Journal of Toxicologic Pathology
Online ISSN : 1881-915X
Print ISSN : 0914-9198
ISSN-L : 0914-9198
Volume 25 , Issue 2
Showing 1-7 articles out of 7 articles from the selected issue
Review
  • Kinji Kobayashi, Takeshi Izawa, Mitsuru Kuwamura, Jyoji Yamate
    2012 Volume 25 Issue 2 Pages 135-147
    Published: 2012
    Released: July 07, 2012
    JOURNALS FREE ACCESS
    Dysferlin (DYSF) is involved in the membrane-repair process, in the intracellular vesicle system and in T-tubule development in skeletal muscle. It interacts with mitsugumin 53, annexins, caveolin-3, AHNAK, affixin, S100A10, calpain-3, tubulin and dihydropyridine receptor. Limb-girdle muscular dystrophy 2B (LGMD2B) and Miyoshi myopathy (MM) are muscular dystrophies associated with recessively inherited mutations in the DYSF gene. The diseases are characterized by weakness and muscle atrophy that progress slowly and symmetrically in the proximal muscles of the limb girdles. LGMD2B and MM, which are collectively termed “dysferlinopathy”, both lead to abnormalities in vesicle traffic and membrane repair at the plasma membrane in muscle fibers. SJL/J (SJL) and A/J mice are naturally occurring animal models for dysferlinopathy. Since there has been no an approach to therapy for dysferlinopathy, the immediate development of a therapeutic method for this genetic disorder is desirable. The murine models are useful in verification experiments for new therapies and they are valuable tools for identifying factors that accelerate dystrophic changes in skeletal muscle. It could be possible that the genetic or immunological background in SJL or A/J mice could modify muscle damage in experiments involving these models, because SJL and A/J mice show differences in the progress and prevalent sites of skeletal muscle lesions as well as in the gene-expression profiles of their skeletal muscle. In this review, we provide up-to-date information on the function of dysferlin, the development of possible therapies for muscle dystrophies (including dysferlinopathy) and the detection of new therapeutic targets for dysferlinopathy by means of experiments using animal models for dysferlinopathy.
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Original Articles
  • Sayaka Kemmochi, Hitomi Hayashi, Eriko Taniai, Keiji Hasumi, Yoshiko S ...
    2012 Volume 25 Issue 2 Pages 149-154
    Published: 2012
    Released: July 07, 2012
    JOURNALS FREE ACCESS
    Activators of tissue proteolysis including Stachybotrys microspora triprenyl phenol (SMTP)-7 are a new class of agents that are expected to be effective for amelioration of chronic tissue destructive diseases. The present study was performed to examine whether SMTP-7 is effective for the amelioration or protection of early-stage IgA nephropathy (IgAN) induced by nivalenol (NIV) in female BALB/c mice. In Experiment 1, mice were administered NIV at 24 ppm in diet for 8 weeks, and during the NIV treatment, they were intraperitoneally injected with SMTP-7 (10 mg/kg) three times a week. In Experiment 2, mice were injected similarly with SMTP-7 during the last 4 weeks of a 16-week NIV treatment. Immunofluorescence analysis revealed an inhibitory effect of SMTP-7 on the glomerular deposition of IgA in Experiment 1; however, it was ineffective in Experiment 2. On the other hand, SMTP-7 did not affect the serum concentration of IgA in both experiments. These results suggest that SMTP-7 has a potential to decrease the progression of IgAN induced by NIV through inhibition of local accumulation of IgA in the glomerular mesangium, while it was ineffective for suppression of IgA production. On the other hand, SMTP-7 was found to be ineffective for already deposited IgA, suggesting that SMTP-7 may not be effective for ameliorating advanced IgAN.
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  • Masako Imaoka, Ayako Sayama, Takami Suzuki, Toshimasa Jindo, Atsushi S ...
    2012 Volume 25 Issue 2 Pages 155-161
    Published: 2012
    Released: July 07, 2012
    JOURNALS FREE ACCESS
    The effect of hypertension on the occurrence of micro-hemorrhage in the pancreatic islet, known to be observed in Sprague-Dawley (SD) rats spontaneously, and endothelial markers were investigated in male Dahl-Iwai salt-sensitive (DIS, derived from SD rats), salt-resistant (DIR), and SD rats. DIS and DIR rats were fed 8% NaCl-containing diet to induce hypertension, with blood pressure measurement once a week, euthanized at 6, 8, or 12 weeks of age, and subjected to the measurement of plasma nitric oxide (NO) and von Willebrand factor (vWF) concentrations combined with histopathological examinations and immunohistochemical detections of vWF in the pancreas and kidney. As a result, hypertension was observed from 7 through 12 weeks of age in DIS rats. At 12 weeks of age, only DIS rats showed decreased plasma NO and increased vWF, indicating endothelial abnormality in the body. Histopathologically, micro-hemorrhage in the islet was observed with a similar incidence and severity in SD and DIS rats aged 12 weeks, and vWF was immunohistochemically localized in the islet endothelium with similar reactivity between age-matched SD rats. On the other hand, in the kidney, glomerular sclerosis was observed in DIS rats aged 12 weeks and accompanied broad stainability of vWF in the sclerotic glomerulus, including endothelium. In conclusion, there was no enhancement/exaggeration in the micro-hemorrhage in the pancreatic islet of hypertensive DIS rats in comparison with that in SD rats under the present experimental conditions. It is suggested that hypertension is not related to the occurrence of islet micro-hemorrhage, spontaneously observed in SD rats.
