Publications by authors named "Takahiro Sato"

329 Publications

Partition of Block Copolymers in Phase-Separating Polymer Solutions.

Langmuir 2021 May 13;37(20):6268-6277. Epub 2021 May 13.

Department of Macromolecular Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan.

The distribution of the AB diblock copolymer in a phase-separating solution composed of immiscible A and B homopolymers in a common solvent has been investigated theoretically. We have utilized the mixing Gibbs energy density for the interfacial phase based on mean-field lattice theory to this four-component system. Distributions of the AB diblock copolymer in the A and B homopolymer-rich bulk phases and the interfacial region between the separating bulk phases are calculated as a function of the B-block content, degrees of polymerization of the copolymer and A and B homopolymers, as well as interaction parameters among the A and B monomer units and the solvent. The copolymer prefers to distribute more in the interfacial region rather than separating bulk phases at a higher copolymer degree of polymerization and a higher interaction parameter between A and B monomer units. The theory is also compared with Asano et al.'s experimental results [ 2015, 31, 7488-7495] for polystyrene--poly(ethylene glycol) copolymer added to the phase-separating solution of polystyrene and poly(ethylene glycol) homopolymers dissolved in chloroform.
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http://dx.doi.org/10.1021/acs.langmuir.1c00704DOI Listing
May 2021

Characterization of putative tachykinin peptides in Caenorhabditis elegans.

Biochem Biophys Res Commun 2021 Jun 1;559:197-202. Epub 2021 May 1.

Division for Identification and Analysis of Bioactive Peptides, Department of Bioactive Peptides, Frontier Science Research, University of Miyazaki, Miyazaki, 889-1692, Japan. Electronic address:

Tachykinin-like peptides, such as substance P, neurokinin A, and neurokinin B, are among the earliest discovered and best-studied neuropeptide families, and research on them has contributed greatly to our understanding of the endocrine control of many physiological processes. However, there are still many orphan tachykinin receptor homologs for which cognate ligands have not yet been identified, especially in small invertebrates, such as the nematode Caenorhabditis elegans (C. elegans). We here show that the C. elegans nlp-58 gene encodes putative ligands for the orphan G protein-coupled receptor (GPCR) TKR-1, which is a worm ortholog of tachykinin receptors. We first determine, through an unbiased biochemical screen, that a peptide derived from the NLP-58 preprotein stimulates TKR-1. Three mature peptides that are predicted to be generated from NLP-58 show potent agonist activity against TKR-1. We designate these peptides as C. elegans tachykinin (CeTK)-1, -2, and -3. The CeTK peptides contain the C-terminal sequence GLR-amide, which is shared by tachykinin-like peptides in other invertebrate species. nlp-58 exhibits a strongly restricted expression pattern in several neurons, implying that CeTKs behave as neuropeptides. The discovery of CeTKs provides important information to aid our understanding of tachykinin-like peptides and their functional interaction with GPCRs.
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http://dx.doi.org/10.1016/j.bbrc.2021.04.063DOI Listing
June 2021

Patient preferences for growth hormone treatment in Japanese children.

Pediatr Int 2021 Apr 30. Epub 2021 Apr 30.

Takeshi Akiyama & Adeeb Tawseef, IQVIA Solutions Japan K.K, RWE & HEOR, Tokyo, Japan.

Background: There are no any clear evidence to date has evaluating patients' and caregiver' preferences for r-hGH (recombinant-human growth hormone) injection in children in Japan. This study quantitatively evaluated the factors driving preferences for daily r-hGH injection among Japanese children with Growth Hormone Deficiency (GHD) or their caregivers and to determine the relative importance of treatment delivery attributes.

Methods: This study was performed among Japanese children with GHD or their caregivers who visited a specialized clinic in Japan as part of their routine care. The participants were asked to complete a web-based discrete choice experiment (DCE) questionnaire.

Results: Choice-based conjoint analysis was used to evaluate the relative importance of attributes as choice predictors and determine utilities for each attribute. Of the 47 respondents who participated in this study, 41 were caregivers who responded on behalf of the patients, and the remaining 6 were patients who completed the DCE themselves. The injection schedule was found to be the most important attribute for both patients and caregivers; a once-weekly injection schedule was preferred over a daily injection schedule. The storage and preparation attribute was deemed more important to patients than it was to caregivers, with patients preferring store in room temperature even if it needed an additional mixing(reconstitution) step. Both patients and caregivers showed a clear preference for devices that offered a dose setting memory.

Conclusions: A less frequent injection schedule may enhance adherence to r-hGH treatment, and expected improve quality of life in GHD patients over the long term.
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http://dx.doi.org/10.1111/ped.14760DOI Listing
April 2021

Characterization of the Micelle Formed by a Hydrophobically Modified Pullulan in Aqueous Solution: Size Exclusion Chromatography.

Polymers (Basel) 2021 Apr 11;13(8). Epub 2021 Apr 11.

Department of Macromolecular Science, Osaka University, Toyonaka Osaka 560-0043, Japan.

Size exclusion chromatography equipped with a multi-angle, light-scattering online detector (SEC-MALS) measurements were carried out on a hydrophobically modified pullulan (PUL-OSA) with degrees of substitution () of 0.14, 0.2, and 0.3 in 0.01 M aqueous NaCl to obtain the degree of polymerization () dependence of the radius of gyration (⟨⟩) for PUL-OSA in the aqueous NaCl. The result was consistent with the loose flower necklace model proposed in a previous study, and the increase in the chain size with introducing OSA groups was explained by the backbone stiffness of the loose flower necklace formed by PUL-OSA. For PUL-OSA samples with = 0.2 and 0.3, ⟨⟩ obtained by SEC-MALS in a high region deviated downward from ⟨⟩ expected by the loose flower necklace model. This deviation came from a tiny amount of the aggregating component of PUL-OSA, taking a branched architecture composed of loose flower necklaces. Although the aggregating component of PUL-OSA was also detected by previous small angle X-ray scattering measurements, its conformation was revealed in this study by SEC-MALS.
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http://dx.doi.org/10.3390/polym13081237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069513PMC
April 2021

The Effect of Aging and Small-Vessel Disease Burden on Hematoma Location in Patients with Acute Intracerebral Hemorrhage.

