Impulse control disorders (ICD) in Parkinson’s disease (PD) are a disabling non-motor symptom with frequencies of 13–35% among patients receiving dopamine replacement therapy. ICD in PD is strongly associated with dopaminergic drug use, especially non-ergot dopamine agonists (DA). However, individual susceptibility and disease-related neural changes are also important contributors to the development of ICD. Discrepancies between nigrostriatal and mesolimbic dopaminergic degeneration and non-physiological administration of dopaminergic drugs may induce abnormal ’hyperstimulation’ of the mesolimbic system, which alters reward-learning behaviors in PD patients. In addition, DA can make patients more impulsive during decision-making and seek risk-taking behaviors. DA intake is also related to the biased representation of rewards. Ultimately, loss of negative feedback control due to dysfunctional frontostriatal connections is necessary for the establishment of ICD in PD. The subsequent behavioral and neural changes are affected by PD treatment and disease progression; thus, proper treatment guidelines for physicians are needed to prevent the development of ICD. Future studies aimed at producing novel therapeutics to control the risk factors for ICD or treat ICD behaviors in PD are warranted. This review summarizes recent advances from epidemiological and pathophysiological studies on ICD in PD. Management principles and limitations of current therapeutics are briefly discussed.
Impulse control disorder; Parkinson’s disease; Dopamine agonist; Reward-learning; Impulsivity; Addiction
Background and Purpose
The aim of this study was to determine the changes in diffusion-tensor images associated with medication-related impulse control disorder (ICD) in Parkinson's disease (PD) patients undergoing chronic dopamine-replacement therapy.
Nineteen PD patients, comprising 10 with ICD (PD-ICD) and 9 without ICD (PD-nonICD), and 18 age-matched healthy controls (HCs) with no cognitive or other psychiatric disorders were analyzed. All subjects underwent 3-T magnetic resonance diffusion-tensor imaging. For all PD patients, clinical data on PD duration, antiparkinsonian medication dosages, Unified Parkinson's Disease Rating Scale and Mini-Mental State Examination were collected. Whole-brain voxel-based measures of fractional anisotropy (FA) and mean diffusivity (MD) were analyzed.
In comparison with HCs, the PD-nonICD subjects had low FA at the bilateral orbitofrontal areas. While the PD-ICD subjects exhibited no such difference, their FA was significantly elevated at the anterior corpus callosum. Analysis of FA between the two PD groups revealed that FA in the anterior corpus callosum, right internal capsule posterior limbs, right posterior cingulum, and right thalamic radiations were significantly higher (corrected p<0.05) in the PD-ICD than in the PD-nonICD patients. MD did not differ between the PD-ICD and PD-nonICD groups in any brain regions.
The PD-ICD patients appear to have relatively preserved white-matter integrity in the regions involved in reward-related behaviors compared to PD-nonICD patients. Further investigation is required to determine whether the difference in FA between PD-ICD and PD-nonICD patients reflects microstructural differences in the pathological progression of PD or is secondary to ICD.
impulse control disorders; Parkinson's disease; diffusion-tensor imaging
Chronic (>24 h) exposure of arsenite, an environmental toxicant, has shown the decreased nitric oxide (NO) production in endothelial cells (EC) by decreasing endothelial NO synthase (eNOS) expression and/or its phosphorylation at serine 1179 (eNOS-Ser1179 in bovine sequence), which is associated with increased risk of vascular diseases. Here, we investigated the acute (<24 h) effect of arsenite on NO production using bovine aortic EC (BAEC). Arsenite acutely increased the phosphorylation of eNOS-Thr497, but not of eNOS-Ser116 or eNOS-Ser1179, which was accompanied by decreased NO production. The level of eNOS expression was unaltered under this condition. Treatment with arsenite also induced reactive oxygen species (ROS) production, and pretreatment with a ROS scavenger N-acetyl-L-cysteine (NAC) completely reversed the observed effect of arsenite on eNOS-Thr497 phosphorylation. Although protein kinase C (PKC) and protein phosphatase 1 (PP1) were reported to be involved in eNOS-Thr497 phosphorylation, treatment with PKC inhibitor, Ro318425, and overexpression of various PKC isoforms did not affect the arsenite-stimulated eNOS-Thr497 phosphorylation. In contrast, treatment with PP1 inhibitor, calyculin A, mimicked the observed effect of arsenite on eNOS-Thr497 phosphorylation. Lastly, we found decreased cellular PP1 activity in arsenite-treated cells, which was reversed by NAC. Overall, our study demonstrates firstly that arsenite acutely decreases NO production at least in part by increasing eNOS-Thr497 phosphorylation via ROS-PP1 signaling pathway, which provide the molecular mechanism underlying arsenite-induced increase in vascular disease.
