The Accuracy of a Portable Accelerometer-Based Navigation System for Tibial Alignment Can be Reliable during Total Knee Arthroplasty for Obese Patients.

A portable accelerometer-based navigation system can be useful for achieving the target alignment. Tibial registration is based on the medial and lateral malleoli; however, the identification of landmarks may be difficult in obese (body mass index [BMI] >30 kg/m2) patients whose bones are not easily palpable from the body surface. This study compared tibial component alignment achieved using a portable accelerometer-based navigation system (Knee Align 2 [KA2]) in obese and control groups and aimed to validate the accuracy of bone cutting in obese patients. A total of 210 knees that underwent primary total knee arthroplasty using the KA2 system were included. After 1:3 propensity score matching, there were 32 and 96 knees in the BMI >30 group (group O) and BMI ≤30 group (group C), respectively. The absolute deviations of the tibial implant from the intended alignment were evaluated in the coronal plane (hip-knee-ankle [HKA] angle and medial proximal tibial angle) and sagittal plane (posterior tibial slope [PTS]). The inlier rate of each cohort, which was defined as tibial component alignment within 2 degrees of the intended alignment, was investigated. In the coronal plane, the absolute deviations of the HKA and MPTA from the intended alignment were 2.2 ± 1.8 degrees and 1.8 ± 1.5 degrees in group C and 1.7 ± 1.5 degrees and 1.7 ± 1.0 degrees in group O (p = 1.26, and p = 0.532). In the sagittal plane, the absolute deviations of the tibial implant were 1.6 ± 1.2 degrees in group C and 1.5 ± 1.1 degrees in group O (p = 0.570). The inlier rate was not significantly different between group C and group O (HKA: 64.6 vs. 71.9%, p = 0.521; MPTA: 67.7 vs. 78.1%, p = 0.372; PTS: 82.2 vs. 77.8%, p = 0.667). The accuracy of tibial bone cutting for the obese group was comparable to that of the control group. An accelerometer-based portable navigation system can be useful when attempting to achieve the target tibial alignment in obese patients. LEVEL OF EVIDENCE: Level IV.

Outcomes and component-positioning in total knee arthroplasty may be comparable between supervised trained surgeons and their supervisor.

PURPOSE: There are concerns that malalignment in total knee arthroplasty (TKA) occurs with less experienced surgeons. This study investigates the influence of surgical experience on TKA outcomes. MATERIALS AND METHODS: Nineteen patients (38 knees) who underwent bilateral TKA between 2011 and 2015 were included. A supervisor performed knee replacements associated with lower Knee Society Scores (KSS); trainee surgeons operated on the other knee. Knees were categorized into two groups: operations by the supervisor (group S) versus operations by trainee surgeons (group T). Range of motion (ROM), KSS, operative time, hip-knee-ankle angle, and femoral and tibial component angle were evaluated. RESULTS: The mean operative time was 92.5 min in group S and 124.2 min in group T (p < 0.01). The mean postoperative maximal flexion was 113.2° in group S and 114.2° in group T (not significant). The mean postoperative KSS was 92.9 in group S and 93.9 in group T (not significant). No significant differences between groups in terms of proportion of inliers for the hip-knee-ankle angle, femoral component angle, or tibial component angle were observed. CONCLUSIONS: Although operative time was significantly longer for trainee surgeons versus the supervisor, no significant differences in ROM, KSS, or component positioning between supervisor and trainee surgeons were observed. LEVEL OF EVIDENCE: IV (retrospective case series design).

Postoperative Adjuvant Chemotherapy Regimen of CAPOX Combined With Ninjin'yoeito in an Elderly Patient With Stage III Colon Cancer: A Case Report.