Cerebrovasc Dis 2021 Apr 23:1-9. Epub 2021 Apr 23.

Department of Neurology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.

Introduction: Intracerebral hemorrhage (ICH) is a devastating hemorrhagic event and is associated with high mortality or severe neurological sequelae. Age-associated differences in hematoma location for nonlobar ICH are not well known. The aims of the present study were to elucidate the relationship between age and hematoma location and to assess the differences in small-vessel disease (SVD) burden as a potential surrogate marker for longstanding hypertension among various hematoma locations.

Methods: From September 2014 through July 2019, consecutive patients with acute, spontaneous ICH were retrospectively enrolled from a prospective registry. Magnetic resonance imaging was performed during admission, and the total SVD burden score (including microbleeds, lacunes, enlarged perivascular spaces, and white matter hyperintensities) was calculated. The relationships of hematoma location with aging and SVD burden were assessed by using multivariate logistic regression analyses.

Results: A total of 444 patients (156 women [35%]; median age 69 [interquartile range 59-79] years; National Institutes of Health Stroke Scale score 9 [17][3-17]) were enrolled in the present study. Multivariate logistic regression analyses showed that advanced age was independently associated with thalamic (odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.19-1.84, p < 0.001 for 10-year increment) and lobar hemorrhage (OR: 1.58, 95% CI: 1.19-2.09, p = 0.002) and was independently and negatively related to putaminal hemorrhage (OR: 0.55, 95% CI: 0.44-0.68, p < 0.001). The total SVD burden score was independently and positively associated with thalamic hemorrhage (OR: 1.27, 95% CI: 1.01-1.59, p = 0.045) and negatively with lobar hemorrhage (OR: 0.74, 95% CI: 0.55-0.99, p = 0.042), even after adjusting by age, but not with putaminal hemorrhage (OR: 0.91, 95% CI: 0.73-1.14, p = 0.395).

Conclusion: Putaminal, thalamic, and lobar hemorrhages are prone to occur in specific ages and SVD states: putaminal in young patients, thalamic in old and high SVD burden patients, and lobar hemorrhages in old and low SVD burden patients. Susceptibility to bleeding with aging or severe SVD accumulation seems to differ considerably among brain locations.
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http://dx.doi.org/10.1159/000515411DOI Listing
April 2021

Subterahertz collective dynamics of polar vortices.

Nature 2021 Apr 14;592(7854):376-380. Epub 2021 Apr 14.

Advanced Photon Source, Argonne National Laboratory, Lemont, IL, USA.

The collective dynamics of topological structures are of interest from both fundamental and applied perspectives. For example, studies of dynamical properties of magnetic vortices and skyrmions have not only deepened our understanding of many-body physics but also offered potential applications in data processing and storage. Topological structures constructed from electrical polarization, rather than electron spin, have recently been realized in ferroelectric superlattices, and these are promising for ultrafast electric-field control of topological orders. However, little is known about the dynamics underlying the functionality of such complex extended nanostructures. Here, using terahertz-field excitation and femtosecond X-ray diffraction measurements, we observe ultrafast collective polarization dynamics that are unique to polar vortices, with orders-of-magnitude higher frequencies and smaller lateral size than those of experimentally realized magnetic vortices. A previously unseen tunable mode, hereafter referred to as a vortexon, emerges in the form of transient arrays of nanoscale circular patterns of atomic displacements, which reverse their vorticity on picosecond timescales. Its frequency is considerably reduced (softened) at a critical strain, indicating a condensation (freezing) of structural dynamics. We use first-principles-based atomistic calculations and phase-field modelling to reveal the microscopic atomic arrangements and corroborate the frequencies of the vortex modes. The discovery of subterahertz collective dynamics in polar vortices opens opportunities for electric-field-driven data processing in topological structures with ultrahigh speed and density.
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http://dx.doi.org/10.1038/s41586-021-03342-4DOI Listing
April 2021

Profiles of 5α-Reduced Androgens in Humans and Eels: 5α-Dihydrotestosterone and 11-Ketodihydrotestosterone Are Active Androgens Produced in Eel Gonads.

Front Endocrinol (Lausanne) 2021 23;12:657360. Epub 2021 Mar 23.

Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University, Kumamoto, Japan.

Although 11-ketotestosterone (11KT) and testosterone (T) are major androgens in both teleosts and humans, their 5α-reduced derivatives produced by steroid 5α-reductase (SRD5A/srd5a), i.e., 11-ketodihydrotestosterone (11KDHT) and 5α-dihydrotestosterone (DHT), remains poorly characterized, especially in teleosts. In this study, we compared the presence and production of DHT and 11KDHT in Japanese eels and humans. Plasma 11KT concentrations were similar in both male and female eels, whereas T levels were much higher in females. In accordance with the levels of their precursors, 11KDHT levels did not show sexual dimorphism, whereas DHT levels were much higher in females. It is noteworthy that plasma DHT levels in female eels were higher than those in men. In addition, plasma 11KDHT was undetectable in both sexes in humans, despite the presence of 11KT. Three srd5a genes (, and ) were cloned from eel gonads. All three genes were expressed in the ovary, whereas only both srd5a2 genes were expressed in the testis. Human was expressed in testis, ovary and adrenal, whereas was expressed only in testis. Human SRD5A1, SRD5A2 and both eel srd5a2 isoforms catalyzed the conversion of T and 11KT into DHT and 11KDHT, respectively, whereas only eel srd5a1 converted T into DHT. DHT and 11KDHT activated eel androgen receptor (ar)α-mediated transactivation as similar fashion to T and 11KT. In contrast, human AR and eel arβ were activated by DHT and11KDHT more strongly than T and 11KT. These results indicate that in teleosts, DHT and 11KDHT may be important 5α-reduced androgens produced in the gonads. In contrast, DHT is the only major 5α-reduced androgens in healthy humans.
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http://dx.doi.org/10.3389/fendo.2021.657360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021924PMC
March 2021

Early anti-SARS-CoV-2 immunoglobulin G response may be associated with disease severity in patients with COVID-19.

Jpn J Infect Dis 2021 Feb 26. Epub 2021 Feb 26.

Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Japan.

