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Article ; Online: A proper sequence of dynamic alignment in transtibial prosthesis: insight through socket reaction moments.

Hashimoto, Hiroshi / Kobayashi, Toshiki / Gao, Fan / Kataoka, Masataka

2023 Volume 13, Issue 1, Page(s) 458

Abstract: Dynamic alignment in prosthetic fitting is important because it affects the user's stability, kinematics, and kinetics such as socket reaction moments. It is performed by tuning the spatial relationship between the transtibial prosthetic socket and the ... ...

Abstract	Dynamic alignment in prosthetic fitting is important because it affects the user's stability, kinematics, and kinetics such as socket reaction moments. It is performed by tuning the spatial relationship between the transtibial prosthetic socket and the foot following sequential observational gait analysis in the three anatomical planes. However, the order of planes in which the adjustment should be performed is still unclear. To investigate the appropriate sequence of dynamic alignment adjustment, ten participants with transtibial amputation were asked to walk in different alignment conditions (flexion, extension, adduction, abduction; lateral, medial, anterior, and posterior translation of the socket, and plantarflexion, dorsiflexion, inversion, and eversion of the foot) to measure socket reaction moments in the out-of-planes (e.g., the effect of sagittal alignment on the coronal moment). A significant difference was found only among socket posterior translation, socket flexion, and baseline alignment in the coronal moment (P = 0.02). The results of the current and previous studies suggest that moments in the coronal plane are affected by alignment changes in all three planes, whereas moments in the sagittal plane are affected only by sagittal alignment changes. It is suggested that the procedure of alignment adjustments should be finalized in the coronal plane.
MeSH term(s)	Humans ; Gait ; Artificial Limbs ; Tibia ; Amputees ; Amputation, Surgical ; Biomechanical Phenomena
Language	English
Publishing date	2023-01-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-27438-1
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Article ; Online: Structural basis for intra- and intermolecular interactions on RAD9 subunit of 9-1-1 checkpoint clamp implies functional 9-1-1 regulation by RHINO.

Hara, Kodai / Tatsukawa, Kensuke / Nagata, Kiho / Iida, Nao / Hishiki, Asami / Ohashi, Eiji / Hashimoto, Hiroshi

The Journal of biological chemistry

2024 Volume 300, Issue 3, Page(s) 105751

Abstract: Eukaryotic DNA clamp is a trimeric protein featuring a toroidal ring structure that binds DNA on the inside of the ring and multiple proteins involved in DNA transactions on the outside. Eukaryotes have two types of DNA clamps: the replication clamp PCNA ...

