Conformation-specific Antibodies Targeting Aggregated Forms of α-synuclein Block the Propagation of Synucleinopathy

Abnormal aggregation of α-synuclein is a key element in the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy. α-synuclein aggregation spreads through various brain regions during the course of disease progression, a propagation that is thought to be mediated by the secretion and subsequent uptake of extracellular α-synuclein aggregates between neuronal cells. Thus, aggregated forms of this protein have emerged as promising targets for disease-modifying therapy for PD and related diseases. Here, we generated and characterized conformation-specific antibodies that preferentially recognize aggregated forms of α-synuclein. These antibodies promoted phagocytosis of extracellular α-synuclein aggregates by microglial cells and interfered with cell-to-cell propagation of α-synuclein. In an α-synuclein transgenic model, passive immunization with aggregate-specific antibodies significantly ameliorated pathological phenotypes, reducing α-synuclein aggregation, gliosis, inflammation, and neuronal loss. These results suggest that conformation-specific antibodies targeting α-synuclein aggregates are promising therapeutic agents for PD and related synucleinopathies.

Overcoming Current Dilemma in Cartilage Regeneration: Will Direct Conversion Provide a Breakthrough?

Direct reprogramming/direct conversion/transdifferentiation is a process that induces conversion between completely different matured (differentiated) cells in higher organisms. Unlike the process of reprogramming of differentiated cells into induced pluripotent stem cells (iPSCs) and re-differentiation into the desired cell types, differentiated cells undergo the conversion into another type of differentiated cells without going through the iPSCs state. Osteoarthritis (OA) is the most common type of arthritis that causes a significant deterioration in patients’ quality of life. The high prevalence of OA as well as the current lack of disease-modifying drugs has led to a rise in regenerative strategy for OA treatment. Regenerative therapy in OA started with the concept of engraftment of the administered cells within the cartilage lesion and differentiation to chondrocytes after the engraftment. However, recent studies show that cells, particularly when injected in suspension, rapidly undergo apoptosis after exerting a transient paracrine effect. In this perspective review, the general overview and current status of direct conversion are introduced along with the conceptual strategy and future directions for possible application of regenerative therapy using stem cells in OA. In vivo direct conversion may open a new stage of regenerative medicine for OA treatment. Recent advances in in vivo gene transfer and smart biomaterials can bring the concept into reality in near future. Direct conversion can be a new type of treatment technology that has the potential to overcome the limitations of current cell therapy.

Stem Cells for the Regeneration of Tendon and Ligament: A Perspective

Tendons are structures that connect muscles to the bones in our body and transmit the force generated by contraction of the muscles to the bones. Ligaments are structures that connect bones to bones, with histological properties similar to tendons. In tendon and ligament tissue, there are very small amounts of cells similar to mesenchymal stem cells (MSCs) called tendon stem/progenitor cells (TSPCs), or tenogenic stem cells. While the role of specific growth factors and transcription factors is well established in the osteogenic and chondrogenic differentiation of stem cells, a consensus has not been established for tenogenic differentiation. Injuries to tendons and ligaments are very common, but natural healing is very slow and inefficient due to limited vascularization. Currently, there is no adequate method for restoring extensive tendon or ligament defects. Procedures addressing the unmet need for regeneration of these tissues are needed. In this review, the current knowledge, as well as the authors’ ideas and perspective on stem cell and regenerative medicine for tendon and ligament defects are presented.

