Publications by authors named "Shinichi Abe"

146 Publications

Superior labial artery and vein anastomosis configuration to be considered in lip augmentation.

Ann Anat 2021 Jul 26:151808. Epub 2021 Jul 26.

Department of Anatomy, Tokyo Dental College, 2-9-18 Misaki-cho, Chiyoda-ku, 101-0061 Tokyo, Japan; Tokyo Dental College Research Branding Project, 2-9-18 Kanda-misakicho, Tokyo, 101-0061, Japan.

The treatment of cleft lip and palate is performed over a long period, starting immediately after birth. However, esthetic problems remain after lip augmentation. Endothelial cells of new capillaries are important for wound healing. Thus, the reconstruction of vascular networks is key to postoperative wound healing during lip augmentation. However, studies describing the superior labial artery (SLA) and superior labial vein (SLV) are rare, and their mutual positional relationship thus remains unclear. We procured 29 adult cadavers and ten fetuses. Macroscopic and histological examinations were performed on adult cadavers. We extracted soft tissues and blood vessels after micro-computed tomography (CT) and 3D tissue reconstruction. We performed histological investigations of vascular networks within the cleft lip in fetal samples. In adults, the SLV was distributed throughout the cutaneous side of the orbicularis oris muscle and the SLA, throughout the mucosal side. The SLV and SLA were separated by this muscle. Micro-CT images revealed that the SLA on the mucosal side transversed the orbicularis oris muscle to the SLV (55%). Histological analysis of fetuses revealed that the SLA was on the mucosal side, similar to that in adults, and traversed the orbicularis oris muscle in continuity with the SLV of the cutaneous side (100%). In lip augmentation, the reconstruction of the vascular structure, which involves the anastomosis of SLA and SLV passing through the orbicularis oris muscle, is an important factor when considering esthetic repair.
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http://dx.doi.org/10.1016/j.aanat.2021.151808DOI Listing
July 2021

Association between the developing sphenoid and adult morphology: A study using sagittal sections of the skull base from human embryos and fetuses.

J Anat 2021 Jul 15. Epub 2021 Jul 15.

Department of Anatomy, Tokyo Dental College, Tokyo, Japan.

The developing sphenoid is regarded as a median cartilage mass (basisphenoid [BS]) with three cartilaginous processes (orbitosphenoid [OS], ala temporalis [AT], and alar process [AP]). The relationships of this initial configuration with the adult morphology are difficult to determine because of extensive membranous ossification along the cartilaginous elements. The purpose of this study was therefore to evaluate the anatomical connections between each element of the fetal sphenoid and adult morphology. Sagittal sections from 25 embryos and fetuses of gestational age 6-34 weeks and crown-rump length 12-295 mm were therefore examined and compared with horizontal and frontal sections from the other 25 late-term fetuses (217-340 mm). The OS was identified as a set of three mutually attached cartilage bars in early fetuses. At all stages, the OS-post was continuous with the anterolateral part of the BS. The BS included the notochord and Rathke's pouch remnant in embryos and early fetuses. The dorsum sellae was absent from embryos, but it protruded from the BS in early fetuses before a fossa for the hypophysis became evident. Although not higher than the hypophysis at midterm, the dorsum sellae elongated superiorly after gestational age 25 weeks. In early fetuses, the AP was located on the side immediately anterior to the otic capsule. The AT developed on the side immediately posterior to the extraocular rectus muscles. At late term, the greater wing was formed by membranous bones from the AT and AP. The AT and AP formed a complex bridge between the BS and the greater wing. A small cartilage, future medial pterygoid process (PTmed) was located inferior to the AT in early fetuses. At midterm, one endochondral bone and multiple membranous bones formed the PTmed. The lateral pterygoid process (PTlat) was formed by a single membranous bone plate. Therefore, we connected fetal elements and the adult morphology as follows. (1) Derivative of the OS makes not only the lesser wing but also the anterior margin of the body of the sphenoid. (2) Derivatives of the BS are the body of the sphenoid including the sella turcica and the dorsum sellae. (3) Most of the greater wing including the foramen rotundum and the foramen oval originate from the AT and AP and multiple membranous bones. (4) The PTmed originate from endochondral bones and multiple membranous bones, while the PTlat derive from a single membranous bone.
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http://dx.doi.org/10.1111/joa.13515DOI Listing
July 2021

Development of the cartilaginous connecting apparatuses in the fetal sphenoid, with a focus on the alar process.

PLoS One 2021 12;16(7):e0251068. Epub 2021 Jul 12.

Department of Anatomy, Tokyo Dental College, Chiyoda-ku, Tokyo, Japan.

The human fetal sphenoid is reported to have a cartilaginous connecting apparatus known as the alar process (AP), which connects the ala temporalis (AT) (angle of the greater wing of the sphenoid) to the basisphenoid (anlage of the sphenoid body). However, how the AP develops in humans is unclear. In addition, although the AP is a common structure of the mammalian chondrocranium, little is known about whether it is really a fundamental feature in mammals. This study examined the histological sections of 20 human embryos and fetuses from 6 to 14 weeks of development, of 20 mouse embryos from embryonic days 12-18, and of 4 rats embryos form embryonic days 17 and 20. In addition, we reconsidered the definition of the AP by comparing humans and rats with mice. In humans, the AP was continuous with the basisphenoid but was separated from the AT by a thick perichondrium. Then, the AP-AT connection had a key-and-keyhole structure. Unlike a joint, no cavitation developed in this connection. In mice, there was no boundary between the AT and the basisphenoid, indicating the absence of the AP in the mouse chondrocranium. In rats, the AP was, however, separated from the AT by a thick perichondrium. Therefore, the AP can be defined as follows: the AP is temporally separated from the AT by a thick perichondrium or a key-and-keyhole structure during the fetal period. This is the first study that confirms the absence of the alar process in the mice skull, and its presence in other mammals skull should be further investigated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251068PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274926PMC
July 2021

Association of Urinary Dickkopf-3 with Residual Renal Function Decline in Patients Undergoing Peritoneal Dialysis.

