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1.  Does the Extent of Osteonecrosis Affect the Survival of Hip Resurfacing? 
The effect of the extent of osteonecrosis on the survival of hip resurfacing for osteonecrosis of the femoral head (ONFH) has not been well documented, but is a potentially important variable in the decision to perform resurfacing.
We examined (1) the relationship between the volume of osteonecrosis in the femoral head before surgery and the extent of the residual necrotic bone after femoral head machining, (2) how the extent of the residual necrotic bone relative to the resurfaced femoral head (after femoral head machining) affected the survival of total hip resurfacing for patients with ONFH, and (3) how the extent of the necrotic bone relative to the entire femoral head (before femoral head machining) affected the survival and clinical outcome scores of patients who underwent total hip resurfacing.
Thirty-three patients (39 hips) who underwent hip resurfacing were reviewed after a mean followup of 8 years. The extent of osteonecrosis in the femoral head and residual osteonecrosis in the implant bony bed after femoral head machining were estimated using a three-dimensional MRI-based templating system.
There was a statistically significant difference in the extent of osteonecrosis before and after femoral head machining, although the two were well correlated (r = 0.97). The mean percentage of osteonecrosis in the implant bony bed after femoral head machining was 5% smaller than that relative to the entire femoral head (range, −9% to 15%). There were no significant differences in implant survival between groups with small and large osteonecrosis classified by either the total amount of osteonecrosis before surgery or residual osteonecrosis after femoral head machining.
The extent of osteonecrosis in the femoral head significantly decreased after femoral head machining. Neither the residual osteonecrosis volume in the implant bony bed after femoral head machining nor the total amount of osteonecrosis before femoral head machining had significant influence on the survival of hip resurfacing.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3706687  PMID: 23397316
2.  Modular acetabular reconstructive cup in acetabular revision total hip arthroplasty at a minimum ten year follow-up 
International Orthopaedics  2013;37(4):605-610.
Modular acetabular reconstructive cups have been introduced in an attempt to offer initial rigid fixation by iliac lag screws and ischial pegs, to support bone grafts with a flanged metal socket, and to restore original hip center in acetabular revision. The purpose of this study was to clarify minimum ten year follow-up results of this cup system with morsellised allografts in revision cases.
We retrospectively investigated 54 acetabular revisions at a mean of 11 years (range, ten to 14 years). The indications were Paprosky’s type 2B (eight hip), 2C (eight hips), 3A (23 hips), 3B (nine hips), and 4 (six hips).
Using aseptic loosening as the endpoints, the survival rate was 89.3 % (95 % CI 81–98). Radiographically, one type 3A hip, three type 3B hips and one type 4 hip showed aseptic loosening while no type 2 hips or no cemented cups showed loosening.
The modular reconstructive cups for acetabular revision showed bone stock restoration and stable implantation.
PMCID: PMC3609976  PMID: 23423427
3.  Alpha-synuclein immunohistochemistry of gastrointestinal and biliary surgical specimens for diagnosis of Lewy body disease 
In Lewy body disease, Lewy pathology (LP: the accumulation of α-synuclein in neuronal perikarya and processes as Lewy bodies and Lewy neurites and dots, respectively) is observed in the central and peripheral nervous systems. Previous autopsy or biopsy studies of individuals with Lewy body diseases (LBDs) indicated that LP could be observed in the peripheral nerves of the gastrointestinal (GI) systems. The aim of this study is to clarify whether examination of GI and biliary surgical specimens would be useful for diagnosing LBD. We analyzed eight patients diagnosed clinically with LBD and with medical histories of GI or biliary surgery at our hospital. LP was identified by using α-synuclein immunohistochemistry in GI and biliary surgical specimens obtained before, at or after the clinical onset of LBD. LP was frequently observed in Auerbach’s plexus, Meissner’s plexus and the subserosal nerve fascicles within the GI and biliary surgical specimens. LP was observed in the specimens obtained 7 years before the onset of LBD. Our approach does not require any invasive procedures for patients. The immunohistochemical analysis of anti- α-synuclein antibody to archival GI or biliary surgical specimens from patients with clinically suspected LBD may contribute to clinical diagnosis of LBD.