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  • Rodolfo Villarreal-Calderon, Gary Dale, Ricardo Delgado-Chávez, ...
    2012 Volume 25 Issue 2 Pages 163-173
    Published: 2012
    Released: July 07, 2012
    JOURNALS FREE ACCESS
    Southwest Mexico City (SWMC) air pollution is characterized by high concentrations of ozone and particulate matter < 10 μm (PM10) containing lipopolysaccharides while in the North PM2.5 is high. These intra-city differences are likely accounting for higher CD14 and IL-1β in SWMC v NMC mice myocardial expression. This pilot study was designed to investigate whether similar intra-city differences exist in the levels of myocardial inflammatory genes in young people. Inflammatory mediator genes and inflammasome arrays were measured in right and left autopsy ventricles of 6 southwest/15 north (18.5 ± 2.6 years) MC residents after fatal sudden accidental deaths. There was a significant S v N right ventricle up-regulation of IL-1β (p=0.008), TNF-α (p=0.001), IL-10 (p=0.001), and CD14 (p=0.002), and a left ventricle difference in TNF-α (p=0.007), and IL-10 (p=0.02). SW right ventricles had significant up-regulation of NLRC1, NLRP3 and of 29/84 inflammasome genes, including NOD factors and caspases. There was significant degranulation of mast cells both in myocardium and epicardial nerve fibers. Differential expression of key inflammatory myocardial genes and inflammasomes are influenced by the location of residence. Myocardial inflammation and inflammasome activation in young hearts is a plausible pathway of heart injury in urbanites and adverse effects on the cardiovascular system are expected.
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Case Reports
  • Kyohei Yasuno, Haruka Sakashita, Saori Araki, Ryosuke Kobayashi, Yosuk ...
    2012 Volume 25 Issue 2 Pages 175-178
    Published: 2012
    Released: July 07, 2012
    JOURNALS FREE ACCESS
    This report describes a spontaneous hybrid cyst in a Sprague-Dawley (SD) rat. A 52-week-old, male SD rat had a cutaneous cyst on the left mystacial pad. Histologically, the cyst wall showed infundibular differentiation with keratohyalin granules in the granular layer and matrical differentiation comprising basaloid epithelial cells with trichohyalin granules. The cyst cavity was filled with lamellar, flaky keratin and aggregates of shadow cells. Immunohistochemically, the infundibular-type epithelium was positive for cytokeratin (CK) AE1/AE3, CK KL1 and CK14 but negative for CK15, whereas the matrical-type epithelium was negative for all four CK isoforms examined. These immunohistochemical properties of the infundibular- and matrical-type epithelia were similar to those of the infundibulum and inferior segment of normal hair follicles, respectively. Based on these findings, the cyst was diagnosed as a hybrid cyst, comprising more than one type of cyst arising from various parts of the pilosebaceous unit.
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  • Tomo Sasaki, Katsuhiko Yoshizawa, Yuichi Kinoshita, Hisanori Miki, Aya ...
    2012 Volume 25 Issue 2 Pages 179-182
    Published: 2012
    Released: July 07, 2012
    JOURNALS FREE ACCESS
    An intracranial lipomatous hamartoma was found in the third ventricle of a 7-week-old female BALB/cAnNCrlCrlj mouse. The nodule was composed of mature white adipose cells, which contained one large fat droplet, and there was no evidence of cytological atypia. The brain parenchyma at the retrosplenial granular cortex and the hippocampus in the cerebrum were slightly compressed, and the choroid plexus was dislocated downward. Scattered capillary vessels penetrated the nodule from the surrounding tissue. Based on these findings, the lesion was diagnosed as a lipomatous hamartoma that occurred from the roof of the third ventricle. This extremely rare tumor-like nodule represents an overgrowth of the mature adipocyte population as a malformation rather than a true neoplasm.
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Technical Report
  • Caroline Bouchez, Fréderic Gervais, Renaud Fleurance, Bernard P ...
    2012 Volume 25 Issue 2 Pages 183-188
    Published: 2012
    Released: July 07, 2012
    JOURNALS FREE ACCESS
    Although a T-dependent antibody response (TDAR) assay is generally recommended as the first-line immune function assay in nonclinical immunotoxicity evaluation, second-line assays such as delayed-type hypersensitivity (DTH) to measure cell-mediated responses can provide helpful additional information. In this study, male Cynomolgus monkeys were injected intramuscularly either once or twice with 1 mg Keyhole Limpet Hemocyanin (KLH) or twice with a commercially available tetanus vaccine (40 IU tetanus toxoid + 0.06 mg aluminum hydroxide). All animals were subsequently challenged by intradermal injections of the same antigen or aluminum hydroxide after 4, 6 and 8 weeks. Clinical reactions at the injection sites were scored 24, 48 and 72 h post challenge. Skin biopsies were taken on completion of the observation period after each challenge for standard histological examination and immunolabeling using CD3 (T lymphocytes), CD19 (B lymphocytes) and CD68 (macrophages) antibodies. Tetanus toxoid induced stronger clinical reactions than KLH, whereas aluminum hydroxide induced no clinical reaction. Perivascular mononuclear cell infiltrates, a histopathological finding consistent with a DTH reaction, were seen after all challenges with tetanus toxoid or KLH, but not with aluminum hydroxide. Immunohistochemistry evidenced the presence of T lymphocytes and macrophages within these infiltrates. These results suggest that tetanus toxoid adjuvanted with aluminum hydroxide can induce a consistent DTH response for use as a model of cell-mediated response in Cynomolgus monkeys.
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