Regenerative Therapy for Osteoarthritis: A Perspective

Osteoarthritis (OA) is the most common type of arthritis and causes a significant deterioration in patients’ quality of life. The high prevalence of OA as well as the current lack of disease-modifying drugs led to a rise in regenerative medicine efforts. The hope is that this will provide a treatment modality with the ability to alter the course of OA via structural modifications of damaged articular cartilage (AC). Regenerative therapy in OA starts with the concept that administered cells may engraft to a lesion site and differentiate into chondrocytes. However, recent studies show that cells, particularly when injected in suspension, rapidly undergo apoptosis after exerting a transient paracrine effect. If the injected stem cells do not lead to structural improvements of a diseased joint, the high cost of cell therapy for OA cannot be justified, particularly when compared with other injection therapeutics such as corticosteroids and hyaluronic acid. Long-term survival of implanted cells that offer prolonged paracrine effects or possible engraftment is essential for a successful cell therapy that will offer durable structural improvements. In this perspective review, the history and current status of regenerative therapy in OA are summarized along with the conceptual strategy and future directionsfor a successful regenerative therapy that can provide structural modifications in OA.

Overcoming Current Dilemma in Cartilage Regeneration: Will Direct Conversion Provide a Breakthrough?

Direct reprogramming/direct conversion/transdifferentiation is a process that induces conversion between completely different matured (differentiated) cells in higher organisms. Unlike the process of reprogramming of differentiated cells into induced pluripotent stem cells (iPSCs) and re-differentiation into the desired cell types, differentiated cells undergo the conversion into another type of differentiated cells without going through the iPSCs state. Osteoarthritis (OA) is the most common type of arthritis that causes a significant deterioration in patients’ quality of life. The high prevalence of OA as well as the current lack of disease-modifying drugs has led to a rise in regenerative strategy for OA treatment. Regenerative therapy in OA started with the concept of engraftment of the administered cells within the cartilage lesion and differentiation to chondrocytes after the engraftment. However, recent studies show that cells, particularly when injected in suspension, rapidly undergo apoptosis after exerting a transient paracrine effect. In this perspective review, the general overview and current status of direct conversion are introduced along with the conceptual strategy and future directions for possible application of regenerative therapy using stem cells in OA. In vivo direct conversion may open a new stage of regenerative medicine for OA treatment. Recent advances in in vivo gene transfer and smart biomaterials can bring the concept into reality in near future. Direct conversion can be a new type of treatment technology that has the potential to overcome the limitations of current cell therapy.

Isolated Focal Cortical Infarction in a Patient with Churg-Strauss Syndrome

No abstract available.

Physical Exercise Counteracts Stress-induced Upregulation of Melanin-concentrating Hormone in the Brain and Stress-induced Persisting Anxiety-like Behaviors

Chronic stress induces anxiety disorders, whereas physical exercise is believed to help people with clinical anxiety. In the present study, we investigated the mechanisms underlying stress-induced anxiety and its counteraction by exercise using an established animal model of anxiety. Mice treated with restraint for 2 h daily for 14 days exhibited anxiety-like behaviors, including social and nonsocial behavioral symptoms, and these behavioral impairments lasted for more than 12 weeks after the stress treatment was removed. Despite these lasting behavioral changes, wheel-running exercise treatment for 1 h daily from post-stress days 1 - 21 counteracted anxiety-like behaviors, and these anxiolytic effects of exercise persisted for more than 2 months, suggesting that anxiolytic effects of exercise stably induced. Repeated restraint treatment up-regulated the expression of the neuropeptide, melanin-concentrating hormone (MCH), in the lateral hypothalamus, hippocampus, and basolateral amygdala, the brain regions important for emotional behaviors. In an in vitro study, treatment of HT22 hippocampal cells with glucocorticoid increased MCH expression, suggesting that MCH upregulation can be initially triggered by the stress hormone, corticosterone. In contrast, post-stress treatment with wheel-running exercise reduced the stress-induced increase in MCH expression to control levels in the lateral hypothalamus, hippocampus and basolateral amygdala. Administration of an MCH receptor antagonist (SNAP94847) to stress-treated mice was therapeutic against stress-induced anxiety-like behaviors. These results suggest that repeated stress produces long-lasting anxiety-like behaviors and upregulates MCH in the brain, while exercise counteracts stress-induced MCH expression and persisting anxiety-like behaviors.

