Publications by authors named "Toshiyuki Tsurumoto"

46 Publications

Morphological divergence in the curvature of human femoral diaphyses: Tracing the central mass distributions of cross-sections.

J Anat 2021 Feb 1. Epub 2021 Feb 1.

Department of Macroscopic Anatomy, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

The diaphysis of the human femoral bone has a physiological anterior curvature; additionally, there is a curvature to the medial side or lateral side. In addition to compression stress from gravity during standing, walking, and running, these bones are continuously exposed to complex stresses from the traction forces of the various strong muscles attached to them. The femoral diaphysis is subjected to these mechanical stresses, and the direction and size of its curvature are defined according to Wolff's law and the mechanostat theory of Frost. The purpose of this study was to quantitatively evaluate the curvature of the femoral diaphysis in Japanese skeletons by determining the curve connecting the central mass distributions (CMD) of cross-sectional images. A total of 90 right femora (46 males and 44 females) were randomly selected from modern Japanese skeletal specimens. Full-length images of these bones were acquired using a clinical computed tomography scanner. The range between the lower end of the lesser trochanter and the adductor tubercle of each femur was divided at regular intervals to obtain ten planes, and nine levels were analyzed. The CMD curve was determined by connecting the CMDs of each of the nine cross-sections. First, the CMD of a cross-section in each of the nine slices was calculated, and the nine trajectories were superimposed from above. Then, by converting the shape of the entire CMD curve to superimpose the coordinates of the endpoint on the starting point, a closed arc representing the curvature of the femur was determined. For both males and females, the patterns varied from mostly medial to largely lateral curvature. The size of the curvature also varied for individuals. By analyzing only the coordinates of the vertex of the CMD curve of each femoral bone, the outlines of the diaphyseal curvatures could be recognized. The femora were thereby divided into two groups: medial bending and lateral bending. Considering males and females together, the number in the lateral-curvature group (n = 51) was larger than that in the medial-curvature group (n = 39). Moreover, the average age of the lateral-curvature group was significantly higher than that of the medial-curvature group (p < 0.05). In males, with an increase in the cortical bone proportion of the cross-sectional area, the anterior vertex of diaphyseal bending tended to be more prominent. This cortical proportion was significantly higher in the medial-curvature groups than in the lateral-curvature group (p < 0.01). The phenomena observed in this study may be related to pathophysiologies such as atypical fractures of the femur and osteoarthritis of the knee joints.
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http://dx.doi.org/10.1111/joa.13399DOI Listing
February 2021

Reduced cortical bone thickness increases stress and strain in the female femoral diaphysis analyzed by a CT-based finite element method: Implications for the anatomical background of fatigue fracture of the femur.

Bone Rep 2020 Dec 12;13:100733. Epub 2020 Nov 12.

Department of Macroscopic Anatomy, Graduate School of Biomedical Science, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, Nagasaki 852-8523, Japan.

The incidence of hip fractures is increasing in Japan and is high among women older than 70 years. While osteoporosis has been identified as one of the causative factors of fracture, atypical femoral fracture has emerged as a potential complication of bisphosphonate therapy. Atypical femoral fracture is prevalent among Asian women and has been attributed to morphological parameters. Age-related decreases in the morphological parameters of the femoral diaphysis, such as cortical bone thickness, cortical cross-sectional area, and the cortical index, were reported in Japanese women prior to bisphosphonate drugs being approved for treatment. Thus, in the present study, the relationships between biomechanical and morphological parameters were analyzed using a CT-based finite element method. Finite element models were constructed from 44 femurs of Japanese women aged 31-87 years using CT data. Loading conditions were set as the single-leg configuration and biomechanical parameters, maximum and minimum principal stresses, Drucker-Prager equivalent stress, maximum and minimum strains, and strain energy density were calculated in 7 zones from the subtrochanteric region to distal diaphysis. Pearson's correlation coefficient test was performed to investigate relationships with morphological parameters. While absolute stresses gradually decreased from the subtrochanteric region to distal diaphysis, absolute strains markedly declined in the proximal diaphysis and were maintained at the same levels as those in the distal regions. All types of stresses and minimum principal strain in the femoral diaphysis scored higher absolute values in the high-risk group (≥70 years, n = 28) than in the low-risk group (<70 years, n = 16) (p < 0.05). The distribution patterns of equivalent stress and strain energy density were similar to that of Young's modulus, except for the region of the linea aspera. All biomechanical parameters correlated with morphological parameters and correlation efficiencies, with the reciprocal of cortical bone thickness showing the strongest correlation. The present results demonstrated that biomechanical parameters may be predicted by calculating the cortical bone thickness of femurs not treated with bisphosphonates. Furthermore, strain appeared to be repressed at a low level despite differences in stress intensities among the regions by bone remodeling. This remodeling is considered to be regulated by Wolff's law driven by equivalent stress and strain energy densities from the proximal to distal femur. The present results will promote further investigations on the contribution of morphological parameters in the femoral diaphysis to the onset of atypical femoral fracture.
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http://dx.doi.org/10.1016/j.bonr.2020.100733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701322PMC
December 2020

Gross anatomical investigation of the muscular head between the vastus lateralis and intermedius in the Japanese population: a cadaver study.

Anat Sci Int 2021 Mar 21;96(2):231-238. Epub 2020 Nov 21.

Department of Macroscopic Anatomy, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, Nagasaki, 852-8523, Japan.

Unlike the general understanding of the quadriceps femoris, the existence of a new muscular head between the vastus lateralis and the vastus intermedius was reported, and named the tensor of the vastus intermedius in the Swedish population. The purpose of this study was to investigate the presence and form of the muscular head in the Japanese population and to clarify its structure by gross anatomical approaches. A total of 35 thighs of 20 Japanese cadavers were investigated. We searched for the muscular head and classified it into four types. In addition, nerve fiber analysis was performed for each classification type. Regarding classification, 11% were the independent type, 29% were the common type, 37% were the vastus lateralis type, and 23% were the vastus intermedius type. Based on nerve fiber analysis, in the common type, the muscular head was under dual nerve supply from the vastus lateralis and intermedius. The other three types were innervated only by nerves from the vastus lateralis. The target muscular head may always be present in Japanese. The nerves from the vastus lateralis were always distributed in the target muscular head based on nerve fiber analysis; therefore, this muscular head may be most closely related to the vastus lateralis. The name of this muscular head should be "the accessory head of the vastus lateralis" rather than "the tensor of the vastus intermedius."
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http://dx.doi.org/10.1007/s12565-020-00579-3DOI Listing
March 2021

Course of the thoracic nerves around the umbilicus within the posterior layer of the rectus sheath: a cadaver study.