Most COVID-19 patients are mild or asymptomatic; a substantial minority of patients develop severe or critical disease. There are many reports on potential risk factors for severe disease, but few reports have reported a relationship between antibody titer and severity in Japan. Antibody-dependent enhancement (ADE) is one such factor theorized to affect the worsening of disease. We have been evaluating IgG responses in COVID-19 patients at our tertiary hospital. A measure of interest is the IgG index, we assigned 1.4 as the cutoff value for a positive result according to the manufacturer indication and observed that patients could be categorised into two distinct groups: early elevation of IgG and late elevation of IgG (IgG elevated in the first 7 days ± 2 days or more than 10 days after symptom onset). We defined the former as early-IgG responders (N=7) and the latter as late-IgG responders (N=14) and compared them. C-reactive protein and D-dimer levels were significantly higher on admission (HD 0) and the respiratory rate was higher, lymphocytes were lower significantly on day 7 of hospitalization (HD 7) in the early-IgG responders. These results might implicate that early production of anti-severe acute respiratory syndrome coronavirus 2 IgG may be associated with clinical indicator for severity.
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http://dx.doi.org/10.7883/yoken.JJID.2020.799DOI Listing
February 2021

11-Ketotestosterone is a major androgen produced in porcine adrenal glands and testes.

J Steroid Biochem Mol Biol 2021 Jun 17;210:105847. Epub 2021 Feb 17.

Center for Animal Disease Control, University of Miyazaki, Miyazaki 889-1692, Japan.

Porcine steroid hormone profiles have some unique characteristics. We previously studied human and murine steroidogenesis using steroidogenic cells-derived from mesenchymal stem cells (MSCs). To investigate porcine steroidogenesis, we induced steroidogenic cells from porcine subcutaneous preadipocytes (PSPA cells), which originate from MSCs. Using cAMP, adenovirus-mediated introduction of steroidogenic factor-1 (SF-1)/adrenal 4-binding protein (Ad4BP) induced the differentiation of PSPA cells into sex steroid-producing cells. Introducing SF-1/Ad4BP also induced the aldo-keto reductase 1C1 (AKR1C1) gene. Porcine AKR1C1 had 17β-hydroxysteroid dehydrogenase activity, which converts androstenedione and 11-ketoandrostenedione into testosterone (T) and 11-ketotestosteorne (11KT). Furthermore, differentiated cells expressed hydroxysteroid 11β-dehydrogenase 2 (HSD11B2) and produced 11KT. HSD11B2 was expressed in testicular Leydig cells and the adrenal cortex. 11KT was present in the plasma of both immature male and female pigs, with slightly higher levels in the male pigs. T levels were much higher in the male pigs. It is noteworthy that in the female pigs, the 11KT levels were >10-fold higher than the T levels. However, castration altered the 11KT and T plasma profiles in the male pigs to near those of the females. 11KT induced endothelial nitric oxide synthase (eNOS) in porcine vascular endothelial cells. These results indicate that 11KT is produced in porcine adrenal glands and testes, and may regulate cardiovascular functions through eNOS expression.
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http://dx.doi.org/10.1016/j.jsbmb.2021.105847DOI Listing
June 2021

A self-referenced in-situ arrival time monitor for X-ray free-electron lasers.

Sci Rep 2021 Feb 11;11(1):3562. Epub 2021 Feb 11.

European XFEL GmbH, Holzkoppel 4, 22869, Schenefeld, Germany.

We present a novel, highly versatile, and self-referenced arrival time monitor for measuring the femtosecond time delay between a hard X-ray pulse from a free-electron laser and an optical laser pulse, measured directly on the same sample used for pump-probe experiments. Two chirped and picosecond long optical supercontinuum pulses traverse the sample with a mutually fixed time delay of 970 fs, while a femtosecond X-ray pulse arrives at an instant in between both pulses. Behind the sample the supercontinuum pulses are temporally overlapped to yield near-perfect destructive interference in the absence of the X-ray pulse. Stimulation of the sample with an X-ray pulse delivers non-zero contributions at certain optical wavelengths, which serve as a measure of the relative arrival time of the X-ray pulse with an accuracy of better than 25 fs. We find an excellent agreement of our monitor with the existing timing diagnostics at the SACLA XFEL with a Pearson correlation value of 0.98. We demonstrate a high sensitivity to measure X-ray pulses with pulse energies as low as 30 [Formula: see text]J. Using a free-flowing liquid jet as interaction sample ensures the full replacement of the sample volume for each X-ray/optical event, thus enabling its utility even at MHz repetition rate XFEL sources.
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http://dx.doi.org/10.1038/s41598-021-82597-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878505PMC
February 2021

A new double level osteotomy procedure to restore a joint line and joint angles in severe varus osteoarthritis. - Double level osteotomy associated with tibial condylar valgus osteotomy (DLOTO).

Asia Pac J Sports Med Arthrosc Rehabil Technol 2021 Apr 31;24:9-13. Epub 2020 Dec 31.

Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Hondo 1-1-1, 010-8543, Akita, Japan.

High tibial valgus osteotomy (HTO) is a well-established surgical procedure to correct a varus malalignment and treat medial compartment osteoarthritis. Recently, double level osteotomy (DLO) was recommended for extensive varus knees as a single level osteotomy (SLO) approach may create an excessive joint line obliquity and eventually result in a new bony deformity. However, a severe varus knee in cases of advanced osteoarthritis involves not only a bony deformity (extra-articular deformity) but also a medial joint space narrowing with a widened lateral joint space (intra-articular deformity). A DLO alone cannot reduce this intra-articular deformity. However, tibial condylar valgus osteotomy (TCVO) can complement DLO as to reduce this intra-articular deformity. This technical note describes a novel modified DLO procedure associated with TCVO which can restore a normal alignment and a joint line and achieve joint preservation even in cases of extensive varus osteoarthritis.
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http://dx.doi.org/10.1016/j.asmart.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787959PMC
April 2021

Visualization of dynamic polaronic strain fields in hybrid lead halide perovskites.

Nat Mater 2021 May 4;20(5):618-623. Epub 2021 Jan 4.

Stanford Institute for Materials and Energy Sciences, SLAC National Accelerator Laboratory, Menlo Park, CA, USA.

