Dysfunction of striatal MeCP2 is associated with cognitive decline in a mouse model of Alzheimer's disease.

Rationale: Cerebral Methyl-CpG binding Protein 2 (MeCP2) is involved in several psychiatric disorders that are concomitant with cognitive dysfunction. However, the regulatory function of striatal MeCP2 and its association with Alzheimer's disease (AD) has been largely neglected due to the absence of amyloid plaque accumulation in the striatal region until the later stages of AD progression. Considerable evidence indicates that neuropsychiatric symptoms related to cognitive decline are involved with striatal dysfunction. To this respect, we investigated the epigenetic function of striatal MeCP2 paralleling the pathogenesis of AD. Methods: We investigated the brain from amyloid precursor protein (APP)/presenilin1 (PS1) transgenic mice and postmortem brain samples from normal subjects and AD patients. The molecular changes in the brain, particularly in the striatal regions, were analyzed with thioflavin S staining, immunohistochemistry, immunoblotting, and MeCP2 chromatin immunoprecipitation sequencing (ChIP-seq). The cognitive function of APP/PS1 mice was assessed via three behavioral tests: 3-chamber test (3CT), Y-maze test (YMT), and passive avoidance test (PA). A multi-electrode array (MEA) was performed to analyze the neuronal activity of the striatum in APP/PS1 mice. Results: Striatal MeCP2 expression was increased in the younger (6 months) and older (10 months) ages of APP/PS1 mice, and the genome-wide occupancy of MeCP2 in the younger APP/PS1 showed dysregulated binding patterns in the striatum. Additionally, we confirmed that APP/PS1 mice showed behavioral deficits in multiple cognitive behaviors. Notably, defective cognitive phenotypes and abnormal neuronal activity in old APP/PS1 mice were rescued through the knock-down of striatal MeCP2. Conclusion: We found that the MeCP2-mediated dysregulation of the epigenome in the striatum is linked to the defects in cognitive behavior and neuronal activity in the AD animal model, and that this alteration is initiated even in the very early stages of AD pathogenesis. Together, our data indicates that MeCP2 may be a potential target for the diagnosis and treatment of AD at asymptomatic and symptomatic stages.

Immunoglobulins and Transcription Factors in Otitis Media.

The causes of otitis media (OM) involve bacterial and viral infection, anatomo-physiological abnormalities of the Eustachian canal and nasopharynx, allergic rhinitis, group childcare centers, second-hand smoking, obesity, immaturity and defects of the immune system, formula feeding, sex, race, and age. OM is accompanied by complex and diverse interactions among bacteria, viruses, inflammatory cells, immune cells, and epithelial cells. The present study summarizes the antibodies that contribute to immune reactions in all types of otitis media, including acute otitis media, otitis media with effusion, and chronic otitis media with or without cholesteatoma, as well as the transcription factors that induce the production of these antibodies. The types and distribution of B cells; the functions of B cells, especially in otorhinolaryngology; antibody formation in patients with otitis media; and antibodies and related transcription factors are described. B cells have important functions in host defenses, including antigen recognition, antigen presentation, antibody production, and immunomodulation. The phenotypes of B cells in the ear, nose, and throat, especially in patients with otitis media, were shown to be CD5low, CD23high, CD43low, B220high, sIgMlow, sIgDhigh, Mac-1low, CD80(B7.1)low, CD86(B7.2)low, and Syndecam-1low. Of the five major classes of immunoglobulins produced by B cells, three (IgG, IgA, and IgM) are mainly involved in otitis media. Serum concentrations of IgG, IgA, and IgM are lower in patients with OM with effusion (OME) than in subjects without otitis media. Moreover, IgG, IgA, and IgM concentrations in the middle ear cavity are increased during immune responses in patients with otitis media. B cell leukemia/lymphoma-6 (Bcl-6) and paired box gene 5 (Pax-5) suppress antibody production, whereas B lymphocyte inducer of maturation program 1 (Blimp-1) and X-box binding protein 1 (XBP-1) promote antibody production during immune responses in patients with otitis media.

Expression of endoplasmic reticulum stress mRNAs in otitis media.

