion: It is necessary to provide care based on the experience of Japanese men with sexual dysfunction after prostate cancer treatment. [ABSTRACT FROM AUTHOR]

Acetic acid bacteria (AAB) are industrial microorganisms used for vinegar fermentation. Herein, we investigated the distribution and genome structures of mitomycin C-inducible temperate phages in AAB. Transmission electron microscopy analysis revealed phage-like particles in 15 out of a total 177 acetic acid bacterial strains, all of which showed morphology similar to myoviridae-type phage. The complete genome sequences of the six phages derived from three strains each of Acetobacter and Komagataeibacter strains were determined, harboring a genome size ranging from 34,100 to 53,798 bp. A phage AP1 from A. pasteurianus NBRC 109446 was predicted as an active phage based on the genomic information, and actually had the ability to infect its phiAP1-cured strain. The attachment sites for phiAP1 were located in the 3'-end region of the tRNAser gene. We also developed a chromosome-integrative vector, p2096int, based on the integrase function of phiAP1, and it was successfully integrated into the attachment site of the phiAP1-cured strain, which may be used as a valuable tool for the genetic engineering. Overall, this study showed the distribution of mitomycin C-inducible temperate phages in AAB, and identified the active temperate phage o f A. pasteurianus. [ABSTRACT FROM AUTHOR]

The Academic Research Consortium (ARC) recently published a definition of patients at high bleeding risk (HBR) undergoing percutaneous coronary intervention. However, the prevalence of the ARC-HBR criteria in patients undergoing endovascular therapy (EVT) for peripheral artery disease in lower extremities has not been thoroughly investigated. This study sought to investigate the prevalence and impact of the ARC-HBR criteria in patients undergoing EVT. We analyzed 277 consecutive patients who underwent their first EVT from July 2011 to September 2019. We applied the full ARC-HBR criteria to the study population. The primary end point was a composite outcome of all-cause mortality, Bleeding Academic Research Consortium 3 or 5 bleeding, and lower limb amputation within 12 months of EVT. Among the 277 patients, 193 (69.7%) met the ARC-HBR criteria. HBR patients had worse clinical outcomes compared with non-HBR patients at 12 months after EVT, including a higher incidence of the composite primary outcome (19.2% vs. 3.6%, p < 0.001) and all-cause death (7.8% vs. 0%, p = 0.007). In a multivariate Cox proportional hazards regression analysis, presence of the ARC-HBR criteria [hazard ratio (HR) 4.15, 95% confidence interval (CI) 1.25–13.80, p = 0.020], body mass index (HR 1.13, 95% CI 1.01–1.27, p = 0.042), diabetes mellitus (HR 2.70, 95% CI 1.28–5.69, p = 0.009), hyperlipidemia (HR 0.41, 95% CI 0.21–0.80, p = 0.009), and infrapopliteal lesions (HR 3.51, 95% CI 1.63–7.56, p = 0.001) were independent predictors of the primary composite outcome. Approximately 70% of Japanese patients undergoing EVT met the ARC-HBR criteria, and its presence was strongly associated with adverse outcomes within 12 months of EVT. [ABSTRACT FROM AUTHOR]

Fire ants (Solenopsis invicta Buren in J Ga Entomol Soc 7:1–26, 1972), an invasive alien ant species, first spread from South America to the United States in the 1930s, the southern part of the United States by the end of the twentieth century, Oceania, Taiwan, and China in the twenty-first century, and finally to Japan and South Korea in 2017. As these ants have significant negative economic, human health, and environmental impacts, the purpose of this research was to accumulate cytogenetic information regarding fire ants and provide basic data for developing management strategies for their control. Fire ants were collected from invasive populations from Taiwan, Florida (USA), and Buenos Aires (Argentina), and a native population from Puerto Iguazu (Argentina), their point of origination, and analyzed with regard to chromosome number, morphology, and polyploidy, silver-stained nucleolar organizer regions (Ag-NORs), and 18S rDNA and telomere fluorescence in situ hybridization (FISH). The results showed that (1) fire ants from invaded populations differed in chromosome morphology compared to those from native populations; (2) the Florida and Taiwanese fire ant populations evinced greater variability in chromosome numbers and polyploidy variations; (3) the Taiwanese population exhibited significantly increased Ag-NOR signals in interphase cells, with signal number significantly positively correlating with distance from native populations; and (4) substantial diversity of signals was also apparent following 18S rDNA and telomere FISH analyses. Variation in these characteristics were hypothesized to be due to (1) the effect of hybridizations and interbreeding between closely related species or genetically distant populations, and (2) the potential effect of large amounts of insecticides sprayed for pest control. [ABSTRACT FROM AUTHOR]