We report the successful management of stage III colon cancer in an elderly patient who received an adjuvant chemotherapy regimen of capecitabine plus oxaliplatin (CAPOX) with the Japanese kampo medicine ninjin'yoeito (NYT). A 75-year-old woman with a medical history of hypertension presented at another institution with fecal occult blood, and a colonoscopy that showed a type II tumor in the sigmoid colon. She was referred to our hospital for tumor resection, where colonoscopy confirmed the location of the type II tumor in the sigmoid colon. Histopathology of the biopsy specimen indicated a moderately differentiated tubular adenocarcinoma. Enhanced computed tomography of the thorax and abdomen indicated thickening of the sigmoid colon wall. Regional lymph node metastasis was suspected, but distant metastasis was not indicated. A blood examination revealed an elevated carcinoembryonic antigen (CEA) concentration (32.7 ng/ml). Following a diagnosis of cancer of the sigmoid colon, clinical stage IIIb [cT4a, N1b, M0], a laparoscopic sigmoid colectomy was performed without complications. The postoperative histopathological examination revealed a moderately differentiated to mucinous adenocarcinoma. Three of 16 retrieved lymph nodes contained malignant cells. The final tumor classification was Stage IIIb [pT4a, pN1b, M0]. The patient recovered uneventfully, and was discharged 10 days after surgery with a recommendation for adjuvant chemotherapy with CAPOX starting 4 weeks after surgery. The patient also received 7.5 g of NYT daily throughout the adjuvant chemotherapy course. She did not report any loss of appetite, general fatigue, peripheral neuropathy, neutropenia, or febrile neutropenia. During a 1-year postoperative follow-up, she has not experienced any recurrence. We conclude that NYT might be useful for reducing the adverse effects of anticancer therapy, particularly in elderly patients.

Identification of a quantitative trait locus for spontaneous osteoarthritis in STR/ort mice.

Osteoarthritis (OA) is the most common joint disorder in humans. Most of the animal models of OA were developed by surgical destabilization of joints or through transgenic approaches, and information from naturally occurring models of OA is very limited. The mouse strain STR/ort is recognized as a spontaneous model of OA. This mouse is unique in that it develops late onset cartilage degeneration of the tibio-femoral joint, similar to human OA. The purpose of this study was to identify quantitative trait loci (QTL) for the OA phenotype in STR/ort. Whereas the trait had been reported to be recessive, a significant population of the F1 generation exhibited OA phenotype. Thus, backcrossed (BC) mice generated by crossing F1 male to C57BL/6N female mice were used for genetic analysis. Degeneration of articular cartilage in BC mice was evaluated by scanning electron microscopy. Linkage analysis was carried out using microsatellite markers covering the entire genome. Cartilage degeneration in STR/ort mice was a polygenic trait. A QTL for the OA phenotype was mapped to a region 20 centimorgans proximal to the centromere of chromosome 4 (LOD = 3.37, p = 0.0065). A QTL associated with the onset of cartilage degeneration in C57BL/6N mice was also identified on chromosome 5 (LOD = 3.04, p = 0.0147). These results suggest that multiple loci are involved in the OA phenotype in mice.

αvß5 integrin promotes dedifferentiation of monolayer-cultured articular chondrocytes.

OBJECTIVE: When cultured in monolayers, articular chondrocytes undergo an obvious phenotypic change. Although the involvement of integrins has been suggested, the exact mechanisms of the change have not been determined. This study was undertaken to clarify the mechanisms underlying the loss of chondrocyte phenotype early after plating. METHODS: Primary cultured human articular chondrocytes were used for the experiments. Involvement of respective integrins in the phenotypic change was investigated in RNA interference (RNAi) experiments. A signaling pathway involved in the change was identified in experiments using specific inhibitors and adenoviruses encoding mutated genes involved in the pathway. Adenoviruses carrying mutated GTPases were used to determine the involvement of small GTPases in the process. RESULTS: In monolayer-cultured chondrocytes, suppression of αv or ß5 integrin expression by RNAi inhibited morphologic changes in the cells and increased (or prevented a reduction in) the expression of various cartilage matrix genes. Consistent results were obtained in experiments using a blocking antibody and a synthetic inhibitor of αvß5 integrin. The decrease in cartilage matrix gene expression in chondrocytes after plating was mediated by ERK signaling, which was promoted primarily by αvß5 integrin. In articular chondrocytes, the affinity of αvß5 integrin for ligands was regulated by the small GTPase R-Ras. R-Ras was gradually activated in monolayer-cultured chondrocytes after plating, which caused a gradual decline in cartilage matrix gene expression through enhanced αvß5 integrin activation and the subsequent increase in ERK signaling. CONCLUSION: Our findings indicate that αvß5 integrin may be involved in the change that occurs in monolayer-cultured chondrocytes after plating.

