Full Text Available In Parkinson’s disease (PD, alteration of dopamine- (DA- dependent striatal functions and pulsatile stimulation of DA receptors caused by the discontinuous administration of levodopa (L-DOPA lead to a complex cascade of events affecting the postsynaptic striatal neurons that might account for the appearance of L-DOPA-induced dyskinesia (LID. Experimental models of LID have been widely used and extensively characterized in rodents and electrophysiological studies provided remarkable insights into the inner mechanisms underlying L-DOPA-induced corticostriatal plastic changes. Here we provide an overview of recent findings that represent a further step into the comprehension of mechanisms underlying maladaptive changes of basal ganglia functions in response to L-DOPA and associated to development of LID.
Full Text Available The emergence of L-DOPA-induced dyskinesia (LID in patients with Parkinson disease (PD could be due to maladaptive plasticity of corticostriatal synapses in response to L-DOPA treatment. A series of recent studies has revealed that LID is associated with marked morphological plasticity of striatal dendritic spines, particularly cell type-specific structural plasticity of medium spiny neurons (MSNs in the striatum. In addition, evidence demonstrating the occurrence of plastic adaptations, including aberrant morphological and functional features, in multiple components of cortico-basal ganglionic circuitry, such as primary motor cortex (M1 and basal ganglia (BG output nuclei. These adaptations have been implicated in the pathophysiology of LID. Here, we briefly review recent studies that have addressed maladaptive plastic changes within the cortico-BG loop in dyskinetic animal models of PD and patients with PD.
Havelund, Jesper F; Andersen, Andreas D; Binzer, Michael; Blaabjerg, Morten; Heegaard, Niels H H; Stenager, Egon; Faergeman, Nils J; Gramsbergen, Jan Bert
L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective drug in the symptomatic treatment of Parkinson's disease, but chronic use is associated with L-DOPA-induced dyskinesia in more than half the patients after 10 years of treatment. L-DOPA treatment may affect tryptophan metabolism via the kynurenine pathway. Altered levels of kynurenine metabolites can affect glutamatergic transmission and may play a role in the development of L-DOPA-induced dyskinesia. In this study, we assessed kynurenine metabolites in plasma and cerebrospinal fluid of Parkinson's disease patients and controls. Parkinson patients (n = 26) were clinically assessed for severity of motor symptoms (UPDRS) and L-DOPA-induced dyskinesia (UDysRS). Plasma and cerebrospinal fluid samples were collected after overnight fasting and 1-2 h after intake of L-DOPA or other anti-Parkinson medication. Metabolites were analyzed in plasma and cerebrospinal fluid of controls (n = 14), Parkinson patients receiving no L-DOPA (n = 8), patients treated with L-DOPA without dyskinesia (n = 8), and patients with L-DOPA-induced dyskinesia (n = 10) using liquid chromatography-mass spectrometry. We observed approximately fourfold increase in the 3-hydroxykynurenine/kynurenic acid ratio in plasma of Parkinson's patients with L-DOPA-induced dyskinesia. Anthranilic acid levels were decreased in plasma and cerebrospinal fluid of this patient group. 5-Hydroxytryptophan levels were twofold increased in all L-DOPA-treated Parkinson's patients. We conclude that a higher 3-hydroxykynurenine/kynurenic acid ratio in plasma may serve as a biomarker for L-DOPA-induced dyskinesia. Longitudinal studies including larger patients cohorts are needed to verify whether the changes observed here may serve as a prognostic marker for L-DOPA-induced dyskinesia. © 2017 International Society for Neurochemistry.
Havelund, Jesper F; Dammann Andersen, Andreas; Binzer, Michael
L-DOPA is the most effective drug in the symptomatic treatment of Parkinson's disease, but chronic use is associated with L-DOPA-induced dyskinesia in more than half the patients after 10 years of treatment. L-DOPA treatment may affect tryptophan metabolism via the kynurenine pathway. Altered...... levels of kynurenine metabolites can affect glutamatergic transmission and may play a role in the development of L-DOPA-induced dyskinesia. In this study we assessed kynurenine metabolites in plasma and cerebrospinal fluid of Parkinson's disease patients and controls. Parkinson patients (n=26) were...... clinically assessed for severity of motor symptoms (UPDRS) and L-DOPA-induced dyskinesia (UDysRS). Plasma and cerebrospinal fluid samples were collected after overnight fasting and 1-2 hours after intake of L-DOPA or other anti-Parkinson medication. Metabolites were analyzed in plasma and cerebrospinal fluid...