Functional Connectivity of Basolateral Amygdala Neurons Carrying Orexin Receptors and Melanin-concentrating Hormone Receptors in Regulating Sociability and Mood-related Behaviors

Chronic stress induces changes in neuronal functions in specific brain regions regulating sociability and mood-related behaviors. Recently we reported that stress-induced persistent upregulation of the neuropeptides orexin and melanin-concentrating hormone (MCH) in the basolateral amygdala (BLA) and the resulting activation of orexin receptors or MCH receptors within the BLA produced deficits in sociability and mood-related behaviors. In the present study, we investigated the neural targets that were innervated by BLA neurons containing orexin receptors or MCH receptors. The viral vector system AAV2-CaMKII-ChR2-eYFP was injected into the BLA to trace the axonal tracts of BLA neurons. This axon labeling analysis led us to identify the prelimbic and infralimbic cortices, nucleus accumbens (NAc), dorsal striatum, paraventricular nucleus (PVN), interstitial nucleus of the posterior limb of the anterior commissure, habenula, CA3 pyramidal neurons, central amygdala, and ventral hippocampus as the neuroanatomical sites receiving synaptic inputs of BLA neurons. Focusing on these regions, we then carried out stimulus-dependent c-Fos induction analysis after activating orexin receptors or MCH receptors of BLA neurons. Stereotaxic injection of an orexin receptor agonist or an MCH receptor agonist in the BLA induced c-Fos expression in the NAc, PVN, central amygdala, ventral hippocampus, lateral habenula and lateral hypothalamus, which are all potentially important for depression-related behaviors. Among these neural correlates, the NAc, PVN and central amygdala were strongly activated by stimulation of orexin receptors or MCH receptors in the BLA, whereas other BLA targets were differentially and weakly activated. These results identify a functional connectivity of BLA neurons regulated by orexin and MCH receptor systems in sociability and mood-related behaviors.

Ischemic Stroke with Extracranial Internal Carotid Artery Occlusion in Essential Thrombocythemia with JAK-2 Mutation

In essential thrombocythemia (ET), cerebral infarction with large cerebral artery occlusion has rarely been reported. A 53-year-old male was admitted with left sided weakness. Brain magnetic resonance images revealed right internal carotid artery (ICA) territory infarction and proximal ICA occlusion. The blood laboratory examination demonstrated continuously increased platelet count (above 617,000/µL). Increased megakaroycytes and JAK2 V617F mutation were confirmed in the bone marrow biopsy. We should consider the possibility of ET in patient with large artery thrombosis and thrombocythemia.

Acute disseminated encephalomyelitis with tremor as the initial symptom

Multiple neurological deficits can occur in acute disseminated encephalomyelitis (ADEM) but rarely movement disorders. A 24-year-old female patient was admitted because of tremor in bothupper limbs. After admission, her mental status progressively declined into coma. Brain magnetic resonance imaging and cerebrospinal fluid analysis were compatible with ADEM. Tests for central nervous system infection and autoimmune diseases were all negative. She was given steroid and IVIG, and the patient fully improved. We report here the first case of adult ADEM, who presented with tremor as the initial neurological manifestation.

Physiological Parameters in the Blood of a Murine Stress-Induced Depression Model before and after Repeated Passive Exercise

BACKGROUND: Animal models are necessary to study the mechanism underlying the effects of exercise on depression but an effective procedure for exercise treatment and exercise effects on physiological parameters in a specific depression model need to be characterized. METHODS: Physiological parameters including lactate, partial pressue of O2 (pO2) and CO2 (pCO2) saturated O2 (sO2), pH, HCO3, total CO2 (TCO2), and base excess extracellular fluid (BEecf) levels in the blood were measured after treatment with passive exercise in normal mice and a stress-induced depression model. RESULTS: Normal mice or mice that were subjected to daily 2-hour restraint for 14 days (2 hoursx14 days of restraint) were placed on a running wheel that was rotating at a speed of 9 m/min for 1 hour per day for 1 to 21 days. After repeated exercise in mice that were previously subjected to 2 hoursx14 days restraint, plasma lactate levels decreased, the levels of pO2, sO2, and pH tended to increase, and the levels of pCO2 decreased in the absence of significant changes in HCO3, TCO2, and BEecf. However, none of these changes were additive to the stress effects or were much more severe than those induced after repeated passive exercise in normal mice. CONCLUSION: These results suggest that passive exercise for 1 hour daily for 14 to 21 consecutive days on a running wheel rotating at a speed of 9 m/min may be used as an exercise protocol without inducing severe additive effects on physiological burdens.

