Ikuo Wada

Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by congenital malformation of the great toes and by progressive heterotopic bone formation in muscle tissue. Recently, a mutation involving a single amino acid substitution in a bone morphogenetic protein (BMP) type I receptor, ALK2, was identified in patients with FOP. We report here that the identical mutation, R206H, was observed in 19 Japanese patients with sporadic FOP. This mutant receptor, ALK2(R206H), activates BMP signaling without ligand binding. Moreover, expression of Smad1 and Smad5 was up-regulated in response to muscular injury. ALK2(R206H) with Smad1 or Smad5 induced osteoblastic differentiation that could be inhibited by Smad7 or dorsomorphin. Taken together, these findings suggest that the heterotopic bone formation in FOP may be induced by a constitutively activated BMP receptor signaling through Smad1 or Smad5. Gene transfer of Smad7 or inhibition of type I receptors with dorsomorphin may represent strategies for blocking the activity induced by ALK2(R206H) in FOP.

A new hand exoskeleton device for rehabilitation using a three-layered sliding spring mechanism

In this paper, a new hand exoskeleton device using a three-layered sliding spring mechanism is presented. In contrast to state of the art hand exoskeleton mechanisms (typically link, wire or pneumatically driven), the proposed mechanism is driven through large deformations of the compliant mechanism body. The mechanism can be made compact and lightweight by adequately positioning the compliant elements. In addition, the mechanism is designed to distribute 1-DOF actuated linear motion into three rotational motions of the finger joints, which translate into natural finger flexion/extension. The primary application of the proposed mechanism is to provide robotic support during physical therapy at the hospital (e.g. Continuous Passive Motion). However, thanks to its light and wearable structure, the proposed device could also be used at home as an assistive/therapeutic device to support activities of daily living. We introduce the mechanical structure of the three-layered sliding spring mechanism, present a prototype implementation as a hand exoskeleton device, and provide a preliminary evaluation.

Application of full-scale three-dimensional models in patients with rheumatoid cervical spine.

Full-scale three-dimensional (3D) models offer a useful tool in preoperative planning, allowing full-scale stereoscopic recognition from any direction and distance with tactile feedback. Although skills and implants have progressed with various innovations, rheumatoid cervical spine surgery remains challenging. No previous studies have documented the usefulness of full-scale 3D models in this complicated situation. The present study assessed the utility of full-scale 3D models in rheumatoid cervical spine surgery. Polyurethane or plaster 3D models of 15 full-sized occipitocervical or upper cervical spines were fabricated using rapid prototyping (stereolithography) techniques from 1-mm slices of individual CT data. A comfortable alignment for patients was reproduced from CT data obtained with the patient in a comfortable occipitocervical position. Usefulness of these models was analyzed. Using models as a template, appropriate shape of the plate-rod construct could be created in advance. No troublesome Halo-vests were needed for preoperative adjustment of occipitocervical angle. No patients complained of dysphasia following surgery. Screw entry points and trajectories were simultaneously determined with full-scale dimensions and perspective, proving particularly valuable in cases involving high-riding vertebral artery. Full-scale stereoscopic recognition has never been achieved with any existing imaging modalities. Full-scale 3D models thus appear useful and applicable to all complicated spinal surgeries. The combination of computer-assisted navigation systems and full-scale 3D models appears likely to provide much better surgical results.

MRI Findings in Residual Hip Dysplasia

Background Residual subluxation of the hip is a major problem in pediatric orthopaedics. Corrective surgery by Salter innominate osteotomy is performed for residual subluxation before school age. Common indications for corrective surgery are determined based on the clinical condition, x-ray images, and arthrographic images. However, the surgical indications vary among institutions. Thus, further information that can predict acetabular growth with certainty is needed for precise decision- making. This study focused on signal intensity changes on magnetic resonance (MR) images within the weight-bearing portion of the acetabulum to determine whether these signal intensity changes could predict acetabular growth. Methods Thirty-six patients who showed residual subluxation after reduction of developmental dysplasia of the hip and whose MRIs were taken when they were around 3 years old were studied. Corrective surgery was performed in 14 patients, whereas the remaining 22 patients were followed conservatively. The presence of a high-signal intensity area (HSIA) within the weight-bearing portion of the acetabular cartilage on T2-weighted MR coronal section images was investigated, and the correlation between HSIA presence and acetabular growth was examined. Results All patients who underwent corrective surgery showed an HSIA within the weight-bearing portion of the acetabular cartilage on T2-weighted MR images before surgery. After surgery, all patients showed HSIA disappearance or decrease. In patients who were followed conservatively, HSIA-positive patients had poor acetabular growth, whereas HSIA-negative patients had favorable acetabular growth. Conclusions HSIAs in the acetabular cartilage may be caused by an extraordinary stress load from the femoral head. The presence of HSIA on MRI may prevent acetabular growth. HSIA on MRI appears to be a significant decision-making tool for corrective surgery. Level of Evidence III.