J Anesth 2020 12 16;34(6):953-957. Epub 2020 Oct 16.

Department of Anesthesiology and Intensive Care Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.

Rectus sheath block is used to anesthetize thoracic nerves around the umbilicus. However, the appropriate point for anesthetic injection during rectus sheath block has not been determined anatomically. Here, we examined the course of thoracic nerve T10 at the posterior layer of the rectus sheath and the anatomical relationship between the nerve and the rectus abdominis and transversus abdominis muscles in formalin-fixed adult cadavers. The cranio-caudal distance from a horizontal line running through the umbilicus to where the thoracic nerve T10 passes through the posterior layer of the rectus sheath was 33.8 ± 14.4 (mean ± standard deviation) mm, while that from the horizontal line running through the umbilicus to the position where the lateral edge of the rectus abdominis muscle and the medial border of the transversus abdominis muscle cross was 33.1 ± 17.1 mm. The position where the lateral edge of the rectus abdominis muscle and the medial border of the transversus abdominis muscle cross approximates the position where thoracic nerves T10 passes through the posterior layer of the rectus sheath. Our results identify effective landmarks to guide the performance of rectus sheath block.
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http://dx.doi.org/10.1007/s00540-020-02863-yDOI Listing
December 2020

Measurement of femoral axial offset.

J Orthop Res 2020 Sep 2. Epub 2020 Sep 2.

Department of Macroscopic Anatomy, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Purpose to examine the accuracy and reproducibility of the femoral axial offset measured from the retrocondylar plane by computed tomography (CT). Bone specimens of the femur of 15 males and 15 females were analyzed. CT imaging was performed and data of the coordinates were collected (center of femoral head, center of an ellipse around greater trochanter, center of an ellipse around the base of femoral neck, posterior edge of great trochanter, and both posterior condyles). The angle between the line connecting center of the femoral head and center of an ellipse around greater trochanter and the line connecting both posterior condyles was set as anteversion 1. The angle between the line connecting the center of femoral head and center of an ellipse around base of the femoral neck and the line connecting both posterior condyles was set as anteversion 2. The femoral axial offset was measured from the retrocondylar plane. Measurements were performed three times on the same subject, and intrarater reliability (ICC) was determined. In addition, interrater reliability (ICC) was determined by comparing data from three raters. The mean value for anteversion 1 was 20.1° for males and 22.7° for females. The values for anteversion 2 were 16.0° and 19.9° for males and females, respectively. Offset was 34.0 and 33.4 mm in males and females, respectively. Intrarater ICC and interrater ICC exceeded 0.81 for both methods, suggesting that the method of measurement was reliable. Accuracy and reproducibility of the measurement of femoral axial offset from the retrocondylar plane were high.
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http://dx.doi.org/10.1002/jor.24843DOI Listing
September 2020

Ancient Jomon genome sequence analysis sheds light on migration patterns of early East Asian populations.

Commun Biol 2020 Aug 25;3(1):437. Epub 2020 Aug 25.

Kitasato University School of Medicine, Sagamihara, Japan.

Anatomically modern humans reached East Asia more than 40,000 years ago. However, key questions still remain unanswered with regard to the route(s) and the number of wave(s) in the dispersal into East Eurasia. Ancient genomes at the edge of the region may elucidate a more detailed picture of the peopling of East Eurasia. Here, we analyze the whole-genome sequence of a 2,500-year-old individual (IK002) from the main-island of Japan that is  characterized with a typical Jomon culture. The phylogenetic analyses support multiple waves of migration, with IK002 forming a basal lineage to the East and Northeast Asian genomes examined, likely representing some of the earliest-wave migrants who went north from Southeast Asia to East Asia. Furthermore, IK002 shows strong genetic affinity with the indigenous Taiwan aborigines, which may support a coastal route of the Jomon-ancestry migration. This study highlights the power of ancient genomics to provide new insights into the complex history of human migration into East Eurasia.
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http://dx.doi.org/10.1038/s42003-020-01162-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447786PMC
August 2020

Sex-based differences in human sacroiliac joint shape: a three-dimensional morphological analysis of the iliac auricular surface of modern Japanese macerated bones.

Anat Sci Int 2020 Mar 2;95(2):219-229. Epub 2019 Dec 2.

Department of Oral Anatomy and Dental Anthropology, Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto 1-7-1, Nagasaki, 852-8588, Japan.

The human pelvis is one of the skeletons where sex differences are expressed, but few detailed studies have been conducted on sex-related differences in the sacroiliac joint morphology. Therefore, we conducted a three-dimensional morphological analysis evaluation of the sacroiliac joints to clarify the sex-related difference of the joint's morphology. Right-side macerated innominate bones of Japanese males (n = 100) and females (n = 70) whose ages at death were recorded were included in the study. Three-dimensional images were created from the subjects' iliac auricular surface images, and 16 measurement parameters were acquired on the basis of 11 defined measurement points. All measurement parameters were compared between the male and female groups. The values of the measurement parameters indicating the size of the iliac auricular surface were significantly larger in the male group than in the female group. In addition, the angle between the short and long arms of the auricular surface was larger in the male group. Furthermore, on the basis of the corrected values of the physical disparity, the long arm dimension of the iliac auricular surface was larger in the male group, while the short arm dimension was larger in the female group. The sex-based differences in the iliac auricular surface morphology that were confirmed in this study may reflect the sex-based differences in the sacroiliac joint function. The findings of this study may contribute to the elucidation of the pathophysiology of the sacroiliac joint dysfunction that frequently occurs in women.
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http://dx.doi.org/10.1007/s12565-019-00513-2DOI Listing
March 2020

The effects of volar locking plates for distal radius fractures on the image quality of high-resolution peripheral quantitative computed tomography.

Bone 2019 10 31;127:620-625. Epub 2019 Jul 31.

Department of Orthopedic Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan.

Introduction: High-resolution peripheral quantitative computed tomography (HR-pQCT) has enabled us to observe changes of bone microstructure during fracture healing. However, a method of analyzing the healing process after osteosynthesis has yet to be established due to implant artifacts. The purpose of this study was to investigate the effects of volar locking plates for distal radius fractures on the image quality of HR-pQCT.