Medicina (Kaunas) 2021 Jun 18;57(6). Epub 2021 Jun 18.

Department of Nephrology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.

: Urinary levels of dickkopf-3 (DKK-3) are associated with poor renal survival in patients with non-dialytic chronic kidney disease. However, it remains unknown whether urinary DKK-3 levels can predict residual renal function (RRF) decline in patients undergoing peritoneal dialysis (PD). Therefore, we investigated the correlation between urinary levels of DKK-3 and the subsequent rate of RRF decline in PD patients. : This study included 36 PD patients who underwent multiple peritoneal equivalent tests during 2011-2021. The relationship between baseline clinical characteristics and the subsequent annual rate of Kt/V decline was investigated. : The annual rate of renal Kt/V decline was 0.29 (range: 0.05-0.48), which correlated with renal Kt/V ( = 0.55, = 0.0005) and 24 h urinary DKK-3 excretion ( = 0.61, < 0.0001). Similarly, 24 h urinary DKK-3 excretion (β = 0.44, = 0.0015) and renal Kt/V (β = 0.38, = 0.0059) were independently associated with the annual rate of renal Kt/V decline in multivariate analyses. : Urinary DKK-3 assessment may help identify PD patients at a high risk of RRF decline.
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http://dx.doi.org/10.3390/medicina57060631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235738PMC
June 2021

Factors Involved in Morphogenesis in the Muscle-Tendon-Bone Complex.

Int J Mol Sci 2021 Jun 14;22(12). Epub 2021 Jun 14.

Department of Anatomy, Tokyo Dental College, 2-9-18 Kanda-misakicho, Chiyoda-ku, Tokyo 101-0061, Japan.

A decline in the body's motor functions has been linked to decreased muscle mass and function in the oral cavity and throat; however, aging of the junctions of the muscles and bones has also been identified as an associated factor. Basic and clinical studies on the muscles, tendons and bones, each considered independently, have been published. In recent years, however, research has focused on muscle attachment as the muscle-tendon-bone complex from various perspectives, and there is a growing body of knowledge on SRY-box9 (Sox9) and Mohawk(Mkx), which has been identified as a common controlling factor and a key element. Myostatin, a factor that inhibits muscle growth, has been identified as a potential key element in the mechanisms of lifetime structural maintenance of the muscle-tendon-bone complex. Findings in recent studies have also uncovered aspects of the mechanisms of motor organ complex morphostasis in the superaged society of today and will lay the groundwork for treatments to prevent motor function decline in older adults.
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http://dx.doi.org/10.3390/ijms22126365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232103PMC
June 2021

Odontoblast death drives cell-rich zone-derived dental tissue regeneration.

Bone 2021 09 18;150:116010. Epub 2021 May 18.

Institute for Oral Science, Matsumoto Dental University, Nagano, Japan; Oral Health Science Center, Tokyo Dental College, Tokyo, Japan. Electronic address:

Severe dental tissue damage induces odontoblast death, after which dental pulp stem and progenitor cells (DPSCs) differentiate into odontoblast-like cells, contributing to reparative dentin. However, the damage-induced mechanism that triggers this regeneration process is still not clear. We aimed to understand the effect of odontoblast death without hard tissue damage on dental regeneration. Herein, using a Cre/LoxP-based strategy, we demonstrated that cell-rich zone (CZ)-localizing Nestin-GFP-positive and Nestin-GFP-negative cells proliferate and differentiate into odontoblast-like cells in response to odontoblast depletion. The regenerated odontoblast-like cells played a role in reparative dentin formation. RNA-sequencing analysis revealed that the expression of odontoblast differentiation- and activation-related genes was upregulated in the pulp in response to odontoblast depletion even without damage to dental tissue. In this regenerative process, the expression of type I parathyroid hormone receptor (PTH1R) increased in the odontoblast-depleted pulp, thereby boosting dentin formation. The levels of PTH1R and its downstream mediator, i.e., phosphorylated cyclic AMP response element-binding protein (Ser133) increased in the physically damaged pulp. Collectively, odontoblast death triggered the PTH1R cascade, which may represent a therapeutic target for inducing CZ-mediated dental regeneration.
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http://dx.doi.org/10.1016/j.bone.2021.116010DOI Listing
September 2021

Discovery of a novel series of GPR119 agonists: Design, synthesis, and biological evaluation of N-(Piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives.

Bioorg Med Chem 2021 Jul 9;41:116208. Epub 2021 May 9.

Cardiovascular & Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

We undertook an optimization effort involving propan-2-yl 4-({6-[5-(methanesulfonyl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate 1, which we had previously discovered as a novel G protein-coupled receptor 119 (GPR119) agonist. To occupy a presumed hydrophobic space between the pyrimidine and piperidine rings in interaction with GPR119, we replaced the linker oxygen with nitrogen. Subsequently, the introduction of a substituent at the bridging nitrogen atom was explored. We found that the installation of N-trifluoromethyl group 10 not only enhanced GPR119 agonist activity but also considerably improved the human ether-à-go-go-related gene (hERG) inhibition profile. These improvements were not observed for non-fluorinated substituents, such as ethyl analog 8b. The next optimization effort focused on the exploration of a new surrogate structure for the indoline ring and the isosteric replacements of the piperidine N-Boc group to improve solubility, metabolic stability, and oral bioavailability. As a result, N-{1-[3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}-6-{[1-(methanesulfonyl)piperidin-4-yl]oxy}-N-(trifluoromethyl)pyrimidin-4-amine (27) was identified as a potent and orally bioavailable GPR119 agonist. This compound augmented insulin secretion and effectively lowered plasma glucose excursion in a diabetic animal model after oral administration. In this study, we discuss the designs, syntheses, and biological activities of a novel series of N-(piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives as GPR119 agonists, and to determine the distinctive effect of the N-trifluoromethyl group on hERG inhibition, we also discuss the conformational preference of representative compounds.
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http://dx.doi.org/10.1016/j.bmc.2021.116208DOI Listing
July 2021

Comparative Study of Morphology and Distribution of Valves in Human Retromandibular Vein.

