Takuya Nikaido

Eos: a novel member of the Ikaros gene family expressed predominantly in the developing nervous system

We identified a novel member of the Ikaros gene family, which has critical roles in the development of lymphoid lineages. This gene, which we named Eos, was expressed predominantly in the developing central and peripheral nervous system. Eos protein could interact with itself and Ikaros protein through its C‐terminal portion in the yeast two hybrid assay. These findings suggested that Eos may have important roles in neural development similarly to the Ikaros family in the development of hemolymphoid tissue.

Upregulation of the pro-apoptotic BH3-only peptide harakiri in spinal neurons of amyotrophic lateral sclerosis patients

DNA fragmentation and activation of caspase-1, implicating involvement of apoptosis, have been reported in the spinal cord of amyotrophic lateral sclerosis (ALS) patients and transgenic mouse models of ALS. Because BH3-only members of the Bcl-2 family have pro-apoptotic activity, we examined the expression of the BH3-only peptide harakiri (Hrk) in the spinal cord of ALS patients. In situ expression of Hrk mRNA and immunoreactivity against the Hrk peptide were verified in the spinal neurons. In the immunoblot analysis, upregulated Hrk protein migrated at 16 kDa. Heterodimerization of Hrk with Bcl-2 was detected by immunoprecipitation, which suggests the competition of Hrk and anti-apoptotic Bcl-2. These findings suggest that Hrk plays a role in apoptotic events in ALS pathogenesis.

Surgical Treatment Assessment Using the Japanese Orthopedic Association Cervical Myelopathy Evaluation Questionnaire in Patients With Cervical Myelopathy: A New Outcome Measure for Cervical Myelopathy

Study Design. Prospective study of assessment of surgical results using a new outcome measure for cervical myelopathy, the Japanese Orthopedic Association cervical myelopathy evaluation questionnaire (JOACMEQ). Objective. To clarify correlations between pre- and postoperative JOACMEQ severity scores for cervical spine operations and grip strength and grip-and-release test, as objective evaluations, as well as correlations with the 8 subscales of the short form-36 (SF-36). Methods. For pre- and postoperative evaluations, we examined 87 subjects who had undergone cervical spine operations and could be followed up for ≥6 months. JOACMEQ and the Japanese version of SF-36 were administered along with grip strength and grip-and-release tests, immediately preoperatively and 6 months postoperatively. Based on JOACMEQ severity scores pre- and postoperatively, treatment effectiveness was determined for cervical spine function, upper extremity function, lower extremity function, bladder function, and quality of life (QOL). We also clarified correlations between JOACMEQ scores and upper extremity function using grip strength and the grip-and-release test. In addition, correlations between the 5 JOACMEQ severity scores and the 8 subscales of SF-36 were analyzed. Results. Effective rate of treatment was lower for upper extremity function than for other items (i.e., lower extremity function, bladder function, and QOL), and upper extremity function showed a different tendency for subjective improvement of symptoms following surgery compared to other items. JOACMEQ scores for upper extremity function, as subjective evaluations, may not necessarily improve even though improvements are seen in objective indicators such as grip strength and grip-and-release tests. Conclusion. JOACMEQ offers an effective method of evaluation from the perspective of patient evaluations of QOL.

Mycobacterium bovis BCG Vertebral Osteomyelitis after Intravesical BCG Therapy, Diagnosed by PCR-Based Genomic Deletion Analysis

ABSTRACT We report a case of Mycobacterium bovis BCG vertebral osteomyelitis 1.8 years after intravesical BCG therapy for bladder cancer. We differentiated BCG from other Mycobacterium tuberculosis complex members by PCR analysis of deletion regions and started an appropriate chemotherapy regimen resulting in the remission of symptoms within 1 month.

Expression of OASIS, a CREB/ATF family transcription factor, in CNS lesion and its transcriptional activity.