The lactate threshold (LT1), which is defined as the first rise in lactate concentration during incremental exercise, has not been non-invasively and conveniently determined in a clinical setting. We aimed to visualize changes in lactate concentration in sweat during exercise using our wearable lactate sensor and investigate the relationship between the lactate threshold (LT1) and ventilatory threshold (VT1). Twenty-three healthy subjects and 42 patients with cardiovascular diseases (CVDs) were enrolled. During exercise, the dynamic changes in lactate values in sweat were visualized in real-time with a sharp continuous increase up to volitional exhaustion and a gradual decrease during the recovery period. The LT1 in sweat was well correlated with the LT1 in blood and the VT1 (r = 0.92 and 0.71, respectively). In addition, the Bland–Altman plot described no bias between the mean values (mean differences: − 4.5 and 2.5 W, respectively). Continuous monitoring of lactate concentrations during exercise can provide additional information for detecting the VT1. [ABSTRACT FROM AUTHOR]

Nerve guidance conduits (NGCs) composed of biocompatible polymers have been attracting attention as an alternative for autograft surgery in peripheral nerve regeneration. However, the nerve tissues repaired by NGCs often tend to be inadequate and lead to functional failure because of the lack of cellular supports. This paper presents a chitosan-collagen hydrogel conduit containing cells to induce peripheral nerve regeneration with cellular support. The conduit composed of two coaxial hydrogel layers of chitosan and collagen is simply made by molding and mechanical anchoring attachment with holes made on the hydrogel tube. A chitosan layer strengthens the conduit mechanically, and a collagen layer provides a scaffold for cells supporting the axonal extension. The conduits of different diameters (outer diameter approximately 2–4 mm) are fabricated. The conduit is bioabsorbable with lysozyme, and biocompatible even under bio absorption. In the neuron culture demonstration, the conduit containing Schwann cells induced the extension of the axon of neurons directed to the conduit. Our easily fabricated conduit could help the high-quality regeneration of peripheral nerves and contribute to the nerve repair surgery. [ABSTRACT FROM AUTHOR]

Background: As both APTT and APTT-based coagulation method cannot distinguish heparin effect from intrinsic coagulation factor deficiency, we implemented thromboelastography (TEG) for the coagulation assessment in a patient with hemophilia A undergoing an endovascular surgery with heparinization. Case presentation: A 68-year-old male with hemophilia A underwent endovascular aortic repair for abdominal aortic aneurism. TEG results showed recovery of coagulation time (R) in both kaolin assay (CK) and kaolin-heparinase assay (CKH) after factor VIII replacement before heparinization. Against our expectations, R-CKH was slightly prolonged (9.0 min) during heparinization. After the administration of protamine sulfate, R in both assays showed similar values within the normal ranges. Conclusions: The combination of CK and CKH assays could be useful to estimate factor VIII (FVIII) level when heparin concentration is low or without heparin; however, caution should be necessary for estimation of FVIII level by TEG under the effect of medium- or high-dose heparin. [ABSTRACT FROM AUTHOR]

It is important to understand the molecular mechanisms of barrier disruption in the central nervous system (CNS) of patients with multiple sclerosis (MS). The purpose of the present study was to clarify whether claudin-11 is involved in the disruption of two endothelial barriers (blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB)) and two epithelial barriers (blood-arachnoid barrier (BAB) and blood-CSF barrier (BCSFB)) in the CNS in MS. Immunohistochemical analysis revealed that, in both normal human and mouse, claudin-11 is co-localized with claudin-5 in the brain and spinal cord capillaries. The absolute protein expression level of claudin-11 was nearly equal to that of claudin-5 in rat brain capillaries, but was 2.81-fold greater in human brain capillaries. The protein expressions of claudin-11 were significantly downregulated in the brain and spinal cord capillaries of an MS patient and experimental autoimmune encephalomyelitis (EAE) mice. Specific downregulation of claudin-11 with siRNA significantly increased the transfer of membrane-impermeable FITC-dextran across human brain capillary endothelial cell (hCMEC/D3) monolayer. As for the epithelial barrier, claudin-11 protein expression was not decreased in choroid plexus epithelial cells forming the BCSFB in EAE mice, whereas it was decreased in brain and spinal cord meninges that form the BAB. Specific downregulation of claudin-11 with siRNA in a rat choroid plexus epithelial cell (TR-CSFB) monolayer significantly increased the permeability of FITC-dextran. In conclusion, our present findings indicate that claudin-11 expression at the BBB, BSCB, and BAB, but not the BCSFB, is downregulated in multiple sclerosis, impairing the functional integrity of these barriers. [ABSTRACT FROM AUTHOR]