Ultrastructural changes at the myotendinous junction induced by exercise

BackgroundAlthough exercise is believed to reduce the risk of rupture of the myotendinous junction, exercise-induced structural changes in this region have not been studied. We examined exercise-induced ultrastructural changes in the myotendinous junction of the lower legs in rats.MethodsTen adult male LETO rats were used. Five rats were randomly placed in the Exercise group; the remaining five were used as controls and placed in the non-Exercise group. Running exercise was performed every day for 4 weeks. The tibialis anterior and gastrocnemius muscles were then removed from both legs from each animal in the two groups. The specimens were subsequently examined by transmission electron microscopy (TEM). Numerous finger-like processes were observed at the myotendinous junction. The changes in frequency of branching of the finger-like process (the number of times one finger-like process branched) and the direction of the processes (the angle of the major axis of a finger-like process to the longitudinal direction of the muscle fiber) were studied. To evaluate the two indicators above, each 10 fingerlike process was randomly and separately selected from the tibialis anterior and gastrocnemius muscles of rats, providing 50 finger-like processes of both muscles for evaluation per group.ResultsIn terms of the frequency of branching of the fingerlike processes, the mean values obtained in the non-Exercise group were 0.04 and 0.18 times, respectively, in the tibialis anterior and gastrocnemius muscles and were 0.38 and 1.16 times, respectively, in these two muscles in the Exercise group. Regarding the direction of the finger-like processes, the values were 4.1° and 3.6°, respectively in the non-Exercise group and 10.4° and 14.5°, respectively in the Exercise group. The differences between the two animal groups were significant.ConclusionsMorphological changes in the myotendinous junction occurred as an adaptation to tension increased by exercise.

Intercellular Communication Within the Rat Anterior Pituitary: XIV Electron Microscopic and Immunohistochemical Study on the Relationship Between the Agranular Cells and GnRH Neurons in the Dorsal Pars Tuberalis of the Pituitary Gland

Although numerous investigators in 1970s to 1980s have reported the distribution of LH‐RH nerve fibers in the median eminence, a few LH‐RH fibers have been shown to be present in the pars tuberalis. The significance of the finding remains to be elucidated, and there are few studies on the distribution of LH‐RH neurons in the pars tuberalis, especially in the dorsal pars tuberalis (DPT). Adult male Wistar‐Imamichi rats were separated into two groups: one for electron microscopy and the other for immunohistochemistry to observe LH‐RH and neurofilaments. Pituitary glands attached to the brain were fixed by perfusion, and the sections were prepared parallel to the sagittal plane. The typical glandular structure of the pars tuberalis was evident beneath the bottom floor of the third ventricle, and the thick glandular structure was present in the foremost region. Closer to the anterior lobe, the glandular structure changed to be a thin layer, and it was again observed at the posterior portion. Then the pituitary stalk was surrounded with the dorsal, lateral, and ventral pars tuberalis. LH‐RH and neurofilaments fibers were noted in the bottom floor, and some of them vertically descended to the gland. Adjacent to the glandular folliculostellate cells in the pars tuberalis, Herring bodies with numerous dense granules invading into the gland were present between the pituitary stalk and DPT. It was postulated that the “message” carried by LH‐RH might have been transmitted to the cells in the DPT to aid in the modulation of LH release. Anat Rec, 290:1388–1398, 2007.

Impaired ability to shift weight onto the non-paretic leg in right-cortical brain-damaged patients

BACKGROUND : Stroke patients experience postural instability that can impede functional improvements in their gait. However, the precise functions of the dominant and non-dominant hemispheres in controlling static standing posture and weight-bearing remain unclear. OBJECTIVE : To investigate differences in balancing ability between right-handed patients with right and left hemispheric lesions. METHODS : Weight shifting was quantitatively evaluated to determine the ability of patients to control their balance in a static posture and during conscious weight shifting onto the paretic or non-paretic leg. Participants were enrolled from a consecutive series of stroke patients attending a rehabilitation program (n=49; 31 male, 18 female; mean age 69.3+/-9.4 years). Age-matched normal controls were recruited as volunteers (n=12; 4 male, 8 female; mean age 67.9+/-4.9 years). RESULTS : Patients with cortical lesions in the right hemisphere were able to shift less weight onto the non-paretic leg than patients with cortical lesions in the left hemisphere (p<0.05). There were no correlations between the existence of unilateral spatial neglect and the percentage of weight shifted onto the non-paretic leg, static standing posture (r=0.27, p=0.40) or dynamic standing posture (r=-0.37, p=0.24). In contrast, there was a significant correlation between the percentage of weight consciously shifted onto the non-paretic leg and the existence of anosognosia (r=0.74, p=0.006), but not between static standing posture and anosognosia (r=-0.15, p=0.63). CONCLUSION : Patients with right cortical hemispheric lesions were able to shift less body weight onto their non-paretic leg. These patients should be encouraged to practice shifting their weight towards their non-paretic leg to improve their balance.