Excitation localization involving dynamic nanoscale distortions is a central aspect of photocatalysis, quantum materials and molecular optoelectronics. Experimental characterization of such distortions requires techniques sensitive to the formation of point-defect-like local structural rearrangements in real time. Here, we visualize excitation-induced strain fields in a prototypical member of the lead halide perovskites via femtosecond resolution diffuse X-ray scattering measurements. This enables momentum-resolved phonon spectroscopy of the locally distorted structure and reveals radially expanding nanometre-scale strain fields associated with the formation and relaxation of polarons in photoexcited perovskites. Quantitative estimates of the magnitude and shape of this polaronic distortion are obtained, providing direct insights into the dynamic structural distortions that occur in these materials. Optical pump-probe reflection spectroscopy corroborates these results and shows how these large polaronic distortions transiently modify the carrier effective mass, providing a unified picture of the coupled structural and electronic dynamics that underlie the optoelectronic functionality of the hybrid perovskites.
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http://dx.doi.org/10.1038/s41563-020-00865-5DOI Listing
May 2021

Comparison of IgG antibodies, SARS-CoV-2 load, and prognostic indicators in patients with severe and mild COVID-19 in Japan.

J Nippon Med Sch 2020 Nov 30. Epub 2020 Nov 30.

Department of Microbiology and Infectious Diseases, Toho University School of Medicine.

We assessed the relationship between disease severity and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) load, IgG antibody levels, and prognostic indicators. Twenty-one patients hospitalized with COVID-19 were classified as having severe or mild disease based on their average respiratory rate during hospitalization (severe: ≥22 breaths/min; mild: <22 breaths/min). The viral load in nasopharyngeal samples, and blood levels of C-reactive protein (CRP), lymphocytes, and D-dimer on admission and plasma immunoglobulin G (IgG) index on Day 7 ±2 from symptom onset were compared according to disease severity. Of the participants, 7 had severe and 14 had mild disease. Participants with severe disease had a significantly higher IgG index (median: 3.75 vs 0.56, p=0.01), CRP (median: 8.6 vs 1.0 mg/dL, p<0.001), and D-dimer levels (median: 1.65 vs 0.75μg/mL; p=0.002), and a significantly lower lymphocyte count (median: 1176 vs 666 cells/μL, p=0.005) and viral load (median: 8.7×10 vs 2.3×10 copies/mL, p=0.005). Furthermore, time from symptom onset to virus disappearance was significantly longer (median: 24 vs 17 days, p=0.03). A high IgG index in the early phase of the disease may be associated with disease severity and might serve as a prognostic indicator.
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http://dx.doi.org/10.1272/jnms.JNMS.2021_88-417DOI Listing
November 2020

Time-resolved characterization of organic compounds in PM collected at Oki Island, Japan, affected by transboundary pollution of biomass and non-biomass burning from Northeast China.

Sci Total Environ 2021 Jan 14;750:142183. Epub 2020 Sep 14.

National Institute for Environmental studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.

To evaluate the transboundary pollution of organic aerosols from Northeast Asia, a highly time-resolved measurement of organic compounds was performed in March 2019 at Oki Island located in Japan, which is a remote site and less affected by local anthropogenic sources. PM, water-soluble organic carbon (WSOC) concentrations, and WSOC fraction in PM showed high values on March 22-23 (high-WSOC period (HWSOC)) when the air mass passed through the area where many fire spots were detected in Northeast China. Biomass burning tracers showed higher concentration, especially levoglucosan exceeded 1 μg/m during the HWSOC than the low-WSOC period (LWSOC). Notably, high time-resolved measurements of biomass burning tracers and back trajectory analysis during HWSOC revealed a difference in the variation of lignin pyrolyzed compounds and anhydrous sugars on 22 and 23 March. The air mass passed to different areas in Northeast China in which fire spots were detected, such as the eastern area on the 22nd and the western area on the 23rd. Almost-organic compounds also showed high concentration and strong correlations with levoglucosan and sulfate during HWSOC. Moreover, low-carbon dicarboxylic acids (e.g., adipic acid) and secondary products from anthropogenic volatile organic compounds (e.g., 2,3-dihydroxy-4-oxopentanoic, phthalic, 5-nitrosalicylic acids), also showed a strong correlation with sulfate ions during the HWSOC and LWSOC, respectively. These higher concentrations and strong correlations with levoglucosan and sulfate during the HWSOC propose that their generation could be enhanced by biomass burning. The ratios of organics (e.g., levoglucosan/mannnosan, pinic/3-methylbutane-1,2,3-tricarboxylic acids) suggest that the high concentrations of PM and WSOC observed during the HWSOC were caused by aged organic aerosols that originated from the combustion of herbaceous plants transported from Northeast China. Our findings indicate that biomass combustion in Northeast China could significantly affect the chemical compositions and the characterization of organic aerosols in downwind regions of Northeast China.
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http://dx.doi.org/10.1016/j.scitotenv.2020.142183DOI Listing
January 2021

Speckle correlation as a monitor of X-ray free-electron laser induced crystal lattice deformation.

J Synchrotron Radiat 2020 Nov 9;27(Pt 6):1470-1476. Epub 2020 Oct 9.

Linac Coherent Light Source, SLAC National Accelerator Laboratory, 2575 Sand Hill Road, Menlo Park, CA 94025, USA.

X-ray free-electron lasers (X-FELs) present new opportunities to study ultrafast lattice dynamics in complex materials. While the unprecedented source brilliance enables high fidelity measurement of structural dynamics, it also raises experimental challenges related to the understanding and control of beam-induced irreversible structural changes in samples that can ultimately impact the interpretation of experimental results. This is also important for designing reliable high performance X-ray optical components. In this work, X-FEL beam-induced lattice alterations are investigated by measuring the shot-to-shot evolution of near-Bragg coherent scattering from a single crystalline germanium sample. It is shown that X-ray photon correlation analysis of sequential speckle patterns measurements can be used to monitor the nature and extent of lattice rearrangements. Abrupt, irreversible changes are observed following intermittent high-fluence monochromatic X-ray pulses, thus revealing the existence of a threshold response to X-FEL pulse intensity.
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http://dx.doi.org/10.1107/S1600577520011509DOI Listing
November 2020

Right ventriculo-pulmonary arterial uncoupling and poor outcomes in pulmonary arterial hypertension.