Methods: Four different types of plates for distal radius fractures were evaluated. The scan region of HR-pQCT was the center of each plate, not including the screw insertion sites. To assess plate-generated noise, each plate was fixed to the top of a water-filled rubber glove, scanned by HR-pQCT, and the signal-to-noise ratio (SNR) of the region under the plates was calculated. To investigate accuracy, 12 cadaveric radii with and without each plate were scanned by HR-pQCT, and differences between the measured values with and without the plate were evaluated. Differences between the measurements of the entire circumference and of the dorsal third of the radius were also compared. Reproducibility of the in vivo measurement was investigated by repeated scans of 10 patients with distal radius fractures who had undergone surgery with a volar locking plate.

Results: The SNR was significantly higher away from the plate than immediately below the plate. Percentage differences of the measurement values between with and without the plate were 1.4%-3.2% for cortical bone mineral density (Ct.BMD) and 7.2%-9.8% for cortical bone thickness (Ct.Th) when the entire circumference was measured. When the dorsal third was measured, they were 0.3%-1.7% for Ct.BMD and 1.8%-2.7% for Ct.Th. The root-mean-square coefficient of variation (RMS%CV) was 1.12% for Ct.BMD and 4.18% for Ct.Th.

Conclusions: The accuracy and reproducibility of cortical bone measurements with a volar locking plate on HR-pQCT were acceptable when the dorsal third of the Ct.BMD was analyzed, and this method would be useful for in vivo analysis of the fracture healing process after osteosynthesis.
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http://dx.doi.org/10.1016/j.bone.2019.07.025DOI Listing
October 2019

Morphological profile of atypical femoral fractures: age-related changes to the cross-sectional geometry of the diaphysis.

J Anat 2019 11 29;235(5):892-902. Epub 2019 Jul 29.

Department of Macroscopic Anatomy, Graduate School of Biomedical Science, Nagasaki University, Nagasaki, Japan.

The use of bisphosphonates for osteoporosis patients has markedly decreased the incidence of femoral neck or trochanteric fractures. However, anti-osteoporosis drugs have been reported to increase the incidence of atypical femoral fractures, which involve stress fractures in the subtrochanteric region or the proximal diaphysis. In this study, the morphological characteristics of the cortical bone in human femoral diaphysis samples were analyzed from individuals who lived before bisphosphonate drugs were available in Japan. A total of 90 right femoral bones were arbitrarily selected (46 males and 44 females) from modern Japanese skeletal specimens. Full-length images of these femurs were acquired using a computed tomography scanner. An image processing method for binarization was used to calculate the threshold values of individual bones for determining their contours. The range between the lower end of the lesser trochanter and the adductor tubercle of each femur was divided at regular intervals to obtain 10 planes. The mean value of cortical bone thickness, periosteal border length, and the cortical cross-sectional area was evaluated for all planes. Moreover, the ratio of the area of the cortical bone to the total area of cross-section at the mid-diaphysis was calculated. A comparison between males and females demonstrated that most females had lower cortical bone area ratios at the mid-diaphysis. The femoral outer shape did not differ markedly according to age or sex; however, substantial individual differences were observed in the shape of the inner surface of the cortical bone. The cortical bone thickness and the cross-sectional area decreased with age in the femoral diaphysis; furthermore, in females, the decrease was higher for the former than for the latter. This may be due to a compensatory increase in the circumference of the femoral diaphysis. In addition, in about half of the subjects there was a discrepancy between the region with maximal value of the cortical bone thickness and that of the total cross-sectional area. Biological responses to mechanical stresses to the femoral diaphysis are thought not to be uniform. Bisphosphonates inhibit bone resorption and may promote non-physiological bone remodeling. Thus, a nonhomogeneous decrease in cortical thickness may be related to the fracture occurrence in the femoral diaphysis in some cases. Thus, long-term administration of bisphosphonates in patients with morphological vulnerability in the femoral cortical bones may increase the occurrence of atypical femoral fractures.
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http://dx.doi.org/10.1111/joa.13060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794203PMC
November 2019

A health crisis during the Japanese Medieval Period: A new paleodemographic perspective.

Int J Paleopathol 2019 09 30;26:145-156. Epub 2019 Mar 30.

Department of Anatomy, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae Ward, Kawasaki, Kanagawa, 216-8511, Japan.

Objective: To test the hypothesis that the "Little Ice Age" (LIA) (in Japan, ˜1440 - 1730 CE) co-occurred with unique age-at-death patterns.

Materials: 810 adult human skeletons from the early Medieval Period (EMP) of Japan, which are contemporaneous with the Medieval Warm Period (10th - mid 13th century AD), and the late Medieval Period (LMP) and Edo Period, which are contemporary with the LIA.

Methods: Age at death and sex was determined for each skeleton and demographic profiles of the Yayoi Period (5th century BC - 3rd century AD), EMP, LMP, and Edo site samples were compared. Paleopathological data from previously published reports were evaluated.

Results: The EMP had the highest mortality among young adults. Longevity increased in the samples (LMP and Edo) contemporaneous with the LIA.

Conclusions: EMP early age-at-death was the result of poor community health, violent death, and frequent large-scale natural catastrophes. The LMP and Edo Period samples have an older age-at-death pattern and higher frequency of stress markers, argued to be a consequence of a colder climate.

Significance: This study is the first to synthesize paleodemographic and paleopathological data on a large scale to assess the possible effects of the Little Ice Age in Japan.

Limitations: Varying skeletal preservation and focus on adult skeletons reduces the ability to evaluate health throughout the life span.

Suggestions For Further Research: Analysis of nonadult remains and multiple health indicators will likely shed more light on the effects of the Little Ice Age in Japan.
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http://dx.doi.org/10.1016/j.ijpp.2019.03.005DOI Listing
September 2019

Correlation between vertebral bone microstructure and estimated strength in elderly women: An ex-vivo HR-pQCT study of cadaveric spine.

Bone 2019 03 14;120:459-464. Epub 2018 Dec 14.

Department of Orthopedic Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan.

Purpose: A vertebral fracture is the most common complication of osteoporosis, and various factors are involved in its occurrence. The purpose of this study was to investigate the role of trabecular and cortical bone microstructure on vertebral strength using high-resolution peripheral quantitative computed tomography (HR-pQCT).

Methods: Three female cadaveric spines were investigated (average age: 80.3 years). The whole spine (T1-L4) was scanned by second-generation HR-pQCT at a voxel size of 60.7 μm. Bone microstructure analysis and micro finite element analysis were performed after excluding the upper and lower endplates and posterior elements of a total of 48 vertebrae. Correlations between trabecular and cortical bone microstructure parameters and estimated vertebral strength were analyzed by univariate and multivariate regression models.