Arsenite; Vascular disease; Nitric oxide; Endothelial nitric oxide synthase; Reactive oxygen species; Protein phosphatase 1
The anti-inflammatory activity of eriodictyol and its mode of action were investigated. Eriodictyol suppressed tumor necrosis factor (mTNF)-α, inducible nitric oxide synthase (miNOS), interleukin (mIL)-6, macrophage inflammatory protein (mMIP)-1, and mMIP-2 cytokine release in LPS-stimulated macrophages. We found that the anti-inflammatory cascade of eriodictyol is mediated through the Toll-like Receptor (TLR)4/CD14, p38 mitogen-activated protein kinases (MAPK), extracellular-signalregulated kinase (ERK), Jun-N terminal kinase (JNK), and cyclooxygenase (COX)-2 pathway. Fluorescence quenching and saturation-transfer difference (STD) NMR experiments showed that eriodictyol exhibits good binding affinity to JNK, 8.79 × 105 M-1. Based on a docking study, we propose a model of eriodictyol and JNK binding, in which eriodictyol forms 3 hydrogen bonds with the side chains of Lys55, Met111, and Asp169 in JNK, and in which the hydroxyl groups of the B ring play key roles in binding interactions with JNK. Therefore, eriodictyol may be a potent anti-inflammatory inhibitor of JNK. [BMB Reports 2013; 46(12): 594-599]
Anti-inflammatory activity; Docking model; Eriodictyol; Flavonoid; STD-NMR
We investigated the inhibitory effects of hesperidin on melanogenesis. To find melanosome transport inhibitor from natural products, we collected the structural information of natural products from Korea Food and Drug Administration (KFDA) and performed pharmacophore-based in silico screening for Rab27A and melanophilin (MLPH). Hesperidin did not inhibit melanin production in B16F10 murine melanoma cells stimulated with α-melanocyte stimulating hormone (α-MSH), and also did not affect the catalytic activity of tyrosinase. But, hesperidin inhibited melanosome transport in melanocyte and showed skin lightening effect in pigmented reconstructed epidermis model. Therefore, we suggest that hesperidin is a useful inhibitor of melanosome transport and it might be applied to whitening agent.
Hesperidin; Melanosome transport; Rab27A; Melanophilin; Pigmented reconstructed epidermis model
Ropinirole prolonged release (RPR) is a once-daily formulation. However, there may be individual pharmacokinetic differences so that multiple dosing may be preferred in some individuals. This study compares once-daily and twice-daily RPR in patients with Parkinson’s disease.
This study was an open-label crossover study. We enrolled Parkinson’s disease patients on dopamine agonist therapy with unsatisfactory control such as motor fluctuation, dyskinesia and sleep-related problems. Agonists were switched into equivalent dose of RPR. Subjects were consecutively enrolled into either once-daily first or twice-daily first groups, and received the same amount of RPR in a single and two divided dosing for 8 weeks respectively in a crossover manner without a washout period.
The primary outcome was a questionnaire of the preference completed by patients in the last visit. The secondary outcome measures included the Unified Parkinson’s Disease Rating Scale part 3 (mUPDRS), Hoehn and Yahr stage (H&Y); sleep questionnaire including overall quality of sleep, nocturnal off symptoms and early morning symptoms; Epworth Sleep Scale (ESS); compliances and patient global impression (PGI).
A total of 82 patients were enrolled and 61 completed the study. 31 patients preferred twice-daily regimen, 17 preferred the once-daily regimen, and 13 had no preference. Their mean mUPDRS, H&Y, ESS, sleep quality, compliance and adverse events were not statistically different in both regimens. PGI-improvement on wearing off defined was better in twice-daily dosing regimen.
RPR is a once-daily formulation, but multiple dosing was preferred in many patients. Multiple dosing of RPR might be a therapeutic option if once-daily dosing is unsatisfactory.
This study is registered with ClinicalTrials.gov, number
Parkinson’s disease; Motor control; Movement disorders; Dopamine agonist
We compared the surgical outcome with electrode positions after bilateral subthalamic nucleus (STN) stimulation surgery for Parkinson's disease. Fifty-seven patients treated with bilateral STN stimulations were included in this study. Electrode positions were determined in the fused images of preoperative MRI and postoperative CT taken at six months after surgery. The patients were divided into three groups: group I, both electrodes in the STN; group II, only one electrode in the STN; group III, neither electrode in the STN. Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr stage, and activities of daily living scores significantly improved at 6 and 12 months after STN stimulation in both group I and II. The off-time UPDRS III speech subscore significantly improved (1.6 ± 0.7 at baseline vs 1.3 ± 0.8 at 6 and 12 months, P < 0.01) with least L-dopa equivalent daily dose (LEDD) (844.6 ± 364.1 mg/day at baseline; 279.4 ± 274.6 mg/day at 6 months; and 276.0 ± 301.6 mg/day at 12 months, P < 0.001) at 6 and 12 months after STN deep brain stimulation (DBS) in the group I. Our findings suggest that the better symptom relief including speech with a reduced LEDD is expected in the patients whose electrodes are accurately positioned in both STN.
