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Lung cancer is the most common cause of death from cancer worldwide, and its incidence is increasing in East Asian and Western countries. To identify genetic factors that modify the risk of lung adenocarcinoma, we conducted a genome-wide association study in a Japanese cohort, with replication in two independent studies in Japanese and Korean individuals, in a total of 2,098 lung adenocarcinoma cases and 11,048 controls. The combined analyses identified two susceptibility loci for lung adenocarcinoma: TERT (rs2736100, combined P = 2.91 × 10⁻¹¹), odds ratio (OR) = 1.27) and TP63 (rs10937405, combined P = 7.26 × 10⁻¹²), OR = 1.31). Fine mapping of the region containing TP63 showed that a SNP (rs4488809) in intron 1 of TP63 showed the most significant association. Our results suggest that genetic variation in TP63 may influence susceptibility to lung adenocarcinoma in East Asian populations.

Several pharmacogenetic studies have revealed strong associations between specific human leukocyte antigen (HLA) alleles and the susceptibility to drug hypersensitivity. Recently, we reported HLA-B*3505 as a strong genetic biomarker for the nevirapine-induced skin rash in Thai population. Here, we developed a new HLA-B*3505 genotyping method by a combination of the Universal Invader assay and sequence-specific primer PCR. From the sequence alignment of 68 HLA-B alleles in the Thai population, we selected the two most discriminative SNPs (rs1140412 and rs4997052) as target SNP sites. When we carried out the assay using 324 Thai individuals, fluorescence intensities of HLA-B*3505-positive and HLA-B*3505-negative samples were apparently discriminated at the endpoint of the reaction. Our results were 100% concordant with those obtained by a sequence-based typing method. As our assay is simple and rapid, we believe our method will be a useful tool for pharmacogenetic testing of the nevirapine-induced skin rash.

Prostate cancer is one of the most common malignancies in males throughout the world, and its incidence is increasing in Asian countries. We carried out a genome-wide association study and replication study using 4,584 Japanese men with prostate cancer and 8,801 control subjects. From the thirty-one associated SNPs reported in previous genome-wide association studies in European populations, we confirmed the association of nine SNPs at P < 1.0 x 10(-7) and ten SNPs at P < 0.05 in the Japanese population. The remaining 12 SNPs showed no association (P > 0.05). In addition, we report here five new loci for prostate cancer susceptibility, at 5p15 (lambda-corrected probability P(GC) = 3.9 x 10(-18)), GPRC6A/RFX6 (P(GC) = 1.6 x 10(-12)), 13q22 (P(GC) = 2.8 x 10(-9)), C2orf43 (P(GC) = 7.5 x 10(-8)) and FOXP4 (P(GC) = 7.6 x 10(-8)). These findings advance our understanding of the genetic basis of prostate carcinogenesis and also highlight the genetic heterogeneity of prostate cancer susceptibility among different ethnic populations.

We earlier reported a significant association between the cytochrome P450 2D6 (CYP2D6) genotype and the clinical outcome in 282 Japanese breast cancer patients receiving tamoxifen monotherapy. Although many research groups have provided evidence indicating the CYP2D6 genotype as one of the strongest predictors of tamoxifen response, the results still remain controversial. We hypothesized that concomitant treatment was one of the causes of these controversial results. We then studied 167 breast cancer patients who received tamoxifen-combined therapy to evaluate the effects of concomitant treatment on the association analysis and observed no significant association between CYP2D6 genotype and recurrence-free survival (P=0.44, hazard ratio: 0.64, 95% confidential interval: 0.20-1.99 in patients with two variant alleles vs. patients without a variant allele). When we carried out two subgroup analyses for nodal status and tumor size, we observed a positive association between the CYP2D6 genotype and the clinical outcome only in patients who received tamoxifen monotherapy. This study explained a part of the discrepancies among the reported results.

Keloid is a dermal fibroproliferative growth that results from dysfunction of the wound healing processes. Through a multistage genome-wide association study using 824 individuals with keloid (cases) and 3,205 unaffected controls in the Japanese population, we identified significant associations of keloid with four SNP loci in three chromosomal regions: 1q41, 3q22.3-23 and 15q21.3. The most significant association with keloid was observed at rs873549 (combined P = 5.89 x 10(-23), odds ratio (OR) = 1.77) on chromosome 1. Associations on chromosome 3 were observed at two separate linkage disequilibrium (LD) blocks: rs1511412 in the LD block including FOXL2 with P = 2.31 x 10(-13) (OR = 1.87) and rs940187 in another LD block with P = 1.80 x 10(-13) (OR = 1.98). Association of rs8032158 located in NEDD4 on chromosome 15 yielded P = 5.96 x 10(-13) (OR = 1.51). Our findings provide new insights into the pathophysiology of keloid formation.

Understanding the structure and frequencies of haplotypes is important for associating genetic polymorphisms with a given trait and for inferring the genetic genealogy of alleles in a population. Single nucleotide polymorphism (SNP) haplotypes can be determined without ambiguity when an individual does not have more than one heterozygous site in a given genomic region. Using genome-wide SNP genotypes for 3397 individuals from the Japanese population, we detected SNP homozygotes in the genomic regions of 1955 genes, determined haplotypes, and examined the efficiency of haplotype frequency estimation based on the proportion of SNP homozygotes in the sample. The estimated haplotype frequencies were very similar to the frequencies obtained by two statistical methods, PHASE and SNPHAP. We applied this approach to the genomic regions of 11 351 genes, and the results suggested that the sum of the frequencies of unobserved haplotypes is negligible for an analysis of a 100 kb genomic region with approximately 20 SNPs. Determination of haplotypes from homozygotes using genotype data from thousands of individuals, without a long computation time, appears to be useful for detecting real haplotypes including some low-frequency haplotypes. In addition, the unambiguously determined haplotypes with their estimated frequencies can be used as a catalog of haplotypes for the population, which is useful for the design of genome-wide association studies.

Study Design: Prospective study., Objective: To examine whether preservation of subaxial deep extensor muscles plays any significant role in reducing axial neck pain and unfavorable radiologic changes after cervical laminoplasty in patients with cervical spondylotic myelopathy and to confirm the benefits of preserving muscles attached to the C2 and C7 spinous processes., Summary of Background Data: Axial neck pain and unfavorable radiologic changes after cervical laminoplasty have been reported to mostly result from detachment of cervical extensor muscles, particularly muscles attached to the C2 and C7 spinous processes. Other surgeons have reported that preservation of subaxial deep extensor muscles reduces these adverse effects after cervical laminoplasty., Methods: Subjects comprised 36 patients with cervical spondylotic myelopathy who underwent C3-C6 open-door laminoplasty and were followed up for >24 months. Of these, 18 consecutive patients underwent our modified laminoplasty (muscles-preserved group) and the remaining 18 consecutive patients underwent the conventional procedure (muscles-disrupted group). Both procedures preserved all muscles attached to the C2 and C7 spinous processes. Subaxial deep extensor muscles on the hinged side were also preserved in the muscles-preserved group. Radiologic and clinical data were prospectively collected., Results: Both groups achieved equal neurologic improvement. Frequencies of axial neck pain showed no significant differences between groups. This value did not vary according to the side of preservation of subaxial deep extensor muscles or the side of muscle disruption. Postoperative loss of lordosis and range of motion of the cervical spine also demonstrated no significant difference between groups., Conclusion: These results indicate that preservation of subaxial deep extensor muscles plays no significant role in reducing axial neck pain and unfavorable radiologic changes after cervical laminoplasty, supporting the hypothesis that these adverse effects after laminoplasty largely result from detachment of muscles attached to the C2 and C7 spinous processes.