Bull Tokyo Dent Coll 2021 Jun 14;62(2):99-106. Epub 2021 May 14.

Department of Histology and Developmental Biology, Tokyo Dental College.

The objective of this study was to analyze the distribution and morphology of the valves in the human retromandibular vein. The retromandibular, internal thoracic, azygos, femoral, and brachial veins were harvested from 46 cadavers donated to the Department of Anatomy at Tokyo Dental College for dissection. The frequency of the valves in each vein, the length of the cusps, and the thickness of the vein itself were measured. Valves were present at high frequency (92.1%) in the veins of the limbs and had cusps at least twice as long as the internal diameter of the vein. Veins in the trunk contained a lower frequency of valves, with cusps that tended to be shorter (1.60±0.77) than those of the venous valves in the limbs (2.12±0.60). The valves of the retromandibular vein tended to resemble venous valves in the trunk in terms of both frequency and morphology. The main function of venous valves in the limbs is to prevent retrograde flow. Conversely, valves in the veins of the trunk and retromandibular vein play a role in retaining blood in the veins, and their relationship to other veins means that they can cause major hemorrhage.
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http://dx.doi.org/10.2209/tdcpublication.2020-0046DOI Listing
June 2021

Arteriovenous Anastomosis in Human Hand Digital Skin.

Bull Tokyo Dent Coll 2021 Jun 14;62(2):63-70. Epub 2021 May 14.

Department of Anatomy, Tokyo Dental College.

While a digital arteriovenous anastomosis (Hoyer-Grosser's organ, Masson's glomus) is a well-known structure, photographic evidence of communication between arterial and venous lumens might not be demonstrated in routine histological or immunohistochemical analysis. Abundant clusters of so-called glomera were found in semi-serial sections of the distal aspect of 14 fingers obtained from 7 donated elderly cadavers. Two to six round or oval clusters were observed in each longitudinal section (over 0.3-0.6 mm in maximum diameter) in subcutaneous tissue 0.5-1.5 mm below the basal layer of the skin, whereas none were often observed in transverse sections. Lumen-to-lumen communication between arteriole and venule at 8 sites in 2 cadavers was identified in these clusters of glomera. The opening in the arteriole was large (50 μm in diameter) at 3 sites in specimens from an 80-year-old man, whereas it was small (10-30 μm) at 5 sites in those from a 91-year-old man. The arterial aspect was tightly surrounded by abundant nerve fibers expressing tyrosine hydroxylase immunoreactivity, whereas the venous part was not. No or little expression of S100 protein immunoreactivity suggested that these nerve fibers were unmyelinated. The morphology at the lumen-to-lumen communication was simple - possibly an end-to-end anastomosis - rather than a sinuous curve of arteriole opening on to a short funnel-shaped venule as seen in the standard textbooks.
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http://dx.doi.org/10.2209/tdcpublication.2020-0036DOI Listing
June 2021

Mixed reality and three dimensional printed models for resection of maxillary tumor: a case report.

Quant Imaging Med Surg 2021 May;11(5):2187-2194

Department of Oral Pathobiological Science and Surgery, Tokyo Dental College, Tokyo, Japan.

In the field of oral and maxillofacial surgery, many institutions have recently begun using three-dimensional printers to create three-dimensional models and mixed reality in a variety of diseases. Here, we report the actual situation model which we made using three-dimensional printer from virtual operation data and the resection that was performed while grasping a maxillary benign tumor and neighboring three-dimensional structure by designing an application for Microsoft® HoloLens, and using Mixed Reality surgery support during the procedure.
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http://dx.doi.org/10.21037/qims-20-597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047357PMC
May 2021

Safety of Renal Biopsy by Physicians with Short Nephrology Experience.

Healthcare (Basel) 2021 Apr 16;9(4). Epub 2021 Apr 16.

Department of Nephrology, Nagasaki University Hospital, Nagasaki 852-8501, Japan.

Percutaneous renal biopsy is an essential tool for diagnosing various renal diseases; however, little is known about whether renal biopsy performed by physicians with short nephrology experience is safe in Japan. This study included 238 patients who underwent percutaneous renal biopsy between April 2017 and September 2020. We retrospectively analyzed the frequency of post-renal biopsy complications (hemoglobin decrease of ≥10%, hypotension, blood transfusion, renal artery embolization, nephrectomy and death) and compared their incidence among physicians with varied experience in nephrology. After renal biopsy, a hemoglobin decrease of ≥10%, hypotension and transfusion occurred in 13.1%, 3.8% and 0.8% of patients, respectively. There were no cases of post-biopsy renal artery embolism, nephrectomy, or death. The composite complication rate was 16.0%. The incidence of post-biopsy complications was similar between physicians with ≥3 years and <3 years of clinical nephrology experience (12.5% vs. 16.8%, = 0.64). Furthermore, the post-biopsy composite complication rates were similar between physicians with ≥6 months and <6 months of clinical nephrology experience (16.3% vs. 15.6%, > 0.99). Under attending nephrologist supervision, a physician with short clinical nephrology experience can safely perform renal biopsy.
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http://dx.doi.org/10.3390/healthcare9040474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072574PMC
April 2021

Persistent bone resorption lacunae on necrotic bone distinguish bisphosphonate-related osteonecrosis of jaw from denosumab-related osteonecrosis.

J Bone Miner Metab 2021 Apr 8. Epub 2021 Apr 8.

Tokyo Dental College Research Branding Project, 2-9-18 Kanda-Misaki-cho, Chiyoda-ku, Tokyo, 101-0061, Japan.

Background: Bisphosphonate and denosumab are widely used for the treatment of osteoporosis and bone metastasis of cancer to prevent excessive bone resorption. Osteonecrosis of the jaw is a serious adverse effect of bisphosphonate or denosumab referred to as bisphosphonate-related osteonecrosis of the jaw (BRONJ) or denosumab-related osteonecrosis of the jaw (DRONJ), respectively. Since bisphosphonate and denosumab inhibit bone resorption by different mechanism, we evaluated whether these drug types result in different histopathological characteristics related to bone resorption.