Abstract	Eukaryotic DNA clamp is a trimeric protein featuring a toroidal ring structure that binds DNA on the inside of the ring and multiple proteins involved in DNA transactions on the outside. Eukaryotes have two types of DNA clamps: the replication clamp PCNA and the checkpoint clamp RAD9-RAD1-HUS1 (9-1-1). 9-1-1 activates the ATR-CHK1 pathway in DNA damage checkpoint, regulating cell cycle progression. Structure of 9-1-1 consists of two moieties: a hetero-trimeric ring formed by PCNA-like domains of three subunits and an intrinsically disordered C-terminal region of the RAD9 subunit, called RAD9 C-tail. The RAD9 C-tail interacts with the 9-1-1 ring and disrupts the interaction between 9-1-1 and DNA, suggesting a negative regulatory role for this intramolecular interaction. In contrast, RHINO, a 9-1-1 binding protein, interacts with both RAD1 and RAD9 subunits, positively regulating checkpoint activation by 9-1-1. This study presents a biochemical and structural analysis of intra- and inter-molecular interactions on the 9-1-1 ring. Biochemical analysis indicates that RAD9 C-tail binds to the hydrophobic pocket on the PCNA-like domain of RAD9, implying that the pocket is involved in multiple protein-protein interactions. The crystal structure of the 9-1-1 ring in complex with a RHINO peptide reveals that RHINO binds to the hydrophobic pocket of RAD9, shedding light on the RAD9-binding motif. Additionally, the study proposes a structural model of the 9-1-1-RHINO quaternary complex. Together, these findings provide functional insights into the intra- and inter-molecular interactions on the front side of RAD9, elucidating the roles of RAD9 C-tail and RHINO in checkpoint activation.
MeSH term(s)	Humans ; Carrier Proteins/metabolism ; Cell Cycle Proteins/chemistry ; Cell Cycle Proteins/metabolism ; Checkpoint Kinase 1 ; DNA/metabolism ; DNA Damage ; DNA Repair ; Hydrophobic and Hydrophilic Interactions ; Multiprotein Complexes/chemistry ; Multiprotein Complexes/metabolism ; Proliferating Cell Nuclear Antigen/metabolism ; Protein Subunits/chemistry ; Protein Subunits/metabolism ; Protein Domains
Chemical Substances	ATR protein, human (EC 2.7.11.1) ; Carrier Proteins ; Cell Cycle Proteins ; Checkpoint Kinase 1 (EC 2.7.11.1) ; CHEK1 protein, human (EC 2.7.11.1) ; DNA (9007-49-2) ; HUS1 protein, human ; Multiprotein Complexes ; PCNA protein, human ; Proliferating Cell Nuclear Antigen ; Protein Subunits ; Rad1 protein, human (EC 3.1.11.-) ; rad9 protein (139691-42-2) ; RHNO1 protein, human
Language	English
Publishing date	2024-02-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2024.105751
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Article: REV7 in Cancer Biology and Management.

Murakumo, Yoshiki / Sakurai, Yasutaka / Kato, Takuya / Hashimoto, Hiroshi / Ichinoe, Masaaki

Cancers

2023 Volume 15, Issue 6

Abstract: DNA repair and cell cycle regulation are potential biological fields to develop molecular targeting therapies for cancer. Human REV7 was originally discovered as a homologous molecule to yeast Rev7, which is involved in DNA damage response and ... ...

Abstract	DNA repair and cell cycle regulation are potential biological fields to develop molecular targeting therapies for cancer. Human REV7 was originally discovered as a homologous molecule to yeast Rev7, which is involved in DNA damage response and mutagenesis, and as the second homolog of yeast Mad2, involved in the spindle assembly checkpoint. Although REV7 principally functions in the fields of DNA repair and cell cycle regulation, many binding partners of REV7 have been identified using comprehensive analyses in the past decade, and the significance of REV7 is expanding in various other biological fields, such as gene transcription, epigenetics, primordial germ cell survival, neurogenesis, intracellular signaling, and microbial infection. In addition, the clinical significance of REV7 has been demonstrated in studies using human cancer tissues, and investigations in cancer cell lines and animal models have revealed the greater impacts of REV7 in cancer biology, which makes it an attractive target molecule for cancer management. This review focuses on the functions of REV7 in human cancer and discusses the utility of REV7 for cancer management with a summary of the recent development of inhibitors targeting REV7.
Language	English
Publishing date	2023-03-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15061721
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Article ; Online: Crystal structure of the sliding DNA clamp from the Gram-positive anaerobic bacterium Clostridioides difficile.

Hishiki, Asami / Okazaki, Sumire / Hara, Kodai / Hashimoto, Hiroshi

Journal of biochemistry

2022

Abstract: The sliding DNA clamp is a ring-shaped protein that encircles DNA within its central channel. It binds to multiple proteins, such as DNA polymerases and DNA repair enzymes, and stimulates their enzymatic activities, thereby playing a crucial role in cell ...