Copy number variations (CNVs) in the CYP2D6 gene contribute to interindividual variation in drug metabolism. As the most common duplicated allele in Asian populations is the nonfunctional CYP2D6*36 allele, the goal of this study was to identify CNV assays that can differentiate between multiple copies of the CYP2D6*36 allele and multiple copies of other CYP2D6 alleles. We determined CYP2D6 gene copy numbers in 32 individuals with known CYP2D6 CNVs from the Coriell Japanese-Chinese panel using four quantitative real-time PCR assays. These assays target different regions of the CYP2D6 gene: 5'-flanking region, intron 2, intron 6, and exon 9 (Ex9). The specific target site of the Ex9 assay was verified by sequencing the PCR amplicon. Three of the CYP2D6 CNV assays (5'-flanking region, intron 2, and intron 6) estimated CYP2D6 copy numbers that were concordant for all 32 individuals. However, the Ex9 assay was concordant in only 10 of 32 samples. The 10 concordant samples did not contain any CYP2D6*36 alleles and the 22 discordant samples contained at least one CYP2D6*36 allele. In addition, the Ex9 assay accurately quantified all of the non-CYP2D6*36 alleles in all samples. Ex9 amplicon sequencing indicated that it targets a region of CYP2D6 exon 9 that undergoes partial gene-conversion in the CYP2D6*36 allele. In conclusion, CYP2D6 Ex9 CNV assay can be used to determine the copy number of non-CYP2D6*36 alleles. Selective amplification of non-CYP2D6*36 sequence by the Ex9 assay should be useful in determining the number of functional copies of CYP2D6 in Asian populations.

Object: Spinal fusion at the L4-5 disc space alters the normal biomechanics of the spine, and the loss of motion at the fused level is compensated by increased motion and load at the other unfused segments. This may lead to deterioration of the adjacent segments of the lumbar spine, called adjacent-segment disease (ASD). In this study, the authors investigate the distracted disc height of the fused segment, caused by cage or bone insertion during surgery, as a novel risk factor for ASD after posterior lumbar interbody fusion (PLIF)., Methods: Radiographic L3-4 ASD is defined by development of spondylolisthesis greater than 3 mm, a decrease in disc height of more than 3 mm, or intervertebral angle at flexion smaller than -5 degrees . Symptomatic ASD is defined by a decrease of 4 points or more on the Japanese Orthopaedic Association scale. Eighty-five patients with L-4 spondylolisthesis treated by L4-5 PLIF underwent follow-up for more than 2 years (mean 38.8 +/- 17.1 months). The patients were divided into 3 groups according to the final outcome. Group A comprised those patients without ASD (58), Group B patients had radiographic ASD (14), and Group C patients had symptomatic ASD (13)., Results: The L4-5 disc space distraction by cage insertion was 3.1 mm in the group without ASD, 4.4 mm in the group with radiographic ASD, and 6.2 mm in the group with symptomatic ASD, as measured using lateral spinal radiographs just after surgery. Multivariate analysis showed that distraction was the most significant risk factor., Conclusions: The excessive distraction of the L4-5 disc space during PLIF surgery is a significant and potentially avoidable risk factor for the development of radiographic, symptomatic ASD.

Previous genome-wide association studies (GWASs) have identified several loci associated with human height; however, such evidence was mostly reported in Caucasian populations. Since the different distributions of height between populations suggest their different genetic backgrounds, analysis in different populations would be useful. Here, we present the results of a GWAS for adult height in 19 633 Japanese subjects. We found eight significantly associated loci that satisfied the genome-wide significance level (P < 5.0 x 10(-8)). Of these, the association to the LHX3-QSOX2 locus was entirely novel (rs12338076, P = 2.2 x 10(-8)). We also identified the association to the IGF1 locus (rs17032362, P = 8.1 x 10(-9)). Conditional association analysis in the IGF1 locus with rs17032362 suggested the existence of an additional independent association with height to this locus (rs1457595, P = 1.2 x 10(-5)). We observed large differences in the allele frequencies of rs17032362 and rs1457595 between Japanese (34 and 9%, respectively) and Caucasian (1.7 and 0%, respectively) populations, thereby suggesting weak statistical powers for the IGF1 locus in the previous Caucasian GWASs for height. We extensively compared our results with those of previous reports on the Caucasian and Korean populations. We were able to replicate all four loci previously reported in Koreans (EFEMP1, ZBTB38, HMGA1 and PLAG1, P < 5.0 x 10(-8)) and 15 loci identified in Caucasians (P < 0.001). The combination of the height-associated loci identified in our study and the previous GWASs demonstrated an effect size of 1.26 cm (95% confidence interval: 1.18-1.34) per 1.0 increase of the normalized Z score for height-increasing alleles, explaining 4.6% of the total variance of adult height.

Rheumatoid arthritis is a common autoimmune disease with a complex genetic etiology. Here, through a genome-wide association study of rheumatoid arthritis, we identified a polymorphism in CCR6, the gene encoding chemokine (C-C motif) receptor 6 (a surface marker for Th17 cells) at 6q27, that was associated with rheumatoid arthritis susceptibility and was validated in two independent replication cohorts from Japan (rs3093024, a total of 7,069 individuals with rheumatoid arthritis (cases) and 20,727 controls, overall odds ratio = 1.19, P = 7.7 x 10(-19)). We identified a triallelic dinucleotide polymorphism of CCR6 (CCR6DNP) in strong linkage disequilibrium with rs3093024 that showed effects on gene transcription. The CCR6DNP genotype was correlated with the expression level of CCR6 and was associated with the presence of interleukin-17 (IL-17) in the sera of subjects with rheumatoid arthritis. Moreover, CCR6DNP was associated with susceptibility to Graves' and Crohn's diseases. These results suggest that CCR6 is critically involved in IL-17-driven autoimmunity in human diseases.

Neutrophils are the most abundant subtype of white blood cells (WBCs). Although the regulation of the numbers of neutrophils would have substantial clinical impacts, the studies on the variations associated with neutrophil count had not been performed further. To investigate genetic variations that regulate neutrophil count, we performed a genome-wide association study in 5771 Japanese subjects and a replication study using independent 1894 Japanese subjects. We identified two genetic loci significantly associated with neutrophil count (rs4794822 in PSMD3-CSF3 at 17q21.1, P = 6.3 x 10(-10); rs2072910 in PLCB4 at 20p12, P = 3.1 x 10(-10)). As these loci did not indicate significant associations with the counts of the other subtypes of WBCs (lymphocytes, monocytes, eosinophils and basophils), their specific associations with neutrophils were suggested. The combination of the single nucleotide polymorphisms (SNPs) in these two loci explained 1.0% of the total variance of the log-transformed values of the neutrophil count in our study populations. The subjects who were homozygous for 'neutrophil-increasing alleles' in both of the SNPs (T alleles for rs4794822 and rs2072910) had 1.17-fold (95% confidence interval: 1.10-1.24) higher neutrophil count when compared with the subjects homozygous for 'neutrophil-decreasing alleles' (C alleles for rs4794822 and rs2072910). In conclusion, our study would demonstrate the significant contribution of PSMD3-CSF3 and PLCB4 loci to the regulation of neutrophil count.

DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstream of IRGM was recently shown to be in strong linkage disequilibrium (LD) with the CD-associated single nucleotide polymorphisms and is itself associated with CD (P < 0.01). The deletion was correlated with increased or reduced expression of IRGM in transformed cells in a cell line-dependent manner, and has been proposed as a likely causal variant. We report here that small insertion/deletion polymorphisms in the promoter and 5' untranslated region of IRGM are, together with the CNV, strongly associated with CD (P = 1.37 x 10(-5) to 1.40 x 10(-9)), and that the CNV and the 5'-untranslated region variant -308(GTTT)(5) contribute independently to CD susceptibility (P = 2.6 x 10(-7) and P = 2 x 10(-5), respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 10(-12)) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD case-control sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires gene-gene or gene-environment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the European-Asian split.

Study Design: Motion analysis on video files that captured grip and release cycles with fingers., Objective: To reveal the kinematic characteristics of finger motion in cervical myelopathy., Summary of Background Data: Myelopathy patients are often unable to smoothly move their fingers in grip and release cycles. Although paradoxical wrist motion (trick motion) and lack of finger coordination are well-known phenomena in myelopathy patients, it is not known which types of myelopathy patients present with these kinematic characteristics, and it is not known why they occur., Methods: Thirty patients with myelopathy were evaluated before and after decompressive surgery and compared with 42 healthy controls. The subjects were asked to grip and release with their fingers as rapidly as possible for 15 seconds. Movies taken with a digital camera were divided into 3 animation files of 5-seconds each. Three physicians independently counted the number of finger grip and release cycles of those files in a blinded manner; they also evaluated trick motion of the wrist and lack of finger coordination., Results: Both the frequency of trick motion and that of uncoordinated finger motion were significantly higher in the preoperative myelopathy group than in the control group (trick motion, 11.7% vs. 4.8% and uncoordinated finger motion, 15.6% vs. 7.1%), but were the same in the pre- and postoperative myelopathy groups. In the preoperative myelopathy group, the number of grip and release cycles of uncoordinated finger motion files, especially ulnar delay type, was significantly smaller than that of coordinated finger motion files, which meant uncoordinated finger motion was related to the severity of myelopathy., Conclusion: Both uncoordinated finger motion and trick motion of the wrist were more frequent in myelopathy patients than in healthy controls, and uncoordinated finger motion was associated with severity of myelopathy, whereas trick motion was not associated with either severity of myelopathy or level of cord compression. These findings contradict the conventional idea that trick motion is associated with the severity of myelopathy.

Purpose: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen., Patients and Methods: We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d., Results: CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with

We report genome-wide association studies for hematological and biochemical traits from approximately 14,700 Japanese individuals. We identified 60 associations for 8 hematological traits and 29 associations for 12 biochemical traits at genome-wide significance levels (P < 5 x 10(-8)). Of these, 46 associations were new to this study and 43 replicated previous reports. We compared these associated loci with those reported in similar GWAS in European populations. When the minor allele frequency was >10% in the Japanese population, 32 (94.1%) and 31 (91.2%) of the 34 hematological loci previously reported to be associated in a European population were replicated with P-values less than 0.05 and 0.01, respectively, and 31 (73.8%) and 27 (64.3%) of the 42 European biochemical loci were replicated.

Glutathione S-transferase mu (GSTM1) is mainly known as a detoxification enzyme but it has also been shown to be a negative regulator of apoptosis-related signaling cascades. Recently GSTM1 has been reported to be a significant risk factor for hematological relapse in childhood acute lymphoblastic leukemia, although the underlying mechanism remains largely unknown. Glucocorticoids play a crucial role in the treatment of childhood acute lymphoblastic leukemia, therefore we hypothesized that GSTM1 plays important roles in glucocorticoid-induced apoptotic pathways. To clarify the relationship between GSTM1 and drug resistance, GSTM1 was transfected into a T-acute lymphoblastic leukemia cell line, CCRF-CEM (CEM), and we established the GSTM1-expressing cell lines CEM/M1-4 and CEM/M1-9. Transduction of GSTM1 into CEM selectively decreased cellular sensitivity to dexamethasone in a manner that was independent of glutathione conjugation, but was due to apoptosis inhibition. Dexamethasone-induced p38-MAPK and Bim activation were concomitantly suppressed. Interestingly, nuclear factor kappa b (NF-kappaB) p50 activity was upregulated in GSTM1-expressing CEM. Inhibition of NF-kappaB by the pharmacological agent BAY11-7082 greatly enhanced the sensitivity of the GSTM1-expressing CEM to dexamethasone and was accompanied by an increase in Bim expression. Thus, we propose that GSTM1, a novel regulator of dexamethasone-induced apoptosis, causes dexamethasone resistance by suppression of Bim through dual mechanisms of both downregulation of p38-MAPK and upregulation of NF-kappaB p50.

We have developed a multiplex, single nucleotide polymorphism (SNP) typing system for forensic identification, based on the Invader assay. Using this system, fluorescence data for 21 SNP loci were collected and analyzed. We used endpoint genotyping, commonly used with the Invader assay, and also developed more reliable typing criteria because endpoint typing was occasionally unable to clearly identify the genotype of some loci. Analysis of the fluorescence data identified criteria that had high reproducibility for each genotype. One such criterion is the climbing angle of the curve resulting from two-dimensional plots of the two kinds of fluorescence used for the Invader assay. The climbing angle was observed at the time during the reaction when either or both of the fluorescence intensities increased most significantly. The angles were remarkably associated with homozygous genotypes. On the other hand, all heterozygote endpoint fluorescence ratios were highly reproducible and had very little aberration. These values enabled SNP typing to be more clearly defined compared with typing using only the endpoint fluorescence ratio, which is commonly used with the Invader assay. The values suggested in this study are easily calculated from raw fluorescence data and will be useful for multiplex SNP typing based on the Invader assay.

Ulcerative colitis is one of the principal forms of inflammatory bowel disease with complex manifestations. Although previous studies have indicated that there is a genetic contribution to the pathogenesis of ulcerative colitis, the genes influencing susceptibility to the disease have not been fully determined. To identify genetic factors conferring risk of ulcerative colitis, here we conducted a two-stage genome-wide association study and subsequent replication study using 1,384 Japanese individuals with ulcerative colitis and 3,057 control subjects. In addition to the expected strong association with the major histocompatibility complex (MHC) region, we identified three new susceptibility loci: the immunoglobulin receptor gene FCGR2A (rs1801274, P = 1.56 x 10(-12)), a locus on chromosome 13q12 (rs17085007, P = 6.64 x 10(-8)) and the glycoprotein gene SLC26A3 (rs2108225, P = 9.50 x 10(-8)). rs1801274 is a nonsynonymous SNP of FCGR2A that is reported to have a critical effect on receptor binding affinity for IgG and to be associated with other autoimmune diseases. Our findings provide insight into the molecular pathogenesis of ulcerative colitis.

Background & Aims: Esophageal squamous cell carcinoma (ESCC) is prevalent among Asian populations, with marked regional variations in incidence and mortality. Patients with ESCC have a very poor prognosis, but detection of ESCC at earlier stages could improve clinical outcome. Therefore, identification of epidemiologic factors that influence the development of ESCC would facilitate prevention and/or early detection of the disease., Methods: We performed a 2-step genome-wide association study with subsequent replication analysis using a total of 1070 Japanese ESCC cases and 2836 controls. We also used logistic regression analysis to estimate the effect of gene-gene and gene-environmental interactions., Results: We identified the significant associations of ESCC with 4q21-23 and 12q24 regions, which include nonsynonymous single nucleotide polymorphisms (SNP) in ADH1B (rs1229984, P = 6.76 x 10(-35)) and ALDH2 (rs671, P = 3.68 x 10(-68)) that were previously shown to be associated with ESCC susceptibility. Multiple logistic regression analysis revealed SNP rs671, rs1229984, alcohol drinking, and smoking as the independent risk factors for ESCC (odds ratios of 1.66, 1.85, 1.92, and 1.79, respectively). Moreover, individuals who had both genetic and lifestyle-related risk factors had a nearly 190 times higher risk of ESCC than those who had neither of these., Conclusions: We found 2 known functional variants involved in the metabolism of alcohol and tobacco by-products as the most significant risk factors for the development of ESCC in a Japanese population. The individuals carrying both risk genotypes have a higher baseline risk of ESCC that is substantially increased by 2 lifestyle risk factors.

