The Tohoku Journal of Experimental Medicine
Online ISSN : 1349-3329
Print ISSN : 0040-8727
ISSN-L : 0040-8727
Volume 221 , Issue 1
May
Showing 1-11 articles out of 11 articles from the selected issue
Invited Review
  • Nobuo Fuse
    2010 Volume 221 Issue 1 Pages 1-10
    Published: 2010
    Released: April 20, 2010
    JOURNALS FREE ACCESS
    Glaucoma is the leading cause of visual impairment and blindness throughout the world. Primary open angle glaucoma (POAG; MIM 137760) is the main type of glaucoma in most populations, and more than 20 genetic loci for POAG have been reported. Only three causative genes have been identified in these loci, viz. myocilin (MYOC), optineurin (OPTN), and WD repeat domain 36 (WDR36). However, mutations in these genes account for only a small percentage of the patients with POAG. Some of these glaucoma cases have a Mendelian inheritance pattern, and a considerable fraction of the cases result from a large number of variants in several genes each contributing small effects. Glaucoma is considered to be a common disease such as diabetes mellitus, coronary disease, Crohn disease, and several common cancers. The main technological approaches used to identify the genes associated with glaucoma are the candidate gene approach, linkage analysis, case-control association study, and genome-wide association study. Association studies have found about 27 genes related to POAG, but the glaucoma-causing effects of these genes need to be investigated in more detail. The current trend is to use case-control association studies or genome-wide association studies to map the genes associated with glaucoma. Such studies are expected to greatly advance our understanding of the genetic basis of glaucoma, and to provide information on the effectiveness of glaucoma therapy. This review gives an overview on the genetic aspects of glaucoma.
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Invited Review for the 90th Anniversary
  • Pilar Esteve, Paola Bovolenta
    2010 Volume 221 Issue 1 Pages 11-17
    Published: 2010
    Released: April 24, 2010
    JOURNALS FREE ACCESS
    Secreted Frizzled Related Proteins (Sfrps) are a family of secreted proteins that can bind both to Wnt ligands and Frizzled receptors, thereby modulating the Wnt signalling cascades. Recent studies have shown that Sfrps can also interact with Wnt unrelated molecules such as RANKL, a member of the tumor necrosis factor family, Tolloid metalloproteinases or integrin-fibronectin complexes. Alterations in the levels of Sfrp expression have been recently associated with different pathological conditions, including tumor formation and bone and myocardial disorders. Here, we summarise the evidence that relates Sfrps with these diseases and discuss how the proposed multiple Sfrp interactions with Wnt related and unrelated pathways may explain their implication in such diverse pathologies.
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Regular Contributions
  • Wei Qiao, Lingying Niu, Zhao Liu, Tong Qiao, Changjian Liu
    2010 Volume 221 Issue 1 Pages 19-27
    Published: 2010
    Released: April 24, 2010
    JOURNALS FREE ACCESS
    Endothelial progenitor cells (EPCs) have been proposed as a promising tool for therapeutic neovascularization, vascular repair, tumor pathology and tissue engineering, though their identification is still a subject of much discussion. EPCs consist of two different subpopulations, termed endothelial cell (EC)-like cells and endothelial outgrowth cells (EOCs). Both types of EPCs are derived from mononuclear cells, but they have different characteristics. Our aim was to characterize and compare the two types of EPCs to find reliable biological features of EPCs that can be used for identification of EPCs. In this study, human peripheral blood mononuclear cells were isolated by density gradient centrifugation and cultured on fibronectin-coated culture plates. While adherent cells were maintained, EC-like cells appeared within 4-7 days of culture, and EOCs developed after 2-3 weeks of culture. EOCs, which were characterized by high proliferation potential, were able to form capillary tubes on Matrigel, but not EC-like cells, despite the higher concentrations of three angiogenic cytokines, vascular endothelial growth factor, granulocyte colony-stimulating factor, and interleukin 8, in the conditioned medium of EC-like cells. In contrast, endothelial nitric oxide synthase (eNOS) was expressed in both types of EPCs, and both cell types could produce nitric oxide (NO), as judged by measuring the total amounts of nitrites and nitrates in culture media. In conclusion, the expression of eNOS and the production of NO could be used as common biological features to identify EPCs. These findings provide new insights into the identification of EPCs.
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  • Kaori Kitamura, Kazutoshi Nakamura, Tomoko Nishiwaki, Kimiko Ueno, Mar ...