Results: Cortical thickness (Ct.Th) and trabecular thickness (Tb.Th) were strongly correlated with estimated failure load on univariate analysis (r = 0.89, 0.82). Trabecular volumetric bone mineral density (Tb.vBMD), bone volume fraction (BV/TV), trabecular number (Tb.N), and Ct.Th were correlated with estimated failure load on multivariate regression analysis.

Conclusions: It was suggested that, in addition to trabecular bone (Tb.vBMD, BV/TV, Tb.N), cortical bone (Ct.Th) contributed significantly to vertebral strength in elderly women.
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http://dx.doi.org/10.1016/j.bone.2018.12.005DOI Listing
March 2019

An Ancient Skeleton with Multiple Osteoblastic Bone Lesions Containing a Scapular Sunburst Appearance from a 5th-6th Century Grave Excavated in Oita, Japan.

Biomed Res Int 2018 6;2018:1659510. Epub 2018 Sep 6.

Department of Macroscopic Anatomy, Graduate School of Biomedical Science, Nagasaki University, Japan.

A human skeleton of a middle-aged adult male was found in a 5th-6th century Kinoue-Kodo stone coffin excavated from the southwest marginal region of the Oita plains, northeast Kyushu, Japan. The skeleton was buried respectfully in the ancient tomb, and red pigment was applied to his face after death. We report herein findings from computed tomography imaging of the skeleton and discuss the multiple osteoblastic lesions identified in the humerus, scapula, clavicle, vertebra, pelvic bones, and skull of this individual. These lesions comprised cortical bone thickening with periosteal reaction localized to the surface and osteosclerotic changes mainly observed in the trabecular structure of cancellous bone. In particular, a typical sunburst pattern was also noted on the left scapula as another characteristic lesion found in this case. By differential diagnosis, the disease suffered by this individual was most likely to be metastatic bone tumors, especially of prostate cancer. This person may have survived until many bone metastases had developed throughout his whole body.
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http://dx.doi.org/10.1155/2018/1659510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148826PMC
January 2019

Diversity in intracortical remodeling in the human femoral bone: A novel view point with the morphological analysis of secondary osteons.

J Orthop Sci 2018 Nov 23;23(6):1079-1086. Epub 2018 Aug 23.

Department of Macroscopic Anatomy, Nagasaki University Graduate School of Biomedical Sciences, Japan.

Introduction: In humans, intracortical bone remodeling is performed by a basic multicellular unit (BMU) composed of osteoclasts and osteoblasts penetrating through cortical bones. As a result, secondary osteons and their boundaries, cement lines, can be observed on the transverse section. There have been few reports mention whether there is diversity within a single individual and on the relevance to bone remodeling. The purpose of this study is to investigate the morphological diversity of secondary osteons in human femoral bone and to examine the relationship with bone remodeling.

Material And Methods: First of all, we developed an original method to get the cross-sectional images of the cortical bones around the whole circumference for the purpose of evaluating the morphology of the secondary osteon exhaustively. Then, a total of ten cross-sectional slices from one right human femoral bone of male were prepared and stained with this method. The osteon population density and complexity of cement lines in osteons were evaluated in detail.

Results: Within this femoral bone, the osteon population density was significantly higher in the periosteal side and in the posterior area. Conversely, the cement line density and the osteon complexity were higher in the endosteal side; the proportion of complexed osteon significantly increased from the periosteal side toward the endosteal side.

Discussion: The results suggested that there were diversities in osteon population densities and osteon morphological pattern within one human femoral bone. It seemed that the BMUs ran to avoid the existing regions of osteon in the periosteal sides and to overlap the existing osteon in the endosteal sides. This seemed to be one of the novel viewpoints in the morphological analysis of secondary osteons. It might be better for the orthopedic surgeons to be aware that the osteon distribution in the cortical bone is not uniform.
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http://dx.doi.org/10.1016/j.jos.2018.07.021DOI Listing
November 2018

Investigating interindividual variations in cortical bone quality: analysis of the morphotypes of secondary osteons and their population densities in the human femoral diaphysis.

Anat Sci Int 2019 Jan 30;94(1):75-85. Epub 2018 Jul 30.

Department of Orthopaedic Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki City, Nagasaki Prefecture, 852-8523, Japan.

Osteons are the primary sites of cortical bone lesions. However, many aspects of osteon microstructure remain poorly understood. This study aimed to explores interindividual differences in the osteon morphotype distributions in the human femoral diaphysis by evaluating the secondary osteon distributions in samples from human femurs. Two anonymized bone fragments from two modern Japanese femurs were examined. Twelve continuous transverse femoral diaphysis specimens were prepared from each fragment. Imaging examinations were conducted using a circularly polarized light microscope, and cross-sectional images were rendered using graphical synthesis software. Osteons in the images were identified as either bright-type osteons, dark-type osteons, or an others type. The two femurs were compared, and the secondary osteon morphotype distributions in different regions of their cross-sections were analyzed. When the two femurs were compared, significant differences in osteon density were observed in some regions and cross-sections. The dark-type osteon presence was strongest in the anterior and posterior regions of the femurs. The analytical method used in this study was found to be able to evaluate osteon microstructure. The results suggest that examining additional specimens and analyzing the biomechanical underpinnings of interindividual differences in osteon distribution patterns may help to improve our understanding of osteon microstructure.
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http://dx.doi.org/10.1007/s12565-018-0452-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315013PMC
January 2019

Anatomical study of the articular branches innervated the hip and knee joint with reference to mechanism of referral pain in hip joint disease patients.

Clin Anat 2018 Jul 16;31(5):705-709. Epub 2018 Apr 16.

Department of Locomotive Rehabilitation Science, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1, Sakamoto Nagasaki, 852-8520, Japan.

Introduction: Referred pain in the anterior knee joint is the most common symptom in hip disease patients. The development of referred pain is considered to be related to dichotomizing peripheral sensory fibers. However, no gross anatomical findings identify any dichotomizing fibers innervating both the hip and knee joints. We dissected the femoral and obturator nerves in human cadavers to investigate the distribution of the articular branches in the hip and knee joints. Fourteen embalmed left lower limbs from 14 Japanese adult cadavers (five from females, nine from males, average age 73.8 ± 14.1 years) were observed macroscopically. The articular branches of the femoral and obturator nerves were dissected at the anterior margin of the groin toward the thigh region. After dissections of the articular nerves of the hip joints, the femoral and obturator nerves were exposed from proximally to distally to identify the articular nerves of the knee joints. The branching pattern of the articular branches in the hip and knee joints was recorded. In six of 14 limbs (42.9%), the femoral nerve supplied articular branches to the anteromedial aspect of both the hip and knee joints. These articular branches were derived from the same bundle of femoral nerve. These gross anatomical findings suggested that dichotomizing peripheral sensory fibers innervate the hip and knee joints and these could relate to the referred pain confirmed in the anterior knee joints of patients with hip disease. Clin. Anat. 31:705-709, 2018. © 2018 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ca.23077DOI Listing
July 2018

Three-dimensional morphological analysis of the human sacroiliac joint: influences on the degenerative changes of the auricular surfaces.