Corrigendum to "Affecting Fatigue in Patients with Type II Diabetes Mellitus in Korea" Asian Nurs Res 9 (2015) 60-64

The author regrets that the second author's name should read Jong Ryeal Hahm as shown here, not Jong-Ryeal Hahm as in the original version.

Factors Affecting Fatigue in Patients with Type II Diabetes Mellitus in Korea

PURPOSE: This study aimed to characterize and identify the factors affecting fatigue in patients with type II diabetes mellitus in Korea. METHODS: A total of 180 patients with type II diabetes mellitus were recruited from the outpatient clinic of a tertiary care hospital. For data collection, a questionnaire survey of diabetes history, hypoglycemia symptoms, and fatigue was conducted between January and February 2011. Data were analyzed using t test, analysis of variance, Pearson's correlation, and hierarchical multiple regression. RESULTS: The mean fatigue and hypoglycemia symptom scores of patients with type II diabetes mellitus were 2.88 +/- 0.61 and 6.18 +/- 12.60, respectively. Hypoglycemia symptoms (p = .004), disease duration (p < .001), and age (p < .001) correlated positively with fatigue. Hierarchical multiple regression analysis revealed that hypoglycemia symptoms was the variable positively influencing fatigue in patients with type II diabetes mellitus after adjustment for influences of demographic and clinical characteristic variables. CONCLUSIONS: Hypoglycemia symptoms were confirmed to be a predictor of fatigue. Consequently, it is essential to consider age, and disease duration as well as hypoglycemia symptoms to intervene fatigue effectively among patients with type II diabetes mellitus.

Implementation of a Two-dimensional Behavior Matrix to Distinguish Individuals with Differential Depression States in a Rodent Model of Depression

Animal models of depression are used to study pathophysiology of depression and to advance therapeutic strategies. Stress-induced depression models in rodents are widely used. However, amenable behavioral criteria and experimental procedures that are suitable for animal models have not been established. Given that depression is clinically diagnosed by multiple symptomatic criteria and stress effects are imposed to the brain non-specifically in stress-induced depression models, analyses of depression states in rodents using multiple symptomatic criteria may provide more power than any methods relying on a single symptomatic criterion. To address this, C57BL/6 inbred mice were restrained for 2 h daily for 14 d, and depression states of individual mice were assessed using the U-field test, behavioral assessment developed to measure animal's sociability, and the tail suspension test and/or forced swim test, which are the typical methods that measure psychomotor withdrawal states. Although the majority of these mice showed severe depressive behaviors in both tests, a significant proportion of them, which were all inbred mice and received the same amount of restraints, expressed differential depression states in the sociability test and psychomotor withdrawal tests. To easily read-out differential depression states of individuals in two different tests, a standard method and basic parameters required to construct two-way behavior matrix were introduced. The utility and features of this two-way behavior analysis method for studies of different depressive states of individuals were discussed.