Hepatoma cells are a candidate cell source for bio-artificial livers. However, they exhibit reduced liver functions compared with primary hepatocytes. In our previous study, genetically engineered mouse hepatoma cells were created by transduction with vectors mediating inducible overexpression of eight liver-enriched transcription factors. Upon the induction of the liver-enriched transcription factors transduced, the cells expressed both phenotypic and genotypic liver functions at high levels. In the present study, we performed three-dimensional culture of these cells using macroporous gelatin beads. When immobilized on the macroporous gelatin beads, these cells exhibited further enhancement in liver functionality, including increased albumin secretion, ammonia removal and cytochrome P450 activity. The levels of these functions were significantly enhanced compared to monolayer culture. The method is simple and scalable, and provides highly functional cells that can be used in basic and applied fields of hepatic research. [ABSTRACT FROM AUTHOR]

Shadows are powerful cues in the perception of shapes. We can perceive shading and cast shadow implicitly. We investigated infants' ability to detect a single discrepant figure that was depicted by shading or cast shadow and examined the influence of the contrast polarity of shadows on this process. In Experiment 1, we manipulated the blur direction of a shadow to create stimuli that appeared either to be partially shaded or to cast a shadow and then used a preference to test whether this difference would allow 5- to 8-month-old infants to discriminate the figures that adults were able to perceive as different shapes. Only 7- to-8-month-old infants could differentiate one shading figure from cast shadow figures, and vice versa. In Experiment 2, we reversed the contrast polarity of the figure (dark object with a light shadow) and tested whether discrimination was affected. As has been found with adults, infants exposed to this condition were unable to discriminate the contrast-reversed shading and cast shadow figures. Our results suggested that an age of around 7 months is important for development of the ability to perceive shape differences from shading and cast shadows. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are a class of extra-cellular and membrane-bound proteases involved in a wide array of physiological and pathological processes including tissue remodeling, inflammation, and cytokine secretion and activation. MMP-13 has been shown to be involved in lung diseases such as acute lung injury, viral infections, and chronic obstructive pulmonary disease; however, the molecular pathogenesis of MMP-13 in these conditions is not well understood. In this study, we investigated the mechanisms and roles of MMP-13 secretion in human small airway epithelial cells (SAECs) and functional polymorphisms of the MMP13 gene. Polyinosinic-polycytidylic acid (poly(I:C)) and interferon β (IFN-β) stimulated the secretion of MMP-13 from SAECs by more than several hundred-fold. Stimulation of the secretion by poly(I:C) was abolished by SB304680 (p38 inhibitor), LY294002 (PI3K inhibitor), Janus kinase (JAK) inhibitor I, RNA-activated protein kinase (PKR) inhibitor, and Bay 11-7082 (NF-κB inhibitor), while stimulation by IFN-β was inhibited by all except Bay 11-7082. These data suggested that the secretion of MMP-13 was mediated through IFN receptor pathways independently of nuclear factor kappa B (NF-κB) and that poly(I:C) stimulated IFN secretion in an NF-κB-dependent manner from SAECs, leading to IFN-stimulated MMP-13 secretion. Chemical MMP-13 inhibitors and MMP-13 small interfering RNA (siRNA) inhibited IFN-stimulated secretion of interferon gamma-inducible protein 10 (IP-10) and regulated on activation, normal T-cell expressed and secreted (RANTES), suggesting that MMP-13 is involved in the secretion of these virus-induced proinflammatory chemokines. We identified a novel functional polymorphism in the promoter region of the MMP13 gene. The MMP13 gene may play important roles in defense mechanisms of airway epithelial cells. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to develop a Japanese version of hand-foot syndrome (HFS)-specific quality of life (QOL) questionnaire (HFS-14) to evaluate and monitor the QOL of patients with a possibility of HFS. Methods: The original English version of HFS-14 was translated and slightly modified into Japanese, and the Japanese HFS-14 was administered to 187 patients receiving chemotherapy with high risk of developing HFS as outpatients in four institutions in Japan. Factor validity, internal consistency, correlation with the Skindex-16 and Dermatology Life Quality Index (DLQI) scores, known group validity, and test-retest reliability were analyzed for 105 patients who developed HFS. Next, we compared HFS-14 with DLQI and Skindex-16. Results: Factor analysis confirmed the factor structure (one putative scale) of the Japanese HFS-14. Cronbach's alpha was over 0.90. The Japanese HFS-14 score was correlated with the Skindex-16 and DLQI score. Intra-class correlation coefficients were over 0.80. Patients with severe HFS reported significantly poorer HFS-14 score than those with mild HFS. The Skindex-16 and DLQI scores were also significantly different in patients with different Common Terminology Criteria for Adverse Events (CTCAE) grades, but with smaller effect sizes than those for the HFS-14 score. Conclusions: The Japanese HFS-14 provides a valid and reliable score for monitoring and evaluating HFS. [ABSTRACT FROM AUTHOR]