Materials And Methods: We histopathologically investigated 10 cases of BRONJ, DRONJ, and suppurative osteomyelitis. Paraffin sections prepared from decalcified dissected jaw bones were used for histopathological observation, second harmonic generation imaging, and bone histomorphometry. The samples were also observed by a scanning electron microscope.

Results: Numerous bone resorption lacunae were observed on the necrotic bone surface in almost all cases of BRONJ; however, such resorption lacunae were limited in DRONJ and suppurative osteomyelitis. Prominent bone resorption lacunae were also confirmed by second harmonic generation imaging and scanning electron microscopy in BRONJ, but not in DRONJ or suppurative osteomyelitis. As determined by bone histomorphometry, the number of bone resorption lacunae and the length of the erosion surface of resorption lacunae were significantly higher in BRONJ group than in the DRONJ and suppurative osteomyelitis groups. These parameters were correlated between the necrotic bones and the vital bones in BRONJ.

Conclusions: Persistent bone resorption lacunae on the necrotic bone surface are unique to BRONJ, providing a basis for distinguishing BRONJ from DRONJ and OM in histopathological diagnosis.
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http://dx.doi.org/10.1007/s00774-021-01223-4DOI Listing
April 2021

Auricular cartilage configuration: A histological study using late-stage human fetuses and adult cadavers.

Anat Rec (Hoboken) 2021 Feb 23. Epub 2021 Feb 23.

Department of Anatomy, Tokyo Dental College, Tokyo, Japan.

The auricular cartilage is considered to develop from a funnel-like arrangement of six embryonic hillocks. However, there is little information as to when and how the initial cartilage plate differentiates into the major three hollows or caves: the concha, the scapha and the triangular fossa. We examined semiserial histological sections from 42 human fetuses as well as from seven cadavers of elderly individuals. Tangential sections from adults suggested that three ring-like cartilages were combined to provide a single auricular cartilage and that the external auditory meatus was attached to the lowest ring or concha. All of the fetuses studied carried the three major hollows delineated by skin folds. These skin folds often contained a cartilage loop as a core in place of a thickening or tubercle. Conversely, some of the skin folds corresponded to a highly wavy cartilage plate without looping. According to whether the cartilage loop was present or absent in horizontal sections from 35 fetuses, we classified the cartilage morphology into four patterns, the most frequent of which was absence of the triangular fossa loop (27 fetuses), followed by absence of the scapha loop (11 fetuses). Each pattern was evenly distributed among small and large fetuses. This suggested that some form of cartilage correction or reconstruction was likely to occur after birth, especially at the triangular fossa and/or scapha. Infants appear to show significant region-specific variation in the postnatal growth of the auricular cartilages, especially at the triangular fossa and/or scapha.
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http://dx.doi.org/10.1002/ar.24608DOI Listing
February 2021

Localization of T-cell factor 4 positive fibroblasts and CD206-positive macrophages during skeletal muscle regeneration in mice.

Ann Anat 2021 May 8;235:151694. Epub 2021 Feb 8.

Department of Anatomy, Tokyo Dental College, Tokyo, Japan; Tokyo Dental College Research Branding Project, Tokyo Dental College, Tokyo, Japan.

Skeletal muscle regeneration is initiated by the activation of the transcription factor paired box 7 (Pax7), which is expressed in the satellite cells. The nuclear transcription factor T-cell factor 4 (Tcf4) is expressed in the fibroblasts and is involved in muscle tissue repair, while M2-like macrophages play an important role in skeletal muscle regeneration. However, the localization of M2-like macrophages and the expression of Tcf4 over a period of time during skeletal muscle regeneration remain unknown. Therefore, the murine masseter muscle was immunofluorescence investigated for the surface protein CD206 of M2-like macrophages and Tcf4 of fibroblasts during skeletal muscle regeneration to understand the changes in the CD206 and Tcf4 expression over time. We observed that CD206 entered the cytoplasm of some regenerating muscle fibers 5-7 days after the experimental muscle damage, that is, in the early stage of maturation of the regenerating muscle fibers with central nuclei. In addition, Tcf4 was expressed in the nuclei of the fibroblasts around the regenerating muscle fibers and in the central nuclei of the regenerating muscle fibers. Furthermore, the expression of laminin adjacent to Tcf4-positive cells was observed to partially disappear, and the shape of this missing part was observed to be identical to that of the nuclei of Tcf4-positive cells adjacent to the laminin. Clathrin was also expressed in these sites, demonstrating endocytosis. Thus, these results suggest that in the early stage of maturation of the regenerating muscle fibers, M2-like macrophages and Tcf4-positive fibroblasts enter the cytoplasm of the regenerating muscle fibers, thereby regulating the expression of various maturation factors.
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http://dx.doi.org/10.1016/j.aanat.2021.151694DOI Listing
May 2021

Discovery of a novel series of indolinylpyrimidine-based GPR119 agonists: Elimination of ether-a-go-go-related gene liability using a hydrogen bond acceptor-focused approach.

Bioorg Med Chem 2021 Mar 23;34:116034. Epub 2021 Jan 23.

Cardiovascular & Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

We previously identified a novel series of indolinylpyrimidine derivatives exemplified by 2 in Figure 1, which is an indoline based derivative, as potent GPR119 agonists. Despite the attractive potency of 2, this compound inhibited the human ether-a-go-go-related gene (hERG) K channel. We elucidated crucial roles of the methylsulfonyl group of 2 in its interaction with the hERG channel and the GPR119 receptor, presumably as a hydrogen bond acceptor (HBA). To remove the undesirable hERG inhibitory activity, a strategy was implemented to arrange an HBA on a less conformationally flexible framework at the indoline 5-position instead of the methylsulfonyl group. This successfully led to the discovery of a piperidinone ring as a desirable motif at the indoline 5-position, which could minimize hERG liability as shown by 24b. Further optimization focused on the reduction of lipophilicity in terms of more favorable drug-like properties. Consequently, the introduction of a hydroxy group at the 3-position of the piperidinone ring effectively reduced lipophilicity without compromising GPR119 potency, resulting in the identification of (3S)-3-hydroxy-1-{1-[6-({1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}oxy)pyrimidin-4-yl]- 2,3-dihydro-1H-indol-5-yl}piperidin-2-one ((S)-29) as a novel, potent, and orally bioavailable GPR119 agonist with a well-balanced profile. The pharmacological effects of this compound were also confirmed after single and chronic oral administration in diabetic animal models.
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http://dx.doi.org/10.1016/j.bmc.2021.116034DOI Listing
March 2021

Fetal development of the human trapezius and sternocleidomastoid muscles.