Anatomical basis of distally based anterolateral thigh flap.

Abstract Soft tissue coverage around the knee has persisted as a challenge for plastic and reconstructive surgeons. The distally-based anterolateral thigh flap is often used for coverage. Nevertheless, few anatomical studies have investigated the retrograde vascular pedicle. This report clarifies the anatomy of the connection between the descending branch of the lateral circumflex femoral artery and the lateral superior genicular artery. This study examined 38 lower limbs from cadavers and recorded the numbers and locations of perforating vessels. Proximal and distal pivot points were also recorded. The proximal pivot point was 1.0–12.1 cm (average = 6.0 cm) from the inguinal ligament. The distal pivot point, found under the vastus lateralis muscle in all 38 specimens, was 4.0–13.6 cm (average = 9.8 cm) from the lateral superior edge of the patella. The most distal perforator was 8.2–28.0 cm (average = 18.9 cm) from the proximal pivot point. The most proximal perforator was 3.0–19.5 cm (average = 8.7 cm) from the distal pivot point. Details of the anastomosis of the descending branch and the superior lateral genicular artery were clarified. The distally-based anterolateral thigh flap presents one option for reconstruction around the knee.

An anatomic study of the accessory anterolateral talar facet

BACKGROUND A small accessory facet with articular surface morphology is occasionally seen on the talus, bordering on the lateral end of the sinus tarsi. This facet has been named the accessory anterolateral talar facet. However, few anatomical studies have addressed this facet. Here we present the precise morphology of accessory anterolateral talar facet with emphasis on anatomical correlation between the presence of this facet and the angle of the infero-lateral surface of the talus (talar infero-lateral surface - TILS angle). MATERIALS AND METHODS A total of 22 (11 male, 11 female) adult cadavers with no known pathological conditions in the talocalcaneal joints were examined during educational dissection at Nagoya City University Medical School in 2013. After exclusion of 1 joint due to the poor condition of the talus, 43 talus (22 right, 21 left) were analysed. We judged the presence of the accessory anterolateral talar facet and measured TILS angle. We performed statistical analysis on the point of laterality, gender difference and the difference in the TILS angles in tali with or without the accessory anterolateral talar facets. RESULTS An accessory anterolateral talar facet was identified in 11 (26%) of the 43 specimens. Of the 21 cadavers with paired talar specimens, 5 displayed the facet bilaterally. CONCLUSIONS There was no sex difference and no significant laterality, however we found that TILS angle was significantly larger in accessory anterolateral talar facet positive samples than in negative ones.

Intercellular communication within the rat anterior pituitary gland. XV. Properties of spontaneous and LHRH-induced Ca2+ transients in the transitional zone of the rat anterior pituitary in situ.

In the transitional zone of the rat anterior pituitary, spontaneous and LHRH-induced Ca(2+) dynamics were visualized using fluo-4 fluorescence Ca(2+) imaging. A majority of cells exhibited spontaneous Ca(2+) transients, while small populations of cells remained quiescent. Approximately 70% of spontaneously active cells generated fast, oscillatory Ca(2+) transients that were inhibited by cyclopiazonic acid (10 μm) but not nicardipine (1 μm), suggesting that Ca(2+) handling by endoplasmic reticulum, but not Ca(2+) influx through voltage-dependent L-type Ca(2+) channels, plays a fundamental role in their generation. In the adult rat anterior pituitary, LHRH (100 μg/ml) caused a transient increase in the Ca(2+) level in a majority of preparations taken from the morning group rats killed between 0930 h and 1030 h. However, the second application of LHRH invariably failed to elevate Ca(2+) levels, suggesting that the long-lasting refractoriness to LHRH stimulation was developed upon the first challenge of LHRH. In contrast, LHRH had no effect in most preparations taken from the afternoon group rats euthanized between 1200 h and 1400 h. In the neonatal rat anterior pituitary, LHRH caused a suppression of spontaneous Ca(2+) transients. Strikingly, the second application of LHRH was capable of reproducing the suppression of Ca(2+) signals, indicating that the refractoriness to LHRH had not been established in neonatal rats. These results suggest that responsiveness to LHRH has a long-term refractoriness in adult rats, and that the physiological LHRH surge may be clocked in the morning. Moreover, LHRH-induced excitation and associated refractoriness appear to be incomplete in neonatal rats and may be acquired during development.