    2010 Volume 221 Issue 1 Pages 29-34
    Published: 2010
    Released: April 24, 2010
    JOURNALS FREE ACCESS
    Japan has a rapidly growing elderly population requiring care. This study aimed to clarify risk factors for two-year mortality in such people. Subjects included 205 community-dwelling elderly people, who were approved for care in the 2003 Yamato Study, an epidemiologic study of individuals utilizing the long-term care service system. Demographic characteristics, Barthel index (measuring activities of daily living), grip strength, thigh muscle volume, psychological evaluation, and blood values including hemoglobin, serum albumin, and serum 25-hydroxyvitamin D levels were investigated at baseline. The average age of subjects was 83.6 (S.D., 8.0) years. Of the 205 subjects, 42 died during the follow-up period. Bivariate analysis showed that older age (p = 0.0015), lower weight (p = 0.0087), lower body mass index (BMI) (p = 0.0001), lower Barthel index (p = 0.0017), lower hemoglobin (p = 0.0180), and lower serum albumin (p = 0.0001) were associated with mortality, but that sex was not (p = 0.1248). Stepwise multiple logistic regression analysis showed that BMI < 17.1 kg/m2 (adjusted OR = 4.0, p = 0.0007), age ≥ 90 years (adjusted OR = 3.3, p = 0.0033), and lower serum albumin levels (adjusted OR = 0.86, p = 0.0007) were independently associated with mortality. We conclude that low BMI and low serum albumin are strong predictors of 2-year mortality in frail elderly individuals, and that nutritional risk should appropriately be evaluated for elderly people requiring home care.
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  • Jiao Liu, Fengqi Hu, Wei Liang, Guirong Wang, Pravin C. Singhal, Guohu ...
    2010 Volume 221 Issue 1 Pages 35-42
    Published: 2010
    Released: April 24, 2010
    JOURNALS FREE ACCESS
    Some risk factors for susceptibility to recurrent urinary tract infection (r-UTI) are well known, but the genetic role in acquiring the disease is poorly understood. Surfactant protein A and D (SP-A and SP-D) play an important role in modulation of lung inflammatory processes. The SP-A1 and SP-A2 genes encoding SP-A and the SP-D gene are highly polymorphic, and some of polymorphisms are associated with several infective diseases, including pyelonephritis. In the present study, we investigated whether some of these polymorphisms are associated with the risk of r-UTI in Chinese population. Genomic DNA was extracted from blood samples of 32 female patients with r-UTI and 30 age-matched, unrelated healthy female subjects. Genotyping of gene polymorphisms was analyzed by PCR. Among 11 single nucleotide polymorphisms (SNPs) (five of SP-A1, four of SP-A2 and two of SP-D) observed in the enrolled subjects, Ala19Val of SP-A1 and Lys223Gln of SP-A2 were associated with susceptibility to r-UTI. The frequencies of 19Ala allele of SP-A1 gene (p = 0.038) and 223Gln allele of SP-A2 gene (p = 0.012) in the patients were significantly higher than those in healthy subjects. The serum SP-A and SP-D levels were increased and the urine SP-A and SP-D levels were decreased in r-UTI patients compared with control subjects (p < 0.05). r-UTI patients with 19Ala/Ala or 223Gln/Gln genotype were associated with high serum and low urine SP-A levels (p < 0.01). Therefore, the 19Ala allele of SP-A1 gene and the 223Gln allele of SP-A2 gene are risk factors for r-UTI.
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  • Maja Antoncic-Svetina, Davor Sentija, Ana Cipak, Davor Milicic, Andrea ...
    2010 Volume 221 Issue 1 Pages 43-48
    Published: 2010
    Released: April 24, 2010
    JOURNALS FREE ACCESS
    Oxidative stress is an important pathogenic factor of cancer and cardiovascular, metabolic and degenerative diseases. On the other hand, mild oxidative stress, as in case of physical exercise, can increase the antioxidant defense system. However, the mechanisms underlying such desirable effects of mild oxidative stress are not well understood, because the production of hydroxyl radical, the most aggressive oxygen free radical, was not yet evaluated under physiological circumstances. Therefore, in this study, we evaluated the overall production of hydroxyl radical using blood samples of ten healthy male students before and 1 h after ergometry. One h before exercise, they took salicylic acid (1g) orally so that hydroxyl radical was trapped with salicylic acid, yielding a measurable reaction product, 2,3-dihydroxybenzoic acid. Oxidative stress response to exercise was also evaluated in the volunteers without premedication by measuring serum peroxides and total antioxidant capacity of serum. These parameters of oxidative stress were then correlated with physical performance of the subjects. Ergometry caused an increase of the plasma hydroxyl radical level by 37.5% (p < 0.05), whereas the levels of total serum peroxides did not change significantly. Total serum antioxidant capacity, measured as uric acid equivalents, was higher after ergometry by 39.7% (p < 0.05), and was in positive correlation (r = 0.81) with anaerobic threshold, an indicator of physical condition. Hence, ergometry induces hydroxyl radical production and systemic oxidative stress response in the healthy subjects. Egometry could be used to study physiological oxidative stress response and to improve antioxidant defense capacities in humans.