Anat Cell Biol 2020 12;53(4):405-410

Department of Anatomy, Tokyo Dental College, Tokyo, Japan.

At present, there is no photographic evidence of splitting of the trapezius and sternocleidomastoid muscles (SCMs), which share a common anlage that extends caudally toward the limb bud in the embryo at a length of 9 mm. Therefore, the aim of the present study was to identify which structures divide the caudal end of the common anlage at the first sign of splitting into two muscles. In 11 mm-long specimens, the SCM and trapezius muscles were identified as a single mesenchymal condensation. In 15 and 18 mm-long specimens, the SCM and trapezius muscles were separated and extended posteriorly and lymphatic tissues appeared in a primitive lateral cervical space surrounded by the SCM (anterior). In 21 mm-long specimens, the lymphatic vessels were dilated and the accompanying afferents were forming connections with the subcutaneous tissue through a space between the SCM and trapezius muscles. In 27 mm-long specimens, cutaneous lymphatic vessels were evident and had entered the deep tissue between the SCM and trapezius muscles. Vascular dilation may be viewed as a result of less mechanical stress or pressure after muscle splitting.
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http://dx.doi.org/10.5115/acb.20.202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769109PMC
December 2020

Renal outcomes of treatment with telmisartan in patients with stage 3-4 chronic kidney disease: A prospective, randomized, controlled trial (JINNAGA).

SAGE Open Med 2020 23;8:2050312120973502. Epub 2020 Nov 23.

Department of Nephrology, Nagasaki University Hospital, Nagasaki, Japan.

Objectives: Although angiotensin II receptor blockers are effective for patients with chronic kidney disease, dose-dependent renoprotective effects of angiotensin II receptor blockers in patients with moderate to severe chronic kidney disease with non-nephrotic proteinuria are not known. Our aim was to elucidate the dose-dependent renoprotective effects of angiotensin II receptor blockers on such patients.

Methods: A multicenter, prospective, randomized trial was conducted from 2009 to 2014. Patients with non-nephrotic stage 3-4 chronic kidney disease were randomized for treatment with either 40 or 80 mg telmisartan and were observed for up to 104 weeks. Overall, 32 and 29 patients were allocated to the 40 and 80 mg telmisartan groups, respectively. The composite primary outcome was renal death, doubling of serum creatinine level, transition to stage 5 chronic kidney disease, and death from any cause. Secondary outcomes included the level of urinary proteins and changes in the estimated glomerular filtration rate.

Results: There was no difference in the primary outcome (p = 0.78) and eGFR (p = 0.53) between the two groups; however, after 24 weeks, urinary protein level was significantly lower in the 80 mg group than in the 40 mg group (p < 0.05). No severe adverse events occurred in either group, and the occurrence of adverse events did not significantly differ between them (p = 0.56).

Conclusion: Our findings do not demonstrate a direct dose-dependent renoprotective effect of telmisartan. The higher telmisartan dose resulted in a decrease in the amount of urinary protein. Even though high-dose angiotensin II receptor blockers may be preferable for patients with stage 3-4 chronic kidney disease, the clinical importance of the study results may be limited. The study was registered in the UMIN-CTR (https://www.umin.ac.jp/ctr) with the registration number UMIN000040875.
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http://dx.doi.org/10.1177/2050312120973502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686635PMC
November 2020

Retromandibular vein position and course patterns in relation to mandible: anatomical morphologies requiring particular vigilance during sagittal split ramus osteotomy.

Anat Cell Biol 2020 Dec;53(4):444-450

epartment of Oral Pathobiological Science and Surgery, Tokyo Dental College, Tokyo, Japan.

Major bleeding associated with sagittal split ramus osteotomy (SSRO) involves vessels such as the inferior alveolar, facial, and maxillary arteries and veins, and the retromandibular vein (RMV). The present study aimed to clarify and classify the three-dimensional variations in RMV position and course direction in relation to the mandible. Specimens comprised a total of 15 scientific cadavers, and the relationship between RMV and the mandible lateral and posterior views was observed. We identified 3 patterns on the lateral view, the mean distance between the RMV and the posterior border of the ramus was 3.9 mm at the height of the lingula. A total of five course patterns were identified on the posterior view. In no course pattern, the RMV inferior to the lingula was lateral to its position superior to the lingual. The present findings suggest that it may be possible to predict correlations with intraoperative bleeding risk. Further study is planned using contrast computed tomography in patients with jaw deformity for skeletal classification.
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http://dx.doi.org/10.5115/acb.20.236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769106PMC
December 2020

A missing distal complex of the external and internal anal sphincters: a macroscopic and histologic study using Japanese and German elderly cadavers.

Surg Radiol Anat 2021 May 2;43(5):775-784. Epub 2020 Nov 2.

Department of Anatomy, Tokyo Dental College, Tokyo, Japan.

