The Pathological Role of Astrocytic MAOB in Parkinsonism Revealed by Genetic Ablation and Over-expression of MAOB

The cause of Parkinson’s disease has been traditionally believed to be the dopaminergic neuronal death in the substantia nigra pars compacta (SNpc).This traditional view has been recently challenged by the proposal that reactive astrocytes serve as key players in the pathology of Parkinson’s disease through excessive GABA release. This aberrant astrocytic GABA is synthesized by the enzymatic action of monoamine oxidase B (MAOB), whose pharmacological inhibition and gene-silencing are reported to significantly alleviate parkinsonian motor symptoms in animal models of Parkinson’s disease. However, whether genetic ablation and over-expression of MAOB can bidirectionally regulate parkinsonian motor symptoms has not been tested. Here we demonstrate that genetic ablation of MAOB blocks the MPTP-induced augmentation of astrocytic GABA-mediated tonic inhibition of neighboring dopaminergic neurons as well as parkinsonian motor symptoms, indicating the necessity of MAOB for parkinsonian motor symptoms. Furthermore, we demonstrate that GFAP-MAOB transgenic mice, in which MAOB is over-expressed under the GFAP promoter for astrocyte-specific over-expression, display exacerbated MPTP-induced tonic inhibition and parkinsonian motor symptoms compared to wild-type mice, indicating the importance of astrocytic MAOB for parkinsonian motor symptoms. Our study provides genetic pieces of evidence for the causal link between the pathological role of astrocytic MAOB-dependent tonic GABA synthesis and parkinsonian motor symptoms.

The Pathological Role of Astrocytic MAOB in Parkinsonism Revealed by Genetic Ablation and Over-expression of MAOB

The cause of Parkinson’s disease has been traditionally believed to be the dopaminergic neuronal death in the substantia nigra pars compacta (SNpc).This traditional view has been recently challenged by the proposal that reactive astrocytes serve as key players in the pathology of Parkinson’s disease through excessive GABA release. This aberrant astrocytic GABA is synthesized by the enzymatic action of monoamine oxidase B (MAOB), whose pharmacological inhibition and gene-silencing are reported to significantly alleviate parkinsonian motor symptoms in animal models of Parkinson’s disease. However, whether genetic ablation and over-expression of MAOB can bidirectionally regulate parkinsonian motor symptoms has not been tested. Here we demonstrate that genetic ablation of MAOB blocks the MPTP-induced augmentation of astrocytic GABA-mediated tonic inhibition of neighboring dopaminergic neurons as well as parkinsonian motor symptoms, indicating the necessity of MAOB for parkinsonian motor symptoms. Furthermore, we demonstrate that GFAP-MAOB transgenic mice, in which MAOB is over-expressed under the GFAP promoter for astrocyte-specific over-expression, display exacerbated MPTP-induced tonic inhibition and parkinsonian motor symptoms compared to wild-type mice, indicating the importance of astrocytic MAOB for parkinsonian motor symptoms. Our study provides genetic pieces of evidence for the causal link between the pathological role of astrocytic MAOB-dependent tonic GABA synthesis and parkinsonian motor symptoms.

Altered Mitochondrial Functions and Morphologies in Epithelial Cells Are Associated With Pathogenesis of Chronic Rhinosinusitis With Nasal Polyps

Purpose@#Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory disease of the nasal and paranasal sinus mucosa. The disease is associated with mitochondrial dysfunction, structural changes in the mitochondria, and reactive oxygen species (ROS) generation. This study investigated whether there are functional and morphological changes in the mitochondria in the epithelial cells of nasal polyps (NPs) and Staphylococcus aureus enterotoxin B (SEB)-stimulated nasal epithelial cells. @*Methods@#In all, 30 patients with CRSwNP and 15 healthy subjects were enrolled. Mitochondrial ROS (mtROS) and changes in mitochondrial functions and structures were investigated in the uncinate tissue (UT) of healthy controls, the UT or NPs of CRSwNP patients, and human nasal epithelial cells with or without SEB stimulation. @*Results@#Oxidative phosphorylation complexes showed various responses following SEB stimulation in the nasal epithelial cells, and their expressions were significantly higher in the NPs of patients with CRSwNP than in the UT of controls. Generation of mtROS was increased following SEB exposure in nasal epithelial cells and was reduced by pretreatment with MitoTEMPO, which is used as an mtROS scavenger. In the tissues, mtROS was significantly increased in the NPs of CRSwNP patients compared to the UT of controls or CRSwNP patients. The expressions of fusion- and fission-related molecules were also significantly higher in SEB-exposed nasal epithelial cells than in non-exposed cells. In tissues, the expression of fission (fission mediator protein 1)- and fusion (membrane and mitofusin-1, and optic atrophy protein 1)-related molecules was significantly higher in the NPs of CRSwNP patients than in UT of controls or CRSwNP patients. Transmission electron microscopy revealed elongated mitochondria in SEB-exposed nasal epithelial cells and epithelial cells of NPs. @*Conclusions@#Production of mtROS, disrupted mitochondrial function, and structural changes in nasal epithelial cells might be involved in the pathogenesis of CRSwNP.