Huang, Luping Z.; Campos, Carla; Ly, Jason; Carroll, F. Ivy; Quik, Maryka
L-dopa therapy for Parkinson's disease leads to dyskinesias or abnormal involuntary movement (AIMs) for which there are few treatment options. Our previous data showed that nicotine administration reduced L-dopa-induced AIMs in parkinsonian monkeys and rats. To further understand how nicotine mediates its antidyskinetic action, we investigated the effect of nicotinic receptor (nAChR) agonists in unilateral 6-OHDA-lesioned rats with varying striatal damage. We first tested the drugs in L-dopa-treated rats with a near-complete striatal dopamine lesion (>99%), the standard rodent dyskinesia model. Varenicline, an agonist that interacts with multiple nAChRs, did not significantly reduce L-dopa-induced AIMs, while 5-iodo-A-85380 (A-85380), which acts selectively at α4β2* and α6β2* subtypes, reduced AIMs by 20%. By contrast, both varenicline and A-85380 reduced L-dopa-induced AIMs by 40–50% in rats with a partial striatal dopamine lesion. Neither drug worsened the antiparkinsonian action of L-dopa. The results show that selective nicotinic agonists reduce dyskinesias, and that they are optimally effective in animals with partial striatal dopamine damage. These findings suggest that presynaptic dopamine terminal α4β2* and α6β2* nAChRs are critical for nicotine’s antidyskinetic action. The current data have important implications for the use of nicotinic receptor-directed drugs for L-dopa-induced dyskinesias, a debilitating motor complication of dopamine replacement therapy for Parkinson’s disease. PMID:21232546
Chotibut, Tanya; Meadows, Samantha; Kasanga, Ella A; McInnis, Tamara; Cantu, Mark A; Bishop, Christopher; Salvatore, Michael F
Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l-dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT-1 expression in a rat 6-hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l-dopa, could reduce l-dopa-induced dyskinesia in an established dyskinesia model. Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post-6-hydroxydopamine lesion (days 7-13) and continued every other week (days 21-27, 35-39) until the end of the study (day 39 postlesion, 20 days of l-dopa). Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l-dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l-dopa was unaffected by ceftriaxone. The ceftriaxone-treated l-dopa group had significantly increased striatal GLT-1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l-dopa alone group. Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l-dopa, may reduce dyskinesia severity without affecting l-dopa efficacy or the reduction of striatal tyrosine hydroxylase loss. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.
Dammann Andersen, Andreas
Parkinson’s disease (PD) is a common disease, affecting 1% of the population older than 60 years of age. Neuropathological characteristics of the disease include the presence of alpha-synuclein containing Lewy bodies in the brain stem and loss of nigrostriatal dopaminergic neurons, which result...... of patients, who are also clinically rated using the Unified Parkinson’s Disease rating scale (UPDRS) and the Unified Dyskinesia Rating Scale (UDysRS). 1. de Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet neurology. 2006;5(6):525-35. 2. Rodriguez-Oroz MC, Jahanshahi M, Krack P, et al....... Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms. Lancet neurology. 2009;8(12):1128-39. 3. Jenner P. Molecular mechanisms of L-DOPA-induced dyskinesia. Nature reviews Neuroscience. 2008;9(9):665-77. 4. Parnetti L, Castrioto A, Chiasserini D, et al...
Cenci, M Angela
The dopamine (DA) precursor l-DOPA has been the most effective treatment for Parkinson's disease (PD) for over 40 years. However, the response to this treatment changes with disease progression, and most patients develop dyskinesias (abnormal involuntary movements) and motor fluctuations within a few years of l-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal DA transmission. Several presynaptic mechanisms converge to generate large DA swings in the brain concomitant with the peaks-and-troughs of plasma l-DOPA levels, while post-synaptic changes engender abnormal functional responses in dopaminoceptive neurons. While this general picture is well-accepted, the relative contribution of different factors remains a matter of debate. A particularly animated debate has been growing around putative players on the presynaptic side of the cascade. To what extent do presynaptic disturbances in DA transmission depend on deficiency/dysfunction of the DA transporter, aberrant release of DA from serotonin neurons, or gliovascular mechanisms? And does noradrenaline (which is synthetized from DA) play a role? This review article will summarize key findings, controversies, and pending questions regarding the presynaptic mechanisms of l-DOPA-induced dyskinesia. Intriguingly, the debate around these mechanisms has spurred research into previously unexplored facets of brain plasticity that have far-reaching implications to the treatment of neuropsychiatric disease.