Background: Cytochrome P450 2D6 (CYP2D6), one of the most important drug-metabolizing enzymes, has been reported to possess variation in the encoding CYP2D6 gene (cytochrome P450, family 2, subfamily D, polypeptide 6) that affects enzymatic activity. For the pharmacogenetic study of CYP2D6, accurate measurement of the dosage of the functional gene is essential; however, current genotyping techniques are insufficient because of their inability to provide the exact copy number of functional CYP2D6 genes., Methods: We developed 3 quantitative real-time PCR (qPCR) assays for estimating the total copy number of the CYP2D6 gene, as well as 24-multiplex PCR-based real-time Invader assays (mPCR-RETINAs) for estimating the allele ratio at each variation locus. After determining the allele copy number at each locus, we estimated the frequencies of CYP2D6 alleles in a population and the diplotype in each individual by a CNVphaser (copy number variation phaser). The qPCR assays and RETINAs used for HapMap Japanese and Chinese samples were applied to 455 Japanese individuals., Results: Forty-two individuals (9.2%) had one CYP2D6 gene copy, 207 (45.5%) had 2 copies, 161 (35.4%) had 3 copies, 40 (8.8%) had 4 copies, and 5 (1.1%) had 5 copies of the CYP2D6 gene. We found 16 different CYP2D6 alleles, with frequencies similar to those described in previous reports. In the diplotype analysis, we observed that CYP2D6*1/*1 and *1/*10-*36 were the most common diplotypes (approximately 20%) in our population., Conclusions: Our method is the first to determine the exact number of functional CYP2D6 gene copies. We believe our method will facilitate and accelerate the detailed pharmacogenetic analysis of CYP2D6.

Object: Double-door laminoplasty using hydroxyapatite (HA) spacers has been widely performed for compressive cervical myelopathy and has provided good neurological outcome. Although HA spacers are used for preventing reclosure of the opened laminae, they are often displaced or dislocated from their original position. The authors investigated the incidence and patterns of postoperative HA spacer displacement to determine the reasons for this unfavorable event., Methods: Eighty-six patients with compressive myelopathy underwent double-door laminoplasty in which a total of 278 HA spacers were used. The displacement of HA spacers and opened laminae were assessed using postoperative lateral radiographs and CT scans., Results: Postoperative dorsal migration > 2 mm was found in 116 (42%) of 278 implanted HA spacers. In addition, 33 (38%) of 86 HA spacers rotated > 10 degrees and 29 (34%) of the 86 opened laminae tilted > 10 degrees. Moreover, deformation of the newly formed spinal canal was observed in 51 (59%) of 86 cases, and bone fusion between the HA spacer and spinous process was achieved in only 15 (8.7%) of 172 cases. Neurological worsening and neck pain, however, were not associated with displacement of HA spacers or deformation of the spinal canal., Conclusions: In double-door laminoplasty, postoperative displacement of the HA spacer with deformation of the enlarged spinal canal occurred frequently. Hydroxyapatite spacers tend to become displaced after surgery. Placing the HA spacer at the base of the spinous process close to the dura mater may prevent postoperative displacement.

Chronic hepatitis B is a serious infectious liver disease that often progresses to liver cirrhosis and hepatocellular carcinoma; however, clinical outcomes after viral exposure vary enormously among individuals. Through a two-stage genome-wide association study using 786 Japanese chronic hepatitis B cases and 2,201 controls, we identified a significant association of chronic hepatitis B with 11 SNPs in a region including HLA-DPA1 and HLA-DPB1. We validated these associations by genotyping two SNPs from the region in three additional Japanese and Thai cohorts consisting of 1,300 cases and 2,100 controls (combined P = 6.34 x 10(-39) and 2.31 x 10(-38), OR = 0.57 and 0.56, respectively). Subsequent analyses revealed risk haplotypes (HLA-DPA1(*)0202-DPB1(*)0501 and HLA-DPA1(*)0202-DPB1(*)0301, OR = 1.45 and 2.31, respectively) and protective haplotypes (HLA-DPA1(*)0103-DPB1(*)0402 and HLA-DPA1(*)0103-DPB1(*)0401, OR = 0.52 and 0.57, respectively). Our findings show that genetic variants in the HLA-DP locus are strongly associated with risk of persistent infection with hepatitis B virus.

Typing of single nucleotide polymorphisms (SNPs) has advantages in forensic DNA identification because SNPs are abundant in genomic DNA and are easily detected using an automated high-throughput system. In this study, we examined the effectiveness of an automated multiplex SNPs typing system based on the "Invader assay". Using this system, multiplex SNPs typing is completed in 40 min without any complex procedures. The typing results were confirmed by direct sequencing, and no inconsistencies were detected between the sequencing results and the typing results. The population data of 21 SNPs from 113 Japanese indicates that the matching probability is about 1.3 x 10(-9). In our experiment, all of 21 SNPs were correctly detected from degraded samples from which typing of short tandem repeat markers was difficult.

Object: Although posterior lumbar interbody fusion (PLIF) is an excellent procedure to attain circumferential decompression, it is technically demanding and can lead to various surgical complications. The authors retrospectively reviewed consecutive patients with nonisthmic spondylolisthesis who underwent PLIF to reveal the incidence and risk factors for perioperative complications of PLIF., Methods: A total of 240 patients underwent PLIF. The fusion level was at L4-5 in 220, L3-4 in 18, and L5-S1 in 2. The medial walls of the fusion segment's facet joints were resected, and the VSP Spine System was used for the pedicle screw instrumentation. The operations were performed by 7 surgeons, who were divided into 4 groups according to their level of experience with spinal surgery., Results: The average operation time was 175 +/- 49 minutes, and the estimated blood loss was 746 +/- 489 ml. A total of 90 patients (37.5%) experienced complications; 41 (17%) experienced transient neurological complications, and 18 (7.5%) experienced permanent neurological complications. The mean neurological score according to the Japanese Orthopaedic Association improved from 14.3 +/- 3.8 to 24.7 +/- 4.0 in the patients without complications and from 14.8 +/- 3.6 to 24.0 +/- 3.9 in the patients with complications. Multivariate analysis concerning the relationship between complications and risk factors (operation time, estimated intraoperative blood loss, and surgeon experience) revealed that operation time was the only significant risk factor for complications., Conclusions: Perioperative complications of PLIF were more frequent in this homogeneous study group than in other studies of various implants. Total excision of the facet joints might preclude neurological complications.

Because population stratification can cause spurious associations in case-control studies, understanding the population structure is important. Here, we examined Japanese population structure by "Eigenanalysis," using the genotypes for 140,387 SNPs in 7003 Japanese individuals, along with 60 European, 60 African, and 90 East-Asian individuals, in the HapMap project. Most Japanese individuals fell into two main clusters, Hondo and Ryukyu; the Hondo cluster includes most of the individuals from the main islands in Japan, and the Ryukyu cluster includes most of the individuals from Okinawa. The SNPs with the greatest frequency differences between the Hondo and Ryukyu clusters were found in the HLA region in chromosome 6. The nonsynonymous SNPs with the greatest frequency differences between the Hondo and Ryukyu clusters were the Val/Ala polymorphism (rs3827760) in the EDAR gene, associated with hair thickness, and the Gly/Ala polymorphism (rs17822931) in the ABCC11 gene, associated with ear-wax type. Genetic differentiation was observed, even among different regions in Honshu Island, the largest island of Japan. Simulation studies showed that the inclusion of different proportions of individuals from different regions of Japan in case and control groups can lead to an inflated rate of false-positive results when the sample sizes are large.