Pulm Circ 2020 Jul-Sep;10(3):2045894020957223. Epub 2020 Oct 5.

First Department of Medicine, Hokkaido University Hospital, Sapporo, Japan.

Right ventricular function critically affects the prognosis of patients with pulmonary arterial hypertension. We aimed to analyze the prognostic value of right ventricular indices calculated using magnetic resonance imaging and right heart catheterization metrics in pulmonary arterial hypertension. We retrospectively collected data from 57 Japanese patients with pulmonary arterial hypertension and 18 controls and calculated six indices of right ventricular function: two indices of contractility (end-systolic elastance calculated with right ventricular maximum pressure and with magnetic resonance imaging metrics); two indices of right ventricular-pulmonary arterial coupling (end-systolic elastance/arterial elastance calculated with the pressure method (end-systolic elastance/arterial elastance (P)) and with the volume method (end-systolic elastance/arterial elastance (V)); and two indices of right ventricular diastolic function (stiffness (β) and end-diastolic elastance). We compared the indices between controls and patients with pulmonary arterial hypertension and examined their prognostic role. In patients with pulmonary arterial hypertension, end-systolic elastance (right ventricular maximum pressure) was higher (pulmonary arterial hypertension 0.94 (median) vs control 0.42 (mmHg/mL),  < 0.001), end-systolic elastance/arterial elastance (V) was lower (pulmonary arterial hypertension 0.72 vs control 1.69,  < 0.001), and β and end-diastolic elastance were significantly higher than those in the controls. According to the log-rank test, end-systolic elastance/arterial elastance (P) and end-diastolic elastance were significantly associated with the composite event rate. According to the multivariate Cox regression analysis, decreased end-systolic elastance/arterial elastance (P) was associated with a higher composite event rate (hazard ratio 11.510, 95% confidence interval: 1.954-67.808). In conclusion, an increased right ventricular contractility, diastolic dysfunction, and a trend of impaired right ventricular-pulmonary arterial coupling were observed in our pulmonary arterial hypertension cohort. According to the multivariate outcome analysis, a decreased end-systolic elastance/arterial elastance (P), suggestive of impaired right ventricular-pulmonary arterial coupling, best predicted the pulmonary arterial hypertension-related event.
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http://dx.doi.org/10.1177/2045894020957223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543138PMC
October 2020

Publisher Correction: Dysregulation of ghrelin in diabetes impairs the vascular reparative response to hindlimb ischemia in a mouse model; clinical relevance to peripheral artery disease.

Sci Rep 2020 Oct 13;10(1):17556. Epub 2020 Oct 13.

Department of Physiology, School of Biomedical Sciences and HeartOtago, University of Otago, 270 Great King Street, Dunedin, 9018, New Zealand.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-73064-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555515PMC
October 2020

Pulmonary capillary hemangiomatosis-predominant vasculopathy in a patient with rheumatoid arthritis-associated interstitial lung disease: An autopsy report.

Respir Med Case Rep 2020 8;31:101215. Epub 2020 Sep 8.

First Department of Medicine, Hokkaido University Hospital, Kita-14, Nishi-5, Kita-ku, Sapporo, 060-8648, Japan.

Pulmonary capillary hemangiomatosis (PCH) is a rare cause of pulmonary hypertension (PH) associated with poor prognosis. Clinically, it is characterized by severe hypoxemia, centrilobular ground-glass opacities on computed tomography, and pulmonary congestion triggered by pulmonary vasodilating therapy. In some cases, PCH has been reported to develop with other disorders including connective tissue disease; however, to date, no reports have described PCH in a patient with rheumatoid arthritis. We report a case of a 59-year-old male PCH patient with rheumatoid arthritis and associated pulmonary fibrosis. He was initially diagnosed with severe group 3 PH and received sildenafil, which generated a favorable hemodynamic response. However, 5 years later, his pulmonary hemodynamics deteriorated, and he died at the age of 67. An autopsy was performed, and thickening of alveolar septa and capillary proliferation, pathological features of PCH, were extensively observed in both lungs. We discuss when PCH developed, how sildenafil improved his hemodynamics, and how PCH could be clinically detected by noninvasive evaluations.
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http://dx.doi.org/10.1016/j.rmcr.2020.101215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527749PMC
September 2020

Successful treatment of a habitual patellar dislocation after a total knee arthroplasty with a closing-wedge distal femoral varus osteotomy and medial patello-femoral ligament reconstruction.

J Exp Orthop 2020 Sep 1;7(1):63. Epub 2020 Sep 1.

Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Hondo 1-1-1, Akita, 010-8543, Japan.

A 68-year-old female suffering from habitual patellar dislocations following a mal-positioned total knee arthroplasty (TKA) was successfully treated with a biplanar closed wedge distal femoral osteotomy (CWDFO) and medial patello-femoral ligament (MPFL) reconstruction. To the best of our knowledge, no such case has been previously described. Our experience with this case suggests that treatment for a patella dislocation following valgus mal-positioning of TKA should be considered positively. LEVEL OF EVIDENCE: V.
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http://dx.doi.org/10.1186/s40634-020-00281-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462943PMC
September 2020

Dysregulation of ghrelin in diabetes impairs the vascular reparative response to hindlimb ischemia in a mouse model; clinical relevance to peripheral artery disease.

Sci Rep 2020 08 12;10(1):13651. Epub 2020 Aug 12.

Department of Physiology, School of Biomedical Sciences and HeartOtago, University of Otago, 270 Great King Street, Dunedin, 9018, New Zealand.