We reported the expression patterns of a novel member of the CREB/ATF family, OASIS, in central nervous system (CNS) lesions and its transcriptional activity. OASIS gene expression was upregulated in the stab-injured spinal cord. Double labeling experiments revealed that the distribution of OASIS mRNA-positive cells overlapped with a population of GFAP-immunoreactive cells. This finding suggested that OASIS might regulate expression of important downstream molecules in certain subset of the reactive astrocytes (e.g. inhibitory substances in injured brain). In gel shift assays, OASIS was able to specifically bind to CRE as CREB family members were. We then examined transcriptional activity of full-length OASIS with GAL4-UAS-luciferase reporter assay in COS7 cells. OASIS protein activated transcription, but did not inhibit basal transcription driven by AdML promoter. To determine critical portion(s) of the OASIS protein in transcriptional activation, we examined the activity of various deletion constructs of OASIS gene. The assay revealed that a strong transcriptional activation domain lay in the N-terminal region where acidic amino acids clustered and a possible repression domain, which had not been reported for other CREB/ATF family members, lay in the more C-terminal region. We therefore proposed that OASIS protein positively regulated gene transcription in a subset of reactive astrocytes, and thereby influenced the reaction of injured CNS tissues.

Lumbar Spinal Stenosis Has a Negative Impact on Quality of Life Compared with Other Comorbidities: An Epidemiological Cross-Sectional Study of 1862 Community-Dwelling Individuals

Lumbar spinal stenosis (LSS) is common in the elderly. However, there have been few reports on its impact on quality of life (QoL) in community-dwelling individuals. The purpose of this study was to clarify how symptomatic LSS affects QoL at the community level. A total of 1862 people (697 males and 1165 females, most subjects were between 40 and 85 y.o.) agreed to participate and were interviewed. The presence of symptomatic LSS was assessed by a specially designed questionnaire. The Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) was also administered. In addition, the presence of comorbid conditions that affect QoL, such as osteoarthritis of the knee and hip, cardiovascular disease, cerebrovascular disease, or respiratory disease, was also analyzed. The prevalence of symptomatic LSS gradually increased with age. Furthermore, the presence of symptomatic LSS had a strong negative effect on all 8 physical and mental domains and the physical component summary (PCS) (OR: 1.547–2.544) but not the mental component summary (MCS). In comparison with comorbid conditions, LSS had a much stronger negative impact on health-related QoL (HR-QoL). The current study confirmed that the presence of symptomatic LSS might have a strong negative influence on HR-QoL in the community setting.

Dysfunction of Nucleus Accumbens Is Associated With Psychiatric Problems in Patients With Chronic Low Back Pain: A Functional Magnetic Resonance Imaging Study

Study Design. A cross-sectional study. Objective. The aim of this study was to evaluate activity of the nucleus accumbens (NAc) in response to lumbar mechanical stimulation in patients with chronic low back pain (cLBP) using functional magnetic resonance imaging (fMRI). Summary of Background Data. Although a modified activity of the NAc was characterized in cLBP patients, its pathological significance has yet to be determined. We hypothesized that NAc activation in response to pain might differ depending on the extent of psychiatric problems, which might be associated with the affective/motivational background of chronic pain. Methods. Twenty-one patients with cLBP (four men, 17 women) were recruited. Subjects were divided into two groups on the basis of scores on the patient version of the Brief Scale for Psychiatric problems in Orthopaedic Patients (BS-POP) scores: ≥17 (High Score, HiS group) and <17 (non-High Score, non-HiS group). Each subject was placed in the prone position on a 3-Tesla magnetic resonance imaging (MRI) scanner and stimulated by mechanical stimulation on the left lower back. Three blocks of 30-second pain stimulus calibrated at either 3 or 5 on an 11-grade numerical rating scale (NRS) were applied with intervening 30-second rest conditions during whole-brain echo-planar imaging. Functional images were analyzed using a multisubject general linear model with Bonferroni multiple comparisons. Results. Subjects in the HiS group had more intense daily pain and lower quality of life than those in the non-HiS group (P < 0.05). Catastrophic thinking in relation to pain experience did not differ between the groups. Activation at the NAc was smaller in the HiS group than in the non-HiS group (P < 0.001). Conclusion. The presence of psychiatric problems was associated with attenuated activity of the NAc in cLBP patients. Dysfunction of the NAc might potentially be involved in the affective/motivational factors in the chronification of LBP. Level of Evidence. N/A

Localization of huntingtin-interacting protein-2 (Hip-2) mRNA in the developing mouse brain.