Abstract	The sliding DNA clamp is a ring-shaped protein that encircles DNA within its central channel. It binds to multiple proteins, such as DNA polymerases and DNA repair enzymes, and stimulates their enzymatic activities, thereby playing a crucial role in cell survival and proliferation. Accordingly, the bacterial clamp DnaN is considered to be a promising target for bacterial infection therapy. In this regard, three-dimensional structures of DnaN from pathogenic bacteria are essential for the development of chemical compounds with antimicrobial activity. Here, the crystal structure of DnaN from a Gram-positive bacterium Clostridioides difficile, a human pathogen causing infectious diarrhea, has been determined at 2.13 Å resolution. Comparison of the structures of DnaN from other bacteria indicates that the structural features of DnaN in terms of overall organization are essentially conserved within Gram-positive and Gram-negative bacteria. However, DnaN from C. difficile has structural differences in the potential binding pocket for partner proteins, implying a non-conventional interaction with its binding partners. Our findings will provide insight into the development of new therapies for C. difficile infection.
Language	English
Publishing date	2022-09-27
Publishing country	England
Document type	Journal Article
ZDB-ID	218073-x
ISSN	1756-2651 ; 0021-924X
ISSN (online)	1756-2651
ISSN	0021-924X
DOI	10.1093/jb/mvac079
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Article ; Online: Structural basis for molecular interactions on the eukaryotic DNA sliding clamps PCNA and RAD9-RAD1-HUS1.

Hashimoto, Hiroshi / Hara, Kodai / Hishiki, Asami

Journal of biochemistry

2022 Volume 172, Issue 4, Page(s) 189–196

Abstract: DNA sliding clamps are widely conserved in all living organisms and play crucial roles in DNA replication and repair. Each DNA sliding clamp is a doughnut-shaped protein with a quaternary structure that encircles the DNA strand and recruits various ... ...

Abstract	DNA sliding clamps are widely conserved in all living organisms and play crucial roles in DNA replication and repair. Each DNA sliding clamp is a doughnut-shaped protein with a quaternary structure that encircles the DNA strand and recruits various factors involved in DNA replication and repair, thereby stimulating their biological functions. Eukaryotes have two types of DNA sliding clamp, proliferating cell nuclear antigen (PCNA) and RAD9-RAD1-HUS1 (9-1-1). The homo-trimer PCNA physically interacts with multiple proteins containing a PCNA-interacting protein box and/or AlkB homologue 2 PCNA-interacting motif. The two motifs bind to PCNA by a similar mechanism; in addition, the bound PCNA structure is similar, implying a universality of PCNA interactions. In contrast to PCNA, 9-1-1 is a hetero-trimer composed of RAD9, RAD1 and HUS1 subunits. Although 9-1-1 forms a trimeric ring structure similar to PCNA, the C-terminal extension of the RAD9 is intrinsically unstructured. Based on the structural similarity between PCNA and 9-1-1, the mechanism underlying the interaction of 9-1-1 with its partners was thought to be analogous to that of PCNA. Unexpectedly, however, the recent structure of the 9-1-1 ring bound to a partner has revealed a novel interaction distinct from that of PCNA, potentially providing a new principle for molecular interactions on DNA sliding clamps.
MeSH term(s)	Cell Cycle Proteins/metabolism ; DNA/metabolism ; DNA Replication ; Eukaryota ; Eukaryotic Cells/metabolism ; Proliferating Cell Nuclear Antigen/chemistry ; Proliferating Cell Nuclear Antigen/genetics ; Proliferating Cell Nuclear Antigen/metabolism
Chemical Substances	Cell Cycle Proteins ; Proliferating Cell Nuclear Antigen ; DNA (9007-49-2)
Language	English
Publishing date	2022-06-22
Publishing country	England
Document type	Journal Article
ZDB-ID	218073-x
ISSN	1756-2651 ; 0021-924X
ISSN (online)	1756-2651
ISSN	0021-924X
DOI	10.1093/jb/mvac053
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Article ; Online: Angulation vs translation of transtibial prosthetic socket: their difference analyzed by socket reaction moments.