Attempts were made to synthesize seven analogs of µ-conotoxin GIIIA, a specific blocker of muscle sodium channels, by replacing the three Hyp residues (Hyp, Hyp, and Hyp) with various amino acids. Replacement with Ala residue at these positions resulted in a very low isolation yield, suggesting that these three Hyp residues are essential for the folding of the molecule. CD spectra of the synthesized analogs suggest that, once synthesized, the replacement did not affect the three dimensional structure. The inhibitory effects on the twitch contractions of the rat diaphragm showed that the hydroxyl group at side chains of Hyp residues are not essential for the activity. [ABSTRACT FROM AUTHOR]

Purpose: We compared two health-related quality of life (HRQOL) instruments used for cancer patients [the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy-General (FACT-G)] to identify which instrument cancer patients most preferred. Methods: Adult cancer patients who had received cancer treatments within the previous 2 years ( n = 395) completed both surveys; participants assessed the importance, necessity, and appropriateness of each as an indicator of their quality of life. Results: The patients significantly preferred the FACT-G over the EORTC QLQ-C30 as a more important (effect size (ES) = 0.37, P < 0.001), necessary (ES = 0.18, P < 0.001), and appropriate questionnaire (ES = 0.14, P = 0.005). The subgroups of patients with good performance status, and those who reported low levels of work disruption, significantly preferred the FACT-G more than the other. The corresponding correlation coefficients were the following: physical functioning and well-being subscale, r = 0.65; emotional functioning and well-being subscale, r = 0.60; social functioning and social/family well-being subscale, r = 0.00; and role functioning and functional well-being subscale, r = 0.41. Conclusions: We recommend using the FACT-G if the performance status of the subject is good, e.g., in outpatient or cancer survivor surveys, based on the observed patient preferences. When performance status is not good, an instrument should be chosen after considering the differences between their scale structures and social domains and based on the availability of disease-specific modules. [ABSTRACT FROM AUTHOR]

Context: Pain is still a major problem for cancer patients, and the effect of a population-based approach on patients' experience of pain is not fully understood. Aims: The primary aim of this study was to clarify the changes in pain intensity in outpatients before and after a regional palliative care program. The secondary aim was to clarify the prevalence of patients who had unmet needs for pain treatment and to clarify the reasons for not wanting pain treatment. Subjects and methods: A regional palliative care program was implemented in four regions of Japan. A region-representative sample of metastatic/locally advanced cancer patients in outpatient settings took part in questionnaire surveys before and after the regional intervention. Responses were obtained from 859 from 1,880 and 857 from 2,123 in the preintervention and postintervention surveys, respectively. Results: After a regional palliative care program, neither worst, average, nor least pain levels in outpatients changed significantly. A total of 134 patients (16 %) reported that they needed more pain treatment. There were various reasons for not wanting pain treatment, namely, minimum interference with daily life, general nonpreference for medicines, longstanding symptoms before the diagnosis of cancer, concerns about tolerance and addiction, and experienced neuropsychiatric symptoms under current medications. Conclusion: The regional palliative care program failed to demonstrate improvement of the pain intensity of cancer outpatients. One possible interpretation is that they are less likely to be regarded as target populations and that the study population experienced generally well-controlled pain. Future study including patients with more severe pain is needed, but to improve pain levels of cancer outpatients, intensive, patient-directed intervention seems to be more promising than region-based intervention. [ABSTRACT FROM AUTHOR]

Seven analogs of μ-conotoxin GIIIA (μ-GIIIA), a specific blocker of muscle sodium channels, were synthesized by replacing stepwise the three cystine residues with Ala. The circular dichroism spectra of the analogs suggested that the deletion of disulfide bonds gradually randamized a conformation. The inhibitory effects on the twitch contractions of the rat diaphragm showed that the deletion of one disulfide bond reduced the potency to less than 1 % of control. Monocyclic analogs and a linear analog were almost inactive. Therefore, all three disulfide bridges are essential for stabilizing the specific conformation of μ-GIIIA to show biological activity. [ABSTRACT FROM AUTHOR]

The smokybrown cockroach Periplaneta fuliginosa has spread all over the world, and is now one of the most undesired invasive alien pests in Japan. Because cockroaches are generally infected by thelastomatid nematodes, they are being distributed around the world with their parasitic nematodes. Nothing is known about parasitic nematode species in P. fuliginosa differences, or similarity of the parasite's population structures between the different countries of the host cockroaches. Here we investigated the P. fuliginosa invasive to Japan and found that 100% of individuals were infected with one nematode species. According to the morphology and the sequence of the D2/D3 expansion segment of the 28S ribosomal RNA gene, we identified the parasite as Leidynema appendiculata. This nematode reproduced by haplodiploidy and its developmental timing under various conditions is quite divergent. Their population in the hindgut of P. fuliginosa was controlled with a few adult females and a male. This is the first report of the thelastomatid nematode isolated from the smokybrown cockroach, and is the basis for our future research examining the origin, distribution route and immigration history of the cockroach and the impact of L. appendiculata on native Japanese cockroach species. [ABSTRACT FROM AUTHOR]