Cloning and characterization of the osteoarthritis-associated gene DVWA.

Osteoarthritis (OA) is one of the most prevalent skeletal diseases. Recently, we identified a novel gene on chromosome 3p24.3, named DVWA (double von Willebrand factor A domains), and its functional variants, which are associated with susceptibility to knee OA. Here we report the cloning and characterization of the DVWA gene. DVWA consisted of seven exons and had four alternative splicing variants, which encoded long (385 amino acid) and short (276 amino acid) proteins (L-DVWA and S-DVWA, respectively). S-DVWA was an N-terminal truncated form of L-DVWA and lacked a signal peptide and a part of a VWA domain. L-DVWA and S-DVWA transcripts were mainly expressed in articular cartilage. Immunoblot analysis using epitope-tagged proteins showed L-DVWA in the conditioned media and S-DVWA only in the cell, consistent with the in silico prediction. We also cloned the murine counterpart of DVWA, which was found to be identical to Col6a4, which has recently been reported. L-DVWA had 73% identity to the N-terminal sequence of the 2,309-amino acid Col6a4 protein. The mouse Dvwa/Col6a4 mRNA was present mainly in the small intestine in embryos and adults, but not in cartilage. The amino acid sequence of L-DVWA was conserved in higher species than chicken, but that of S-DVWA was unique in human. Knockdown of DVWA by siRNAs increased expression of chondrocyte matrix genes. Our study indicates that DVWA is evolutionally very unique, which, together with its specific expression in articular cartilage, suggests its specific role in human cartilage metabolism.

SNPs in BRAP associated with risk of myocardial infarction in Asian populations.

Myocardial infarction is a common disease and among the leading causes of death in the world. We previously reported association of variants in LGALS2, encoding galectin-2, with myocardial infarction susceptibility in a case-control association study in a Japanese population. Here we identify BRAP (BRCA1-associated protein) as a galectin-2-binding protein. We report an association of SNPs in BRAP with myocardial infarction risk in a large Japanese cohort (P = 3.0 x 10(-18), OR = 1.48, 2,475 cases and 2,778 controls), with replication in additional Japanese and Taiwanese cohorts (P = 4.4 x 10(-6), 862 cases and 1,113 controls and P = 4.7 x 10(-3), 349 cases and 994 controls, respectively). BRAP expression was observed in smooth muscle cells (SMCs) and macrophages in human atherosclerotic lesions. BRAP knockdown by siRNA using cultured coronary endothelial cells suppressed activation of NF-kappaB, a central mediator of inflammation.

Zonal gene expression of chondrocytes in osteoarthritic cartilage.

OBJECTIVE: To determine the chondrocyte metabolism in respective zones of osteoarthritic (OA) cartilage. METHODS: OA cartilage was obtained from macroscopically intact areas of 4 knee joints with end-stage OA. The cartilage was divided into 3 zones, and gene expression profiles were determined in the respective zones by a custom-designed microarray that focused on chondrocyte-related genes. For the genes whose expression was significantly different among the zones, the expression was compared between OA and control cartilage in the respective zones by an analysis using laser capture microdissection and real-time polymerase chain reaction (PCR). For some genes, the correlation of expression was investigated in specific cartilage zones. RESULTS: A total of 198 genes (approximately 40% of those investigated) were found to be expressed at significantly different levels among the zones. Expression of 26 of those genes was evaluated by laser capture microdissection and real-time PCR, which confirmed the validity of microarray analysis. The expression of cartilage matrix genes was mostly enhanced in OA cartilage, at similar levels across the zones but at different magnitudes among the genes. The expression of bone-related genes was induced either in the superficial zone or in the deep zone, and positive correlations were found among their expression in the respective zones. The expression of 5 proteinase genes was most enhanced in the superficial zone, where their expression was correlated, suggesting the presence of a common regulatory mechanism(s) for their expression. CONCLUSION: In OA cartilage, the metabolic activity of chondrocytes differed considerably among zones. Characteristic changes were observed in the superficial and deep zones.

Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis.

Susceptibility to osteoarthritis, the most common human arthritis, is known to be influenced by genetic factors. Through a genome-wide association study using approximately 100,000 SNPs, we have identified a previously unknown gene on chromosome 3p24.3, DVWA, which is associated with susceptibility to knee osteoarthritis. Expressed specifically in cartilage, DVWA encodes a 276-amino-acid protein with two regions corresponding to the von Willebrand factor type A domain (VWA domain). Several DVWA SNPs are significantly associated with knee osteoarthritis in two independent Japanese case-control cohorts. This association was replicated in a Japanese population cohort and a Han Chinese case-control cohort (combined P = 7.3 x 10(-11)). DVWA protein binds to beta-tubulin, and the binding is influenced by two highly associated missense SNPs (rs11718863 and rs7639618) located in the VWA domain. The Tyr169-Cys260 isoform of DVWA, which is overrepresented in knee osteoarthritis, showed weaker interaction. Our findings reveal a new paradigm for study of osteoarthritis etiology and pathogenesis.

A functional SNP in EDG2 increases susceptibility to knee osteoarthritis in Japanese.

Osteoarthritis (OA) is the most common form of arthritis and is characterized by the gradual loss of articular cartilage. Several OA-susceptibility genes have been identified; however, there are few pharmaceutical targets that can be targeted with small-molecule compounds. To investigate whether a susceptibility gene for OA exists among G-protein-coupled receptors (GPCRs), we performed a stepwise association study for 167 single nucleotide polymorphisms (SNPs) in 44 GPCR genes that were present in cartilage. Through the stepwise association study, an SNP located in the promoter region of EDG2 [endothelial differentiation, lysophosphatidic acid (LPA) GPCR, 2] (-2,820G/A; rs10980705) showed significant association with knee OA in two independent populations (pooled P = 2.6 x 10(-5)). Luciferase and electrophoretic mobility shift assays indicate that this SNP exerts an allelic difference on transcriptional activity and DNA binding in synovial cells, with the susceptibility allele showing increased activity and binding. EDG2 encodes an LPA receptor dominantly expressed in the synovium. The LPA receptor increased the expression of inflammatory cytokines and matrix metalloproteases in synovial cells. Our findings suggest that the LPA-EDG2 signal is involved in the pathogenesis of OA via catabolic process.

Association of the MSX2 gene polymorphisms with ankylosing spondylitis in Japanese.

Several genes have been implicated in the etiology of ankylosing spondylitis (AS); however, the significance of these genes except HLA-B27 remains to be elucidated. In this study, we examined the association of AS with novel candidate genes and previously reported genes other than HLA-B27. We examined a total of 45 single nucleotide polymorphisms (SNPs) in 15 genes by a sequential screening. We first genotyped 170 Japanese AS patients and 896 controls for the SNPs (first screen). Then, we genotyped eight SNPs with P < 0.05 in the first screen for 108 additional Japanese patients (second screen). We checked the replication of the association of the most significant SNP by genotyping 219 Taiwanese AS patients and 185 controls. When the first and second screens were combined, four SNPs showed nominal significance of P < 0.05. An intronic SNP (IVS1 + 996G > A) in MSX2, a novel candidate gene, showed the most significant association (P = 0.0030). The association was not replicated in our Taiwanese population; however, there was the same trend with the Japanese population in the allelic frequency distribution of the SNP. In the genes previously reported to have association with AS, only one synonymous SNP, c.963T > G in ANKH, showed a marginal association in the Japanese population (P = 0.045).

Lack of association of single nucleotide polymorphism in LRCH1 with knee osteoarthritis susceptibility.