Study Design: Prospective study., Objective: To examine whether preservation of the funicular section of the nuchal ligament attached to the C6 and C7 spinous processes could prevent unfavorable radiologic changes such as kyphotic deformity and destabilization at the C6/7 segment, and to investigate possible correlations between adverse radiologic changes and neurologic recovery or incidence of axial neck pain after laminoplasty in patients with cervical spondylotic myelopathy., Summary of Background Data: Adverse radiologic changes after cervical laminoplasty have been reported to result from detachment of cervical extensor muscles., Methods: Subjects comprised 37 patients who underwent modified C3-6 laminoplasty. Our procedure preserves the funicular section of the nuchal ligament attached to the C6 and/or C7 spinous processes in addition to all muscles attached to the C2 and C7 spinous processes and the subaxial deep extensor muscles on the hinged side. The funicular section of the ligament attached only to the C7 spinous process was preserved in 18 patients (C7 group). This funicular section attaching both to the C7 and C6 spinous processes was preserved in 19 patients (C6+7 group). Radiologic and clinical data were prospectively collected., Results: Postoperative loss of lordosis and destabilization at the C6/7 segment were significantly reduced in the C6+7 group compared with the C7 group. As of final follow-up, neurologic recovery was significantly poorer in the 3 patients with kyphosis than in the 34 patients with straight spinal alignment or lordosis. Frequencies of axial pain showed no significant differences between groups. This value did not vary with the differences in sagittal alignment., Conclusions: These results indicate that the preserved funicular section of the nuchal ligament attached both to the C6 and C7 spinous processes plays an important role in preventing undesirable radiologic changes after laminoplasty.

The clinical outcomes of breast cancer patients treated with tamoxifen may be influenced by the activity of cytochrome P450 2D6 (CYP2D6) enzyme because tamixifen is metabolized by CYP2D6 to its active forms of antiestrogenic metabolite, 4-hydroxytamoxifen and endoxifen. We investigated the predictive value of the CYP2D6*10 allele, which decreased CYP2D6 activity, for clinical outcomes of patients that received adjuvant tamoxifen monotherapy after surgical operation on breast cancer. Among 67 patients examined, those homozygous for the CYP2D6*10 alleles revealed a significantly higher incidence of recurrence within 10 years after the operation (P = 0.0057; odds ratio, 16.63; 95% confidence interval, 1.75-158.12), compared with those homozygous for the wild-type CYP2D6*1 alleles. The elevated risk of recurrence seemed to be dependent on the number of CYP2D6*10 alleles (P = 0.0031 for trend). Cox proportional hazard analysis demonstrated that the CYP2D6 genotype and tumor size were independent factors affecting recurrence-free survival. Patients with the CYP2D6*10/*10 genotype showed a significantly shorter recurrence-free survival period (P = 0.036; adjusted hazard ratio, 10.04; 95% confidence interval, 1.17-86.27) compared to patients with CYP2D6*1/*1 after adjustment of other prognosis factors. The present study suggests that the CYP2D6 genotype should be considered when selecting adjuvant hormonal therapy for breast cancer patients.

A 69-year-old Japanese man was diagnosed as having primary plasma cell leukemia. His malignant plasma cells had a chromosomal translocation t(11;14)(q13;q32) that created overexpression of cyclin D1. Two courses of VAD (vincristine, doxorubicin, dexamethasone) therapy failed to achieve complete remission. Three subsequent courses of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) therapy successfully induced remission with negative FISH test for t(11;14)(q13;q32). Thereafter, the patient received high-dose melphalan (125 mg/m(2)) followed by autologous peripheral blood stem cell transplantation. Cyclin D1 that was present prior to the high-dose chemotherapy, was no longer detected by qualitative PCR analysis. Despite complete cytogenetic remission, the disease relapsed 6 months later, and the patient eventually died 16 months following the diagnosis. Plasma cell leukemia is a rare hematological malignancy with a poor prognosis. The treatment has not been standardized yet. The present case suggested the effectiveness of the combination of hyper-CVAD and high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation. Nevertheless, because of the short remission duration, intensification using tandem high-dose chemotherapy or maintenance using new agents such as bortezomib and thalidomide should be considered for improving the prognosis.

We report the development of a real-time Invader assay combined with multiplex PCR (mPCR-RETINA), an SNP-based approach that can measure the allelic ratio in copy number variation (CNV) regions of a genome. RETINA monitors the real-time fluorescence intensity of each allele during the Invader assay and detects allelic asymmetries caused by genomic duplication/multiplication in heterozygous individuals. By combining mPCR-RETINA and real-time quantitative PCR that detects total copy number, we can estimate the copy number of each allele in CNV regions, which should be useful for investigating the functional significance of allele copy number with disease susceptibilities and drug responses. Also, mPCR-RETINA can efficiently refine the detailed structures of CNV regions. Due to the combination of RETINA with multiplex PCR, mPCR-RETINA requires a very small amount of genomic DNA for analysis (0.1-0.38 ng/locus). Additionally, mPCR-RETINA has clear advantages in its simple protocol and target-specific reaction, even in nonunique regions. We believe mPCR-RETINA will provide a significant contribution to identifying functional alleles in CNV regions., ((c) 2007 Wiley-Liss, Inc.)

Systemic lupus erythematosus (SLE) is one of the common autoimmune diseases, with complex genetic components. Here, we report on a case-control association study of 178 SLE patients and 899 control subjects, using genome-wide gene-based single nucleotide polymorphism (SNP) markers. An SNP, rs3130342, in a 5' flanking region of the TNXB gene revealed a significant association with SLE [P = 0.000000930, odds ratio (OR) 3.11, with 95% confidence interval (95%CI) of 1.89-5.28] in a Japanese population. This association was replicated independently with 203 cases and 294 controls (P = 0.0440, OR 1.52, with 95%CI of 1.01-2.78). Although a copy number variation (CNV) of the C4 gene adjacent to the TNXB gene was reported to be associated with SLE, our analysis on this CNV revealed that the association of CNV of the C4 gene was weaker than the SNP in the TNXB gene and likely to reflect the linkage disequilibrium between C4 CNV and this particular SNP. Stratified analysis also revealed that the association of SNP rs3130342 with SLE was independent of the HLA-DRB1*1501 allele that has been shown to be associated with SLE. Our findings strongly imply that the TNXB gene is a candidate gene susceptible to SLE in the Japanese population.