Parkinson Disease; Bilateral STN Stimulation; Clinical Outcome; Electrode Position; Fused Images
The purpose of this study was to evaluate the chest radiographic and CT findings of novel influenza A (H1N1) virus infection in children, the population that is more vulnerable to respiratory infection than adults.
Materials and Methods
The study population comprised 410 children who were diagnosed with an H1N1 infection from August 24, 2009 to November 11, 2009 and underwent chest radiography at Dankook University Hospital in Korea. Six of these patients also underwent chest CT. The initial chest radiographs were classified as normal or abnormal. The abnormal chest radiographs and high resolution CT scans were assessed for the pattern and distribution of parenchymal lesions, and the presence of complications such as atelectasis, pleural effusion, and pneumomediastinum.
The initial chest radiograph was normal in 384 of 410 (94%) patients and abnormal in 26 of 410 (6%) patients. Parenchymal abnormalities seen on the initial chest radiographs included prominent peribronchial marking (25 of 26, 96%), consolidation (22 of 26, 85%), and ground-glass opacities without consolidation (2 of 26, 8%). The involvement was usually bilateral (19 of 26, 73%) with the lower lung zone predominance (22 of 26, 85%). Atelectasis was observed in 12 (46%) and pleural effusion in 11 (42%) patients. CT (n = 6) scans showed peribronchovascular interstitial thickening (n = 6), ground-glass opacities (n = 5), centrilobular nodules (n = 4), consolidation (n = 3), mediastinal lymph node enlargement (n = 5), pleural effusion (n = 3), and pneumomediastinum (n = 3).
Abnormal chest radiographs were uncommon in children with a swine-origin influenza A (H1N1) virus (S-OIV) infection. In children, H1N1 virus infection can be included in the differential diagnosis, when chest radiographs and CT scans show prominent peribronchial markings and ill-defined patchy consolidation with mediastinal lymph node enlargement, pleural effusion and pneumomediastinum.
H1N1; Influenza virus; Infection, chest radiography; Chest CT; Children
Here we report a case in a 41-year-old woman histologically proven cystic embryonal sarcoma of the kidney, with emphasis on the imaging findings and pathological features. A large lobulated solid mass in the cystically dilated pelvocalyceal region was accompanied with hydroureter as depicted on both ultrasound and contrast-enhanced CT images.
Kidney; Sarcoma; Cystic renal tumor
Prospective controlled study.
The results of conventional open surgery was compared with those from minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) for lumbar fusion to determine which approach resulted in less postoperative paraspinal muscle degeneration.
Overview of Literature
MI TLIF is new surgical technique that appears to minimize iatrogenic injury. However, there aren't any reports yet that have quantitatively analyzed and proved whether there's difference in back muscle injury and degeneration between the minimally invasive surgery and conventional open surgery in more than 1 year follow-up after surgery.
This study examined a consecutive series of 48 patients who underwent lumbar fusion in our hospital during the period, March 2006 to March 2008, with a 1-year follow-up evaluation using MRI. There were 17 cases of conventional open surgery and 31 cases of MI-TLIF (31 cases of single segment fusion and 17 cases of multi-segment fusion). The digital images of the paravertebral back muscles were analyzed and compared using the T2-weighted axial images. The point of interest was the paraspinal muscle of the intervertebral disc level from L1 to L5. Picture archiving and communication system viewing software was used for quantitative analysis of the change in fat infiltration percentage and the change in cross-sectional area of the paraspinal muscle, before and after surgery.
A comparison of the traditional posterior fusion method with MI-TLIF revealed single segment fusion to result in an average increase in fat infiltration in the paraspinal muscle of 4.30% and 1.37% and a decrease in cross-sectional area of 0.10 and 0.07 before and after surgery, respectively. Multi-segment fusion showed an average 7.90% and 2.79% increase in fat infiltration and a 0.16 and 0.10 decrease in cross-sectional area, respectively. Both single and multi segment fusion showed less change in the fat infiltration percentage and cross-sectional area, particularly in multi segment fusion. There was no significant difference between the two groups in terms of the radiologic results.