BACKGROUND: Endoplasmic reticulum (ER) stress is a cellular defense mechanism that occurs when ER function is impaired. OBJECTIVE: This study was designed to evaluate the expression of major mRNAs of ER stress in patients with otitis media with effusion (OME), chronic otitis media (COM), and COM with cholesteatoma (CholeOM). MATERIAL AND METHODS: Specimens were collected during surgery from patients with OME, COM, and CholeOM, and the levels of ER stress mRNAs measured by real-time polymerase chain reaction. Levels of ER stress mRNAs were compared in the three groups and correlated with clinical findings and pus culture results. RESULTS: The level of CHOP mRNA was higher, and the levels of sXBP1 and ATF6 mRNAs lower, in the OME than in the other two groups (p < .05 each). Evaluation of bacterial pus culture negative patients showed that the level of ATF6 mRNA was higher in the CholeOM than in the other two groups (p < .05), whereas evaluation of bacterial pus culture positive patients showed that the level of CHOP mRNA was higher in the OME than in the other groups (p < .05). CONCLUSIONS AND SIGNIFICANCE: ER stress may be involved in the pathophysiology of OM and the levels of ER stress mRNAs were expressed differently in each type of otitis media according to bacterial culture test results.

Biomarkers Suggesting Favorable Prognostic Outcomes in Sudden Sensorineural Hearing Loss.

Sudden sensorineural hearing loss (SSNHL) is a medical emergency, making detailed examination to determine possible causes and early treatment important. However, etiological examinations in SSNHL do not always reveal a cause, and several factors have been found to affect treatment outcomes. Various studies are being performed to determine the prognosis and effects of treatment in patients who experience sudden hearing loss, and to identify biomarkers associated with this condition. Embase, PubMed, and the Cochrane database were searched using the key words SSNHL, prognostic, and biomarker. This search identified 4 articles in Embase, 28 articles in PubMed, and 36 in the Cochrane database. Of these 68 articles, 3 were duplicates and 37 were unrelated to the research topic. After excluding these articles, the remaining 28 articles were reviewed. Factors associated with SSNHL were divided into six categories: metabolic, hemostatic, inflammatory, immunologic, oxidative, and other factors. The associations between these factors with the occurrence of SSNHL and with patient prognosis were analyzed. Low monocyte counts, low neutrophil/lymphocyte ratio (NLR) and monocyte/high-density lipoproteins (HDL) cholesterol ratio (MHR), and low concentrations of fibrinogen, platelet glycoprotein (GP) IIIa, and TNF-α were found to be associated with good prognosis. However, these factors alone could not completely determine the onset of and recovery from SSNHL, suggesting the need for future basic and clinical studies.

Ginger and 6-shogaol protect intestinal tight junction and enteric dopaminergic neurons against 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine in mice.

Objective: Ginger and its compound, 6-shogaol, have been known for improving gastrointestinal (GI) function and reducing inflammatory responses in GI tract. Recently, the treatment of GI dysfunction has been recognized as an important part of the management of neurodegenerative diseases, especially for Parkinson's disease (PD). In this study, we investigated whether ginger and 6-shogaol attenuate disruptions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the intestinal barrier and the enteric dopaminergic neurons.Methods: C57BL/6J mice received MPTP (30 mg/kg) for 5 days to induce GI alterations. Ginger (30, 100, 300 mg/kg) and 6-shogaol (10 mg/kg) were treated by gavage feeding for 15 days including the period of MPTP injection.Results: Ginger and 6-shogaol protected intestinal tight junction proteins disrupted by MPTP in mouse colon. In addition, ginger and 6-shogaol suppressed the increase of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α and IL-1ß activated by macrophage. Moreover, ginger and 6-shogaol suppressed the MPTP-induced enteric dopaminergic neuronal damage via increasing the cell survival signaling pathway.Conclusion: These results indicate that ginger and 6-shogaol restore the disruption of intestinal integrity and enteric dopaminergic neurons in an MPTP-injected mouse PD model by inhibiting the processes of inflammation and apoptosis, suggesting that they may attenuate the GI dysfunction in PD patients.

Comprehensive MicroRNAome Analysis of the Relationship Between Alzheimer Disease and Cancer in PSEN Double-Knockout Mice.