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  • Yosuke Kakisaka, Keisuke Wakusawa, Kazuhiro Haginoya, Mitsugu Uematsu, ...
    2010 Volume 221 Issue 1 Pages 49-51
    Published: 2010
    Released: April 28, 2010
    JOURNALS FREE ACCESS
    Abdominal migraine is one subcategory of migraine-related syndromes. Migraine is sometimes associated with facial ecchymosis, which may be accounted for by trigeminovascular activation. However, the precise mechanism of this concurrence remains unknown. Here, we describe a 9-year-old girl, who presented ecchymosis of the legs and buttock associated with recurrent, severe, non-localized midline abdominal pain. The patient has positive family history of migraine. Investigations during an attack revealed no obvious abnormalities. According to the International Classification of Headache Disorders (Second Edition), she was diagnosed with abdominal migraine. Her abdominal pain was relieved with sumatriptan, a migraine-specific serotonin1B/1D agonist. The ecchymosis always occurred in conjunction with abdominal pain and tended to regress after pain relief. In contrast to the local trigeminovascular activation theory that explains the ecchymosis in a migraine-related condition, the findings gained from the presented patient suggest a mechanism that involves the initial activation of the visceral nerves responsible for abdominal nociception under the predisposition of visceral hypersensitivity associated with abdominal migraine. Subsequently, ecchymosis developed in the skin region innerved by the activated nerves, possibly involving dichotomizing afferent fibers and afferent-afferent interactions via sacral spinal cord pathway or a sympathetic reflex. Taken together with the probable common mechanism of migraine and abdominal migraine, we suggest that the skin changes in migraine are associated with somatic referral of migraine headache via the trigeminal nerve pathway.
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  • Naohisa Miyakoshi, Yuji Kasukawa, Yoshinori Ishikawa, Koji Nozaka, Yoi ...
    2010 Volume 221 Issue 1 Pages 53-59
    Published: 2010
    Released: April 28, 2010
    JOURNALS FREE ACCESS
    Chronic low back pain (LBP) is influenced by numerous factors and often shows a decline in walking abilities. However, the impact of spinal alignment and mobility on this condition and walking disturbance in the general population is unclear. A total of 672 community-dwelling individuals aged 20-94 years (mean, 69 years) in Kamikoani, Akita, Japan were divided into four groups: controls, subjects with no history of LBP (n = 121); HLBP group, subjects with a history of LBP (n = 323); CLBP group, subjects with chronic LBP without walking disturbance (n = 89); and CLBP-WD group, subjects with chronic LBP with walking disturbance (n = 139). Differences among groups were investigated in terms of angle of kyphosis, mobility, and inclination of the spine in upright, flexed, and extended positions, all measured using a computer-assisted device. HLBP, CLBP, and CLBP-WD groups showed significantly limited lumbar extension compared to controls (P < 0.05). The CLBP-WD group showed significantly increased thoracic and lumbar kyphosis angles and spinal inclination compared to the other groups (P < 0.05). Among subjects with chronic LBP (CLBP and CLBP-WD groups), associations between walking disturbance and measured variables were examined using logistic regression. According to multivariate analysis, lumbar kyphosis angle in upright position and spinal inclination in extended position were identified as indices associated with the presence of walking disturbance in subjects with chronic LBP. These results indicate that increased lumbar kyphosis and limitation of total spinal extension are important risk factors for walking disturbance in subjects with chronic LBP.
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  • Aiqun Wei, Anthony Leong, Lisa Williams, Sylvia Chung, Bojiang Shen, D ...