In vivo three-dimensional (3D) kinematics of the lumbar spine has not been well evaluated by the conventional methods because of their methodological limitations, while 3D intervertebral motions have been quantitatively determined by cadaver studies. We thus developed a novel 3D analyzing system for the relative motions of individual vertebrae using 3D magnetic resonance imaging (MRI) and analyzed in vivo 3D intervertebral motions of the lumbar spine during trunk rotation. Ten healthy volunteers underwent 3D MRI of the lumbar spine in nine positions with 15 degrees increments during trunk rotation (0 degrees , 15 degrees , 30 degrees , 45 degrees , and maximum). Relative motions of the lumbar spine were calculated by automatically superimposing a segmented 3D MRI of the vertebra in the neutral position over images of each position using the voxel-based registration method. These 3D motions were represented with 6 degrees of freedom by Euler angles and translations on the coordinate system. The mean axial rotation of ten healthy volunteers of each lumbar spinal segment in 45 degrees trunk rotation to each side ranged from 1.2 degrees to 1.7 degrees . Coupled flexion with axial rotation was observed at the segments from L1/2 to L5/S1. Coupled lateral bending of the segments from L1/2 to L4/5 was in the opposite direction of the trunk rotation, while that of T12/L1 and L5/S1 was in the same direction. The direction of the coupled lateral bending in the present study was different from that in the previous cadaver study only at L4/5. This difference might result from the non-load state of the supine position in the current study and/or the non-physiological state in the cadaver study. Our system has two limitations: (1) the study was conducted with each volunteer in the supine position, and (2) because the rotation device regulated trunk rotation, trunk rotation might not have been physiological. In vivo 3D intervertebral motions of the lumbar spine during trunk rotation were evaluated using our novel motion analysis system. These data may be useful for the optimal orthopaedic management of lumbar spinal disorders.

The differences in formation and structural properties of polymer networks consisting of end-linked flexible or rigid chains were studied by molecular dynamics simulation. Networks were formed from monodisperse, linear, short, flexible or rigid chains with functional end groups and a stoichiometric ratio of trifunctional cross-linkers. The rigid chains had a rodlike shape defined by an angle potential, while the flexible chains had no angle potential. In order to understand the influence of chain rigidity, all parameters of precursor chains (length, reactivity, bond potential, nonbonding potential) were the same, with the exception of the angle potential. The system density rho, corresponding to the concentration of monomer in solvent, was varied from 0.01 to 0.11. Different network structures resulting from the different processes of network formation were observed. Simulations showed that the flexible chains created an inhomogeneous network on a large scale via microgel cluster formation, in agreement with experimental observations, whereas the rigid chains rapidly created a homogeneous network in the entire system volume without first generating microgel clusters, with the additional difference that they gave rise to mutually interpenetrating networks at the local scale.

Several articles reported the association between the development of subaxial kyphosis and the hyperlordotic fixation of C1-C2. However, their patients were heterogeneous in both primary disease and operative procedure. Transarticular screw fixation has become a popular procedure for C1-C2 arthrodesis instead of wiring techniques in which C1-C2 is difficult to fix in the intended alignment. Furthermore, in rheumatoid arthritis (RA) patients, subaxial lesions play an important role in potential subaxial alignment changes. The subaxial influences after C1-C2 transarticular screw fixation in patients with RA are unclear. To investigate the radiographic features of the subaxial cervical spine after C1-C2 transarticular screw fixation for RA, we reviewed 28 cases of C1-C2 transarticular screw fixation for rheumatoid atlanto-axial subluxation. The sagittal alignment of C1-C2 and the subaxial cervical spine was measured and the factors that affect subaxial alignment were investigated. Subaxial alignment became less lordotic in the postoperative course. The C1-C2 fixation angle and subaxial alignment showed a negative linear correlation. However, no significant correlation was found between changes in the C1-C2 angle and changes in the subaxial alignment. Four patients had a postoperative kyphotic subaxial deformity. Neurologic deterioration recurred in 4 patients, because of the postoperative development of subaxial subluxation. Common radiographic changes included an increase in C1-C2 lordosis, constant inclination of C1, an anterior shift of C2, and a decrease in C2-C7 lordosis. Many factors, not only C1-C2 angle, are associated with subaxial sagittal alignment change after C1-C2 transarticular screw fixation.

Many surgeons have investigated local pain associated with posterior spine surgery for cervical or lumbar lesions. However, little information is available concerning local pain after posterior thoracic spine surgery. This prospective study was, thus, performed to investigate the frequency and clinical features of local pain after posterior spine surgery for thoracic lesions. In 29 consecutive patients undergoing posterior spine surgery for various thoracic spinal disorders, local pain was investigated before and after surgery. In all 19 patients with preoperative back pain presumably due to thoracic lesions, pain was well alleviated after surgery. In contrast, 6 patients (21%) newly developed persistent shoulder angle pain after surgery, which resembled axial pain after cervical laminoplasty. In 5 of these 6 patients surgical exposure was extended to the cervicothoracic junction, whereas persistent shoulder angle pain was independent of disease etiologies and surgical procedure, and all of the 5 patients had no other etiologies of local pain such as surgical site infections, hardware failures, pseudoarthrosis, other metastasis, and vertebral fractures. These results suggest that dissection of muscle attachments to the cervicothoracic junction would play some part in the development of persistent local pain after posterior spine surgery for thoracic lesions, although surgical exposure of the zygapophysial joints at the cervicothoracic junction might be a possible source of postoperative shoulder pain. Therefore, to minimize such surgical complications, muscle insertions into the cervicothoracic junction should be preserved as far as possible.

Poly(amide acid) gels containing photosensitive azobenzene groups in the main chain have been synthesized and their viscoelastic properties before and after light irradiation have been investigated by dynamic viscoelasticity measurements. It was found that 405 nm light induced a local volume change and a two-fold increase in the storage modulus of the gels. We discuss the change in storage modulus upon light irradiation quite simply in terms of classical rubber elasticity theory, which cannot explain this large increase in storage modulus. The photo-induced increase in storage modulus may result from an increase in entanglement interactions of topological constraints fixed in the network structure, caused by photoisomerization of the azobenzene moieties. We suggest that topological constraints in the network structure of the gels were realized by light irradiation and calculate the resulting slip link ratio (index of the topological constraints) in the gel network.

We have developed a magnetic grip-and-release motion detection system to measure time differences among fingers during motion. We designed a magnetic sensing system consisting of a magnetic oscillation coil, sensing coil, and circuit unit. We measured wave forms of grip-and-release motion (15 s) of seven healthy volunteers using the system. To provide the grip-and-release timing of each finger, we used the reference voltage of each subject in the state of grasping a rod with a 30 mm diameter. Using the reference voltage, the time differences in the finger movements of all volunteers were detected. The detected grip-and-release time difference of both dominant and nondominant hands had a main tendency in which the closing movement of the little finger is fast, within 10 ms, and the opening movement is slow, within 13 ms. Our data suggest that the new magnetic sensing system has the potential to detect the quantitative value of the time difference in grip-and-release motion among fingers.

Study Design: A prospective study., Objective: To examine the prevalence and clinical manifestations of segmental motor paralysis after cervical laminoplasty and to investigate the presence of intramedullary high-signal intensity area (HIA) on postoperative T2-weighted magnetic resonance imaging (MRI)., Summary of Background Data: Almost all previous studies had been retrospectively conducted, and MRIs of all subjects, including a control population, have never been investigated., Methods: In the 79 patients of the prospective group, the sole examiner evaluated muscle strengths daily for perioperative 3 weeks and MRI scans were performed before and after surgery. Medical records of the 79 consecutive patients before this study were also investigated (control group)., Results: Ten patients from the prospective group developed segmental motor paralysis (proximal in 5, distal in 2, and diffuse in 3), whereas paralysis occurred in only 4 patients from the control group (proximal in 3 and diffuse in 1). On postoperative MRI, a linear HIA corresponded to the paralyzed segment more frequently than a focal or no HIA., Conclusion: In the prospective cases, distal or diffuse paralysis was found more frequently than in the retrospective control group. Linear HIAs were significantly more likely to present in the paralyzed segments.