PMCID: PMC4014253  PMID: 24817969
α-synuclein; gastrointestinal and biliary tract; Lewy body disease; Lewy pathology; surgical specimen
4.  Imaging spectrum of sporadic cerebral amyloid angiopathy: multifaceted features of a single pathological condition 
Insights into Imaging  2014;5(3):375-385.
Sporadic cerebral amyloid angiopathy (CAA) is common cause of cerebrovascular disorders that predominantly affect elderly patients. When symptomatic, cortical-subcortical intracerebral haemorrhage (ICH) in the elderly is the most well-known manifestation of CAA. Furthermore, the clinical presentation varies from a sudden neurological deficit to seizures, transient symptoms and acute progressive cognitive decline. Despite its clinical importance, this multifaceted nature poses a diagnostic challenge for radiologists. The aims of this study were to expound the characteristics of neuroimaging modalities, which cover a wide spectrum of CAA-related imaging findings, and to review the various abnormal findings for which CAA could be responsible.
Radiologically, in addition to typical ICH, CAA leads to various types of abnormal findings, including microbleed, subarachnoid haemorrhage, superficial siderosis, microinfarction, reversible oedema, and irreversible leukoaraiosis. Taking into consideration the clinical importance of CAA-related disorders such as haemorrhagic risks and treatable oedema, it is necessary for radiologists to understand the wide spectrum of CAA-related imaging findings.
Teaching Points
• To describe the characteristics of imaging modalities and findings of CAA-related disorders.
• MRI, especially gradient echo sequences, provides the useful information of CAA-related haemosiderin depositions.
• To understand the wide spectrum of CAA-related neuroimaging and clinical features is important.
PMCID: PMC4035487  PMID: 24519790
Cerebral amyloid angiopathy; Imaging; Subarachnoid haemorrhage; Microbleed; Superficial siderosis; CAA-related inflammation
5.  Superficial siderosis associated with abundant τ and α-synuclein accumulation 
BMJ Case Reports  2011;2011:bcr1020114925.
A Japanese male developed deafness, pyramidal signs and ataxia at age 50. A cerebrospinal fluid examination showed elevated levels of iron, transferrin and ferritin. Brain MRI showed atrophy of the cerebellum and pons as well as potential iron deposits on the surface of the brain. At autopsy, the brain weighed 1090 g and showed severe atrophy and necrosis of the cerebellum. No vascular malformation was observed. Extensive deposits of hemosiderin that were well stained with Berlin blue and ferritin immunohistochemistry were present at the surface and in the superficial layers of the cerebrum, brainstem, cerebellum and spinal cord. In these regions, numerous AT8 (p-τ)-immunopositive deposits were present in neurons and glia. In addition, phosphorylated α-synuclein-immunopositive Lewy bodies and neurites were observed in the brainstem nuclei. In the present report, the authors derive the novel insight that superficial siderosis is a distinctive entity associated with tauopathy and synucleinopathy.
PMCID: PMC3229431  PMID: 22674955
6.  Does CT-Based Navigation Improve the Long-Term Survival in Ceramic-on-Ceramic THA? 
Although navigated THA provides improved precision in implant positioning and alignment, it is unclear whether these translate into long-term implant survival.
We compared survivorship, dislocation rate, and incidence of radiographic failures such as loosening and bearing breakage after THA with and without navigation at a minimum 10-year followup.
We retrospectively reviewed 46 patients (60 hips) and 97 patients (120 hips) receiving THA with or without a CT-based navigation system, respectively, using cementless THA ceramic-on-ceramic bearing couples. There were no differences in age, sex, diagnosis, height, weight, BMI, or preoperative clinical score between groups. We evaluated survivorship, mode of acetabular and femoral component fixation, osteolysis, and implant wear or breakage at a minimum followup of 10 years (average, 11 years; range, 10–13 years).
Survival at 13 years was 100% with navigation and 95.6% (95% CI, 88.4%–98.4%) without navigation. With navigation, all cups were placed within a zone of 40° (range, 30°–50°) of radiographic inclination and 15° (range, 5°–15°) of radiographic anteversion; without navigation, 31 cups (26%) were placed outside this zone. Hips treated without navigation had a higher rate of dislocation (8%) than the navigated cases (0%). Revision was performed in four nonnavigated cases, all of which showed evidence of neck impingement on the ceramic liner. Moreover, seven other cases without navigation showed posterior neck erosion on radiographs. These 11 impingement-related mechanical complications correlated with cup malorientation, and the incidence of impingement-related complications was higher in nonnavigated cases.