Trenkwalder, Claudia; Stocchi, Fabrizio; Poewe, Werner; Dronamraju, Nalina; Kenney, Chris; Shah, Amy; von Raison, Florian; Graf, Ana
Two phase 2 randomized, double-blind studies were designed to evaluate efficacy and safety of immediate-release (study 1) and modified-release (study 2) mavoglurant formulations in PD l-dopa-induced dyskinesia. Patients were randomized to mavoglurant 100-mg or placebo (4:3) groups (study 1) and mavoglurant 200-mg, mavoglurant 150-mg, or placebo (2:1:1) groups (study 2). Primary outcome was antidyskinetic efficacy, as measured by change from baseline to week 12 in modified Abnormal Involuntary Movement Scale total score. Differences in least-squares mean (standard error) change in modified Abnormal Involuntary Movement Scale total score in week 12 did not reach statistical significance in either study (study 1: mavoglurant 100 mg twice a day versus placebo, 1.7 [1.31]; study 2: mavoglurant 150 mg twice a day (-1.3 [1.16]) and 200 mg twice a day (-0.2 [1.03]) versus placebo). Adverse events incidence was higher with mavoglurant than with placebo. Both studies failed to meet the primary objective of demonstrating improvement of dyskinesia with mavoglurant treatment. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.
Romina Aron Badin
Full Text Available The development of dyskinesias following chronic L-DOPA replacement therapy remains a major problem in the long-term treatment of Parkinson's disease. This study aimed at evaluating the effect of IRC-082451 (base of BN82451, a novel multitargeting hybrid molecule, on L-DOPA-induced dyskinesias (LIDs and hypolocomotor activity in a non-human primate model of PD. IRC-082451 displays multiple properties: it inhibits neuronal excitotoxicity (sodium channel blocker, oxidative stress (antioxidant and neuroinflammation (cyclooxygenase inhibitor and is endowed with mitochondrial protective properties. Animals received daily MPTP injections until stably parkinsonian. A daily treatment with increasing doses of L-DOPA was administered to parkinsonian primates until the appearance of dyskinesias. Then, different treatment regimens and doses of IRC-082451 were tested and compared to the benchmark molecule amantadine. Primates were regularly filmed and videos were analyzed with specialized software. A novel approach combining the analysis of dyskinesias and locomotor activity was used to determine efficacy. This analysis yielded the quantification of the total distance travelled and the incidence of dyskinesias in 7 different body parts. A dose-dependent efficacy of IRC-082451 against dyskinesias was observed. The 5 mg/kg dose was best at attenuating the severity of fully established LIDs. Its effect was significantly different from that of amantadine since it increased spontaneous locomotor activity while reducing LIDs. This dose was effective both acutely and in a 5-day sub-chronic treatment. Moreover, positron emission tomography scans using radiolabelled dopamine demonstrated that there was no direct interference between treatment with IRC-082451 and dopamine metabolism in the brain. Finally, post-mortem analysis indicated that this reduction in dyskinesias was associated with changes in cFOS, FosB and ARC mRNA expression levels in the putamen. The data
Guridi, Jorge; Obeso, Jose A; Rodriguez-Oroz, Maria C; Lozano, Andres A; Manrique, Miguel
To assess the impact of different surgical targets and techniques, such as ablation and deep brain stimulation, to treat patients with L-dopa-induced dyskinesia (LID), a major therapeutic complication of Parkinson's disease. This review analyzes the effects of early surgical procedures to treat hyperkinesia and the current methods and targets used to combat LID in Parkinson's disease, which are mainly thalamotomy, pallidotomy, and deep brain stimulation of the globus pallidus internus and the subthalamic nucleus. Available information indicates that surgery of the globus pallidus internus and thalamus (the pallidal receiving area) and of the subthalamic nucleus has a pronounced antidyskinetic effect. This effect is associated with a concomitant improvement in the parkinsonian ("off"-medication) state. Although it is more profound with pallidal and subthalamic surgery, such an effect can also be observed to some extent with thalamic surgery. The latter is attributable to the fact that surgery of the ventralis intermedius is primarily effective for treating tremor. An integral pallidothalamic pathway is needed for dyskinesia to be expressed. Thus, LID is less frequent after subthalamotomy or deep brain stimulation of the subthalamic nucleus through a functional effect mediated by the physiological normalization of the motor system and by an indirect effect associated with a reduction in the daily dose of L-dopa. Surgery is the only treatment available for Parkinson's disease that can predictably improve both the parkinsonian motor syndrome and LID. The exact mechanisms involved in these effects are not well understood. Pallidal and thalamic surgery affecting pallidal relays reduce LID frequency by disrupting the pallidothalamic circuit, probably eliminating the neuronal activity associated with dyskinesia. Alternatively, the antidyskinetic effect of subthalamic nucleus surgery may in part be attributable to a reduction in the L-dopa dose as well as to the
Feyder, Michael; Södersten, Erik; Santini, Emanuela
BACKGROUND: Abnormal regulation of extracellular signal-regulated kinases 1 and 2 has been implicated in 3,4-dihydroxy-l-phenylalanine (L-DOPA)-induced dyskinesia (LID), a motor complication affecting Parkinson's disease patients subjected to standard pharmacotherapy. We examined the involvement ...