J Anat 2018 02 25;232(2):238-249. Epub 2017 Dec 25.

Department of Macroscopic Anatomy, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

The sacroiliac joint (SIJ) is responsible for weight transmission between the spine and lower extremity. However, details of the structure and function of the SIJ remain unclear. In a previous study, we devised a method of quantitatively evaluating the level of degeneration of the SIJ using an age estimation procedure for the auricular surface of the ilium. Our results in that study suggested that the degree of degeneration of the joint surface may be associated with the morphology of the auricular surface of the ilium. In that study, however, the morphology of the auricular surface of the ilium was simplified for analysis, meaning that more detailed investigations were required in future. In the present study, we focused on individual differences in the shape of SIJ and carried out three-dimensional quantitative evaluation of the morphology of the auricular surface of the ilium to ascertain its association with joint degeneration. We produced three-dimensional images of the right auricular surfaces of the ilium of 100 modern Japanese men (age 19-83), and obtained the three-dimensional rectangular coordinates of 11 defined measurement points. We then calculated 16 parameters indicating the morphological characteristics of the auricular surfaces of the ilium from the three-dimensional rectangular coordinates of these measurement points, and used these to perform principal component analysis to investigate trends in the morphology of the auricular surface of the ilium. We found that the morphology of the auricular surface of the ilium could be characterized in terms of (i) size, (ii) concavity of the posterior border and (iii) amount of undulation. An investigation of the correlation between these parameters and age suggested that the amount of undulation of the auricular surface of the ilium tends to diminish with advancing age. In an investigation of the association between morphology of the auricular surface of the ilium and degeneration of the articular surface when the subjects were divided into a high-degeneration group (n = 55) and a low-degeneration group (n = 45) and the 16 parameters were compared, there was a significant difference in the amount of undulation of the auricular surface of the ilium. In an investigation limited to older subjects aged ≥ 60 (n = 47) at the time of death, there were significant differences between the high-degeneration group (n = 27) and low-degeneration group (n = 20) in terms not only of the parameters indicating the amount of undulation of the auricular surface of the ilium but also of those indicating the amount of the concavity of the posterior border. These results suggested that the amount of undulation of the auricular surface of the ilium may affect the degree of degeneration of the articular surface. In addition, in older subjects, the degree of concavity of the posterior border of the SIJ may also affect the degree of degeneration of the articular surface. It is thus likely that differences in the morphology of the auricular surface of the ilium may affect degenerative changes in the SIJ.
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http://dx.doi.org/10.1111/joa.12765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770301PMC
February 2018

Deep and superficial circumflex iliac arteries and their relationship to the ultrasound-guided femoral nerve block procedure: A cadaver study.

Clin Anat 2017 Apr 9;30(3):413-420. Epub 2017 Mar 9.

Department of Macroscopic Anatomy, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

The in-plane lateral to medial approach is a standard technique for ultrasound-guided femoral nerve block (USG-FNB). The first bifurcation of the femoral artery, which consists of the deep artery of the thigh (DAT) or occasionally the lateral circumflex femoral artery (LCFA), is regarded as the distal border for this procedure. We sometimes detect arteries along the estimated needle trajectory for USG-FNB. The superficial (SCIA) and deep (DCIA) circumflex iliac arteries run laterally parallel to the inguinal ligament from the femoral or external iliac artery. The relationship between the SCIA and DCIA and other anatomical structures related to USG-FNB around the femoral triangle region was studied by gross anatomical examination of 100 formalin-fixed adult cadavers. At least one SCIA and one DCIA were identified around each femoral triangle; 81.8% of SCIA and 58% of DCIA originated from the femoral artery. All DCIA coursed between the fascia lata and fascia iliaca and 80% of SCIA penetrated the fascia lata. In 94% of femoral triangles, at least one arterial branch heading towards the lateral part of the thigh originated from the femoral artery from the level of the inguinal ligament to the first bifurcation of the femoral artery. The presence of SCIA and DCIA should be considered during USG-FNB using the in-plane lateral to medial approach to avoid inadvertently injuring them, as they are occasionally located along the presumed needle trajectory superficial to the fascia iliaca. Clin. Anat. 30:413-420, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ca.22852DOI Listing
April 2017

Sex differences of dental pathology in early modern samurai and commoners at Kokura in Japan.

Odontology 2017 Jul 16;105(3):267-274. Epub 2016 Nov 16.

Department of Oral Anatomy and Dental Anthropology, Unit of Basic Medical Sciences, Course of Medical and Dental Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan.

So-called "Ohaguro", teeth blackening, in the married females was a general custom regardless of class in the early modern period. As a result, Ohaguro was thought to have enhanced the acid resistance of tooth substance and tightened gingiva and prevented tooth morbidity due to periodontal disease. For investigation into the influence of Ohaguro, the skeletal remains of early modern samurai and commoners at Kokura were examined for differences in the dental pathology based on sex. Though females from archeological sites have significantly more carious teeth and antemortem tooth loss (AMTL) than males in the previous studies, the prevalence of caries and AMTL in males was higher than in females among the early modern samurai and commoners in Kokura. The efficacies of Ohaguro may influence the good dental health of females. On the other hand, as females were considered inferior to males under the feudal system in Japan, males, including children, might tend to consume more nutritious foods compared to females. However, those foods are certainly not better with regard to dental health, since those foods are more highly cariogenic. These factors may have caused higher caries and AMTL prevalence among males compared to females in early modern Kokura.
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http://dx.doi.org/10.1007/s10266-016-0275-0DOI Listing
July 2017

Degenerative changes of the sacroiliac auricular joint surface-validation of influential factors.

Anat Sci Int 2017 Sep 24;92(4):530-538. Epub 2016 Jun 24.

Department of Macroscopic Anatomy, Graduate School of Biomedical Science, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.