Navigation reduced the rates of dislocation and impingement-related mechanical complications leading to revision in cementless THA using ceramic-on-ceramic bearing couples over a minimum 10-year followup.
Level of Evidence
Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3462880  PMID: 22569720
7.  High Survival of Dome Pelvic Osteotomy in Patients with Early Osteoarthritis from Hip Dysplasia 
The Chiari osteotomy reportedly has a 60% to 91% survival rate at a minimum 20 years followup. The dome pelvic osteotomy (DPO) has the advantage of allowing a larger weightbearing surface, and congruity in the sagittal plane presumably would reduce the joint contact stress and perhaps increase longevity.
We determined: (1) the survival after DPO at a minimum 25-year followup, (2) patient function, (3) acetabular coverage, and (4) factors influencing conversion to THA.
We retrospectively reviewed 50 patients (59 hips) with developmental dysplasia of the hip (DDH) treated with DPO. The preoperative radiographic stages were graded as prearthritis (18 hips), early osteoarthritis (25 hips), and advanced osteoarthritis (16 hips). We performed a Kaplan-Meier survival analysis with THA conversion as the end point. We determined various radiographic parameters reflecting coverage, and compared demographic information for hips without and with THA conversion using multivariate logistic regression analysis. The minimum followup was 25 years (mean, 27.5 years; range, 25–32 years).
Survival for all hips was 63.6% (95% CI, 51–76) at 27.5 years and that for hips with prearthritis and early osteoarthritis before the surgery was 79.1% (95% CI, 63–91). Twenty-one hips (36%) had undergone THAs at a mean 18.3 years (range, 2.5–25 years). At the last followup, pain, walking ability, and acetabular coverage improved. We identified four factors predicting THA conversion: greater age, presence of a preoperative Trendelenburg sign, higher preoperative radiographic osteoarthritis grade, and smaller postoperative acetabular head index (AHI) predicted conversion to THA.
DPO is a reasonable treatment option for patients with DDH and prearthritis or early osteoarthritis, with high survival at greater than 25 years.
Level of Evidence
Level IV, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3830085  PMID: 22354611
8.  The long non-coding RNA nuclear-enriched abundant transcript 1_2 induces paraspeckle formation in the motor neuron during the early phase of amyotrophic lateral sclerosis 
Molecular Brain  2013;6:31.
A long non-coding RNA (lncRNA), nuclear-enriched abundant transcript 1_2 (NEAT1_2), constitutes nuclear bodies known as “paraspeckles”. Mutations of RNA binding proteins, including TAR DNA-binding protein-43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS), have been described in amyotrophic lateral sclerosis (ALS). ALS is a devastating motor neuron disease, which progresses rapidly to a total loss of upper and lower motor neurons, with consciousness sustained. The aim of this study was to clarify the interaction of paraspeckles with ALS-associated RNA-binding proteins, and to identify increased occurrence of paraspeckles in the nucleus of ALS spinal motor neurons.
In situ hybridization (ISH) and ultraviolet cross-linking and immunoprecipitation were carried out to investigate interactions of NEAT1_2 lncRNA with ALS-associated RNA-binding proteins, and to test if paraspeckles form in ALS spinal motor neurons. As the results, TDP-43 and FUS/TLS were enriched in paraspeckles and bound to NEAT1_2 lncRNA directly. The paraspeckles were localized apart from the Cajal bodies, which were also known to be related to RNA metabolism. Analyses of 633 human spinal motor neurons in six ALS cases showed NEAT1_2 lncRNA was upregulated during the early stage of ALS pathogenesis. In addition, localization of NEAT1_2 lncRNA was identified in detail by electron microscopic analysis combined with ISH for NEAT1_2 lncRNA. The observation indicating specific assembly of NEAT1_2 lncRNA around the interchromatin granule-associated zone in the nucleus of ALS spinal motor neurons verified characteristic paraspeckle formation.
NEAT1_2 lncRNA may act as a scaffold of RNAs and RNA binding proteins in the nuclei of ALS motor neurons, thereby modulating the functions of ALS-associated RNA-binding proteins during the early phase of ALS. These findings provide the first evidence of a direct association between paraspeckle formation and a neurodegenerative disease, and may shed light on the development of novel therapeutic targets for the treatment of ALS.