Cortés, Marisol; Malave, Lauren; Castello, Julia; Flajolet, Marc; Cenci, M Angela; Friedman, Eitan; Rebholz, Heike
We have previously shown that casein kinase 2 (CK2) negatively regulates dopamine D1 and adenosine A 2A receptor signaling in the striatum. Ablation of CK2 in D1 receptor-positive striatal neurons caused enhanced locomotion and exploration at baseline, whereas CK2 ablation in D2 receptor-positive neurons caused increased locomotion after treatment with A 2A antagonist, caffeine. Because both, D1 and A 2A receptors, play major roles in the cellular responses to l-DOPA in the striatum, these findings prompted us to examine the impact of CK2 ablation on the effects of l-DOPA treatment in the unilateral 6-OHDA lesioned mouse model of Parkinson's disease. We report here that knock-out of CK2 in striatonigral neurons reduces the severity of l-DOPA-induced dyskinesia (LID), a finding that correlates with lowered pERK but unchanged pPKA substrate levels in D1 medium spiny neurons as well as in cholinergic interneurons. In contrast, lack of CK2 in striatopallidal neurons enhances LID and ERK phosphorylation. Coadministration of caffeine with a low dose of l-DOPA reduces dyskinesia in animals with striatopallidal knock-out to wild-type levels, suggesting a dependence on adenosine receptor activity. We also detect reduced G olf levels in the striatonigral but not in the striatopallidal knock-out in response to l-DOPA treatment.Our work shows, in a rodent model of PD, that treatment-induced dyskinesia and striatal ERK activation are bidirectionally modulated by ablating CK2 in D1- or D2-positive projection neurons, in male and female mice. The results reveal that CK2 regulates signaling events critical to LID in each of the two main populations of striatal neurons. SIGNIFICANCE STATEMENT To date, l-DOPA is the most effective treatment for PD. Over time, however, its efficacy decreases, and side effects including l-DOPA-induced dyskinesia (LID) increase, affecting up to 78% of patients within 10 years of therapy (Hauser et al., 2007). It is understood that supersensitivity of
Fernando Eduardo Padovan-Neto
Full Text Available Inhibitors of neuronal and endothelial nitric oxide synthase decrease l-3,4-dihidroxifenilalanine (L-DOPA-induced dyskinesias in rodents. The mechanism of nitric oxide inhibitor action is unknown. The aims of the present study were to investigate the decrease of L-DOPA-induced abnormal involuntary movements in 6-hydroxydopamine (6-OHDA-lesioned rats by nitric oxide inhibitors following either acute or chronic treatment. The primary findings of this study were that NG-nitro-L-Arginine, an inhibitor of endothelial and neuronal nitric oxide synthase, attenuated abnormal involuntary movements induced by chronic and acute L-DOPA. In contrast, rotational behavior was attenuated only after chronic L-DOPA. L-DOPA improved stepping test performance, and its chronic administration did not alter open field behavior. Our results indicated a correlation between apomorphine-induced rotation and the decrease in the number of adjusting steps performed with the contralateral forepaw in the 6-OHDA-lesioned rats.The 6-OHDA lesion and the L-DOPA treatment induced a bilateral increase (1.5 times in the nNOS protein and nNOS mRNA in the striatum and in the frontal cortex. There was a parallel increase, bilaterally, of the FosB/ΔFosB, primarily in the ipsilateral striatum. The exception was in the contralateral striatum and the ipsilateral frontal cortex, where chronic L-DOPA treatment induced an increase of approximately 10 times the nNOS mRNA. Our results provided further evidence of an anti-dyskinetic effect of NOS inhibitor. The effect appeared under L-DOPA acute and chronic treatment. The L-DOPA treatment also revealed an over-expression of the neuronal NOS in the frontal cortex and striatum. Our results corroborated findings that L-DOPA-induced rotation differs between acute and chronic treatment. The effect of the NOS inhibitor conceivably relied on the L-DOPA structural modifications in the parkinsonian brain. Taken together, these data provided a rationale
Ryu, Young-Kyoung; Park, Hye-Yeon; Go, Jun; Choi, Dong-Hee; Kim, Yong-Hoon; Hwang, Jung Hwan; Noh, Jung-Ran; Lee, Tae Geol; Lee, Chul-Ho; Kim, Kyoung-Shim