The purpose of this study was to clarify the relevance of degenerative changes in the sacroiliac joint (SIJ) and the joints in the lower limb and lumbar spine using age estimation methods. We also examined the shape of the auricular surface to determine the effect of degenerative changes on each joint. A total of 200 iliac auricular surfaces from 100 Japanese male skeletons were examined macroscopically in accordance with conventional methods of age estimation. From the obtained estimated age, we calculated the deflection values, which represented the degree of degenerative changes of the joints. For comparison, we used osteophyte score data of the hip, knee, and zygapophyseal joints in lumbar spines from previous studies which had used the same bone specimens. As a quantitative indicator of auricular surface morphology, we defined the constriction ratio (CR) of the auricular surface and compared the CR values obtained with various measured values. Degenerative changes in the SIJ were positively correlated with those in both the hip joint and zygapophyseal joint, but a correlation with knee joints was found only on the left side. In skeletons from individuals aged ≥60 years as time of death, the CR was significantly different between the group with high scores and those with low scores in both the hip and sacroiliac joints. It has been suggested that degenerative changes in SIJs interact with those in the hip joint and zygapophyseal joint. In addition, the shape of the auricular surface may also be a relevant factor for degenerative changes in these joints.
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http://dx.doi.org/10.1007/s12565-016-0354-xDOI Listing
September 2017

Biofilm-forming Staphylococcus epidermidis expressing vancomycin resistance early after adhesion to a metal surface.

Biomed Res Int 2015 31;2015:943056. Epub 2015 Jan 31.

Department of Orthopaedic Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan.

We investigated biofilm formation and time of vancomycin (VCM) resistance expression after adhesion to a metal surface in Staphylococcus epidermidis. Biofilm-forming Staphylococcus epidermidis with a VCM MIC of 1 μg/mL was used. The bacteria were made to adhere to a stainless steel washer and treated with VCM at different times and concentrations. VCM was administered 0, 2, 4, and 8 hours after adhesion. The amount of biofilm formed was evaluated based on the biofilm coverage rates (BCRs) before and after VCM administration, bacterial viability in biofilm was visually observed using the fluorescence staining method, and the viable bacterial count in biofilm was measured. The VCM concentration required to decrease BCR significantly compared with that of VCM-untreated bacteria was 4 μg/mL, even in the 0 hr group. In the 4 and 8 hr groups, VCM could not inhibit biofilm growth even at 1,024 μg/mL. In the 8 hr group, viable bacteria remained in biofilm at a count of 10(4) CFU even at a high VCM concentration (1,024 μg/mL). It was suggested that biofilm-forming Staphylococcus epidermidis expresses resistance to VCM early after adhesion to a metal surface. Resistance increased over time after adhesion as the biofilm formed, and strong resistance was expressed 4-8 hours after adhesion.
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http://dx.doi.org/10.1155/2015/943056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329865PMC
May 2016

Characterization of individuals with sacroiliac joint bridging in a skeletal population: analysis of degenerative changes in spinal vertebrae.

Biomed Res Int 2014 8;2014:879645. Epub 2014 Sep 8.

Department of Macroscopic Anatomy, Graduate School of Biomedical Science, Nagasaki University, Nagasaki 852-8523, Japan.

The aim of this study was to characterize the individuals with sacroiliac joint bridging (SIB) by analyzing the degenerative changes in their whole vertebral column and comparing them with the controls. A total of 291 modern Japanese male skeletons, with an average age at death of 60.8 years, were examined macroscopically. They were divided into two groups: individuals with SIB and those without bridging (Non-SIB). The degenerative changes in their whole vertebral column were evaluated, and marginal osteophyte scores (MOS) of the vertebral bodies and degenerative joint scores in zygapophyseal joints were calculated. SIB was recognized in 30 individuals from a total of 291 males (10.3%). The average of age at death in SIB group was significantly higher than that in Non-SIB group. The values of MOS in the thoracic spines, particularly in the anterior part of the vertebral bodies, were consecutively higher in SIB group than in Non-SIB group. Incidence of fused vertebral bodies intervertebral levels was obviously higher in SIB group than in Non-SIB group. SIB and marginal osteophyte formation in vertebral bodies could coexist in a skeletal population of men. Some systemic factors might act on these degenerative changes simultaneously both in sacroiliac joint and in vertebral column.
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http://dx.doi.org/10.1155/2014/879645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172928PMC
June 2015

Investigation and macroscopic anatomical study of referred pain in patients with hip disease.

J Phys Ther Sci 2014 Feb 28;26(2):203-8. Epub 2014 Feb 28.

Department of Macroscopic Morphology, Unit of Basic Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Japan.

[Purpose] The aim of this study was to examine the incidence and patterns of referred pain in patients with hip disease, as well as the nerve distribution in the hip and knee joints of 2 cadavers. [Subjects and Methods] A total of 113 patients with hip joint disease were included in the investigation. The incidence of regional pain and referred pain patterns were evaluated before and after arthroplasty. Two cadavers were macroscopically observed to verify the nerve innervation of the hip and knee joints. [Results] Anterior knee pain was observed preoperatively in 13.3% (in resting) and 33.6% (in motion) of the patients, which was comparable with the incidence of greater trochanter pain. In addition, the preoperative incidence rates of knee pain in resting and motion markedly decreased postoperatively. Of note is the remarkable incidence of pain radiating to the ventral lower limb. An anteromedial innervation was determined in the cadavers by the articular branches of the obturator and femoral nerve, which supply small branches to the knee joints. [Conclusion] Our results suggest that the distribution of the incidence of pain among the patients with hip disease is diverse owing to the sensory distribution of the femoral and obturator nerves.
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http://dx.doi.org/10.1589/jpts.26.203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944289PMC
February 2014

Case of retroesophageal right subclavian artery, with special reference to the second intercostal artery, retroesophageal right vertebral artery, and thoracic duct.

Anat Sci Int 2013 Sep 16;88(4):234-8. Epub 2013 May 16.

Department of Macroscopic Morphology, Unit of Basic Medical Sciences, Graduate School of Biomedical Science, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.

We report a case of retroesophageal right subclavian artery identified in a 59-year-old Japanese female during routine dissection in Nagasaki University School of Medicine. This kind of variation is relatively rare; however, reports of such cases have accumulated. We paid attention to the intersegmental arteries and above all, the second intercostal artery. On the other hand, there have been reports of a retroesophageal right vertebral artery, although such cases are extremely rare. It is considered that both retroesophageal arteries are formed by similar mechanisms. In other words, the distal part of the right dorsal aorta remained in such cases. However, in the case of a retroesophageal right vertebral artery, there might be the possibility of intercostal arteries developing into the vertebral artery, and we discuss such points here.
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http://dx.doi.org/10.1007/s12565-013-0178-xDOI Listing
September 2013

Relation between bilateral differences in internal jugular vein caliber and flow patterns of dural venous sinuses.