Background Context: Recent reports have described the long-term efficacy and safety of infliximab as a treatment for ankylosing spondylitis (AS). The most important adverse effects of infliximab are infections, malignancies, autoimmunities, and hypersensitivity reactions. There has never been a reported case of paraparesis after infliximab therapy for AS., Purpose: To describe a case with paraparesis caused by rapid exacerbation of preexisting spinal pseudoarthrosis after infliximab therapy for advanced AS., Study Design/setting: Case report/Osaka University Graduate School of Medicine, Suita, Japan., Patient Sample: A 55-year-old man with a 27-year history of AS., Outcome Measures: Case report., Methods: A 55-year-old man with a 27-year history of AS was treated with infliximab, which provided considerable pain relief and improvement of activities of daily living. However, as the patient resumed vigorous daily activity, he felt back pain and subsequently developed paraparesis. Radiographs showed rapid exacerbation of preexisting spinal pseudoarthrosis at the T11-T12 level after infliximab therapy., Results: After laminectomy and posterolateral fusion, the back pain and paraparesis improved sufficiently to allow independent walking, but moderate bladder dysfunction persisted., Conclusions: Although this patient could have certainly become myelopathic over time without undergoing infliximab therapy, the patient's history and radiographic course suggest that suppression of inflammation by infliximab improved his activities of daily living, which paradoxically exacerbated preexisting spinal pseudoarthrosis and quickened the onset of subsequent myelopathy.

Objective: To examine whether lumbar disc herniation with massive extrusion and/or segmental instability can be an indicator for spinal fusion or not, by comparing the outcome of posterior lumbar interbody fusion (PLIF) and discectomy alone., Methods: One hundred seventy-four patients with PLIF and 177 patients with discectomy were retrospectively analyzed. We hypothesized two criteria for fusion: massive herniation and segmental instability. The patients were divided into four groups according to our original criteria: group F-F (n = 96) consisted of the patients who fulfilled the criteria for fusion and underwent PLIF; group nF-F (n = 78) consisted of those who did not fulfill the criteria but had PLIF; group F-nF (n = 30) consisted of those who fulfilled the criteria but underwent discectomy; group nF-nF (n = 147) comprised those who did not fulfill the criteria and underwent discectomy. Each patient was evaluated clinically and radiologically at 5 years after operation., Results: Groups F-F and nF-F had significantly superior results on low back pain compared with group F-nF (F-F vs F-nF, P < 0.05; nF-F vs F-nF, P < 0.01). The frequency of additional operation at the involved level was significantly higher in group F-nF (10.0%) than in group F-F (2.0%) (P < 0.05). Postoperative instability of the adjacent segment developed in 15 cases (8.6%) in groups F-F and nF-F and in 3 cases (1.7%) in groups F-nF and nF-nF (P < 0.01)., Conclusion: Lumbar disc herniation with massive herniation or segmental instability can be well treated with PLIF.

Study Design: Kinematics of the cervical spine during lateral bending were investigated using a novel system of three-dimensional motion analysis., Objectives: To demonstrate in vivo intervertebral coupled motions of the cervical spine during lateral bending of the neck., Summary of Background Data: No previous studies have successfully documented in vivo three-dimensional intervertebral motions of the cervical spine during lateral bending., Methods: Twelve healthy volunteers underwent three-dimensional magnetic resonance imaging (MRI) of the cervical spine in 7 positions with 10 degrees increments of lateral bending. Relative motions of the cervical spine were calculated automatically by superimposing a segmented three-dimensional-MRI of the vertebra in the neutral position over images of each position using volume registration., Results: Mean maximum lateral bending of the cervical spine to one side was 1.6 degrees to 5.7 degrees at each level. Coupled axial rotation opposite to lateral bending was observed in the upper cervical levels (Oc-C1, 0.2 degrees ; C1-C2, 17.1 degrees ), while in the subaxial cervical levels, it was observed in the same direction as lateral bending except for at C7-T1. Coupled flexion-extension motion was small at all vertebral levels (<1.1 degrees)., Conclusions: We succeeded in identifying in vivo coupled motions of the cervical spine in lateral bending for the first time.

Background Context: There have been only five reported cases with cerebellar hemorrhagic infarction after spinal surgery, and the underlying pathomechanism remains obscure., Purpose: To describe a case with multiple cerebellar hemorrhagic infarctions after surgery for a huge atlantoaxial neurinoma., Study Design/setting: Case report, Methods: A 36-year-old man underwent uneventful surgery for a huge atlantoaxial neurinoma. After surgery, the patient was lethargic with slurred speech and subsequently developed cerebellar symptoms, although preoperative myelopathic symptoms did not worsen. The clinical and radiological findings are presented, and possible causes of the hemorrhages are discussed., Results: Magnetic resonance imaging of the brain after surgery showed multiple cerebellar hemorrhagic infarctions. However, magnetic resonance angiography revealed no occlusion or stenosis in the vertebrobasilar system, and a duplex scan of the neck vessels confirmed normal flow in the vertebral arteries after surgery. In response to the conservative treatment, the patient exhibited neurological recovery with disappearance of cerebellar symptoms., Conclusions: In the present case with multiple cerebellar hemorrhagic infarctions, venous infarction appears more likely to be the cause of cerebellar hemorrhagic infarction than arterial infarction. The most likely underlying pathomechanism is a cerebellar venous disturbance precipitated by loss of a large amount of cerebrospinal fluid, although the exact etiology remains elusive.

Object: Although conducting cervical laminoplasty in patients with multisegmental cord compression provides good neurological results, it is not without shortcomings, including C-5 palsy, axial neck pain, and undesirable radiologically detectable changes. Postoperative kyphosis and segmental instability can cause neurological problems and are believed mainly to result from neck muscle disruption. The authors developed a new laminoplasty technique, with the aim of preserving optimal muscle function., Methods: The present technique is a modification of unilateral open-door laminoplasty. By using an ultrasonic osteotome in small gaps of muscle bellies, a gutter is made without disrupting muscles, spinous processes, or their connections on the hinged side. Ceramic spacers are then positioned between elevated laminae and lateral masses at C-3, C-5, and C-7 on the opened side, which is exposed in a conventional manner. This new procedure was used to treat 37 consecutive patients with compression myelopathy. Postoperative computerized tomography (CT) scanning revealed a significant difference in a cross-sectional area of muscles between the hinged and opened side. The mean follow-up period was 40.2 months (range 24-54 months). Changes in alignment were observed in only one patient, and vertebral slippage developed in two. Performed at regular intervals, CT scanning demonstrated that the elevated laminae remained in situ throughout the study period., Conclusions: In using the present unilateral open-door laminoplasty technique, deep extensor muscles are left intact along with their junctions to spinous processes on the hinged side. Radiologically documented changes were minimal because the preserved muscles functioned normally immediately after the operation.

Unlabelled: Medical and surgical advances allow surgical treatment of many patients with spinal metastases. Although emerging surgical techniques facilitate stabilization of the collapsed spine, surgical candidates should be carefully selected. However, the lack of confirmed criteria to determine survival of these patients makes selection for surgery difficult. Clinical symptoms have been considered possible factors associated with prognosis, but their relevance has not been confirmed because of inadequate power for proper statistical analysis. We retrospectively reviewed 165 patients who had surgery for spinal metastases from various cancers. Clinical symptoms including pain, paresis, and walking status were recorded. Multivariate analysis indicated that the histologic type of the primary tumor was the strongest prognostic factor, followed by preoperative paresis and pain. Myeloma, thyroid cancer, renal cell cancer, breast cancer, and prostate cancer had better prognoses than other kinds of cancer. Patients without paresis before surgery had a better prognosis than patients with paresis, and patients with no pain before surgery had a better prognosis than those with pain. Preoperative walking status was not an independent prognostic factor., Level of Evidence: Therapeutic study, Level IV (case series--no, or historical control group). See the Guidelines for Authors for a complete description of levels of evidence.