Metformin is a medication that is widely prescribed for the management of type 2 diabetes. In addition to its anti-diabetic uses, metformin has been proposed as a therapeutically effective drug candidate in various central nervous system disorders, including Parkinson's disease (PD). PD is characterized by severe movement defects and is commonly treated with the dopamine (DA) precursor 3,4-dihydroxyphenyl-l-alanine (L-DOPA). However, prolonged use of L-DOPA can lead to the development of L-DOPA-induced dyskinesia (LID). Here, we hypothesized that metformin co-treatment would improve LID in the 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Metformin did not interfere the pharmacotherapeutic effects of L-DOPA in the cylinder test. Furthermore, metformin co-treatment with L-DOPA attenuated the development of LID in unilaterally 6-OHDA-lesioned mice. Metformin showed a long-lasting effect on axial, limb, and orofacial abnormal involuntary movement scores for up to 20 days after treatment initiation. Interestingly, persistent enhancement of the mammalian target of rapamycin, dopamine D1 receptor, and extracellular signaling-regulated kinase 1/2 signaling was maintained in the DA-denervated striatum during metformin treatment. Metformin globally normalized the increased glycogen synthase kinase 3β activity induced by chronic treatment of L-DOPA in a manner associated with Akt activation in unilaterally 6-OHDA-lesioned mice. These findings suggest that metformin may have therapeutic potential for the suppression or management of L-DOPA-induced motor complications in patients with PD.
Bido, Simone; Solari, Nicola; Indrigo, Marzia; D’Antoni, Angela; Brambilla, Riccardo; Morari, Michele; Fasano, Stefania
Objective Recent findings have shown that pharmacogenetic manipulations of the Ras-ERK pathway provide a therapeutic means to tackle l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID). First, we investigated whether a prolonged l-DOPA treatment differentially affected ERK signaling in medium spiny neurons of the direct pathway (dMSNs) and in cholinergic aspiny interneurons (ChIs) and assessed the role of Ras-GRF1 in both subpopulations. Second, using viral-assisted technology, we probed Ras-GRF1 and Ras-GRF2 as potential targets in this pathway. We investigated how selective blockade of striatal Ras-GRF1 or Ras-GRF2 expression impacted on LID (induction, maintenance, and reversion) and its neurochemical correlates. Methods We used both Ras-GRF1 knockout mice and lentiviral vectors (LVs) delivering short-hairpin RNA sequences (shRNAs) to obtain striatum-specific gene knockdown of Ras-GRF1 and Ras-GRF2. The consequences of these genetic manipulations were evaluated in the 6-hydroxydopamine mouse model of Parkinson’s disease. Escalating doses of l-DOPA were administered and then behavioral analysis with immunohistochemical assays and in vivo microdialysis were performed. Results Ras-GRF1 was found essential in controlling ERK signaling in dMSNs, but its ablation did not prevent ERK activation in ChIs. Moreover, striatal injection of LV-shRNA/Ras-GRF1 attenuated dyskinesia development and ERK-dependent signaling, whereas LV-shRNA/Ras-GRF2 was without effect, ruling out the involvement of Ras-GRF2 in LID expression. Accordingly, Ras-GRF1 but not Ras-GRF2 striatal gene-knockdown reduced l-DOPA-induced GABA and glutamate release in the substantia nigra pars reticulata, a neurochemical correlate of dyskinesia. Finally, inactivation of Ras-GRF1 provided a prolonged anti-dyskinetic effect for up to 7 weeks and significantly attenuated symptoms in animals with established LID. Interpretation Our results suggest that Ras-GRF1 is a promising target for LID
Nevalainen, Nina; af Bjerkén, Sara; Lundblad, Martin; Gerhardt, Greg A.; Strömberg, Ingrid
L-DOPA (3,4-dihydroxyphenyl-L-alanine) is the most commonly used treatment for symptomatic control in patients with Parkinson’s disease. Unfortunately, most patients develop severe side effects, such as dyskinesia, upon chronic L-DOPA treatment. The patophysiology of dyskinesia is unclear, however, involvement of serotonergic nerve fibers in converting L-DOPA to dopamine has been suggested. Therefore, potassium-evoked dopamine release was studied after local application of L-DOPA in the stria...