Hashimoto, Hiroshi / Kobayashi, Toshiki / Kataoka, Masataka / Okuda, Kuniharu

Gait & posture

2022 Volume 97, Page(s) 137–146

Abstract: Background: Previous studies investigated the effects of alignment changes in transtibial prostheses on socket reaction moments. However, the effects of angular and translational alignment changes with equal displacement between the foot and the socket ... ...

Abstract	Background: Previous studies investigated the effects of alignment changes in transtibial prostheses on socket reaction moments. However, the effects of angular and translational alignment changes with equal displacement between the foot and the socket were not directly compared. Research questions: What are the different effects of angular and translational alignment changes in transtibial prostheses? Methods: Ten individuals with transtibial prostheses participated in the measurement of temporo-spatial parameters, socket reaction moments, and their timings under nine alignment conditions (3° flexion/extension, anterior/posterior translation, 6° adduction/abduction, medial/lateral translation, and baseline). The displacement of the prosthetic feet was set to be equal between the angular and translational changes. Results: No significant changes in walking speed were found. Similar effects were observed in the magnitudes, but not in timing, of the moments under angular and translational changes in the sagittal plane (p < 0.01 for the differences in peak extension moment among anterior translation, baseline, and extension conditions, and in peak flexion moment among anterior translation, baseline, and extension conditions). In the coronal plane, similar effects were found in the magnitudes of the moments in the early stance (p < 0.01 at 5 %, 20 %, and 75 % stance). A significant difference in magnitude was observed in the late stance (p < 0.01 between adduction and medial translation conditions). Significance: The timing of the socket reaction moment may be different in the sagittal plane, while the magnitudes of the socket reaction moment in the late stance may be different in the coronal plane between the angular and translational alignment changes.
MeSH term(s)	Amputees ; Artificial Limbs ; Biomechanical Phenomena ; Gait ; Humans ; Tibia ; Walking
Language	English
Publishing date	2022-07-04
Publishing country	England
Document type	Journal Article
ZDB-ID	1162323-8
ISSN	1879-2219 ; 0966-6362
ISSN (online)	1879-2219
ISSN	0966-6362
DOI	10.1016/j.gaitpost.2022.06.014
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Article: Successful salvage surgery followed by second ALK-TKI after alectinib failure in a patient with ALK-positive NSCLC.

Hashimoto, Hiroshi / Komori, Kazuyuki / Kameda, Koji / Taguchi, Shinichi / Ozeki, Yuichi

Surgical case reports

2022 Volume 8, Issue 1, Page(s) 59

Abstract: Background: Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) have been approved for the therapy of locally advanced non-small cell lung cancer (NSCLC) caused by ALK rearrangement. However, its treatment after failure of initial ALK-TKI ...

Abstract	Background: Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) have been approved for the therapy of locally advanced non-small cell lung cancer (NSCLC) caused by ALK rearrangement. However, its treatment after failure of initial ALK-TKI therapy remains controversial. Case presentation: A 47-year-old woman with a hemosputum was diagnosed with adenocarcinoma of the left lung (cT2bN3M0, stage IIIB). Gene mutation analysis indicated positive ALK translocation. Alectinib was selected as the first-line treatment. Although the treatment effect was determined as a partial response, the main tumor regrew. Alectinib was discontinued, and salvage surgery was performed without causing morbidity. The pathological diagnosis was pleomorphic carcinoma without lymph node metastasis (yp-T2bN0). After surgery, lorlatinib was administered as the second-line treatment for 8 months until the patient could not tolerate continuation. Computed tomography scan revealed no lung cancer recurrence 14 months after discontinuation. Conclusions: Our experience with this case suggests that salvage surgery after alectinib treatment followed by lorlatinib therapy may be effective for initially unresectable ALK-positive NSCLC.
Language	English
Publishing date	2022-04-02
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2809613-7
ISSN	2198-7793
ISSN	2198-7793
DOI	10.1186/s40792-022-01408-7
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Article: [Relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia responding to retreatment with inotuzumab ozogamicin].