Type 2 diabetes is a prominent risk factor for peripheral artery disease (PAD). Yet, the mechanistic link between diabetes and PAD remains unclear. This study proposes that dysregulation of the endogenous hormone ghrelin, a potent modulator of vascular function, underpins the causal link between diabetes and PAD. Moreover, this study aimed to demonstrate the therapeutic potential of exogenous ghrelin in a diabetic mouse model of PAD. Standard ELISA analysis was used to quantify and compare circulating levels of ghrelin between (i) human diabetic patients with or without PAD (clinic) and (ii) db/db diabetic and non-diabetic mice (lab). Db/db mice underwent unilateral hindlimb ischaemia (HLI) for 14 days and treated with or without exogenous ghrelin (150 µg/kg/day.) Subsequently vascular reparation, angiogenesis, hindlimb perfusion, structure and function were assessed using laser Doppler imaging, micro-CT, microangiography, and protein and micro-RNA (miRNA) analysis. We further examined hindlimb perfusion recovery of ghrelin KO mice to determine whether an impaired vascular response to HLI is linked to ghrelin dysregulation in diabetes. Patients with PAD, with or without diabetes, had significantly lower circulating levels of endogenous ghrelin, compared to healthy individuals. Diabetic db/db mice had ghrelin levels that were only 7% of non-diabetic mice. The vascular reparative capacity of diabetic db/db mice in response to HLI was impaired compared to non-diabetic mice and, importantly, comparable to ghrelin KO mice. Daily therapeutic treatment of db/db mice with ghrelin for 14 days post HLI, stimulated angiogenesis, and improved skeletal muscle architecture and cell survival, which was associated with an increase in pro-angiogenic miRNAs-126 and -132. These findings unmask an important role for endogenous ghrelin in vascular repair following limb ischemia, which appears to be downregulated in diabetic patients. Moreover, these results implicate exogenous ghrelin as a potential novel therapy to enhance perfusion in patients with lower limb PAD, especially in diabetics.
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http://dx.doi.org/10.1038/s41598-020-70391-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423620PMC
August 2020

Multiple Association-Dissociation Equilibria in Solutions of Amphiphilic Molecules.

Langmuir 2020 07 14;36(29):8323-8343. Epub 2020 Jul 14.

Department of Macromolecular Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan.

Amphiphilic molecules form micelles and complexes with proteins in solutions to provide unique functions, utilized in various fields of chemistry and biology, and multiple association-dissociation equilibria, governing the micellization and complexation, are key issues in these fields. The present feature article first presents an overview of theoretical backgrounds of the multiple association-dissociation equilibria in solutions of amphiphiles and then applies the theoretical results to the following four solution systems of amphiphilic molecules to understand their micellization and complexation behavior: the reverse micelle of the polymer living anion, the hydrophobe-uptake spherical micelle, the cylindrical micelle of surfactants, and the protein-surfactant complex.
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http://dx.doi.org/10.1021/acs.langmuir.0c01067DOI Listing
July 2020

Conformation of Pullulan in Aqueous Solution Studied by Small-Angle X-Ray Scattering.

Polymers (Basel) 2020 Jun 1;12(6). Epub 2020 Jun 1.

Department of Macromolecular Science, Osaka University, Toyonaka Osaka 560-0043, Japan.

Small-angle X-ray scattering functions were measured for six pullulan samples with molecular weights ranging from 2.3 × 10 to 7.4 × 10 in 0.05 M aqueous NaCl at 25 °C and fitted by the perturbed wormlike chain model, comprising touched-bead sub-bodies, to obtain wormlike chain parameters. The parameter values determined were consistent with those determined from previously reported dilute solution properties of aqueous pullulan. Because radii of gyration of not only pullulan polymers, but also pullulan oligomers were consistently explained by the touched-bead wormlike chain model perturbed by the excluded volume effect, the pullulan chain takes a local conformation considerably different from the amylose chain, although both polysaccharides are flexible polymers with an approximately same characteristic ratio.
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http://dx.doi.org/10.3390/polym12061266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362014PMC
June 2020

Empagliflozin attenuates neointimal hyperplasia after drug-eluting-stent implantation in patients with type 2 diabetes.

Heart Vessels 2020 Oct 12;35(10):1378-1389. Epub 2020 May 12.

Department of Cardiology, NTT Medical Center Tokyo, 5-9-22 Higashigotanda, Shinagawa, Tokyo, 141-0022, Japan.

The effects of empagliflozin, a sodium-glucose co-transporter 2 inhibitor, on neointimal response after drug-eluting-stent (DES) implantation remains unknown. Insufficiently controlled diabetes patients with coronary artery disease planned for DES stenting were consecutively enrolled. The patients were assigned to receive empagliflozin in addition to standard therapy or intensive therapy using other glucose-lowering drugs (oGLD). The primary endpoint was thickness of neointimal hyperplasia (NIH) 12 months after stenting assessed by optical coherence tomography (OCT). A total of 28 patients were analyzed (n = 15 in the empagliflozin group, n = 13 in the oGLD group). The levels of glucose profile were not significantly different between both groups at follow-up [HbA1c; 7.2 ± 0.8 vs 7.3 ± 0.9%, p = 0.46]. In OCT analysis, neointima was significantly less in the empagliflozin group than the oGLD group [mean NIH thickness: 137 ± 32 vs 168 ± 39 μm, p = 0.02]. Changes of systolic and diastolic blood pressure (BP), changes of body mass index, and changes of hematocrit after additional treatment were significantly associated with NIH attenuation, whereas no correlation was observed in changes in blood glucose parameters. Multivariate logistic regression analysis revealed that changes in systolic BP was the strongest predictor for NIH attenuation, followed by changes in diastolic BP. In patients with type 2 diabetes, standard plus empagliflozin attenuated neointimal progression as compared with intensive standard therapy after DES implantation. Our data possibly support a beneficial effect of empagliflozin in type 2 diabetes required for coronary revascularization therapy.
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http://dx.doi.org/10.1007/s00380-020-01621-0DOI Listing
October 2020

Multi-Beat Right Ventricular-Arterial Coupling Predicts Clinical Worsening in Pulmonary Arterial Hypertension.

J Am Heart Assoc 2020 05 8;9(10):e016031. Epub 2020 May 8.

Department of Medicine Medical University of South Carolina Charleston SC.