Anat Sci Int 2013 Jun 10;88(3):141-50. Epub 2013 Apr 10.

Unit of Translational Medical Science, Department of Macroscopic Morphology, Nagasaki University, Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.

We measured the calibers of the left and right internal jugular veins (IJV) and sizes of the left and right transverse sinuses (TS) in 91 cadavers, compared them between the left and right sides, and also evaluated the drainage patterns of the superior sagittal sinus (SSS) and straight sinus (=rectal sinus, RS) in the torcular Herophili. In addition, the running type of groove for the SSS was investigated. The results were as follows: (1) The right IJV was larger in 81.3 %, while the left IJV was larger in only 11.0 %. (2) The drainage pattern of the SSS was the right type in 73.6 %, intermediate type in 14.3 %, and left type in 12.1 %. (3) The drainage pattern of the RS was the right type in 27.5 %, intermediate type in 25.3 %, and left type in 47.3 %. (4) The running type of groove for the SSS was mostly consistent with the drainage pattern of this sinus. (5) Concerning the relationships among these findings including the size of the TS, the drainage pattern of the SSS was mostly consistent with the side showing a larger TS as well as the side showing a larger IJV. These results suggest that the pattern of drainage of the SSS into the left and right TS affects the size of the TS and the running type of groove for the SSS, and is also closely involved in the caliber of the IJV. A discussion of the embryological, genetic, and clinical implications of these results is presented.
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http://dx.doi.org/10.1007/s12565-013-0176-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654179PMC
June 2013

Periarticular osteophytes as an appendicular joint stress marker (JSM): analysis in a contemporary Japanese skeletal collection.

PLoS One 2013 20;8(2):e57049. Epub 2013 Feb 20.

Department of Macroscopic Anatomy, Graduate School of Biomedical Science, Nagasaki University, Nagasaki, Japan.

Objective: The aim of this study was to investigate the possibility that periarticular osteophytes plays a role as a appendicular joint stress marker (JSM) which reflects the biomechanical stresses on individuals and populations.

Methods: A total of 366 contemporary Japanese skeletons (231 males, 135 females) were examined closely to evaluate the periarticular osteophytes of six major joints, the shoulder, elbow, wrist, hip, knee, and ankle and osteophyte scores (OS) were determined using an original grading system. These scores were aggregated and analyzed statistically from some viewpoints.

Results: All of the OS for the respective joints were correlated logarithmically with the age-at-death of the individuals. For 70 individuals, in whom both sides of all six joints were evaluated without missing values, the age-standardized OS were calculated. A right side dominancy was recognized in the joints of the upper extremities, shoulder and wrist joints, and the bilateral correlations were large in the three joints on the lower extremity. For the shoulder joint and the hip joint, it was inferred by some distinctions that systemic factors were relatively large. All of these six joints could be assorted by the extent of systemic and local factors on osteophytes formation. Moreover, when the age-standardized OS of all the joints was summed up, some individuals had significantly high total scores, and others had significantly low total scores; namely, all of the individuals varied greatly in their systemic predisposition for osteophytes formation.

Conclusions: This study demonstrated the significance of periarticular osteophytes; the evaluating system for OS could be used to detect differences among joints and individuals. Periarticular osteophytes could be applied as an appendicular joint stress marker (JSM); by applying OS evaluating system for skeletal populations, intra-skeletal and inter-skeletal variations in biomechanical stresses throughout the lives could be clarified.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057049PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577756PMC
August 2013

The nerves to the plantaris muscle and a bipennate part of the soleus muscle.

Anat Sci Int 2013 Jan 25;88(1):17-24. Epub 2012 Sep 25.

Department of Macroscopic Morphology, Unit of Basic Medical Sciences, Graduate School of Biomedical Science, Nagasaki University, Sakamoto, Nagasaki, Japan.

We performed nerve fiber analysis of the nerve to the plantaris muscle in ten cases. Macroscopically, the nerve to the plantaris muscle has a tendency to branch off from the tibial nerve itself independent of the nerves to the gastrocnemius and soleus muscles (the triceps surae muscle). After removing the epineurium of the tibial nerve, it was revealed that, in all ten cases, the nerve to the plantaris muscle formed a common funicular trunk with the nerve to a bipennate part of the soleus. This trunk is akin to the nerves to the deep muscles of the calf. In addition, in five of the ten cases, the nerve to the plantaris muscle had another component, which arose from the branch to the popliteus muscle. By removing the perineurium of the nerves concerned, it became clear that the elements of the nerve to the plantaris muscle, and of the nerve to the bipennate part of the soleus, had an intimate relation (inseparable). On the other hand, the elements of the nerve to the plantaris muscle and those to the popliteus were separable and they showed different routes proximally. Based on the present findings derived from nerve fiber analysis, we postulate that the plantaris muscle and bipennate part of the soleus muscle were probably derived from the deep muscle anlage of the calf in spite of their topographical closeness to the superficial muscles of the calf.
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http://dx.doi.org/10.1007/s12565-012-0153-yDOI Listing
January 2013

Geographic variation in body form of prehistoric Jomon males in the Japanese archipelago: its ecogeographic implications.

Am J Phys Anthropol 2012 Sep 13;149(1):125-35. Epub 2012 Jul 13.

Division of Human Evolution Studies, Graduate School of Medicine, Hokkaido University, Japan.

Diversity of human body size and shape is often biogeographically interpreted in association with climatic conditions. According to Bergmann's and Allen's rules, populations in regions with a cold climate are expected to display an overall larger body and smaller/shorter extremities than those in warm/hot environments. In the present study, the skeletal limb size and proportions of prehistoric Jomon hunter-gatherers, who extensively inhabited subarctic to subtropical areas in the ancient Japanese archipelago, were examined to evaluate whether or not the inter-regional differences follow such ecogeographic patterns. Results showed that the Jomon intralimb proportions including relative distal limb lengths did not differ significantly among five regions from northern Hokkaido to the southern Okinawa Islands. This suggests a limited co-variability of the intralimb proportions with climate, particularly within genealogically close populations. In contrast, femoral head breadth (associated with body mass) and skeletal limb lengths were found to be significantly and positively correlated with latitude, suggesting a north-south geographical cline in the body size. This gradient therefore comprehensively conforms to Bergmann's rule, and may stem from multiple potential factors such as phylogenetic constraints, microevolutionary adaptation to climatic/geographic conditions during the Jomon period, and nutritional and physiological response during ontogeny. Specifically, the remarkably small-bodied Jomon in the Okinawa Islands can also be explained as an adjustment to subtropical and insular environments. Thus, the findings obtained in this study indicate that Jomon people, while maintaining fundamental intralimb proportions, displayed body size variation in concert with ambient surroundings.
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http://dx.doi.org/10.1002/ajpa.22112DOI Listing
September 2012

Post-transcriptional regulation of IL-6 production by Zc3h12a in fibroblast-like synovial cells.

