ymptoms of Parkinson’s disease (PD) caused by loss of dopaminergic neurons are accompanied by movement disorders, including tremors, rigidity, bradykinesia, and akinesia. Non-human primate (NHP) models with PD play an essential role in the analysis of PD pathophysiology and behavior symptoms. As impairments of hand dexterity function can affect activities of daily living in patients with PD, research on hand dexterity function in NHP models with chronic PD is essential. Traditional rating scales previously used in the evaluation of animal spontaneous behavior were insufficient due to factors related to subjectivity and passivity. Thus, experimentally designed applications for an appropriate apparatus are necessary. In this study, we aimed to longitudinally assess hand dexterity function using hand dexterity task (HDT) in NHP-PD models. To validate this assessment, we analyzed the alteration in Parkinsonian tremor signs and the functionality of presynaptic dopaminergic neuron using positron emission tomography imaging of dopamine transporters in these models. In addition, a significant inverse correlation between HDT and DAT level was identified, but no local bias was found. The correlation with intention tremor signs was lower than the resting tremor. In conclusion, the evaluation of HDT may reflect behavioral symptoms of NHP-PD models. Furthermore, HDT was effectively used to experimentally distinguish intention tremors from other tremors.

Mitochondria continuously fuse and divide to maintain homeostasis. An impairment in the balance between the fusion and fission processes can trigger mitochondrial dysfunction. Accumulating evidence suggests that mitochondrial dysfunction is related to neurodegenerative diseases such as Parkinson's disease (PD), with excessive mitochondrial fission in dopaminergic neurons being one of the pathological mechanisms of PD. Here, we investigated the balance between mitochondrial fusion and fission in the substantia nigra of a non-human primate model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. We found that MPTP induced shorter and abnormally distributed mitochondria. This phenomenon was accompanied by the activation of dynamin-related protein 1 (Drp1), a mitochondrial fission protein, through increased phosphorylation at S616. Thereafter, we assessed for activation of the components of the cyclin-dependent kinase 5 (CDK5) and extracellular signal-regulated kinase (ERK) signaling cascades, which are known regulators of Drp1(S616) phosphorylation. MPTP induced an increase in p25 and p35, which are required for CDK5 activation. Together, these findings suggest that the phosphorylation of Drp1(S616) by CDK5 is involved in mitochondrial fission in the substantia nigra of a non-human primate model of MPTP-induced PD.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Cyclin-Dependent Kinase 5 ; Cyclin-Dependent Kinases ; Dopaminergic Neurons ; Homeostasis ; Mitochondria ; Mitochondrial Dynamics ; Neurodegenerative Diseases ; Parkinson Disease ; Phosphorylation ; Phosphotransferases ; Primates ; Substantia Nigra

BACKGROUNDS: Type I diabetes mellitus (T1DM), an autoimmune disease, is associated with insulin deficiency due to the death of beta-cells. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are capable of tissue repair and thus are a promising source of beta-cell surrogates. METHODS: In this study, the therapeutic potential of BM-MSCs as beta-cell replacements was analyzed both in vitro and in vivo. First, we used retinoic acid (RA) to induce rat BM-MSCs to differentiate into cells of endodermal/pancreatic lineage. Then, differentiated rat BM-MSCs were syngeneically injected under the renal capsule of rats. RESULTS: Analysis of gene expression revealed that rat BM-MSCs showed signs of early pancreatic development, and differentiated cells were qualitatively and quantitatively confirmed to produce insulin in vitro. In vivo study was performed for short-term (3 weeks) and long-term (8 weeks) period of time. Rats that were injected with differentiated MSCs exhibited a reduction in blood glucose levels throughout 8 weeks, and grafted cells survived in vivo for at least 3 weeks. CONCLUSIONS: These findings show that RA can induce differentiation of MSCs into the beta-cell lineage and demonstrate the potential of BM-MSCs to serve as therapeutic tools for T1DM.
Animals ; Autoimmune Diseases ; Blood Glucose ; Diabetes Mellitus ; Diabetes Mellitus, Type 1 ; Gene Expression ; Insulin ; Insulin-Secreting Cells ; Mesenchymal Stromal Cells* ; Rats* ; Transplants ; Tretinoin