Full Text Available We simultaneously recorded local field potentials in the primary motor cortex and sensorimotor striatum in awake, freely behaving, 6-OHDA lesioned hemi-parkinsonian rats in order to study the features directly related to pathological states such as parkinsonian state and levodopa-induced dyskinesia. We analysed the spectral characteristics of the obtained signals and observed that during dyskinesia the most prominent feature was a relative power increase in the high gamma frequency range at around 80 Hz, while for the parkinsonian state it was in the beta frequency range. Here we show that during both pathological states effective connectivity in terms of Granger causality is bidirectional with an accent on the striatal influence on the cortex. In the case of dyskinesia, we also found a high increase in effective connectivity at 80 Hz. In order to further understand the 80- Hz phenomenon, we performed cross-frequency analysis and observed characteristic patterns in the case of dyskinesia but not in the case of the parkinsonian state or the healthy state. We noted a large decrease in the modulation of the amplitude at 80 Hz by the phase of low frequency oscillations (up to ~10 Hz across both structures in the case of dyskinesia. This may suggest a lack of coupling between the low frequency activity of the recorded network and the group of neurons active at ~80 Hz.
Scott J. Sherman
Full Text Available Ketamine is an FDA-approved drug with a known safety profile. Low-dose subanesthetic intravenous ketamine infusion treatment has led to long-term reduction of treatment-resistant depression and of chronic pain states. We report on low-dose subanesthetic intravenous ketamine infusion treatment in Parkinson's disease (PD patients by 5 case studies and show a long-lasting therapeutic benefit to reduce L-DOPA-induced dyskinesia (LID, improve on time, and reduce depression. Based on the literature we hypothesize that low-dose ketamine may act as a ‘chemical deep brain stimulation', by desynchronizing hypersynchronous oscillatory brain activity, including in the basal ganglia and the motor cortex. The presented PD case reports indicate tolerability, safety and long-term beneficial effects of low-dose ketamine infusion that should be further investigated in a properly controlled prospective clinical trial for treatment of LID, as well as the prevalent nonmotor features pain and depression in PD patients.