PMCID: PMC3729541  PMID: 23835137
Long non-coding RNA; Paraspeckle; NEAT1_2; TDP-43; FUS/TLS; Amyotrophic lateral sclerosis; Electron microscopy
9.  Spinocerebellar ataxia type 2 is associated with Parkinsonism and Lewy body pathology 
BMJ Case Reports  2011;2011:bcr0120113685.
Clinical phenotype of individuals with spinocerebellar ataxia 2 (SCA2) is characterised by cerebellar ataxia and cognitive impairment. Although L-dopa-responsive Parkinsonism is considered as a rare clinical presentation in SCA2, it has been brought to the attention of many neurologists in several studies. The authors report an autopsy case of SCA2 with Parkinsonism from a Japanese family using archival materials of our Brain Bank to describe unique neuropathologic findings. The individual clinically showed Parkinsonism as a predominant phenotype instead of cerebellar ataxia. Besides the classic SCA2 neuropathologic alterations, Lewy bodies and Lewy neurites were present in the brainstem nuclei. Genetic analysis revealed shorter abnormal expansion of CAG repeats (less than 39). In contrast, the authors could not find α-synuclein pathology in two SCA2 cases without Parkinsonism. The present case will provide a neuropathologic evidence of correlation between α-synucleinopathy and Parkinsonism of SCA2 as well as shed light on understanding the pathomechanism of Parkinsonism in SCA2.
PMCID: PMC3079476  PMID: 22700602
10.  Is the transverse acetabular ligament a reliable cup orientation guide? 
Acta Orthopaedica  2012;83(5):474-480.
Background and purpose
It is controversial whether the transverse acetabular ligament (TAL) is a reliable guide for determining the cup orientation during total hip arthroplasty (THA). We investigated the variations in TAL anatomy and the TAL-guided cup orientation.
80 hips with osteoarthritis secondary to hip dysplasia (OA) and 80 hips with osteonecrosis of the femoral head (ON) were examined. We compared the anatomical anteversion of TAL and the TAL-guided cup orientation in relation to both disease and gender using 3D reconstruction of computed tomography (CT) images.
Mean TAL anteversion was 11° (SD 10, range –12 to 35). The OA group (least-square mean 16°, 95% confidence interval (CI): 14–18) had larger anteversion than the ON group (least-square mean 6.2°, CI: 3.8 – 7.5). Females (least-square mean 20°, CI: 17–23) had larger anteversion than males (least-square mean 7.0°, CI: 4.6–9.3) in the OA group, while there were no differences between the sexes in the ON group. When TAL was used for anteversion guidance with the radiographic cup inclination fixed at 40°, 39% of OA hips and 9% of ON hips had more than 10° variance from the target anteversion, which was 15°.
In ON hips, TAL is a good guide for determining cup orientation during THA, although it is not a reliable guide in hips with OA secondary to dysplasia. This is because TAL orientation has large individual variation and is influenced by disease and gender.
PMCID: PMC3488173  PMID: 22974185
11.  Molecular Distinction between Pathogenic and Infectious Properties of the Prion Protein 
Journal of Virology  2003;77(13):7611-7622.
Tg(PG14) mice express a prion protein (PrP) with a nine-octapeptide insertion associated with a human familial prion disease. These animals spontaneously develop a fatal neurodegenerative disorder characterized by ataxia, neuronal apoptosis, and accumulation in the brain of an aggregated and weakly protease-resistant form of mutant PrP (designated PG14spon). Brain homogenates from Tg(PG14) mice fail to transmit disease after intracerebral inoculation into recipient mice, indicating that PG14spon, although pathogenic, is distinct from PrPSc, the infectious form of PrP. In contrast, inoculation of Tg(PG14) mice with exogenous prions of the RML strain induces accumulation of PG14RML, a PrPSc form of the mutant protein that is infectious and highly protease resistant. Like PrPSc, both PG14spon and PG14RML display conformationally masked epitopes in the central and octapeptide repeat regions. However, these two forms differ profoundly in their oligomeric states, with PG14RML aggregates being much larger and more resistant to dissociation. Our analysis provides new molecular insight into an emerging puzzle in prion biology, the discrepancy between the infectious and neurotoxic properties of PrP.
PMCID: PMC164780  PMID: 12805461

Results 1-11 (11)