Importance of the Time Interval between Bowel Preparation and Colonoscopy in Determining the Quality of Bowel Preparation for Full-Dose Polyethylene Glycol Preparation

BACKGROUND/AIMS: The quality of bowel preparation (QBP) is the important factor in performing a successful colonoscopy. Several factors influencing QBP have been reported; however, some factors, such as the optimal preparation-to-colonoscopy time interval, remain controversial. This study aimed to determine the factors influencing QBP and the optimal time interval for full-dose polyethylene glycol (PEG) preparation. METHODS: A total of 165 patients who underwent colonoscopy from June 2012 to August 2012 were prospectively evaluated. The QBP was assessed using the Ottawa Bowel Preparation Scale (Ottawa) score according to several factors influencing the QBP were analyzed. RESULTS: Colonoscopies with a time interval of 5 to 6 hours had the best Ottawa score in all parts of the colon. Patients with time intervals of 6 hours or less had the better QBP than those with time intervals of more than 6 hours (p=0.046). In the multivariate analysis, the time interval (odds ratio, 1.897; 95% confidence interval, 1.006 to 3.577; p=0.048) was the only significant contributor to a satisfactory bowel preparation. CONCLUSIONS: The optimal time was 5 to 6 hours for the full-dose PEG method, and the time interval was the only significant contributor to a satisfactory bowel preparation.

Perioperative Risk Assessment in Patients Aged 75 Years or Older: Comparison between Bilateral and Unilateral Total Knee Arthroplasty

PURPOSE: The purpose of this study is to evaluate the risk of sequential bilateral total knee arthroplasty (TKA) under 1 anesthesia in patients 75 years or older. MATERIALS AND METHODS: Patients aged 75 years or older who underwent sequential bilateral TKA (bilateral group, n=159) and unilateral TKA (unilateral group, n=159) between 2002 and 2012 were selected. All patients were evaluated for underlying medical diseases, such as cardiac, pulmonary, and renal problems, and high-risk patients were recommended to postpone the surgery. We compared the underlying diseases, major postoperative complications, and the length of hospital stay between bilateral and unilateral groups. RESULTS: The prevalence of underlying diseases of the bilateral group was 74.8% and major complications occurred in 6 patients (3.8%). The prevalence of underlying diseases of the unilateral group was 52.4% and complications were observed in 4 patients (2.4%). Although the complication rate of the bilateral group was slightly higher than that of the unilateral group, the difference was not statistically meaningful (p=0.204). The length of hospital stay was 21.9 days for the bilateral group and 24.9 days for the unilateral group. CONCLUSIONS: There was no significant difference in postoperative complications between groups. The result shows that bilateral TKA can be relatively safe compared with unilateral TKA in patients 75 years or older. However, careful selection of low-risk patients is advised.

Large Cavernous Hemangioma of the Subscapularis Muscle: A Case Report

We report a case of intramuscular hemangioma in the subscapularis muscle and the resulting impairment of shoulder function in an adult patient. A nineteen-year-old female complained of shoulder pain and the development of a mass in the absence of previous trauma. Physical examinations, including lift-off and belly-press tests, showed abnormality. X-ray showed multiple calcifications in the front of the scapula. Magnetic resonance imaging showed a soft-tissue mass occupying almost the entire intramuscular portion of the subscapularis muscle. An arthroscopic examination excluded the possibility of a joint invasion, after which the entire mass was successfully removed by open excision. The displacement of the subscapularis by the mass was relieved after the surgery. Pathological diagnosis of the tissue confirmed a cavernous hemangioma. Both shoulder pain and function was improved after operation. There was no evidence of recurrence even at the 2-year follow-up. Rare forms of hemangioma adjacent to the shoulder joint could be successfully managed with surgical excision. Differential diagnosis, such as synovial chondromatosis, pigmented villonodular synovitis, and malignant sarcoma, should also be considered.