Context: The Japan Outreach Palliative Care Trial of Integrated Model (OPTIM) study, a mixed-methods study to evaluate the effects of a comprehensive regional palliative care program, revealed that the program provided broad positive outcomes at the regional level: increased home death, palliative care use, patient- and family-reported qualities of care, and health care professionals' difficulties. Not all participants however obtained positive outcomes and thus exploring the reasons why expected outcomes were observed in individual levels could be of value.Aims: The primary aims were to explore why expected outcomes were not obtained in individual participants, and the perceived changes in daily practices of physicians and nurses were explored.Subjects and Methods: Postintervention questionnaire survey on 857 patients, 1,137 bereaved family members, 706 physicians, and 2,236 nurses were analyzed.Results: The reasons for not achieving home deaths included unexpected rapid deterioration, caregivers unavailable, concerns about adequate responses to sudden changes, and physical symptoms uncontrolled, while lack of physician availability at home and lack of information from physicians were less frequently reported. The reasons for not receiving specialized palliative care services were the lack of recommendations from physicians and no information about palliative care services. The reason for evaluating the quality of palliative care as not high was that clinicians tried to relieve symptoms, but there were limited effects and insufficient time. Many physicians and nurses reported that they became more aware of palliative care, that the availability of palliative care specialists and knowledge about palliative care improved, and that they cooperated with other regional health care providers more easily.Conclusion: The OPTIM study seemed to succeed in optimizing physician availability at home, improves physician information about home care, achieved maximum efforts to relieve patient distress by clinicians, and increased communication among regional health care professionals. To achieve further better outcomes, multiple interventions to the health care system to be performed on the basis of a comprehensive regional palliative care program are proposed. [ABSTRACT FROM AUTHOR]

Background: Right ventricular myocardial infarction (RVMI) is a complication of acute inferior myocardial infarction and sometimes causes severe hemodynamic disturbance. It is therefore important to promptly detect RVMI and assess the severity of right ventricular (RV) dysfunction. Tissue Doppler imaging (TDI) is a useful method to assess left ventricular function and RV function. In this study, we investigated the possibility of diagnosing RVMI using tricuspid annular velocity determined by TDI. Methods: Thirty consecutive patients with first acute inferior myocardial infarction were studied. The diagnosis of RVMI was based on an ST-segment elevation of at least 0.1 mV in lead V4R. The patients were classified into 12 patients with RVMI (the RVMI group) and 18 patients without RVMI (non-RVMI group). All patients underwent two-dimensional echocardiography, pulsed Doppler and TDI, and coronary angiography within 48 h after onset of myocardial infarction. Tricuspid inflow velocity was recorded by pulsed Doppler and early diastolic tricuspid inflow velocity (TVE) was measured. Peak early diastolic velocity of the tricuspid annulus (TVe') at the RV free wall was recorded using TDI. The ratio of TVE to TVe' (TVE/TVe') was calculated. Results: TVe' was significantly lower in the RVMI group compared to that in the non-RVMI group (5.9 ± 1.3 vs. 9.1 ± 3.1; p = 0.0025). On the basis of a TVe' cutoff value of less than 8.3 cm/s, RVMI was diagnosed with 100 % sensitivity and 61 % specificity. Conclusions: The early diastolic tricuspid annular velocity determined by TDI is a noninvasive and sensitive index for diagnosing RVMI. [ABSTRACT FROM AUTHOR]

In contrast to the general tendency of hydrophobicity-toxicity relationship of amyloid β peptide, we have previously found that the replacement of Asn of amyloid β(25-35) peptide with Ala yielded a more hydrophobic but less toxic analog and that of Met gave a less hydrophobic but more toxic one. To reveal the unique role of these two residues in the neurotoxicity of amyloid β(1-42) peptide, the major peptide constituent of amyloid plaques in human brain, we synthesized two analogs N27A and M35A in which Asn and Met of amyloid β(1-42) peptide was replaced with Ala, respectively. The former showed much weaker toxicity than the native peptide, while the latter showed almost an equivalent toxicity, indicating that the side chain amide group of Asn has an essential role for the toxicity of amyloid β peptides. [ABSTRACT FROM AUTHOR]