Nevalainen, Nina; af Bjerkén, Sara; Lundblad, Martin; Gerhardt, Greg A.; Strömberg, Ingrid
L-DOPA (3,4-dihydroxyphenyl-L-alanine) is the most commonly used treatment for symptomatic control in patients with Parkinson’s disease. Unfortunately, most patients develop severe side effects, such as dyskinesia, upon chronic L-DOPA treatment. The patophysiology of dyskinesia is unclear, however, involvement of serotonergic nerve fibers in converting L-DOPA to dopamine has been suggested. Therefore, potassium-evoked dopamine release was studied after local application of L-DOPA in the striata of normal, dopamine- and dopamine/serotonin-lesioned L-DOPA naïve, and dopamine-denervated chronically L-DOPA-treated dyskinetic rats using in vivo chronoamperometry. The results revealed that local L-DOPA administration into normal and intact hemisphere of dopamine-lesioned L-DOPA naïve animals significantly increased the potassium-evoked dopamine release. L-DOPA application also increased the dopamine peak amplitude in the dopamine-depleted L-DOPA naïve striatum, although these dopamine levels were several-folds lower than in the normal striatum, while no increased dopamine release was found in the dopamine/serotonin-denervated striatum. In dyskinetic animals, local L-DOPA application did not affect the dopamine release, resulting in significantly attenuated dopamine levels compared to those measured in L-DOPA naïve dopamine-denervated striatum. To conclude, L-DOPA is most likely converted to dopamine in serotonergic nerve fibers in the dopamine-depleted striatum, but the dopamine release is several-fold lower than in normal striatum. Furthermore, L-DOPA loading does not increase the dopamine release in dyskinetic animals as found in L-DOPA naïve animals, despite similar density of serotonergic innervation. Thus, the dopamine overflow produced from the serotonergic nerve fibers appears not to be the major cause of dyskinetic behavior. PMID:21534956
Full Text Available L-DOPA-induced dyskinesia is a troublesome complication of L-DOPA pharmacotherapy of Parkinson's disease and has been associated with disturbed brain opioid transmission. However, so far the results of clinical and preclinical studies on the effects of opioids agonists and antagonists have been contradictory at best. Prodynorphin mRNA levels correlate well with the severity of dyskinesia in animal models of Parkinson's disease; however the identities of the actual neuroactive opioid effectors in their target basal ganglia output structures have not yet been determined. For the first time MALDI-TOF imaging mass spectrometry (IMS was used for unbiased assessment and topographical elucidation of prodynorphin-derived peptides in the substantia nigra of a unilateral rat model of Parkinson's disease and L-DOPA induced dyskinesia. Nigral levels of dynorphin B and alpha-neoendorphin strongly correlated with the severity of dyskinesia. Even if dynorphin peptide levels were elevated in both the medial and lateral part of the substantia nigra, MALDI IMS analysis revealed that the most prominent changes were localized to the lateral part of the substantia nigra. MALDI IMS is advantageous compared with traditional molecular methods, such as radioimmunoassay, in that neither the molecular identity analyzed, nor the specific localization needs to be predetermined. Indeed, MALDI IMS revealed that the bioconverted metabolite leu-enkephalin-arg also correlated positively with severity of dyskinesia. Multiplexing DynB and leu-enkephalin-arg ion images revealed small (0.25 by 0.5 mm nigral subregions with complementing ion intensities, indicating localized peptide release followed by bioconversion. The nigral dynorphins associated with L-DOPA-induced dyskinesia were not those with high affinity to kappa opioid receptors, but consisted of shorter peptides, mainly dynorphin B and alpha-neoendorphin that are known to bind and activate mu and delta opioid receptors
Levandis, Giovanna; Bazzini, Eleonora; Armentero, Marie-Thérèse; Nappi, Giuseppe; Blandini, Fabio
Altered glutamatergic neurotransmission is central to the expression of Parkinson's disease (PD) symptoms and may underlie l-DOPA-induced dyskinesias. Drugs acting on glutamate metabotropic receptors (mGluR) of group I can modulate subthalamic nucleus (STN) overactivity, which plays a pivotal role in these phenomena, and may counteract dyskinesias. To address these issues, we investigated the effects of a 3-week treatment with mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), or of a subthalamic lesion, on abnormal involuntary movements (AIMs) and associated striatal expression of transcription factor FosB/Delta FosB caused by chronic l-DOPA administration, in rats with a nigrostriatal lesion. MPEP virtually abolished AIMs and reduced, dramatically, striatal expression of FosB/Delta FosB. Reduced FosB/Delta FosB expression, coupled with nonsignificant reduction of AIMs, was also observed in STN-lesioned rats. Our data confirm the role of glutamatergic neurotransmission in the pathogenesis of dyskinesias and the potential of mGluR5 antagonists in the treatment of l-DOPA-induced dyskinesias.