Huntingtin-interacting protein-2 (Hip-2) was identified as a human protein specifically associated with huntingtin in vitro, a gene product affected in patients with Huntington disease (HD). It is a ubiquitin-conjugating enzyme identical to the previously characterized bovine E2-25k. We identified the mouse Hip-2 homologue (mHip-2) and examined its distribution patterns in the developing mouse brain in order to gain an insight into the functional significance of the Hip-2 protein in the normal brain as well as in the pathogenesis of HD. As reported with huntingtin, the mHip-2 mRNA expression developed in parallel with neuronal maturation and became distributed widely in the postnatal mouse brain. This spatiotemporal pattern of mHip-2 mRNA expression resembled that of huntingtin. We further demonstrated that mHip-2 mRNA was colocalized with huntingtin-like immunoreactivity in a single neuron. These findings suggested that the Hip-2 interacted with huntingtin in vivo and played an important role in HD pathogenesis.

Vertebral fracture at the caudal end of a surgical fusion for thoracic vertebral fracture in a patient with diffuse idiopathic skeletal hyperostosis (DISH)

The patient was an 86-year-old woman with back pain after a fall. She had no neurological findings at the initial visit. Plain radiographs and magnetic resonance imaging (MRI) showed diffuse idiopathic skeletal hyperostosis (DISH) and a Th10 fracture. Two weeks later, she started gait exercise with immobilization by a rigid orthosis. Twenty-five days later, she presented with paralysis and numbness of her legs. Computed tomography (CT) showed anterior expansion in the vertebral body of Th10. MRI showed an intramedullary high-intensity area on T2-weighted images at the same level. She was diagnosed as having delayed paraplegia after a Th10 fracture and transferred to our hospital for surgery. Laminectomy of Th10, posterior fusion from Th7 to L1 with pedicle screws and hooks to Th6 and L1 laminae, anterior fusion from Th9 to Th11 with a plate, and autologous bone grafting were performed simultaneously. The patients paralysis improved, and she started gait exercise with no limitation of bed rest and without an orthosis after surgery. At 8 days after surgery, she again presented with low back pain and paralysis in her legs. CT revealed an L1 fracture, which was the caudal end of the surgical fusion. The decreased kyphosis after surgery compared to that at pre-injury might have caused a subsequent horizontal shear force to L1 when the patient sat on the bed and when she walked. In conclusion, to avoid postoperative adjacent vertebral fracture after fusion, appropriate correction of spinal alignment to that at pre-injury is needed for vertebral fractures in patients with DISH.

The pro-apoptotic human BH3-only peptide harakiri is expressed in Cryptococcus-infected perivascular macrophages in HIV-1 encephalitis patients

In the central nervous system (CNS), HIV-1 targets mainly microglia/macrophages. Like the CD4+ T cell depletion and neuronal loss in AIDS, apoptosis is thought to be involved in eliminating infected macrophages. In this study, we examined the expression of the pro-apoptotic BH3-peptide harakiri (Hrk) in brain tissues of AIDS patients. Immunoreactivity against Hrk was positive in perivascular macrophages infiltrated into some restricted lesions. Most of these immunopositive cells contained small inclusions positive for Grocotts methenamine silver staining. Confocal laser microscopy demonstrated that Hrk expression coincided with immunoreactivities against HIV-1 and Cryptococcus neoformans. Expression of Hrk mRNA was demonstrated in these cells by in situ hybridization, which indicated that Hrk is not phagocytosed material. Some pro-apoptotic bcl-family members, including Hrk, may contribute to the delayed hypersensitive reaction in AIDS, in macrophages eliminating opportunistic infection.