Purpose: Our goal was to better facilitate the desire of terminally ill patients to die in a favorite place, which may not always be the case for patients admitted to palliative care units. Our aims were to assess the perspectives of bereaved family members about (1) available and preferred places of care when their ill loved one was admitted to a palliative care unit and (2) why patients preferred to live at home but could not. Methods: A questionnaire was answered by 407 of 663 bereaved family members of cancer patients who were admitted to 95 inpatient palliative care units in Japan. Results: Seventy-three percent of respondents answered that a palliative care unit was the only available option. Patients lacking other places for care preferred their home (49%), a hospital (26%), or a long-term care facility (28%). Only 9% retrospectively considered that living at home was feasible for the following reasons: anxiety about the patient's deteriorating physical condition (85%), insufficient care at home compared to a hospital (84%), imminent hospitalization (63%), and the patient's concern about being burdensome (60%). Conclusion: Seventy-three percent of terminally ill cancer patients admitted to palliative care units had no other options for care. Improving outpatient treatment at palliative care units and establishing a palliative care system in patients' homes would greatly benefit patients and their families. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to clarify factors related to the preference of place for end-of-life cancer care and death, from the perspective of the bereaved family.Methods: In June 2007, in Japan, a cross-sectional anonymous questionnaire, which included a well-validated scale of component factors of hospice outcome, was administered to the bereaved family members (N = 294) of cancer patients who had died at home at least 6 months ago. Participants were recruited from 14 home hospices across the nation. We asked the preference of place for end-of-life care and death.Results: Fifty-eight percent of participants preferred home settings for end-of-life care and 68% preferred to die at home. Multivariate logistic regression identified: (1) males, participant who had other caregivers, a higher-good death concept, and those who experienced mastery as a consequence of caregiving were more likely to prefer home for end-of-life cancer care and (2) males, participant who had other caregivers, and experienced reprioritization as a consequence of caregiving and those who were enrolled in home hospice services for more than 60 days were more likely to prefer to die at home.Conclusions: Home hospice services need to be developed in Japan so that family support programs can be initiated early enough to support the family burden of household maintenance and caring for the patient. Quality improvement of home hospice services will support patients and families through end-of-life care and facilitate a good death at home. [ABSTRACT FROM AUTHOR]

Goals: In Japan, most cancer patients die in the hospital. The aim of this study was to assess the quality of end-of-life treatment for dying cancer patients in general wards and palliative care unit (PCU).Materials and Methods: A retrospective chart review study was conducted. The following data on cancer patients who died in general wards (N = 104) and PCU (N = 201) at a regional cancer center were collected: do-not-resuscitate (DNR) decisions, treatments in the last 48 h of life, and aggressiveness of cancer care for dying patients.Main Results: DNR orders were documented for most patients (94% in general wards, 98% in PCU, p = 0.067) and families usually consented (97%, 97%, p = 0.307). Comparison of general wards with PCU showed that, in the last 48 h of life, significantly more patients in general wards received life-sustaining treatment (resuscitation, 3.8%, 0%, p = 0.001; mechanical ventilation, 4.8%, 0%, p = 0.004), large volume hydration (>1,000 ml/day, 67%, 10%, p < 0.001) with continuous administration (83%, 5%, p = 0.002) and fewer palliative care drugs (strong opioids, 68%, 92%, p < 0.001; corticosteroids, 49%, 70%, p < 0.001; nonsteroidal anti-inflammatory drugs, 34%, 85%, p < 0.001). Regarding aggressiveness of cancer care, patients received a new chemotherapy regimen within 30 days of death (3.0%), chemotherapy within 14 days of death (4.3%), and intensive care unit admission in the last month of life (3.3%).Conclusion: We found that families, not patients, consented to DNR, and life-sustaining treatments were appropriately withheld; however, patients on general wards received excessive hydration, and the use of palliative care drugs could be improved. Application of our findings can be used to improve clinical care in general wards. [ABSTRACT FROM AUTHOR]

Activation of the superoxide-producing phagocyte NADPH oxidase, crucial in host defense, requires the cytosolic proteins p67phox and p47phox. They translocate to the membrane upon cell stimulation and activate flavocytochrome b558, the membrane-integrated catalytic core of this enzyme system. The activators p67phox and p47phox form a ternary complex together with p40phox, an adaptor protein with unknown function, comprising the PX/PB2, SH3 and PC motif-containing domains: p40phox associates with p67phox via binding of the p40phox PC motif to the p67phox PB1 domain, while p47phox directly interacts with p67phox but not with p40phox. Here we show that p40phox enhances membrane translocation of p67phox and p47phox in stimulated cells, which leads to facilitated production of superoxide. The enhancement cannot be elicited by a mutant p40phox carrying the D289A substitution in PC or a p67phox with the K355A substitution in PB1, each being defective in binding to its respective partner. Thus p40phox participates in activation of the phagocyte oxidase by regulating membrane recruitment of p67phox and p47phox via the PB1-PC interaction with p67phox. [ABSTRACT FROM AUTHOR]