The lower margin of the internal anal sphincter (IAS) is considered to lie on a J-shaped, subcutaneous part (SCP) of the external anal sphincter (EAS). The lower IAS is united with the J-shaped SCP to form a smooth-striated muscle complex. In the first part of this study, we ensured the presence of the J-shaped EAS in the lateral wall of the anal canal from 12 near-term fetuses. Second, in the lateral anal wall, the examination of the longitudinal section from 20 male and 24 female Japanese cadavers (72-95 years-old) demonstrated that the J-shaped EAS was lost in 15 (34%) due to the very small SCP. Third, we demonstrated that the J-shaped EAS was restricted in the latera anal wall using longitudinal histological sections of the anal canal from 11 male Japanese cadavers (75-89 years-old). Therefore, a site-dependent difference in the IAS-EAS configuration was evident. Finally, we compared a frequency of the lost J-shape between human populations using 10 mm-thick frontal slices from 36 Japanese and 28 German cadavers. The two groups of cadavers were compatible in age (a 0.2-years' difference in males). The macroscopic observations revealed that the J-shaped EAS was absent from 13 (36%) Japanese and six (20%) German specimens, suggesting that the SCP degeneration occurred more frequent in elderly Japanese than elderly German individuals (p < 0.05). The distal IAS-EAS complex seemed to push residual feces out of the anal canal at a transient phase from evacuation to closure. The absence might be the first sigh of anal dysfunction.
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http://dx.doi.org/10.1007/s00276-020-02606-4DOI Listing
May 2021

Cervical nerve roots and the dural sheath: a histological study using human fetuses near term.

Anat Cell Biol 2020 Dec;53(4):451-459

Department of Anatomy, Tokyo Dental College, Tokyo, Japan.

We have previously reported that the thoracolumbar posterior nerve root shows a tortuous epidural course, based on studies of human fetuses near term. For comparison with the cervical nerve, examinations were conducted using frontal, sagittal and horizontal sections of cervical vertebrae from 22 fetuses at 30-38 weeks of gestation. The cervical nerve root showed a short, straight and lateral course near the zygapophysial joint. Multiple rather than single bundles of the cervical posterior root seemed to account for the majority of sensory nerve fibers innervating the upper extremity. Fasciculation of rootlets was evident near the thoracolumbar spinal cord, whereas it was seen in the dural pocket at the nerve exit from the dural sac although both sites were subdural. As in the thoracolumbar region, the nerve sheath was continuous with the dura mater and independently surrounded each of the anterior and posterior roots. Radicular arteries were few in the cervical region. In 2 of the 22 fetuses (31 weeks and 33 weeks), there was a segmental, unilateral abnormality of nerve rootlet fasciculation where the dorsal root ganglion was located lateral or peripheral to the intervertebral region. Long nerve roots running inferiorly are a necessary adaptation to the delayed and marked growth of the thoracolumbar vertebral column. In children, the cervical nerve roots are likely to be affected by movement or dislocation of the vertebrae. The segmental abnormality of the cervical nerve root may be linked to rare variations in the brachial plexus.
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http://dx.doi.org/10.5115/acb.20.081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769102PMC
December 2020

Risk Reduction for End-Stage Renal Disease by Dietary Guidance Using the Gustatory Threshold Test for Salty Taste.

Nutrients 2020 Sep 4;12(9). Epub 2020 Sep 4.

Department of Nephrology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.

Educational hospitalization of patients with chronic kidney disease (CKD) may slow the progression of renal dysfunction. However, the educational aspect that is more effective has not been identified to date. In this study, patients with CKD were evaluated for gustatory threshold for salty taste and received augmented salt reduction guidance under educational hospitalization at Nagasaki University Hospital from October 2016. In total, 277 eligible patients were enrolled and hospitalized from 2012 to 2019 (mean age of 69.2 years; men comprised 62.1%). We compared 141 patients (Group A) who were educated in the hospital after October 2016 and 136 patients (Group B) who received standard education in the hospital before October 2016. The changes in the estimated glomerular filtration rate (ΔeGFR) after hospitalization and dialysis induction rate within one year after hospitalization were evaluated. The ΔeGFR was significantly improved in Group A compared to Group B (A: 1.05 mL/min/1.73 m/month, B: 0.55 mL/min/1.73 m/month; = 0.02). The dialysis induction rate was significantly lower in Group A than in Group B (A: 8.5%, B: 15.5%; = 0.001). These trends were also observed by multivariate analyses. In conclusion, educational hospitalization with enhanced salt reduction guidance may reduce the risk of end-stage renal disease.
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http://dx.doi.org/10.3390/nu12092703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551153PMC
September 2020

Topographical anatomy of the tentorium cerebelli and venous confluences in human midterm fetuses.

Ann Anat 2021 Jan 6;233:151596. Epub 2020 Sep 6.

Department of Anatomy, Tokyo Dental College, Tokyo, Japan.

Early development of veins and sinuses at and around the posterior cranial fossa seemed not to be shown by photographs except for our recent study (Ann Anat, 2020). Examination of histological sections of 38 fetuses at 10-16 weeks gestational age (GA) demonstrated that: (1) the superior petrosal sinus passed posterosuperiorly through the tentorium cerebelli and, distant and lateral to both the cerebellum and internal ear, drained into the transverse sinus; (2) the superior sagittal sinus was underdeveloped, and the inferior sagittal sinus was not yet evident; (3) the straight sinus (STS) originated from a joining of the bilateral pial veins from the lateral ventricular choroid plexus, passed through the inferoposterior part of the falx cerebri, reached the initial confluens sinuum, and then divided into the bilateral transverse sinuses. The STS origin was immediately behind the pineal body, and near the inferoposterior end of the third ventricle. The falx had a thick attachment to the tentorium below the entire course of the STS and was behind other parts of the brain. Therefore, the development and growth of the posterior dural system seemed to be independent from brain growth, and occurred well before the cerebellum grew to fill the posterior cranial fossa. A basic configuration of intracranial veins and sinuses, including embryonic transient veins (such as the vena capitis prima) seemed to be established by venous return from the choroid plexus and cranial wall, without greatly increasing the abundance of neuronal or glial cells in the brain.
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http://dx.doi.org/10.1016/j.aanat.2020.151596DOI Listing
January 2021

Relationship between the immunohistological examination and fluorescence visualization of oral squamous cell carcinoma.

Oncol Lett 2020 Sep 24;20(3):2153-2160. Epub 2020 Jun 24.

Department of Oral Pathobiological Science and Surgery, Tokyo Dental College, Tokyo 101-0061, Japan.