    2010 Volume 221 Issue 1 Pages 61-68
    Published: 2010
    Released: April 28, 2010
    JOURNALS FREE ACCESS
    In postmenopausal women, estrogen withdrawal results in decrease in bone density or osteoporosis. Osteoporosis leads to fracture and retards bone-healing response. Bone morphogenetic protein-7 (BMP-7), a member of the transforming-growth factor-β superfamily, has been shown as a promising candidate that stimulates bone growth in its application to fracture healing. The purpose of this study was to determine whether BMP-7 could enhance bone formation in the absence of estrogen. Female rats underwent a controlled closed fracture at the midshaft of the right femur. The callus tissues were harvested from the fracture site eight days following the fracture, and were cultured in serum-free media. The explanted callus tissues were then treated with BMP-7, estrogen (E2) or both. We assessed bone formation by measuring alkaline phosphatase (AP) activity, expression of an osteogenic transcription factor, Runt-related transcription factor-2 (Runx2), production of nitric oxide (NO), and calcium mineralization. Supplementation of serum-free cultures with BMP-7 alone increased cell proliferation by twofold, caused a 6.5-fold increase in AP activity, and enhanced calcium mineralization after 48 h. Moreover, BMP-7 in combination with E2 caused a 8.2-fold increase in the AP activity. Runx2 protein expression was increased following stimulation with BMP-7 and E2. Interestingly, E2 induced the amount of NO production by twofold, whereas BMP-7 did not, either alone or with E2. Thus, BMP-7 could enhance early and late markers of bone fracture healing in callus explant cultures, except for NO. BMP-7 could be a promising growth factor in the treatment of fractures as a consequence of osteoporosis.
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  • Andreja Leskovac, Dragana Vujic, Marija Guc-Scekic, Sandra Petrovic, I ...
    2010 Volume 221 Issue 1 Pages 69-76
    Published: 2010
    Released: April 28, 2010
    JOURNALS FREE ACCESS
    Among patients with bone marrow failure (BMF) syndrome, some are happened to have underlying Fanconi anemia (FA), a genetically heterogeneous disease, which is characterized by progressive pancytopenia and cancer susceptibility. Due to heterogeneous nature of the disease, a single genetic test, as in vitro response to DNA cross-linking agents, usually is not enough to make correct diagnosis. The aim of this study was to evaluate whether measuring repair kinetics of radiation-induced DNA double-strand breaks (DSBs) can distinguish Fanconi anemia from other BMF patients. An early step in repair of DSBs is phosphorylation of the histone H2AX, generating γ-H2AX histone, which extends over mega base-pair regions of DNA from the break site and is visualised as foci (γ-H2AX foci) with specific antibodies. The primary fibroblasts, established from FA patients, were exposed to γ-rays, a dose of 2 Gy (60Co), incubated for up to 24 hours under repair-permissive conditions, and assayed for the level of γ-H2AX foci and apoptosis at different recovery times after the treatment. Cell lines originating from FA patients displayed a significant delay in the repair of radiation-induced DNA DSBs relative to non-FA bone marrow failure (non-FA BMF) and control cell lines. The delay is especially evident at recovery time of 24 hours, and is seen as about 8-fold increase of residual γ-H2AX foci compared to self-state before irradiation. The delay in repair kinetics of FA cells represents the unique feature of FA cellular phenotype, which should be exploited to distinguish FA cellular phenotype.
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  • Yoshio Takano, Yoshihiro Haneda, Takashi Maeda, Yutaka Sakai, Hiroo Ma ...
    2010 Volume 221 Issue 1 Pages 77-85
    Published: 2010
    Released: April 28, 2010
    JOURNALS FREE ACCESS
    The “Hybrid training” (HYBT) method utilizing combined electrical stimulation and voluntary muscle contraction has been developed as a muscle training method. It has already been shown that the method is technically sound and clinically effective in healthy young subjects. The purpose of this study was to investigate the effect of the HYBT method on the knee extensor strength considering safety for elderly people. Twenty subjects were randomly divided into two groups: the HYBT group and the weight machine training (WMT) group. All the subjects performed knee flexion and extension for 19 min per session, twice a week for 12 weeks. At the baseline and after the training, the subjects' maximal isometric torque of knee extension and cross-sectional area (CSA) of quadriceps femoris muscle were measured. The subjects completed the study without adverse effects. The knee extension torque significantly increased in both groups (39% in HYBT group and 42% in WMT group, P < 0.05). The CSA of quadriceps whole significantly increased in both groups (9% in HYBT group and 14% in WMT group, P < 0.05). These results indicate that the HYBT method increases muscle strength and mass, and that this method is as effective as the WMT. In addition, unlike the WMT, the HYBT device, which is portable and not large in size, is so easy to handle that it can be placed at the bedside. Therefore, the HYBT has potential to become a safe, effective method of muscle training for elderly people.
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