PURPOSE: Presenilins are functionally important components of γ-secretase, which cleaves a number of transmembrane proteins. Manipulations of PSEN1 and PSEN2 have been separately studied in Alzheimer disease (AD) and cancer because both involve substrates of γ-secretase. However, numerous clinical studies have reported an inverse correlation between AD and cancer. Interestingly, AD is a neurodegenerative disorder, whereas cancer is characterized by the proliferation of malignant cells. However, this inverse correlation in the PSEN double-knockout (PSEN dKO) mouse model of AD has been not elucidated, although doing so would shed light onto the relationship between AD and cancer. METHODS: To investigate the inverse relationship of AD and cancer under conditions of PSEN loss, we used the hippocampus of 7-month-old and 18-month-old PSEN dKO mice for a microRNA (miRNA) microarray analysis, and explored the tumorsuppressive or oncogenic role of differentially-expressed miRNAs. RESULTS: The total number of miRNAs that showed changes in expression level was greater at 18 months of age than at 7 months. Most of the putative target genes of the differentially-expressed miRNAs involved Cancer pathways. CONCLUSION: Based on literature reviews, many of the miRNAs involved in Cancer pathways were found to be known tumorsuppressive miRNAs, and their target genes were known or putative oncogenes. In conclusion, the expression levels of known tumor-suppressive miRNAs increased at 7 and 18 months, in the PSEN dKO mouse model of AD, supporting the negative correlation between AD and cancer.

Influence of Early Bisphosphonate Administration for Fracture Healing in Patients with Osteoporotic Proximal Humerus Fractures.

BACKGROUND: Bisphosphonates are generally known to adversely affect fracture healing because they inhibit osteoclastic bone resorption. However, some authors argue that bisphosphonates have no adverse effect on the restoration of the mechanical integrity of long bones after fractures. It is unclear whether bisphosphonates can be initiated safely in patients with acute proximal humerus fractures. The aim of this study was to determine whether the early use of a bisphosphonate affects healing and outcomes of osteoporotic proximal humerus fractures treated with a locking compression plate. METHODS: Between August 2004 and June 2013, a total of 82 osteoporotic patients who underwent locking plate fixation of proximal humerus fractures were enrolled retrospectively. The patients were divided into two groups according to the timing of the commencement of treatment with alendronate after surgery: group A (n = 34, initiation of the bisphosphonate treatment within two weeks after surgery) and group B (n = 48, control group, initiation of the treatment three months after surgery). Patients were assessed for radiographic union at 2, 6, 10, and 16 weeks, 6 months, and 1 year after surgery. Clinical assessments were performed using the Constant score and American Shoulder and Elbow Surgeons (ASES) score at 1 year after surgery. RESULTS: No significant differences were observed between the two groups with respect to radiographic and clinical outcomes after locking plate fixation. All patients obtained fracture union, and the mean time to radiographic union was similar in group A and group B (6.3 and 6.6 weeks, respectively; p = 0.67). CONCLUSIONS: This study shows that the early initiation of bisphosphonate treatment does not affect bone union or clinical outcomes in patients with an osteoporotic proximal humerus fracture treated by locking compression plate fixation.

The Efficacy and Safety of Autologous Transfusion in Unilateral Total Knee Arthroplasty.

PURPOSE: Although allogeneic blood transfusion is the most common method of transfusion in total knee arthroplasty (TKA), there are reports showing significant decrease in the amount of allogeneic transfusion and incidence of side effects after combined use of autologous transfusion. The purpose of this study is to investigate the efficacy of using an autologous transfusion device in TKA. MATERIALS AND METHODS: Patients who underwent TKA at our institution from January 2003 to January 2014 were divided into two groups: group A (n=127) who received allogeneic transfusion only in TKA and group B (n=118) who received autologous transfusion via an autologous transfusion device and allogeneic transfusion. In both groups, the patients were transfused when the hemoglobin level was below 9 g/dL. In group B, blood collected by the autologous transfusion device was transfused only once after surgery. The total blood loss volume, total transfusion volume, and the presence of side effects were assessed based on medical records. RESULTS: Group A received 294.6 mL more allogeneic transfusion than group B (p<0.001). There were no significant differences with regard to the development of side effects between groups. CONCLUSIONS: Application of an autologous transfusion device during TKA can be effective in reducing the allogeneic transfusion volume. Moreover, allogeneic transfusion was not necessary after autologous transfusion in some patients.

Sonoelastography findings of supraspinatus tendon in rotator cuff tendinopathy without tear: comparison with magnetic resonance images and conventional ultrasonography.