Disorders of the oral mucosa are considered easy to diagnose since they can be visualized and examined directly. A change in the color of the oral mucosa reflects histopathological changes and is an important diagnostic parameter. However, the subjective perception of color varies. To determine the extent of resection for oral mucosa conditions, it is necessary to digitize the color and perform objective assessments. In recent years, fluorescence visualization devices and analysis software that measure tissue luminance G have been employed for the identification of oral mucosa diseases. Fluorescence visualization is presumably based on the decrease in epithelial flavin adenine dinucleotide content and luminance G values due to the destruction of collagen cross-links [fluorescence visualization loss (FVL)]. However, cases with differences between luminance values and histopathological presentation exist. Therefore, additional factors may affect fluorescence visualization. The present study used a portable, non-contact oral mucosa fluorescence visualization device for luminance measurements in seven patients with oral squamous cell carcinoma. Furthermore, Picro-Sirius Red and immunohistochemical staining were performed for CK13, CK17, Ki67, p53 and E-cadherin in the FVL(+) (lesion) and FVL(-) (resection stump) areas to elucidate the principle of fluorescence visualization. Fluorescence was significantly lower in the FVL(+) than in the FVL(-) areas, and the mean luminance G value was 56. The Picro-Sirius Red stain revealed collagen destruction in the FVL(+) areas but no collagen disruption in the FVL(-) areas. CK13 was negative in the FVL(+) and positive in the FVL(-) areas, whereas the opposite pattern was observed for CK17. In the FVL(+) area, p53 staining was positive. E-cadherin expression was enhanced in the FVL(-) areas and reduced in the FVL(+) areas. Furthermore, the luminance G value tended to be lower in cases with weaker E-cadherin staining. The aforementioned results suggest that decreased E-cadherin expression may be a factor that regulates fluorescence visualization.
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http://dx.doi.org/10.3892/ol.2020.11772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400981PMC
September 2020

Left/right difference in the course and division of the pulmonary arterial branches in the lung upper lobe: A study using human embryos and early fetuses.

J Anat 2020 11 24;237(5):854-860. Epub 2020 Jul 24.

Department of Anatomy, Tokyo Dental College, Tokyo, Japan.

Although left/right differences in a configuration of the pulmonary artery (PA) and its branches are well known, there is little information as to when and how such differences are established. Examination of serial sagittal sections of 25 embryos and fetuses at 6-7 weeks of gestation demonstrated that, at O'Rahilly stages 18-20, the right earliest first branch of PA originated in the anterior side of the upper lobar bronchus and overlay the upper bronchi, in contrast to the left branch which was located posteriorly and constricted medially by the upper posterior bronchus B1 + 2b. The right earliest branch was most likely to correspond to the future superior trunk, while the left branch might be a lingual artery. At stages 21-23, the upper posterior parenchyma was still underdeveloped in the left lung, since the ductus arteriosus and the left common cardinal vein seemed to make the left upper thoracic cavity narrow. Conversely, in the right lung, the thick S2 seemed to require a double arterial supply from both the superior and inferior arterial trunks. On the left, A3 originated at the lung apex and took a long descending course along the lung anterior surface. This high position of A3 might soon be corrected by an increased volume of S3. Overall, in contrast to the lower and middle lobes, early-developed branches of the PA did not accompany upper segmental and subsegmental bronchi. A mechanism "differential growth" seemed to explain how to correct the fetal morphology to provide the adult morphology with variations.
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http://dx.doi.org/10.1111/joa.13264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542188PMC
November 2020

Extraction of Maxillary Impacted Teeth with Simultaneous Immediate Full Mouth Loading Using Long Implant: A Case Report.

Bull Tokyo Dent Coll 2020 Jul 5;61(2):135-143. Epub 2020 Jun 5.

Department of Anatomy, Tokyo Dental College.

Here, we describe the provision of an implant-supported prosthesis in a patient with impacted teeth in the maxilla, which complicated implant placement and necessitated utilization of the extraction sockets of previously impacted teeth and residual submerged roots. The patient was a 63-year-old man who visited our clinic with the chief complaint of difficulty in mastication. Numerous residual roots were observed in the maxilla, and radiographic imaging revealed that the residual roots of teeth #13 and #16 were fully impacted. The patient complained of a strong sensation of a foreign body in the area of a denture support overlying these residual roots. Therefore, the impacted teeth were extracted, 5 implants placed, and a temporary prosthesis provided. Given the necessity of placing the implant through the extraction socket of the impacted canine (#13), favorable initial stability was achieved using a long (>20 mm) implant. Moreover, autogenous bone obtained by osteotomy was grafted onto the extracted impacted tooth socket. The clinical condition was stable at approximately 1 year after implant placement and so the final prosthesis was delivered, with periodic check-ups being performed every 3 months thereafter. After 4 years, the patient has reported no symptoms. Clinically, there are no signs of inflammation, and the postoperative condition is deemed to be very favorable.
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http://dx.doi.org/10.2209/tdcpublication.2019-0004DOI Listing
July 2020

Switching of Sox9 expression during musculoskeletal system development.

Sci Rep 2020 05 21;10(1):8425. Epub 2020 May 21.

Department of Anatomy, Tokyo Dental College, 2-9-18 Misaki-cho, Chiyoda-ku, Tokyo, 101-0061, Japan.

The musculoskeletal system, which comprises muscles, tendons, and bones, is an efficient tissue complex that coordinates body movement and maintains structural stability. The process of its construction into a single functional and complex organization is unclear. SRY-box containing gene 9 (Sox9) is expressed initially in pluripotent cells and subsequently in ectodermal, endodermal, and mesodermal derivatives. This study investigated how Sox9 controls the development of each component of the musculoskeletal system. Sox9 was expressed in MTJ, tendon, and bone progenitor cells at E13 and in bone at E16. We detected Sox9 expression in muscle progenitor cells using double-transgenic mice and myoblastic cell lines. However, we found no Sox9 expression in developed muscle. A decrease in Sox9 expression in muscle-associated connective tissues, tendons, and bones led to hypoplasia of the cartilage and its attachment to tendons and muscle. These results showed that switching on Sox9 expression in each component (muscle, tendon, and bone) is essential for the development of the musculoskeletal system. Sox9 is expressed in not only tendon and bone progenitor cells but also muscle progenitor cells, and it controls musculoskeletal system development.
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http://dx.doi.org/10.1038/s41598-020-65339-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242482PMC
May 2020

Micro- and nano-bone analyses of the human mandible coronoid process and tendon-bone entheses.