A genetic association of knee osteoarthritis (OA) and a C/T transition single nucleotide polymorphism (SNP) (rs912428) located in intron 1 of the LRCH1 gene has recently been reported in European Caucasians; however, the results are inconsistent. Our objective was to evaluate the association in different knee OA populations. Three case-control association studies were conducted in Han Chinese, Japanese, and Greek Caucasian populations. The LRCH1 SNP was genotyped in patients who had primary symptomatic knee OA with radiographic confirmation and in matched controls, and the association was examined. We performed a meta-analysis for the studies together with results of two previous papers using the DerSimonian-Laird procedure and calculated the power of the pooled studies by the software R. A total of 1,145 OA patients and 1,266 controls were genotyped. No significant difference was detected in genotype or allele frequencies between knee OA and control groups in the three populations (all P > 0.05). Association was not observed even after stratification by gender and Kellgren/Lawrence (K/L) scores. Meta-analysis also supported the lack of association between LRCH1 and knee OA. The strong heterogeneity between original and replication studies was detected in Caucasian populations. However, a tendency for the increase of TT genotype was observed in the European populations (OR = 1.46, P = 0.06). The powers for European and Asian replication studies were less than 0.8. Our results suggest that there is no association between LRCH1 and knee OA. However, lack of association should be concluded by further replication studies.

Meta-analysis of association between the ASPN D-repeat and osteoarthritis.

Osteoarthritis (OA) is the most common form of human arthritis. Genetic factors have been implicated in OA. It was reported that an aspartic acid (D)-repeat polymorphism in the gene encoding asporin (ASPN) was associated with OA of knee and hip joints in Japanese; in the three independent studies performed, the D14 allele of the ASPN polymorphism was over-represented and the D13 allele was under-represented. Subsequently, four replication studies, three in Europeans and one in Chinese populations, have been reported; however, they showed inconsistent results. To evaluate between-study heterogeneity and to estimate the common genetic effect of the D-repeat polymorphism on OA, we performed a meta-analysis of the five reports that include seven association studies, using the DerSimonian-Laird procedure. We detected association between knee OA and the susceptible D14 allele [P = 0.003, summary odds ratio (OR) = 1.46] with significant heterogeneity (P = 0.047) among the studies. We also detected positive association between knee OA and the protective D13 allele (P = 0.026, summary OR = 0.84) with significant heterogeneity (P = 0.040) among the studies. Because of significant heterogeneity, we stratified the studies by ethnicity. We detected positive association between knee OA and the D14 allele (P = 0.0000013, summary OR = 1.95) with non-significant heterogeneity (P = 0.535) in Asian populations. In hip OA, significant heterogeneity was identified and there was no positive association for any allele in any comparison. The present results suggest that the association of the ASPN D14 allele and knee OA has global relevance, but that its effect has ethnic differences.

The Shwachman-Bodian-Diamond syndrome gene mutations cause a neonatal form of spondylometaphysial dysplasia (SMD) resembling SMD Sedaghatian type.

The Shwachman-Bodian-Diamond syndrome (SBDS) gene is a causative gene for Shwachman-Diamond syndrome, an autosomal recessive disorder with exocrine pancreatic insufficiency, bone marrow dysfunction and skeletal dysplasia. We report here on two patients with skeletal manifestations at the severest end of the phenotypic spectrum of SBDS mutations. An 11-year-old Japanese girl presented with neonatal respiratory failure necessitating lifelong ventilation support, severe short stature and severe developmental delay. She developed neutropenia in infancy, and decreased serum amylase was noted in childhood. A British boy was a stillbirth with pulmonary hypoplasia and hepatic fibrosis found on autopsy. Both cases had neonatal skeletal manifestations that included platyspondyly, lacy iliac crests and severe metaphysial dysplasia, and thus did not fall in the range of the known Shwachman-Diamond syndrome skeletal phenotype but resembled spondylometaphysial dysplasia (SMD) Sedaghatian type. The girl harboured a recurrent mutation (183TA-->CT) and a novel missense mutation (79T-->C), whereas the boy carried two recurrent mutations (183TA-->CT and 258+2T-->C). We also examined SBDS in one typical case with SMD Sedaghantian type and eight additional cases with neonatal SMD, but failed to discover SBDS mutations. Our experience expands the phenotypic spectrum of SBDS mutations, which, at its severest end, results in severe neonatal SMD.