Study Design: A retrospective study was conducted., Objective: To compare the long-term outcomes after laminoplasty and anterior spinal fusion (ASF) for cervical myelopathy secondary to disc herniation., Summary of Background Data: There have been no reports of long-term comparative studies of laminoplasty and ASF for cervical myelopathy due to disc herniation., Methods: Of 21 patients who underwent ASF only between 1984 and 1987, 15 were followed up. Of 22 patients who underwent laminoplasty only between 1987 and 1994, 18 were followed up. There were no significant differences in preoperative prognostic factors between the 2 groups. Average follow-up was 15 years in the ASF group and 10 years in the laminoplasty group. Neurologic and radiologic results were examined., Results: Laminoplasty and ASF provided equal neurologic improvement. In the ASF group, additional surgery was required for bone graft complications in 2 patients and for adjacent spondylosis in 1. In the laminoplasty group, one patient had C5 palsy, and intractable axial pain developed in 5 patients after surgery, but no patients needed additional surgery., Conclusions: Because the 2 procedures provided the same neurologic improvement, the risks of bone graft complication with ASF must be weighed against the risks of chronic neck pain associated with laminoplasty for determining the best technique. Therefore, because our present surgical strategy for cervical myelopathy due to disc herniation, laminoplasty is the procedure of choice except for a patient with single level disc herniation without developmental canal stenosis, who is considered to be a good candidate for ASF.

The authors describe a rare case of a congenital absence of the right L5 pedicle in a 54-year-old man presenting with low back pain and radicular pain of his left leg. Plain x-ray films, computed tomography scan (CT) after myelography, and three-dimensional CT revealed the absence of the L5 pedicle and anomaly of the L4-L5 facet joint on his right side. On the left side, there were severe degenerative changes that were thought to be the result of an overload and instability. The degenerative changes led to late-onset neurologic impairment of the contralateral side, which was treated with spinal fusion. To our knowledge, this is the first report of contralateral symptoms due to unilateral defect of the facet joint accompanied by aplasia of a pedicle.

Study Design: Three-dimensional intervertebral motions of the subaxial cervical spine during head rotation were investigated in healthy volunteers using three-dimensional magnetic resonance imaging (MRI)., Objectives: To document intervertebral coupled motions of the subaxial cervical spine during rotation., Summary of Background Data: In vivo three-dimensional kinematics of the subaxial cervical spine in rotation have not previously been well described, since they are too complicated to follow using conventional radiography or computed tomography techniques., Methods: Ten healthy volunteers underwent three-dimensional MRI of the cervical spine in 11 positions with 15 degrees increments during head rotation using a 1.0-T imager. Relative motions of the subaxial cervical spine were calculated by automatically superimposing a segmented three-dimensional MRI of the vertebra in the neutral position over images of each position using volume registration. Three-dimensional motions of adjacent vertebrae were represented with 6 df (6 degrees of freedoms) by Euler angles and translations on the coordinate system defined by Panjabi, then visualized in animations using surface bone models., Results: Mean axial rotation of the subaxial cervical spine in maximum head rotation (69.5 degrees ) was 2.2 degrees at C2-C3, 4.5 degrees at C3-C4, 4.6 degrees at C4-C5, 4.0 degrees at C5-C6, 1.6 degrees at C6-C7, and 1.5 degrees at C7-T1. Coupled lateral bending with axial rotation was observed in the same direction as axial rotation at all levels (C2-C3, 3.6 degrees ; C3-C4, 5.4 degrees; C4-C5, 5.0 degrees ; C5-C6, 5.3 degrees ; C6-C7, 4.9 degrees ; C7-T1, 1.2 degrees ). Coupled extension with axial rotation occurred in the middle cervical region (C2-C3, 1.4 degrees ; C3-C4, 2.3 degrees ; C4-C5, 1.5 degrees ), while in the lower cervical region, flexion was coupled with axial rotation (C5-C6, 0.9 degrees ; C6-C7, 2.4 degrees ; C7-T1, 3.0 degrees )., Conclusions: We investigated intervertebral motions of the subaxial cervical spine during head rotation using a three-dimensional imaging system, and obtained the first accurate depictions of in vivo coupled motion. These findings will be helpful as the basis for understanding abnormal conditions.

Background: Total en bloc spondylectomy (TES) was devised to minimize the incidence of local recurrence following resection of spinal tumor. Successful local control with TES has been reported for patients with primary malignant or aggressive benign spinal tumors. As for metastatic spinal tumors, however, only a few surgeons except for the inventor group have reported the outcome of TES. The purpose of this study was to investigate whether TES could provide radical resection of the tumor in patients with solitary spinal metastases., Methods: Twelve patients underwent TES for a solitary metastatic tumor of the thoracolumbar spine. Primary malignancies included breast cancer in four patients, thyroid cancer in three, renal cell carcinoma in three, lung cancer in one, and unknown in one. All patients were regularly followed up with plain radiographs, computed tomography scans, and magnetic resonance imaging to detect local recurrence., Results: In two of the four cases with paraspinal tumor extension, local recurrences developed at 25 months after surgery. Seven patients have survived for an average of 61 months, while the remaining five died of disseminated metastases with a mean survival of 23 months after surgery. Local recurrences were common in patients with paraspinal extensions. TES for lesions with paraspinal extensions failed to provide curative resection of the tumor., Conclusion: Given the great technical demands and potential risks of TES, the indication for TES with spinal metastases should be limited to cases with solitary lesions that do not extend to the paraspinal area.

Study Design: Kinematics of the upper cervical spine during head rotation were investigated using three-dimensional magnetic resonance imaging (MRI) in healthy volunteers., Objectives: To demonstrate in vivo intervertebral coupled motions of the upper cervical spine., Summary of Background Data: Although various in vivo and in vitro studies have identified the normal movement patterns of the upper cervical spine, no previous studies have accurately analyzed in vivo three-dimensional intervertebral motions of the upper cervical spine during head rotation., Methods: Fifteen healthy volunteers underwent three-dimensional MRI of the upper cervical spine using a 1.0-T imager in progressive 15 degrees steps during head rotation. Segmented three-dimensional MRIs of each vertebra in the neutral position were superimposed over images taken at other positions, using voxel-based registration. Relative motions between occiput (Oc) and atlas (C1) and between C1 and axis (C2) were measured and described with 6 degrees of freedom by rigid body Euler angles and translations., Results: Mean (+/- SD) maximum angles of axial rotation in Oc-C1 and C1-C2 were 1.7 +/- 1.5 degrees and 36.2 +/- 4.5 degrees to each side, respectively. Increases in angle of axial rotation in C1-C2 became smaller with increased head rotation, indicating axial rotation in C1-C2 displayed nonlinear motion. Coupled lateral bending with axial rotation was observed in the direction opposition to that of axial rotation in Oc-C1 (mean, 4.1 +/- 1.4 degrees) and C1-C2 (mean, 3.8 +/- 3.0 degrees). Coupled extension with axial rotation occurred at both C0-C1 (mean, 13.3 +/- 4.9 degrees) and C1-C2 (mean, 6.9 +/- 3.0 degrees)., Conclusions: We developed an innovative in vivo three-dimensional motion analysis system using three-dimensional MRI. In vivo coupled motions of the upper cervical spine investigated using this system supported the results of the previous in vitro study.