Neurotransmitter release involves the assembly of a heterotrimeric SNARE complex composed of the vesicle protein synaptobrevin (VAMP 2) and two plasma membrane partners, syntaxin 1 and SNAP-25. Calcium influx is thought to control this process via Ca2+-binding proteins that associate with components of the SNARE complex. Ca2+/calmodulin or phospho- lipids bind in a mutually exclusive fashion to a C-terminal domain of VAMP (VAMP77-90), and residues involved were identified by plasmon resonance spectroscopy. Microinjection of wild-type VAMP77-90, but not mutant peptides, inhibited catecholamine release from chromaffin cells monitored by carbon fibre amperometry. Pre-incubation of PC12 pheochromocytoma cells with the irreversible calmodutin antagonist ophiobolin A inhibited Ca2+-dependent human growth hormone release in a permeabilized cell assay. Treatment of permeabilized cells with tetanus toxin tight chain (TeNT) also suppressed secretion. In the presence of TeNT, exocytosis was restored by transfection of TeNT-resistant (Q76V, F77W) VAMP, but additional targeted mutations in VAMP77-90 abolished its ability to rescue release. The calmodulin- and phospholipid-binding domain of VAMP 2 is thus required for Ca2+-dependent exocytosis, possibly to regulate SNARE complex assembly. [ABSTRACT FROM AUTHOR]

Bone proteins in mandibular alveolar bone from young adult rabbits (3-month-old) were extracted with 4 M guanidine hydrochloride (GuHCl), followed by 0.5M ethylenediaminetetraacetic acid (EDTA). The proteins in the EDTA extract were fractionated on Sepharose CL-6B in the presence of 4 M GuHCl, followed by HPLC using hydroxyapatite and then 'Mono Q' resin in the presence of 7 M urea, and a 28 kDa protein was isolated. The purified 28-kDa protein showed intense staining with silver following SDS-PAGE separation under reducing conditions. When the protein was digested with bacterial collagenase, a 19-kDa fragment was produced. However, the protein was not susceptible to cyanogen bromide. On SDS-PAGE under non-reducing conditions, the protein migrated as two bands; a new band at about 85-kDa, and the original 28-kDa band. The amino acid composition of the protein was similar to that of α1-pN-propeptide of type I procollagen from other tissues. Moreover, the characteristics of the purified 28-kDa protein were similar to those of a 28-kDa protein synthesized by rabbit alveolar bone-derived cells in vitro. [ABSTRACT FROM AUTHOR]

A new strategy is described for the production of peptides enriched with stable isotopes. Peptides of interest are expressed in Escherichia coli (E. coli) cells as recombinant fusion proteins with Saccharomyces cerevisiae ubiquitin. This method yields as much as 30–100 mg/l of isotope-enriched fusion proteins in minimal media. A decahistidine tag attached to the N-terminus of ubiquitin enables a one-step purification of the fusion protein via Ni2+-chelating affinity chromatography. The ubiquitin moiety is then easily and specifically cleaved off by a protease, yeast ubiquitin hydrolase. Since this enzyme is also expressed at a high level in E. coli cells and can be purified in one step, the presented strategy has an advantage in view of costs over others that use commercially available proteases. In addition, since ubiquitin fusion proteins easily refold, the fusion protein can be expressed either in a soluble form or as inclusion bodies. This flexibility enables us to prepare peptides that are unstable in a soluble state in E. coli cells. As an example, the expression and the uniform stable isotope enrichment with 15N and/or13 C are described for mastoparan-X, a tetradecapeptide known to activate GTP-binding regulatory proteins. An amide group at the C-terminus of this peptide can also be formed by our method. The presented system is considered powerful for the stable isotope enrichment of short peptides with proton resonances that are too severely overlapped to be analyzed solely by proton NMR. [ABSTRACT FROM AUTHOR]

Regular aerobic physical activity is of utmost importance in maintaining a good health status and preventing cardiovascular diseases (CVDs). Although cardiopulmonary exercise testing (CPX) is an essential examination for noninvasive estimation of ventilatory threshold (VT), defined as the clinically equivalent to aerobic exercise, its evaluation requires an expensive respiratory gas analyzer and expertize. To address these inconveniences, this study investigated the feasibility of a deep learning (DL) algorithm with single-lead electrocardiography (ECG) for estimating the aerobic exercise threshold. Two hundred sixty consecutive patients with CVDs who underwent CPX were analyzed. Single-lead ECG data were stored as time-series voltage data with a sampling rate of 1000 Hz. The data of preprocessed ECG and time point at VT calculated by respiratory gas analyzer were used to train a neural network. The trained model was applied on an independent test cohort, and the DL threshold (DLT; a time of VT estimated through the DL algorithm) was calculated. We compared the correlation between oxygen uptake of the VT (VT–VO2) and the DLT (DLT–VO2). Our DL model showed that the DLT–VO2 was confirmed to be significantly correlated with the VT–VO2 (r = 0.875; P < 0.001), and the mean difference was nonsignificant (−0.05 ml/kg/min, P > 0.05), which displayed strong agreements between the VT and the DLT. The DL algorithm using single-lead ECG data enabled accurate estimation of VT in patients with CVDs. The DL algorithm may be a novel way for estimating aerobic exercise threshold. [ABSTRACT FROM AUTHOR]