A recurrent mutation in type II collagen gene causes Legg-Calvé-Perthes disease in a Japanese family.

Legg-Calvé-Perthes disease (LCPD) is a common childhood hip disorder characterized by sequential stages of involvement of the capital femoral epiphyses, including subchondral fracture, fragmentation, re-ossification and healing with residual deformity. Most cases are sporadic, but familial cases have been described, with some families having multiple affected members. Genetic factors have been implicated in the etiology of LCPD, but the causal gene has not been identified. We have located a missense mutation (p.G1170S) in the type II collagen gene (COL2A1) in a Japanese family with an autosomal dominant hip disorder manifesting as LCPD and showing considerable intra-familial phenotypic variation. This is the first report of a mutation in hereditary LCPD. COL2A1 mutations may be more common in LCPD patients than currently thought, particularly in familial and/or bilateral cases.

A functional polymorphism in the 5' UTR of GDF5 is associated with susceptibility to osteoarthritis.

Osteoarthritis (MIM 165720), characterized by degeneration of articular cartilage, is the most common form of human arthritis and a major concern for aging societies worldwide. Epidemiological and genetic studies have shown that osteoarthritis is a polygenic disease. Here, we report that the gene encoding growth differentiation factor 5 (GDF5) is associated with osteoarthritis in Asian populations. A SNP in the 5' UTR of GDF5 (+104T/C; rs143383) showed significant association (P = 1.8 x 10(-13)) with hip osteoarthritis in two independent Japanese populations. This association was replicated for knee osteoarthritis in Japanese (P = 0.0021) and Han Chinese (P = 0.00028) populations. This SNP, located in the GDF5 core promoter, exerts allelic differences on transcriptional activity in chondrogenic cells, with the susceptibility allele showing reduced activity. Our findings implicate GDF5 as a susceptibility gene for osteoarthritis and suggest that decreased GDF5 expression is involved in the pathogenesis of osteoarthritis.

A functional SNP in ITIH3 is associated with susceptibility to myocardial infarction.

Myocardial infarction (MI) results from complex interactions of multiple genetic and environmental factors. To disclose genetic backgrounds of MI, we performed a large-scale, case-control association study using 52,608 gene-based single-nucleotide polymorphism (SNP) markers, and identified a candidate SNP located on chromosome 3p21.2-p21.1. Subsequent linkage-disequilibrium mapping indicated very significant association between MI and a SNP in exon 2 of the inter-alpha (globulin) inhibitor 3 gene (ITIH3; chi(2) = 24.88, P = 6.1 x 10(-7), 3,353 affected individuals versus 3,807 controls). In vitro functional analyses showed that this SNP enhanced the transcriptional level of the ITIH3 gene. Furthermore, we found expression of the ITIH3 protein in the vascular smooth muscle cells and macrophages in the human atherosclerotic lesions, suggesting ITIH3 SNP to be a novel genetic risk factor of MI.

Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction.

Through a large-scale case-control association study using 52,608 haplotype-based single nucleotide polymorphism (SNP) markers, we identified a susceptible locus for myocardial infarction (MI) on chromosome 22q12.1. Following linkage disequilibrium (LD) mapping, haplotype analyses revealed that six SNPs in this locus, all of which were in complete LD, showed markedly significant association with MI (chi2=25.27, P=0.0000005; comparison of allele frequency, 3,435 affected individuals versus 3,774 controls, in the case of intron 1 5,338 C>T; rs2331291). Within this locus, we isolated a complete cDNA of a novel gene, designated myocardial infarction associated transcript (MIAT). MIAT has five exons, and in vitro translation assay showed that MIAT did not encode any translational product, indicating that this is likely to be a functional RNA. In vitro functional analyses revealed that the minor variant of one SNP in exon 5 increased transcriptional level of the novel gene. Moreover, unidentified nuclear protein(s) bound more intensely to risk allele than non-risk allele. These results indicate that the altered expression of MIAT by the SNP may play some role in the pathogenesis of MI.