Altered Mitochondrial Functions and Morphologies in Epithelial Cells Are Associated With Pathogenesis of Chronic Rhinosinusitis With Nasal Polyps

Purpose@#Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory disease of the nasal and paranasal sinus mucosa. The disease is associated with mitochondrial dysfunction, structural changes in the mitochondria, and reactive oxygen species (ROS) generation. This study investigated whether there are functional and morphological changes in the mitochondria in the epithelial cells of nasal polyps (NPs) and Staphylococcus aureus enterotoxin B (SEB)-stimulated nasal epithelial cells. @*Methods@#In all, 30 patients with CRSwNP and 15 healthy subjects were enrolled. Mitochondrial ROS (mtROS) and changes in mitochondrial functions and structures were investigated in the uncinate tissue (UT) of healthy controls, the UT or NPs of CRSwNP patients, and human nasal epithelial cells with or without SEB stimulation. @*Results@#Oxidative phosphorylation complexes showed various responses following SEB stimulation in the nasal epithelial cells, and their expressions were significantly higher in the NPs of patients with CRSwNP than in the UT of controls. Generation of mtROS was increased following SEB exposure in nasal epithelial cells and was reduced by pretreatment with MitoTEMPO, which is used as an mtROS scavenger. In the tissues, mtROS was significantly increased in the NPs of CRSwNP patients compared to the UT of controls or CRSwNP patients. The expressions of fusion- and fission-related molecules were also significantly higher in SEB-exposed nasal epithelial cells than in non-exposed cells. In tissues, the expression of fission (fission mediator protein 1)- and fusion (membrane and mitofusin-1, and optic atrophy protein 1)-related molecules was significantly higher in the NPs of CRSwNP patients than in UT of controls or CRSwNP patients. Transmission electron microscopy revealed elongated mitochondria in SEB-exposed nasal epithelial cells and epithelial cells of NPs. @*Conclusions@#Production of mtROS, disrupted mitochondrial function, and structural changes in nasal epithelial cells might be involved in the pathogenesis of CRSwNP.

Local Injection of Growth Hormone for Temporomandibular Joint Osteoarthritis

PURPOSE: Osteoarthritis (OA) of the temporomandibular joint (TMJ) elicits cartilage and subchondral bone defects. Growth hormone (GH) promotes chondrocyte growth. The aim of this study was to evaluate the efficacy of intra-articular injections of GH to treat TMJ-OA.MATERIALS AND METHODS: Monosodium iodoacetate (MIA) was used to induce OA in the TMJs of rats. After confirming the induction of OA, recombinant human GH was injected into the articular cavities of rats. Concentrations of GH and IGF-1 were measured in the blood and synovial fluid, and OA grades of cartilage and subchondral bone degradation were recorded by histological examination and micro-computed tomography.RESULTS: MIA-induced OA in the rat TMJ upregulated insulin-like growth factor-1 (IGF-1) rather than GH levels. GH and IGF-1 concentrations were increased after local injection of GH, compared with controls. Locally injected GH lowered osteoarthritic scores in the cartilage and subchondral bone of the TMJ.CONCLUSION: Intra-articular injection of GH improved OA scores in rat TMJs in both cartilage and subchondral bone of the condyles without affecting condylar bone growth. These results suggest that intra-articular injection of human GH could be a suitable treatment option for TMJ-OA patients in the future.