Clin Exp Rheumatol 2011 Nov-Dec;29(6):906-12. Epub 2011 Dec 22.

Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Objectives: Zc3h12a is an RNA binding protein with a CCCH-type finger motif and is known to regulate mRNA metabolism. Previous reports suggest that Zc3h12a acts as a negative regulator of inflammatory processes because it is involved in the degradation of IL-6 mRNA. We investigate the effect of Zc3h12a on IL-6 production in fibroblast-like synovial cells (FLS) from rheumatoid arthritis (RA) patients.

Methods: The expression of Zc3h12a in FLS was determined by polymerase chain reaction. To knock down Zc3h12a expression in FLS, siRNA for Zc3h12a was transfected by the lipofection method. The supernatants were collected after siRNA transfection for the quantification of IL-6 production. The phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was examined by Western blotting. Cell proliferation was analysed by the Cell Counting Kit-8 assay after Zc3h12a knockdown.

Results: mRNA for Zc3h12a were demonstrated in FLS from RA patients. Zc3h12a transcripts were induced by LPS or IL-1β in FLS. The production of IL-6 as well as its mRNA expression was significantly increased by the Zc3h12a knockdown. The Zc3h12a knockdown also induced the activation of STAT3, which the anti IL-6 receptor antibody inhibited. Proliferation of Zc3h12a-knockdown FLS increased significantly in the presence of recombinant soluble IL-6 receptor (sIL-6R).

Conclusions: Our data suggest that Zc3h12a is a novel IL-6 regulator in FLS, which may be involved in the progression of RA.
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March 2012

Biofilm deficiency in polysaccharide intercellular adhesin-negative variants of Staphylococcus epidermidis selected by subminimal inhibitory concentrations of gentamicin.

Jpn J Infect Dis 2011 ;64(4):304-8

Department of Orthopedic Surgery, Graduate School of Biomedical Science, Nagasaki University, Nagasaki 852-8501, Japan.

Staphylococcus epidermidis is a cause of orthopedic device-related infection, and to treat such infection, biofilms should be controlled. Polysaccharide intercellular adhesin (PIA) is associated with the biofilm-forming ability of staphylococcal strains. PIA in biofilm-positive staphylococcal strains can be detected by the Congo red agar (CRA) method. In this study, we used the CRA method to examine the effects of subminimal inhibitory concentrations (sub-MICs) of 11 antibacterial agents on PIA production by S. epidermidis. We found that the PIA-negative variants were selected only by sub-MICs of gentamicin (GM). This PIA-negative phenotype was maintained over several generations in the absence of GM. Such selection occurred in six of eight clinical isolates, as well as in the biofilm-positive control strain. No such selection occurred with aminoglycoside antibiotics except for GM. Most of the PIA-negative variants that were selected by GM showed a markedly lower biofilm-forming ability on stainless steel washers than their untreated parent strains. In conclusion, variants with lower biofilm-forming ability may be selected by a sub-MIC of GM. Investigation of the reason why variants with reduced biofilm-forming ability can be selected in the presence of sub-MICs of GM may contribute to strategies against biofilm-related infections.
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November 2011

Methotrexate chronotherapy is effective against rheumatoid arthritis.

Chronobiol Int 2011 Apr;28(3):267-74

Department of Medical Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Japan.

Methotrexate (MTX) is the most important drug for treating rheumatoid arthritis (RA). It has been stated that cytokines play an important role in the pathogenesis of RA, and that cytokine levels increase and show 24-h rhythms in RA patients. Previously, we found that arthritis was relieved after the administration of MTX at specific times in synchronization with the 24-h rhythm of tumor necrosis factor (TNF)-α in collagen-induced arthritis (CIA) animals. Based on our findings in an earlier study of the dosing time-dependent effects of MTX in MRL/lpr mice, which develop autoimmune disorders that share similarities with human RA, we examined here the utility of MTX chronotherapy in Japanese RA patients. In an initial animal modeling study, we collected blood from MRL/lpr mice at different times (2, 6, 10, 14, 18, or 22 hours after the light was turned on [HALO]), and we measured TNF-α mRNA expression in leukocytes. MTX was administered to the mice at two different dosing times (6 or 18 HALO), and various blood parameters were measured to estimate arthritis activity. TNF-α mRNA levels showed a clear 24-h rhythm with a peak at 22 HALO and a trough at 18 HALO after RA had developed. In these MRL/lpr mice, inflammation and TNF-α were markedly reduced when the MTX dosing time was matched to the time (18 HALO) when the TNF-α level began to increase. We then applied these findings to Japanese RA patients by switching them from the standard MTX three times/wk (day 1: after breakfast and supper; day 2: after breakfast schedule), to chronotherapy, in which the dose and number of doses/wk were not changed but MTX was administered once-a-day at bedtime. Disease Activity Score (DAS)28, modified health assessment questionnaire (MHAQ), and adverse effects were assessed. With MTX chronotherapy, DAS28, which is commonly used to quantitatively assess RA symptoms, was significantly improved at all follow-up clinical visit times compared with the baseline (vs. 1 mo: p = .0197, 2 mos: p = .0107, 3 mos: p = .0087). Significant symptom recovery was observed in 41.2% of patients, and 23.5% of patients achieved clinical remission during the 3 mos of follow-up. Functional capacity of RA patients, as indicated by the MHAQ, was markedly improved by chronotherapy. There were no severe adverse effects. Thus, we demonstrated (i) inflammation and plasma TNF-α concentrations were significantly reduced in MRL/lpr mice treated with MTX at 18 HALO, the time when TNF-α mRNA level began to increase; and (ii) MTX bedtime chronotherapy was safe, markedly reduced disease activity, and improved the functional capacity of RA patients. The findings on RA patients show that bedtime MTX chronotherapy can improve RA symptoms compared to the current standard dosing methods.
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http://dx.doi.org/10.3109/07420528.2011.553017DOI Listing
April 2011