BACKGROUND AND PURPOSE: Sonoelastography (SE) is a new technique that can assess differences in tissue stiffness. This study investigated the performance of SE for the differentiation of supraspinatus (SSP) tendon alterations of tendinopathy compared to magnetic resonance imaging (MRI) and conventional ultrasonography (US). METHODS: One hundred and eighteen consecutively registered patients with symptoms and MRI findings of SSP tendinopathy were assessed with US and SE. Coronal images of the SSP tendon were obtained using US and SE. Increased signal intensity on T2-weighted images in the coronal planes were graded according to the extent of the signal changes from ventral to dorsal. SE images were evaluated by reviewers using an experimentally proven color grading system. RESULTS: Using SE, 7.6 % of the SSP tendons were categorized as grade 0, 30.5 % as grade 1, 19.5 % as grade 2, and 42.4 % as grade 3. Evaluation of the interobserver reliability of the SE findings showed "almost perfect agreement", with a weighted kappa coefficient of 0.83. By comparing the MRI findings with the SE findings, grades of MRI and SE had a positive correlation (r = 0.829, p = <0.001). Furthermore, grades of US and SE also had a positive correlation (r = 0.723, p = <0.001). CONCLUSIONS: SE is valuable in the detection of the intratendinous and peritendinous alterations of the SSP tendon and has excellent interobserver reliability and excellent correlation with MRI findings and conventional ultrasonography findings.

The accuracy of sonoelastography in fatty degeneration of the supraspinatus: a comparison of magnetic resonance imaging and conventional ultrasonography.

OBJECTIVE: Sonolastography (SE) technique is one of the new functional ultrasonic imaging techniques, which was developed in the past few years and can obtain the distributions of elasticity in tissues. Using magnetic resonance imaging (MRI) as the standard of reference, the purpose of this study was to evaluate the ability of SE to assess the fatty degeneration of suprasupinatus (SSP) and to compare it to the MRI and the conventional ultrasonography (US) findings. MATERIALS AND METHODS: The institutional review board approved the study, and a retrospective analysis between January 2013 and September 2013 was performed on 101 shoulders of 98 consecutive patients using MRI, US, and SE for the evaluation of shoulder lesion. Oblique sagittal images of SSP were obtained using SE. The SE images were evaluated by reviewers using an experimentally proven color grading system. RESULTS: When comparing SE to standard MRI findings, the mean sensitivity of SE was 95.6 %, the specificity 87.5 %, and the accuracy 91.1 %. The interobserver reliability of the SE findings was "almost perfect agreement" with a weighted kappa coefficient of 0.81. On comparing MRI with the SE findings, the grades of MRI and SE have a positive correlation (r = 0.855, P = <0.001). Furthermore, the grades of US and SE also have a positive correlation (r = 0.793, P = <0.001). CONCLUSION: SE is valuable in the quantitative assessment of the severity of the fatty atrophy of the supraspinatus and has an excellent accuracy, an excellent correlation with MRI and the conventional US, and an excellent interobserver reliability.

Sonoelastography findings of biceps tendinitis and tendinosis.

OBJECTIVE: The purpose of this study was to evaluate sonoelastography (SE) in the assessment of the long head of biceps tendon (LHBT) in patients with symptoms of biceps tendinitis or tendinosis and in patients without biceps lesion. The findings were compared with those obtained at clinical examination, using ultrasonography (US). MATERIALS AND METHODS: 36 shoulders of 34 consecutively registered patients with clinical symptoms and US findings of biceps tendinitis or tendinosis, and 114 shoulders of 98 patients without biceps lesions were assessed with SE. Transverse and longitudinal images of LHBT were obtained using SE. SE images were evaluated by reviewers using an experimentally proven color grading system. RESULTS: The transverse images of SE showed a mean sensitivity of 69.4 %, a mean specificity of 95.6 % and a mean accuracy of 89.3 %. Good correlation of conventional ultrasound findings was found (p < 0.001, r = 0.763). The longitudinal images of SE showed a mean sensitivity of 94.4 %, a mean specificity of 92.1 % and a mean accuracy of 92.7 %. Good correlation of conventional ultrasound findings was found (p < 0.001, r = 0.585). Inter-observer reliability of SE was in "almost perfect agreement" with a weighted kappa coefficient of 0.84. CONCLUSIONS: SE has potential to be clinically useful in the detection of the intratendinous and peritendinous alterations of LHBT and has excellent accuracy and excellent correlation with conventional ultrasound findings.