Adenine attenuates lipopolysaccharide-induced inflammatory reactions

A nucleobase adenine is a fundamental component of nucleic acids and adenine nucleotides. Various biological roles of adenine have been discovered. It is not produced from degradation of adenine nucleotides in mammals but produced mainly during polyamine synthesis by dividing cells. Anti-inflammatory roles of adenine have been supported in IgE-mediated allergic reactions, immunological functions of lymphocytes and dextran sodium sulfate-induced colitis. However adenine effects on Toll-like receptor 4 (TLR4)-mediated inflammation by lipopolysaccharide (LPS), a cell wall component of Gram negative bacteria, is not examined. Here we investigated anti-inflammatory roles of adenine in LPS-stimulated immune cells, including a macrophage cell line RAW264.7 and bone marrow derived mast cells (BMMCs) and peritoneal cells in mice. In RAW264.7 cells stimulated with LPS, adenine inhibited production of pro-inflammatory cytokines TNF-α and IL-6 and inflammatory lipid mediators, prostaglandin E₂ and leukotriene B₄. Adenine impeded signaling pathways eliciting production of these inflammatory mediators. It suppressed IκB phosphorylation, nuclear translocation of nuclear factor κB (NF-κB), phosphorylation of Akt and mitogen activated protein kinases (MAPKs) JNK and ERK. Although adenine raised cellular AMP which could activate AMP-dependent protein kinase (AMPK), the enzyme activity was not enhanced. In BMMCs, adenine inhibited the LPS-induced production of TNF-α, IL-6 and IL-13 and also hindered phosphorylation of NF-κB and Akt. In peritoneal cavity, adenine suppressed the LPS-induced production of TNF-α and IL-6 by peritoneal cells in mice. These results show that adenine attenuates the LPS-induced inflammatory reactions.

A High-fat Diet Induces a Loss of Midbrain Dopaminergic Neuronal Function That Underlies Motor Abnormalities

Movement defects in obesity are associated with peripheral muscle defects, arthritis, and dysfunction of motor control by the brain. Although movement functionality is negatively correlated with obesity, the brain regions and downstream signaling pathways associated with movement defects in obesity are unclear. A dopaminergic neuronal pathway from the substantia nigra (SN) to the striatum is responsible for regulating grip strength and motor initiation through tyrosine hydroxylase (TH) activity-dependent dopamine release. We found that mice fed a high-fat diet exhibited decreased movement in open-field tests and an increase in missteps in a vertical grid test compared with normally fed mice. This motor abnormality was associated with a significant reduction of TH in the SN and striatum. We further found that phosphorylation of c-Jun N-terminal kinase (JNK), which modulates TH expression in the SN and striatum, was decreased under excess-energy conditions. Our findings suggest that high calorie intake impairs motor function through JNK-dependent dysregulation of TH in the SN and striatum.

Tryptophan Negatively Regulates IgE-mediated Mast Cell Activation / 체질인류학회지

Mast cells are major immune cells in allergy to secrete allergic mediators by a degranulation process and make and secrete inflammatory lipids and cytokines in response to antigen stimulation. An amino acid tryptophan regulates immune functions. Tryptophan ameliorates inflammatory colitis in which mast cells are engaged. However, its effects on mast cells remain to be solved. We investigated the effect of tryptophan on IgE-mediated allergic responses in the mast cells and mice. IgE-mediated passive cutaneous anaphylaxis (PCA) in mice were examined. Also IgE-mediated mast cell activation responses such as degranulation of stored granules and secretion of inflammatory lipid LTB₄ and cytokines (TNF-α and IL-4) were measured. Intraperitoneal administration of tryptophan suppressed PCA in mice. Also, in the cellular level tryptophan inhibited IgE-mediated mast cell activation such as IgE-mediated degranulation and the production of LTB₄. Also, it inhibited production of inflammatory cytokines TNF-α and IL-4. In summary, tryptophan suppressed IgE-mediated allergic activation in vivo and in vitro. Tryptophan supplementation is beneficial for IgE-mediated allergy.

Management for traumatic neuropathy after dental treatment

Whereas a somatic pain notifies tissue damage, a neuropathic pain presents disorder of the nerve itself. The causes of neuropathic pains are trauma, infection, chronic irritation by adjacent tissue and so on. The iatrogenic trauma or infection also causes traumatic neuropathy, which may exert a bad influence on doctor-patient relationship. Some of related dental treatments are implantation (directly or indirectly through heating), root canal treatment, teeth extraction, block anesthesia, mandibular surgery. If inappropriate management is performed after nerve trauma, there will be many chances to develop chronic neuropathy for the patient. It is important that the sign of nerve trauma have to be caught by the practitioner as soon as possible and treated properly.