Background Although right ventricular (RV) to pulmonary arterial (RV-PA) coupling is considered the gold standard in assessing RV dysfunction, its ability to predict clinically significant outcomes is poorly understood. We assessed the ability of RV-PA coupling, determined by the ratio of multi-beat (MB) end-systolic elastance (Ees) to effective arterial elastance (Ea), to predict clinical outcomes. Methods and Results Twenty-six subjects with pulmonary arterial hypertension (PAH) underwent same-day cardiac magnetic resonance imaging, right heart catheterization, and RV pressure-volume assessment with MB determination of Ees/Ea. RV ejection fraction (RVEF), stroke volume/end-systolic volume, and single beat-estimated Ees/Ea were also determined. Patients were treated with standard therapies and followed prospectively until they met criteria of clinical worsening (CW), as defined by ≥10% decline in 6-minute walk distance, worsening World Health Organization (WHO) functional class, PAH therapy escalation, RV failure hospitalization, or transplant/death. Subjects were 57±14 years, largely WHO class III (50%) at enrollment, with preserved average RV ejection fraction (RVEF) (47±11%). Mean follow-up was 3.2±1.3 years. Sixteen (62%) subjects met CW criteria. MB Ees/Ea was significantly lower in CW subjects (0.7±0.5 versus 1.3±0.8, =0.02). The optimal MB Ees/Ea cut-point predictive of CW was 0.65, defined by ROC (AUC 0.78, =0.01). MB Ees/Ea below this cut-point was significantly associated with time to CW (hazard ratio 5.1, =0.001). MB Ees/Ea remained predictive of outcomes following multivariate adjustment for timing of PAH diagnosis and PAH diagnosis subtype. Conclusions RV-PA coupling as measured by MB Ees/Ea has prognostic significance in human PAH, even in a cohort with preserved RVEF.
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http://dx.doi.org/10.1161/JAHA.119.016031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660856PMC
May 2020

The ePix10k 2-megapixel hard X-ray detector at LCLS.

J Synchrotron Radiat 2020 May 17;27(Pt 3):608-615. Epub 2020 Apr 17.

SLAC National Accelerator Laboratory, 2575 Sand Hill Road, Menlo Park, CA 94025, USA.

The ePix10ka2M (ePix10k) is a new large area detector specifically developed for X-ray free-electron laser (XFEL) applications. The hybrid pixel detector was developed at SLAC to provide a hard X-ray area detector with a high dynamic range, running at the 120 Hz repetition rate of the Linac Coherent Light Source (LCLS). The ePix10k consists of 16 modules, each with 352 × 384 pixels of 100 µm × 100 µm distributed on four ASICs, resulting in a 2.16 megapixel detector, with a 16.5 cm × 16.5 cm active area and ∼80% coverage. The high dynamic range is achieved with three distinct gain settings (low, medium, high) as well as two auto-ranging modes (high-to-low and medium-to-low). Here the three fixed gain modes are evaluated. The resulting dynamic range (from single photon counting to 10000 photons pixel pulse at 8 keV) makes it suitable for a large number of different XFEL experiments. The ePix10k replaces the large CSPAD in operation since 2011. The dimensions of the two detectors are similar, making the upgrade from CSPAD to ePix10k straightforward for most setups, with the ePix10k improving on experimental performance. The SLAC-developed ePix cameras all utilize a similar platform, are tailored to target different experimental conditions and are designed to provide an upgrade path for future high-repetition-rate XFELs. Here the first measurements on this new ePix10k detector are presented and the performance under typical XFEL conditions evaluated during an LCLS X-ray diffuse scattering experiment measuring the 9.5 keV X-ray photons scattered from a thin liquid jet.
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http://dx.doi.org/10.1107/S1600577520004257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206547PMC
May 2020

Serum Biomarkers Identify Patients Who Will Develop Inflammatory Bowel Diseases Up to 5 Years Before Diagnosis.

Gastroenterology 2020 07 9;159(1):96-104. Epub 2020 Mar 9.

Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background & Aims: Biomarkers are needed to identify patients at risk for development of inflammatory bowel diseases. We aimed to identify serum biomarkers of Crohn's disease and ulcerative colitis that can be detected and quantified before diagnosis.

Methods: We obtained serum samples from patients archived before a diagnosis of Crohn's disease (n = 200) or ulcerative colitis (n = 199), as well as from 200 healthy individuals (controls), collected from 1998 through 2013 as part of the US Defense Medical Surveillance System. We measured levels of antibodies against microbes (anti-Saccharomyces cerevisiae IgA or IgG, anti-Escherichiacoli outer membrane porin C, anti-CBir1, anti-flagellin 2, anti-flagellin X, and perinuclear anti-neutrophil cytoplasmic antibodies) and 1129 proteins in each sample. We then used functional principal component analysis to derive the time-varying trajectory for each marker, which then was used in a multivariate model to predict disease status. Predictive performances at different prediagnosis timepoints were evaluated using area under the receiver operating characteristic curves (AUROCs). Biological pathways that were up-regulated in serum from patients with Crohn's disease were identified based on changes in protein abundance at different time periods preceding diagnosis.

Results: We identified a panel of 51 protein biomarkers that were predictive of Crohn's disease within 5 years with an AUROC of 0.76 and a diagnosis within 1 year with an AUROC of 0.87. Based on the proteins included in the panel, imminent development of CD was associated with changes in the complement cascade, lysosomes, innate immune response, and glycosaminoglycan metabolism. Serum antibodies and proteins identified patients who received a diagnosis of ulcerative colitis within 5 years with an AUROC of only 0.56 and within 1 year with an AUROC of 0.72.

Conclusions: We identified a panel of serum antibodies and proteins that were predictive of patients who will receive a diagnosis of Crohn's disease within 5 years with high accuracy. By contrast we did not identify biomarkers associated with future diagnosis of ulcerative colitis.
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http://dx.doi.org/10.1053/j.gastro.2020.03.007DOI Listing
July 2020

Functional Impact of Human Genetic Variants of /Endostatin on Pulmonary Endothelium.

Am J Respir Cell Mol Biol 2020 04;62(4):524-534

Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.