BACKGROUND: AEB071, an orally available PKC inhibitor, prevents organ rejection after transplantation in rodents and man. Furthermore, pro-inflammatory cytokines and inflammatory processes are important mediators of transplanted organ rejection. We therefore examined whether single or combination therapies of AEB071 and/or tacrolimus affect cytokine profiles in a rat cardiac allograft model. METHODS: AEB071 (60 mg/kg twice a day) and tacrolimus (0.6 or 1.2 mg/kg once a day) were orally administered daily after cardiac transplantation. Interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10, and tumor necrosis factor (TNF)-alpha levels in serum were subsequently measured 5 days after cardiac transplantation using a multiplex protein assay system. RESULTS: All cytokine levels were significantly depressed in cardiac transplanted rats treated with AEB071, whereas tacrolimus only reduced IFN-gamma, IL-2, IL-4, IL-6, and IL-10 levels. When administered in combination, AEB071 and low- or high-dose tacrolimus had additive effects on IFN-gamma, IL-4, IL-6, and TNF-alpha. CONCLUSIONS: These results suggest that AEB071 inhibits T cell activation by blocking the production of proinflammatory cytokines, and that tacrolimus combined with AEB071 can effectively regulate inflammatory cytokines in the transplantation setting.
Animals ; Cytokines ; Heart Transplantation ; Immunosuppression ; Interferons ; Interleukin-10 ; Interleukin-2 ; Interleukin-4 ; Interleukin-6 ; Interleukins ; Pyrroles ; Quinazolines ; Rats ; Rejection (Psychology) ; Rodentia ; Tacrolimus ; Transplantation, Homologous ; Transplants ; Tumor Necrosis Factor-alpha

Neurofibromatosis is an autosomal dominant hereditary disorder characterized by skin abnormalities such as cafe au-lait spots, and soft tissue legion such as generalized subcutaneous neurofibroma. Malignant peripheral nerve sheath tumor is a spindle cell sarcoma that mostly arises in the soft tissue but rarely arises in the head and neck region. Malignant peripheral nerve sheath tumor can develop from the pre-existing neurofibromas or schwannomas, and from the peripheral nerves. They can also occur after radiation therapy. Malignant peripheral nerve sheath tumor is usually associated with neurofibromatosis type I. The authors recently experienced a case of malignant peripheral nerve sheath tumor associated with neurofibromatosis type I in a 20-year-old female patient who presented with a well marginated oval shape mass in the left neck.
Female ; Head ; Humans ; Neck ; Nerve Sheath Neoplasms ; Neurilemmoma ; Neurofibroma ; Neurofibromatoses ; Neurofibromatosis 1 ; Peripheral Nerves ; Sarcoma ; Skin Abnormalities ; Young Adult

BACKGROUND AND OBJECTIVES: Sudden deafness, an important disease characterized by abrupt sensorineural hearing loss, is rare in children and the prognosis in children is accepted to be worse than that in adults. However, clinical studies are not sufficient to define the clinical characteristics and prognosis of sudden deafness in children. The author analyzed clinical manifestation of sudden deafness in children and compared the treatment results of children with those of adults. SUBJECTS AND METHOD: A retrospective analysis was performed in 25 patients (29 ears) who were treated for sudden deafness from January 1993 to May 2008. RESULTS: 1) The overall hearing recovery rate (79%) was significantly higher in adults (53.7%). The prognosis in children less than 10 years old (73%) was also higher than that in adults. 2) The rate of complete recovery (61%) was higher in children than in adults (38.5%). CONCLUSION: The sudden deafness in children has unique clinical characteristics and the recovery rate is more favorable than in adults.
Adult ; Child ; Hearing ; Hearing Loss, Sensorineural ; Hearing Loss, Sudden ; Humans ; Prognosis ; Retrospective Studies

Parathyroid adenoma usually manifests with symptoms related to hypercalcemia, such as urinary stone and bone fracture. It may also present with asymptomatic hypercalcemia. However, spontaneous cervical hematoma may occur very rarely as a result of extracapsular hemorrhage of a cervical parathyroid adenoma causing acute painful cervical swelling, bruising, dyspnea, hoarseness and dysphagia. We report a 44-year-old woman who manifested as a spontaneous cervical hematoma without any clinical evidence of hyperparathyroidism.
Acute Pain ; Adult ; Deglutition Disorders ; Dyspnea ; Female ; Fractures, Bone ; Hematoma ; Hemorrhage ; Hoarseness ; Humans ; Hypercalcemia ; Hyperparathyroidism ; Neck ; Parathyroid Neoplasms ; Urinary Calculi