Hashimoto, Hiroshi / Tamura, Yuhei / Yamada, Kaori / Katoh, Yuriko / Shimada, Takahiro / Fujiwara, Ryosuke / Hanamoto, Hitoshi

Rinsho ketsueki] The Japanese journal of clinical hematology

2023 Volume 64, Issue 8, Page(s) 746–750

Abstract: A 72-year-old man with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) was treated with dasatinib (week1: 50 mg/day, week2: 70 mg/day, week3-: 100 mg/day) and prednisolone from June 2017. However, in January 2018, it relapsed with ... ...

Abstract	A 72-year-old man with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) was treated with dasatinib (week1: 50 mg/day, week2: 70 mg/day, week3-: 100 mg/day) and prednisolone from June 2017. However, in January 2018, it relapsed with the T315I mutation. Although the treatment was changed to ponatinib 30 mg/day, he experienced a second relapse in June 2018. Following confirmation of CD22 positivity, he was treated with three cycles of inotuzumab ozogamicin (InO), resulting in CR. He was CR for 2.9 years before relapsing for the third time in May 2021. Because the patient was still CD22-positive, InO was given again, and the patient achieved CR at the end of the second cycle. We had a case where re-administering InO was effective as a salvage therapy for relapsed/refractory Ph+ALL (r/r Ph+ALL) in an elderly patient.
MeSH term(s)	Aged ; Male ; Humans ; Inotuzumab Ozogamicin/therapeutic use ; Philadelphia Chromosome ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Retreatment ; Dasatinib
Chemical Substances	Inotuzumab Ozogamicin (P93RUU11P7) ; Dasatinib (RBZ1571X5H)
Language	Japanese
Publishing date	2023-08-10
Publishing country	Japan
Document type	Case Reports ; English Abstract ; Journal Article
ZDB-ID	390900-1
ISSN	0485-1439
ISSN	0485-1439
DOI	10.11406/rinketsu.64.746
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Article ; Online: Utility of Coproporphyrin-I Determination in First-in-Human Study for Early Evaluation of OATP1B Inhibitory Potential Based on Investigation of Ensitrelvir, an Oral SARS-CoV-2 3C-Like Protease Inhibitor.

Watari, Ryosuke / Sawada, Hiromi / Hashimoto, Hiroshi / Kasai, Yasuyuki / Oka, Ryoko / Shimizu, Ryosuke / Matsuzaki, Takanobu

Journal of pharmaceutical sciences

2023 Volume 113, Issue 3, Page(s) 798–805

Abstract: Coproporphyrin-I (CP-I) has been investigated as an endogenous biomarker of organic anion transporting polypeptide (OATP) 1B. Here, we determined the CP-I concentrations in a cocktail drug-drug interaction (DDI) study of ensitrelvir to evaluate the ... ...