A comparison of conventional open surgery with MI-TLIF upon degeneration of the paraspinal muscle with a 1 year follow-up evaluation revealed that both single and multi segment fusion showed less change in fat infiltration percentage and cross-sectional area in the MI-TLIF but there was no significant difference between the two groups. This suggests that as time passes after surgery, there is no significant difference in the level of degeneration of the paraspinal muscle between surgical techniques.
Paraspainal muscle; Fat degeneration; MRI; Posterior fusion
Coxsackievirus is the most important cause of meningitis and encephalitis in infants; an infection is sometimes fatal or may lead to neurodevelopmental defects. Here, we show that coxsackievirus B4 (CVB4) induces an autophagy pathway for replication in rat primary neurons. Notably, calpain inhibitors reduce autophagosome formation. Conversely, the inhibition of the autophagy pathway with 3-methyladenine inhibits calpain activation. This work reveals, for the first time, that calpain is essential for the autophagy pathway and viral replication in CVB4-infected neurons.
The concurrence of ankylosing spondylitis (AS) in a patient with mixed connective tissue disease (MCTD) is rarely described in the literature. Significant and sustained efficacy with tumor necrosis factor (TNF)-α blockers has been demonstrated in AS patients. However, evidence to date has revealed associated side effects, including antinuclear antibody induction and development of a lupus-like syndrome. Several authors have reported lupus-like manifestations in MCTD patients treated with TNF-α blockers used to control peripheral polyarthritis. In our case report, we demonstrate a good response to etanercept therapy for refractory sacroiliitis in a patient with coexisting AS and MCTD, without development of a lupus-like syndrome. This demonstrates that etanercept therapy may be an appropriate therapeutic agent for sacroiliitis in MCTD patients, as it is in AS alone.
Ankylosing spondylitis; mixed connective tissue disease; etanercept
Centronuclear myopathies are clinically and genetically heterogenous diseases with common histological findings, namely, centrally located nuclei in muscle fibers with a predominance and hypotrophy of type 1 fibers. We describe two cases from one family with autosomal dominant centronuclear myopathy with unusual clinical features that had initially suggested distal myopathy. Clinically, the patients presented with muscle weakness and atrophy localized mainly to the posterior compartment of the distal lower extremities. Magnetic resonance imaging revealed predominant atrophy and fatty changes of bilateral gastrocnemius and soleus muscles. This report demonstrates the expanding clinical heterogeneity of autosomal dominant centronuclear myopathy.
Myopathies, Structural, Congenital; Autosomal Dominant Inheritance; Distal Myopathies
Hyperhomocysteinemia associated with methylene terahydrofolate reductase (MTHFR) mutation can be a risk factor for idiopathic cerebral venous thrombosis. We describe the first case of MTHFR 677TT homozygote with cerebral venous thrombosis and livedo reticularis. A 45-year-old man presented with seizures and mottled-like skin lesions, that were aggravated by cold temperature. Hemorrhagic infarct in the right frontoparietal area with superior sagittal sinus thrombosis was observed. He had hyperhomocysteinemia, low plasma folate level, and MTHFR 677TT homozygote genotype, which might be associated with livedo reticularis and increase the risk for cerebral venous thrombosis.
Livedo reticularis; Methylene tetrahydrofolate reductase; Cerebral venous thrombosis
Spontaneous primary medullary hemorrhage is a rare event. A 64-year-old man was admitted for sudden-onset vertigo and vomiting. His clinical features were similar to those of lateral medullary syndrome. The patient had no anticoagulant therapy, vascular malformation, or a caudal extension of a pontine hemorrhage. The patient had multiple hypertensive changes, including retinopathy, left ventricular hypertrophy on electrocardiography, multiple cerebral microbleeds, and small-vessel changes on MRI. T2*-weighted gradient echo MRI performed 3 months prior to admission and contrast-enhanced MRI showed no evidence of vascular malformation. We concluded that the patient had uncontrolled hypertension that may have lead to primary medullary hemorrhage.
Hemorrhage; Medulla; Hypertension; MRI
Migraine often runs in families and is associated with both genetic and environmental factors. Clinical and genetic heterogeneity as well as the influence of environmental factors have hampered the identification of the gene responsible for migraine disorder. Family/twin studies suggest the presence of hereditary susceptibility. Several different types of mutations or association studies with genetic polymorphism in neurotransmitters, inflammatory cytokines, homocysteine metabolism, mitochondria, or other risk genes in cerebrovascular disorders have been reported. Recently, progress of molecular genetics in familial hemiplegic migraine has provided important insights, a channelopathy, and now extending to a growing list of membrane excitability disorders. Further identification of candidate genes for migraine and exploring the correlation between phenotype and genotype are expected in the future for the understanding of migraine pathophysiology.