OBJECTIVE: MTA1 has been identified as a metastasis-promiting gene, and its gene expression is correlated with invasion and metastasis in several cancers. We examined MTA1 expression levels in epithelial ovarian neoplasm. METHODS: Expression of MTA1 was evaluated by immunohistochemistry and tissue array in 53 benign tumors, 27 borderline tumors and 68 malignant tumors. The data was analyzed in reference to various clinicopathological parameters. RESULTS: Increased expression of MTA1 was significantly correlated with histologic grade and FIGO stage. There was no relationship between MTA1 expression and age, histologic type, tumor size. CONCLUSION: These results suggest that MTA1 is closely related to invasiveness and progression in epithelial ovarian neoplasm. The MTA1 could thus potentially provide information on the mechanism of cancer invasion and metastasis.
Gene Expression ; Immunohistochemistry ; Neoplasm Metastasis ; Ovarian Neoplasms*

BACKGROUND: The monoclonal antibody M30 recognizes a neoepitope of cytokeratin 18 that's produced during the process of apoptosis, and it is reactive in formalin-fixed, paraffin-embedded tissue. The detailed nature of apoptosis in colorectal cancer is unclear, especially in regard to the MSI status and the clinicopathologic factors. The purpose of this study was to elucidate the apoptosis assessed by M30 immunoreactivity in colorectal cancer and its relationship with the MSI status and the various clinicopathologic factors of colorectal cancers. METHODS: 101 colorectal cancers were classified according to levels of MSI as 12 MSI-H, 4 MSI-L and 85 MSS. Apoptosis was quantified by immunohistochemistry with using M30 CytoDEATH anti-body. RESULTS: The apoptotic index assessed by M30 was significantly increased in the MSI-H and MSI-L colorectal cancer compared to that in the MSS colorectal cancer. Right sided colon cancer showed a significant higher apoptotic index than did the left sided colon cancer. There was also a tendency for decreased apoptosis in metastatic colorectal cancers (Duke's stage D). There was somewhat of an increase of apoptosis in colorectal cancers with mucinous carcinoma and medullary carcinoma, and also in the colorectal cancers with an increased TIL count, but this was not statistically significant. CONCLUSION: M30 immunoreactivity is a valuable method to detect apoptosis in formalin-fixed, paraffin-embedded tissue and it might explain that MSI-H colorectal cancer shows better clinical behavior than MSS colorectal cancer in regard to the increased apoptosis.
Adenocarcinoma, Mucinous ; Apoptosis* ; Carcinoma, Medullary ; Colonic Neoplasms ; Colorectal Neoplasms* ; Immunohistochemistry ; Keratin-18 ; Microsatellite Instability

BACKGROUND: Disturbances of the cell cycle regulatory proteins are key events underlying the development and/or progression of human malignancies. The aim of this study was to evaluate the expression of G1/S cell cycle regulatory proteins in ovarian epithelial tumor. METHODS: We simultaneously evaluated the expression of cyclin D1, cyclin E, CDK4, CDK2, p16, Rb, E2F1, p53 and the Ki67 labelling index (LI) by immunohistochemical methods in 148 cases of ovarian epithelial tumor of the benign (n=47), borderline (n=29), and malignant type (n=72). RESULTS: The expression of cyclin E, CDK2, p16, Rb, E2F1, p53 and the Ki67 LI gradually increased from the benign type, through the borderline type, to the malignant tumors. Between the borderline and malignant tumors, the increased expression of cyclin E, E2F1, and p53, and the decreased expression of Rb were significantly associated with malignancy. The reduced Rb expression and the increased E2F1 expression were correlated with the FIGO stage and the histologic grade in the malignant ovarian epithelial tumors. CONCLUSIONS: Cyclin E, E2F1, and p53 overexpressions and the loss of Rb are the important components during carcinogenesis of ovarian epithelial tumors. Our results suggest that in- creased expression of E2F1 should be considered as a new parameter for the prognosis of patients with malignant ovarian epithelial tumors.
Carcinogenesis ; Cell Cycle Proteins* ; Cell Cycle* ; Cyclin D1 ; Cyclin E ; Cyclins ; E2F1 Transcription Factor ; Female ; Humans ; Neoplasms, Glandular and Epithelial ; Ovary ; Prognosis