Intramedullary Nailing of Distal Tibial Fractures with Percutaneous Reduction by Pointed Reduction Forceps

PURPOSE: The purpose of this study is to analyze the radiographic and clinical results of intramedullary nailing after percutaneous reduction using pointed reduction forceps for spiral or oblique fractures of the distal tibia. The benefit of percutaneous reduction using pointed reduction forceps in anatomical reduction and maintenance was assessed. MATERIALS AND METHODS: From January 2005 to December 2009, 47 cases of distal one-third tibial fracture were managed by intramedullary nailing using pointed reduction forceps. Thirty-eight cases were spiral fracture and nine cases were oblique fracture. In all cases, the percutaneous reduction was achieved using pointed reduction forceps under fluoroscopy control. While maintaining the reduction with the pointed reduction forceps, the intramedullary nail was inserted. The pointed reduction forceps were removed after insertion of proximal and distal inter-locking screws. Alignment was evaluated with anterior-posterior and lateral radiographs taken immediately post-operation and at the time of union. RESULTS: At immediate post-operation, the mean displacement of valgus and anterior angulation was 0.57degrees and 0.24degrees, respectively. That of valgus and anterior angulation at bone union was 0.37degrees and 0.16degrees, respectively. The average duration of bone union was 16.1 weeks. CONCLUSION: Intramedullary nailing with percutaneous reduction using pointed reduction forceps for distal tibial fractures was an easy and effective method for achievement of accurate alignment intra-operatively. Accurate alignment was successfully maintained until bone union.

Large Cavernous Hemangioma of the Subscapularis Muscle: A Case Report

We report a case of intramuscular hemangioma in the subscapularis muscle and the resulting impairment of shoulder function in an adult patient. A nineteen-year-old female complained of shoulder pain and the development of a mass in the absence of previous trauma. Physical examinations, including lift-off and belly-press tests, showed abnormality. X-ray showed multiple calcifications in the front of the scapula. Magnetic resonance imaging showed a soft-tissue mass occupying almost the entire intramuscular portion of the subscapularis muscle. An arthroscopic examination excluded the possibility of a joint invasion, after which the entire mass was successfully removed by open excision. The displacement of the subscapularis by the mass was relieved after the surgery. Pathological diagnosis of the tissue confirmed a cavernous hemangioma. Both shoulder pain and function was improved after operation. There was no evidence of recurrence even at the 2-year follow-up. Rare forms of hemangioma adjacent to the shoulder joint could be successfully managed with surgical excision. Differential diagnosis, such as synovial chondromatosis, pigmented villonodular synovitis, and malignant sarcoma, should also be considered.

Activation of Autophagy Pathway Suppresses the Expression of iNOS, IL6 and Cell Death of LPS-Stimulated Microglia Cells

Microglia play a role in maintaining and resolving brain tissue homeostasis. In pathological conditions, microglia release pro-inflammatory cytokines and cytotoxic factors, which aggravate the progression of neurodegenerative diseases. Autophagy pathway might be involved in the production of pro-inflammatory cytokines and cytotoxic factors in microglia, though details of the mechanism remain largely unknown. In the present study, we examined the role of the autophagy pathway in activated BV2 microglia cells. In BV2 cells, rapamycin treatment activated the formation of anti-LC3-labeled autophagosomes, whereas the ATG5 depletion using siRNA-ATG5 prevented the formation of LC3-labeled autophagosomes, indicating that BV2 cells exhibit an active classical autophagy system. When treated with LPS, BV2 cells expressed an increase of anti-LC3-labeled dots. The levels of LC3-labeled dots were not suppressed, instead tended to be enhanced, by the inhibition of the autophagy pathway with siRNA-ATG5 or wortmannin, suggesting that LPS-induced LC3-labeled dots in nature were distinct from the typical autophagosomes. The levels of LPS-induced expression of iNOS and IL6 were suppressed by treatment with rapamycin, and conversely, their expressions were enhanced by siRNA-ATG5 treatment. Moreover, the activation of the autophagy pathway using rapamycin inhibited cell death of LPS-stimulated microglia. These results suggest that although microglia possess a typical autophagy pathway, the glial cells express a non-typical autophagy pathway in response to LPS, and the activation of the autophagy pathway suppresses the expression of iNOS and IL6, and the cell death of LPS-stimulated microglia.