Drusini's and Takei's Methods for Age Estimation in Korean Adults / 대한법의학회지

Estimation of an individual's age has received considerable attention in forensic science. Several methods have been described, and abundant results have been obtained and evaluated. Among the numerous methods for dental age prediction in adults, the progressive diminution of the coronal pulp cavity and dental attrition have been primarily used. Although the reliability of age estimation methods using teeth has been demonstrated, correlation between methods has not been reported. Therefore, the aim of this study was to evaluate concurrence between Drusini's methods. We reanalyzed the age of 107 patients (64 male, 43 female) using Drusini's method. The ages had been previously estimated as ranging from 24 to 69 years using Takei's method. Our results revealed a strong correlation between the two methods (r=0.762) and suggest both methods to be suitable for application in Korean individuals younger than 50 years old. A previous study has shown Takei's and Drusini's methods to be reliable for forensic purposes. The strong correlation between the two methods in the present study suggests that it would be reasonable to use the most appropriate method for age estimation dependent on oral state.

A Case of Cochlear Implantation in a Postligual Deaf Patient with Osteogenesis Imperfecta / 대한이비인후과학회지

Osteogenesis imperfecta is a systemic heritable disorder of connective tissues with the predominant manifestation of spontaneous bone fractures. It features an abnormal biosynthesis of collagen with the formation of pathologic, immature collagen, resulting in a triad of brittle bones, blue sclera and hearing impairment. A 39-year-old woman with osteogenesis imperfecta began noticing hearing loss as a teenager. At the time of her presentation, she was aided by a hearing aid, which she had been using for 25 years but had not been benefited from. Her temporal CT shows severe otospongiosis, with radiolucent bone surrounding the cochlea. The patient underwent cochlear implantation to her left ear with no postoperative complication. She has obtained significant hearing improvement after the cochlear implantation. Cochlear implantation in cases of osteogenesis imperfecta with otospongiosis appears to be extremely rare and we present this case with a review of the related literature.

Two Cases of Spontaneous Cerebrospinal Fluid Rhinorrhea by Idiopathic Bony Defects / 대한이비인후과학회지

Cerebrospinal fluid rhinorrhea can be caused by head trauma, brain or sinus surgery or neoplastic sinonasal disease. In addition, CSF rhinorrhea may develop spontaneously in some cases. We experienced two cases of spontaneous CSF rhinorrhea caused by idiopathic bony defect. The first case was a 47-year old female who complained of a persistent rhinorrhea for 2 months without surgical or traumatic history. The second case was a 40-year old female. Having no surgical or traumatic history, she also suffered from a persistent rhinorrhea for thirteen years. For diagnosis of CSF rhinorrhea, we carried out endoscopic examination, glucose test of rhinorrhea, computed tomograph, magnetic resonance imaging and (99m)Tc-DTPA cisternography. We found bony defect in the cribriform plate of the two cases. Patients were treated successfully with endoscopic approach. Leak sites were repaired with free graft materials. There has not been any recurrence or complications since the endoscopic closure.

The Significance of Radiologic Positive Finding of Paranasal Sinus in Bone Marrow Transplant Patients

BACKGROUND: Bone marrow transplantation (BMT) is a beneficial and curative technique used in different hematologic conditions or malignant neoplastic diseases. However, bone marrow transplant patients are at a higher risk of developing infections and complications due to previous chemotherapy, radiotherapy, immunosuppression, antibiotics therapy, multiple viral infections, and GVHD (graft-versus-host disease). OBJECTIVES: The purpose of this study is to determine the prevalence and clinical data of rhinosinusitis among patients with BMT. We also investigated whether pre-BMT positive radiologic finding could predispose patients to the development of post-BMT rhinosinusitis or not. MATERIALS AND METHODS: We reviewed the records of 203 patients who had received BMT in Kyungpook National University's hospital from September 1998 to August 2006. RESULT: Sixteen patients (7.8%) had radiologic positive finding before BMT. Fifteen patients had no sinonasal symptoms and did not get any treatment. Only one patient had rhinosinusitis so that BMT was delayed and treated with antibiotics. Among these patients, one patient got newly developed rhinosinusitis after BMT. After BMT, sinusitis developed in ten patients (4.9%), including one patient who had invasive fungal sinusitis. Our study revealed a higher incidence of rhinosinusitis among allogenic BMT patients than among autologous BMT patients. The most common symptoms and signs were fever. Only one patient complained of typical sinonasal symptoms. CONCLUSION: Even though the prevalence of rhinosinusitis is low (4.9%) among post-BMT patients, maintenance of a high index of suspicion among these patients is necessary because sinonasal symptoms and signs are generally minimized after BMT. The study concluded that pre-BMT positive radiologic findings without sinonasal symptoms is unlikely to develop post-BMT rhinosinusitis.