Pulmonary arterial hypertension (PAH) is an incurable disease characterized by disordered and dysfunctional angiogenesis leading to small-vessel loss and an obliterative vasculopathy. The pathogenesis of PAH is not fully understood, but multiple studies have demonstrated links between elevated angiostatic factors, disease severity, and adverse clinical outcomes. ES (endostatin), one such circulating angiostatic peptide, is the cleavage product of the proteoglycan (collagen α1[XVIII] chain). Elevated serum ES is associated with increased mortality and disease severity in PAH. A nonsynonymous variant of ES (aspartic acid-to-asparagine substitution at amino acid 104; p.D104N) is associated with differences in PAH survival. Although /ES expression is markedly increased in remodeled pulmonary vessels in PAH, the impact of ES on pulmonary endothelial cell (PEC) biology and molecular contributions to PAH severity remain undetermined. In the present study, we characterized the effects of exogenous ES on human PEC biology and signaling. We demonstrated that ES inhibits PEC migration, proliferation, and cell survival, with significant differences between human variants, indicating that they are functional genetic variants. ES promotes proteasome-mediated degradation of the transcriptional repressor ID1, increasing expression and release of TSP-1 (thrombospondin 1). ES inhibits PEC migration via an ID1/TSP-1/CD36-dependent pathway, in contrast to proliferation and apoptosis, which require both CD36 and CD47. Collectively, the data implicate ES as a novel negative regulator of ID1 and an upstream propagator of an angiostatic signal cascade converging on CD36 and CD47, providing insight into the cellular and molecular effects of a functional genetic variant linked to altered outcomes in PAH.
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http://dx.doi.org/10.1165/rcmb.2019-0056OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7110972PMC
April 2020

Delivery and Effectiveness of Carboplatin via Targeted Delivery Compared to Passive Accumulation of Intravenously Injected Particles Releasing Carboplatin upon Irradiation.

Radiat Res 2020 03 7;193(3):263-273. Epub 2020 Jan 7.

Department of Radiology, School of Medicine, Iwate Medical University, Morioka, Iwate 020-8505 Japan.

In this study, nanoparticles that release anticancer drugs upon irradiation were developed. Here, MM46 and MM48 tumors in C3He/N mice were irradiated. Furthermore, the intravenously (i.v.) injected nanoparticles were tested for their ability to deliver the anticancer drug, increase the antitumor effect via a synergistic effect of combining targeted anticancer drugs with radiation and decrease adverse effects by localizing the anticancer drug. The nanoparticles were prepared by spraying a mixture of hyaluronic acid and alginate, supplemented with carboplatin, into a solution of CaCl and FeCl through a 0.8-lm-pore stainless mesh filter. Nanoparticles (1 × 10) were i.v. injected and irradiated (100-KeV soft X rays, 10-40 Gy) when the accumulation of particles peaked. The nanoparticles were 547 ± 43 nm in diameter. The i.v.-injected nanoparticles accumulated around tumors. Maximum accumulations were observed 9 h post-injection. Subsequently, 10-40 Gy of radiation was administered. The accumulated nanoparticles released the carboplatin and gelatinized their outer shells, which prolonged the intra-tumor concentration of carboplatin and increased the radiation-induced synergistic antitumor effect. The localization of carboplatin by nanoparticles significantly reduced the adverse effects of the anticancer drug.
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http://dx.doi.org/10.1667/RR15357.1DOI Listing
March 2020

A histopathological report of a 16-year-old male with peripheral pulmonary artery stenosis and Moyamoya disease with a homozygous mutation.

Respir Med Case Rep 2020 14;29:100977. Epub 2019 Dec 14.

First Department of Medicine, Hokkaido University School of Medicine, North 15, West 7, Kita-ku, Sapporo, 060-8638, Japan.

Peripheral pulmonary artery stenosis (PPAS) is a rare pulmonary vasculopathy characterized by multiple stenoses and obstructions in the peripheral pulmonary arteries. PPAS often develops in children with congenital diseases such as Williams syndrome and Alagille syndrome; however, recent studies have reported PPAS cases in adults with Moyamoya disease (MMD). Recent genetic studies have demonstrated that ring finger protein 213 (RNF213) is a susceptibility gene for MMD. However, the pathophysiology of combined PPAS and MMD and the relationship between the two diseases remain largely unknown. Here we report a case of PPAS in a 16-year-old male, with a history of MMD, who died suddenly at 24. An autopsy was performed, and remarkable pathological changes were identified in the pulmonary arteries and in other arteries. Furthermore, genetic analysis revealed that the patient had a homozygous c.14576G > A (p.R4859K) mutation in RNF213. This is the first report to demonstrate the histopathology of systemic arteriopathy in a case with MMD and PPAS with a confirmed homozygous RNF213 mutation. We also review immunohistochemical data from the case and discuss how RNF213 mutation could have resulted in the observed vascular abnormalities.
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http://dx.doi.org/10.1016/j.rmcr.2019.100977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938952PMC
December 2019

Long-term safety and treatment outcomes of pegvisomant in Japanese patients with acromegaly: results from the post-marketing surveillance.

Endocr J 2020 Feb 13;67(2):201-210. Epub 2019 Nov 13.

Pfizer Japan Inc., Tokyo 151-8589, Japan.

This post-marketing surveillance is to investigate the long-term safety and effectiveness of the growth hormone receptor antagonist pegvisomant, which is used in patients with acromegaly in routine clinical practice. This surveillance included all cases treated with pegvisomant during the study period from the start of marketing (June 5, 2007) to December 2015. Data for 251 patients with acromegaly treated with pegvisomant were collected from 119 institutions nationwide in Japan. Eighty-five patients received pegvisomant monotherapy throughout their treatment, while 165 patients were treated with somatostatin analogue or dopamine agonist in combination with pegvisomant. Mean dose of pegvisomant was 10.6 ± 6.1 mg/day in the entire treatment period (except for initial loading dose). The incidence of adverse drug reactions was 35.6% (89/250). No new safety concerns related to long-term treatment were observed. The major investigation items of incidence of abnormal liver function and tumor enlargement were 16.0% (40/250), and 5.2% (13/250) respectively. Efficacy at the final evaluation point was 96.4% (217/225) based on the overall clinical judgement of attending physicians, and efficacy in each observation period was over 94%. Improvement in IGF-I levels and clinical symptoms scores were also observed by comparing the data at baseline with each observation point during treatment. IGF-I normalization rate was 68.2% at 5 years. Pegvisomant monotherapy showed similar improvement here as well. These results suggest that long-term treatment with pegvisomant is effective in clinical practice.
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http://dx.doi.org/10.1507/endocrj.EJ19-0266DOI Listing
February 2020