Smoking is thought to be a risk factor for osteoporosis development; however, the consequences of stopping smoking for bone homeostasis remain unknown. Here we conducted two separate human studies and show that bone mineral density was significantly lower in smokers than in non-smokers. The first was an observational study of pre- and post-menopausal healthy female smokers and non-smokers; the second included 139 current smokers determined to stop smoking. In the second study, levels of bone formation markers such as osteocalcin and uncarboxylated osteocalcin significantly increased after successful smoking cessation, as verified by significantly reduced levels of serum cotinine, a nicotine metabolite. Moreover, nicotine administration to mice reduced bone mineral density and significantly increased the number of osteoclasts in bone. Reduced bone mass phenotypes seen in nicotine-treated mice were significantly increased following nicotine withdrawal, an outcome accompanied by significantly reduced serum levels of tartrate-resistant acid phosphatase, a bone resorption marker. Taken together, our findings suggest that bone homeostasis is perturbed but can be rescued by smoking cessation. [ABSTRACT FROM AUTHOR]

Small interfering RNAs (siRNAs) are potential tools for gene-silencing therapy, but their instability is one of the obstacles in the development of siRNA-based drugs. To improve siRNA stability, we synthesised a double-stranded RNA-binding cationic oligodiaminogalactose 4mer (ODAGal4) and investigated here its characteristics for siRNA stabilisation in vitro. ODAGal4 improved the resistance of various siRNAs against serum degradation. The effect of ODAGal4 on siRNA stabilisation was further amplified by introduction of modified nucleotides into the siRNA. In particular, a combination of ODAGal4 and incorporation of phosphorothioate linkages into the siRNA prominently prevented degradation by serum. The half-lives of fully phosphorothioate-modified RNA duplexes with ODAGal4 were more than 15 times longer than those of unmodified siRNAs without ODAGal4; this improvement in serum stability was superior to that observed for other chemical modifications. Serum degradation assays of RNAs with multiple chemical modifications showed that ODAGal4 preferentially improves the stability of RNAs with phosphorothioate modification among chemical modifications. Furthermore, melting temperature analysis showed that ODAGal4 greatly increases the thermal stability of phosphorothioate RNAs. Importantly, ODAGal4 did not interrupt gene-silencing activity of all the RNAs tested. Collectively, these findings demonstrate that ODAGal4 is a potent stabiliser of siRNAs, particularly nucleotides with phosphorothioate linkages, representing a promising tool in the development of gene-silencing therapies. [ABSTRACT FROM AUTHOR]

We consider the dominant equations for the motion of the non-Newtonian fluid in a domain from an energetic point of view. We apply an energetic variational approach and the first law of thermodynamics to derive the generalized compressible non-Newtonian fluid system. We also derive the generalized incompressible non-Newtonian fluid system by using an energetic variational approach. Moreover, we investigate the enthalpy, entropy, free energy, and conservation laws of our compressible fluid system. The key idea of making our mathematical models for non-Newtonian fluid flow is that we use the Riemannian metric induced by a flow map in the domain to study our energy densities for non-Newtonian fluid. [ABSTRACT FROM AUTHOR]

The nicotinic receptor α7nAchR reportedly regulates vagal nerve targets in brain and cardiac tissue. Here we show that nAchR7−/− mice exhibit increased bone mass due to decreased osteoclast formation, accompanied by elevated osteoprotegerin/RANKL ratios in serum. Vagotomy in wild-type mice also significantly increased the serum osteoprotegerin/RANKL ratio, and elevated bone mass seen in nAchR7−/− mice was reversed in α7nAchR/osteoprotegerin-doubly-deficient mice. α7nAchR loss significantly increased TNFα expression in Mac1-positive macrophages, and TNFα increased the osteoprotegerin/RANKL ratio in osteoblasts. Targeting TNFα in nAchR7−/− mice normalized both serum osteoprotegerin/RANKL ratios and bone mass. Administration of nicotine, an α7nAchR ligand, to wild-type mice increased serum RANKL levels. Thus, vagal nerve stimulation of macrophages via α7nAchR regulates bone mass by modulating osteoclast formation. [ABSTRACT FROM AUTHOR]