J Biomed Mater Res B Appl Biomater 2020 10 19;108(7):2799-2806. Epub 2020 Mar 19.

Department of Dental Materials Science, Tokyo Dental College, Tokyo, Japan.

The coronoid process provides attachment to temporalis and masseter muscles, and thus plays an important role in mastication. Tendons connect muscles and bones, mediating the transmission of functional loads to bones. Thus, tendon-bone entheses govern mechanical stress in bones. The preferential orientation of biological apatite (BAp) crystallites, the main mineral component in bones, is an important index for bone quality and function, and is largely influenced by locally applied stress. In this study, we analyzed BAp orientation, Young's modulus, and bone mineral density (BMD) at different sites in the human coronoid process. No differences in BMD were found among the analyzed sites, but BAp crystal orientation was observed to differ. BAp crystallites showed a uni-directional orientation in the mesiodistal direction at the coronoid process apex, but were oriented in the direction vertical to the occlusal plane at other sites. Young's modulus tended to vary according to the BAp orientation. At the apex, a tendon form with characteristics different from those at other sites, including the presence of a fibrocartilaginous layer that may act as a stretching brake to control stress concentration, was observed. These findings suggest that the functional pressure of the temporalis muscle affects bone quality and strength.
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http://dx.doi.org/10.1002/jbm.b.34609DOI Listing
October 2020

Cavernous sinus and abducens nerve in human fetuses near term.

Surg Radiol Anat 2020 Jul 28;42(7):761-770. Epub 2020 Feb 28.

Department of Anatomy, Tokyo Dental College, Tokyo, Japan.

A long tortuous course of the abducens nerve (ABN) crossing a highly curved siphon of the internal carotid artery is of interest to neurosurgeons for cavernous sinus surgery. Although a "straight" intracavernous carotid artery in fetuses can change into an adult-like siphon in infants, there is no information on when or how the unique course of ABN is established. Histological observations of 18 near-term fetuses (12 specimens of frontal sections and 6 specimens of sagittal sections) demonstrated the following: (I) the ABN consistently took a straight course crossing the lateral side of an almost straight intracavernous carotid artery; (II) the straight course was maintained when sympathetic nerves joined; (III) few parasellar veins of the developing cavernous sinus separated the ABN from the ophthalmic nerve; and (IV) immediately before the developing tendinous annulus for a common origin of extraocular recti, the ABN bent laterally to avoid a passage of the thick oculomotor nerve. Since the present observations strongly suggested morphologies at birth and in infants, major angulations of the ABN as well as the well-known course independent of the other nerves in the cavernous sinus seemed to be established during childhood. In the human body, the ABN might be a limited example showing a drastic postnatal change in course. Consequently, it might be important to know the unique course of ABN before performing endovascular interventions and skull base surgery for petroclival and cavernous sinus lesions without causing inadvertent neurovascular injuries to neonates or infants.
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http://dx.doi.org/10.1007/s00276-020-02443-5DOI Listing
July 2020

High-Level Expression of Alkaline Phosphatase by Adeno-Associated Virus Vector Ameliorates Pathological Bone Structure in a Hypophosphatasia Mouse Model.

Calcif Tissue Int 2020 06 19;106(6):665-677. Epub 2020 Feb 19.

Department of Pharmacology, Tokyo Dental College, 2-9-18, Kandamisaki-cho, Chiyoda-ku, Tokyo, 101-0061, Japan.

Hypophosphatasia (HPP) is a systemic skeletal disease caused by mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP). We recently reported that survival of HPP model mice can be prolonged using an adeno-associated virus (AAV) vector expressing bone-targeted TNALP with deca-aspartate at the C terminus (TNALP-D); however, abnormal bone structure and hypomineralization remained in the treated mice. Here, to develop a more effective and clinically applicable approach, we assessed whether transfection with TNALP-D expressing virus vector at a higher dose than previously used would ameliorate bone structure defects. We constructed a self-complementary AAV8 vector expressing TNALP driven by the chicken beta-actin (CBA) promoter (scAAV8-CB-TNALP-D). The vector was injected into both quadriceps femoris muscles of newborn HPP mice at a dose of 4.5 × 10 vector genome (v.g.)/body, resulting in 20 U/mL of serum ALP activity. The 4.5 × 10 v.g./body-treated HPP mice grew normally and displayed improved bone structure at the knee joints in X-ray images. Micro-CT analysis showed normal trabecular bone structure and mineralization. The mechanical properties of the femur were also recovered. Histological analysis of the femurs demonstrated that ALP replacement levels were sufficient to promote normal, growth plate cartilage arrangement. These results suggest that AAV vector-mediated high-dose TNALP-D therapy is a promising option for improving the quality of life (QOL) of patients with the infantile form of HPP.
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http://dx.doi.org/10.1007/s00223-020-00676-5DOI Listing
June 2020

Effects of unloading by tail suspension on biological apatite crystallite alignment in mouse femur.

Dent Mater J 2020 Aug 7;39(4):670-677. Epub 2020 Feb 7.

Department of Oral and Maxillofacial Implantology, Tokyo Dental College.

The aim of this study was clarify the effects of reducing various functional pressures essential for the maintenance of bone homeostasis. Femoral bone mineral density (BMD) and biological apatite (BAp) crystallite alignment were measured in conventionally reared and hindlimb-unloaded mice. The femur was divided into 10 equal segments perpendicular to the longitudinal axis of the bone and measurements were performed on the cortical bone in the five segments closest to the midpoint of the femur. Significantly lower BMD and BAp alignment in the longitudinal (Z-axis) direction were observed in the hindlimb-unloaded group. The present findings suggest that unloading by tail suspension significantly decreases not only mouse femoral bone mass but also BAp crystallite alignment, although minimal uniaxial preferential alignment is retained.
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http://dx.doi.org/10.4012/dmj.2019-187DOI Listing
August 2020
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