Abstract	Coproporphyrin-I (CP-I) has been investigated as an endogenous biomarker of organic anion transporting polypeptide (OATP) 1B. Here, we determined the CP-I concentrations in a cocktail drug-drug interaction (DDI) study of ensitrelvir to evaluate the OATP1B inhibitory potential because ensitrelvir had increased plasma concentrations of rosuvastatin in this study, raising concerns about breast cancer resistance protein and OATP1B inhibition. Furthermore, CP-I concentrations were compared between active and placebo groups in a first-in-human (FIH) study of ensitrelvir to verify whether the OATP1B inhibitory potential could be estimated at an early drug development stage. In the cocktail DDI study, CP-I did not differ between with/without administration of ensitrelvir, indicating that ensitrelvir has no OATP1B inhibitory effect. Although there were some individual variabilities in CP-I concentrations among the treatment groups in the FIH study, the normalization of CP-I concentrations with pre-dose values minimized these variabilities, suggesting that this normalized method would be helpful for comparing the CP-I from different participants. Finally, we concluded that CP-I concentrations were not affected by ensitrelvir in the FIH study. These results suggested that the CP-I determination in an FIH study and its normalized method can be useful for an early evaluation of the OATP1B-mediated DDI potential in humans.
MeSH term(s)	Humans ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; SARS-CoV-2 ; Protease Inhibitors ; Coproporphyrins/metabolism ; Coproporphyrins/pharmacology ; Liver-Specific Organic Anion Transporter 1/metabolism ; COVID-19 ; Neoplasm Proteins/metabolism ; Enzyme Inhibitors ; Anti-Infective Agents ; Antiviral Agents/pharmacology ; Drug Interactions ; Indazoles ; Triazines ; Triazoles
Chemical Substances	ensitrelvir (PX665RAA3H) ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Protease Inhibitors ; Coproporphyrins ; Liver-Specific Organic Anion Transporter 1 ; Neoplasm Proteins ; Enzyme Inhibitors ; Anti-Infective Agents ; Antiviral Agents ; Indazoles ; Triazines ; Triazoles
Language	English
Publishing date	2023-09-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1016/j.xphs.2023.09.016
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Article ; Online: Influence of coronal and sagittal prosthetic foot alignment on socket reaction moments in transtibial prostheses during walking.

Hashimoto, Hiroshi / Kobayashi, Toshiki / Kataoka, Masataka / Okuda, Kuniharu

Gait & posture

2021 Volume 90, Page(s) 252–260

Abstract: Background: The socket reaction moment (SRM) has been reported to change because of alignment changes in transtibial prosthetic sockets. However, the influence of prosthetic foot alignment on SRM remains unclear.: Research question: Are SRMs ... ...

Abstract	Background: The socket reaction moment (SRM) has been reported to change because of alignment changes in transtibial prosthetic sockets. However, the influence of prosthetic foot alignment on SRM remains unclear. Research question: Are SRMs predictable from alignment changes of prosthetic feet? Methods: Ten users of transtibial prostheses participated in this study. Under five alignment conditions (3 ° plantarflexion and dorsiflexion, 6 ° inversion and eversion, and baseline alignment), temporal-spatial parameters and sagittal and coronal SRMs were measured during walking. Cadence, walking speed, step time, single support time, and step length were compared. The maximum/minimum SRM, % stance (timing) of the maximum/minimum SRM, Zero-cross, and SRMs at 5 %, 20 %, and 75 % stance were extracted and compared. Repeated measures analysis of variance or Friedman tests, and linear regression analyses were conducted for statistical analyses (i.e., alignment conditions as independent variables and SRM parameters as dependent variables). Results: The SRMs at 5%, 20 %, and 75 % stance showed significant differences under coronal angular changes. The minimum SRM, % stance of the minimum/maximum SRM, and Zero-cross showed significant differences under sagittal alignment changes. In linear regression analysis, the minimum SRM, % stance of the minimum/maximum SRM, SRM at 20 % stance, and Zero-cross were significant dependent variables in the sagittal plane. The maximum/minimum SRM, SRM at 20 % and 75 % stance, and % stance of the minimum SRM were significant dependent variables in the coronal plane. Significance: The results indicated that the changes in prosthetic feet angles may predict the magnitude of SRM (maximum/minimum SRM, SRM at 20 % and 75 % stance) in the coronal plane, and the timing of SRM (Zero-cross, % stance of the maximum/minimum SRM) in the sagittal plane. These findings suggest that the SRM may be useful for evaluating foot alignment in transtibial prostheses.
MeSH term(s)	Amputees ; Artificial Limbs ; Biomechanical Phenomena ; Foot ; Gait ; Humans ; Prosthesis Design ; Walking
Language	English
Publishing date	2021-08-16
Publishing country	England
Document type	Journal Article
ZDB-ID	1162323-8
ISSN	1879-2219 ; 0966-6362
ISSN (online)	1879-2219
ISSN	0966-6362
DOI	10.1016/j.gaitpost.2021.08.011
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