Tronci, Elisabetta; Napolitano, Francesco; Muñoz, Ana; Fidalgo, Camino; Rossi, Francesca; Björklund, Anders; Usiello, Alessandro; Carta, Manolo
In addition to its role in neuronal survival, the brain neurotrophic factor (BDNF) has been shown to influence serotonin transmission and synaptic plasticity, events strongly implicated in the appearance of l-DOPA-induced dyskinesia (LID), a motor complication occurring in parkinsonian patients after long-term treatment with the dopamine precursor. In order to evaluate a possible influence of BDNF in the appearance of LID, 6-OHDA-lesioned rats received a striatal injection of different concentrations of an adeno-associated viral (AAV) vector over-expressing either BDNF or GFP, as control vector. Eight weeks later, animals started to receive a daily treatment with l-DOPA (4-6mg/kg plus benserazide 4-6mg/kg, s.c.) or saline, and dyskinesias, as well as l-DOPA-induced rotations, were evaluated at several time-points. Moreover, molecular changes in striatal D1 receptor-dependent cAMP/PKA and ERK/mTORC signaling pathways, as well as, sprouting of striatal serotonin axons, were measured. Results showed that the AAV-BDNF vector injection induced striatal over-expression of BDNF, as well as striatal and pallidal serotonin axon hyperinnervation. Moreover, rats that over-expressed BDNF were more prone to develop LID and l-DOPA-induced rotations, compared to the GFP-treated control group. Finally, rats that over-expressed BDNF showed increased levels of striatal D1R-dependent signaling phospho-proteins in response to l-DOPA administration. This study suggests that BDNF over-expression, by inducing changes in pre-synaptic serotonin axonal trophism, is able to exacerbate maladaptive responses to l-DOPA administration. Copyright © 2017 Elsevier Inc. All rights reserved.
Bhide, Nirmal; Lindenbach, David; Barnum, Christopher J.; George, Jessica A.; Surrena, Margaret A.; Bishop, Christopher
Dopamine (DA) replacement therapy with L-DOPA continues to be the primary treatment of Parkinson's disease; however, long-term therapy is accompanied by L-DOPA-induced dyskinesias (LID). Several experimental and clinical studies have established that Propranolol, a β-adrenergic receptor antagonist, reduces LID without affecting L-DOPA's efficacy. However, the exact mechanisms underlying these effects remain to be elucidated. The aim of the current study was to evaluate the anti-dyskinetic profile of Propranolol against a panel of DA replacement strategies, as well as elucidate the underlying neurochemical mechanisms. Results indicated that Propranolol, in a dose-dependent manner, reduced LID, without affecting motor performance. Propranolol failed to alter dyskinesia produced by the D1 receptor agonist, SKF81297 (0.08 mg/kg, sc), or the D2 receptor agonist, Quinpirole (0.05 mg/kg, sc). These findings suggested a presynaptic mechanism for Propranolol's anti-dyskinetic effects, possibly through modulating L-DOPA-mediated DA efflux. To evaluate this possibility, microdialysis studies were carried out in the DA-lesioned striatum of dyskinetic rats and results indicated that co-administration of Propranolol (20 mg/kg, ip) was able to attenuate L-DOPA- (6 mg/kg, sc) induced DA efflux. Therefore, Propranolol's anti-dyskinetic properties appear to be mediated via attenuation of L-DOPA-induced extraphysiological efflux of DA. PMID:25866285
Gerlach, Manfred; Halley, Paul; Riederer, Peter; van den Buuse, Maarten
Piribedil is a non-ergoline, dopamine D(2)/D(3) receptor agonist with α(2) adrenoceptor antagonist properties that has been used in the treatment of Parkinson's disease (PD). Noradrenergic neurotransmission may be involved in the pathogenesis of dyskinesias induced by chronic treatment with L-DOPA (3,4-dihydroxyphenylalanine, levodopa), but its role in the in vivo action of piribedil or on different subclasses of abnormal involuntary movements (AIMs) remains unclear. The aims of this study were therefore (1) to investigate the anti-dyskinetic effects of piribedil on L-DOPA-induced contralateral turning behaviour, locomotive dyskinesias (LD), axial dystonia (AD), orolingual dyskinesia (OD) and forelimb dyskinesia (FD) and (2) to compare these effects to the α(2) adrenoceptor antagonist, idazoxan, or the α(2) adrenoceptor agonist, clonidine. Rats were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) and injected intraperitoneally twice daily with L-DOPA methylester (12.5 mg/kg) and benserazide (3.25 mg/kg). After 3 weeks, the effects of piribedil (5, 15, 40 mg/kg), clonidine (0.15 mg/kg), idazoxan (10 mg/kg) and combinations of these drugs were scored during 2 h. Pre-treatment with 5 and 40 mg/kg, but not 15 mg/kg, of piribedil reduced turning behaviour and AD, OD and FD, but piribedil increased LD at the 40 mg/kg doses compared to the L-DOPA group. Idazoxan induced similar effects as piribedil (40 mg/kg), except that it had no effect on LD. Idazoxan blocked the effect of piribedil on AD and FD. Clonidine reduced all AIMs except OD, possibly because of its sedative effect. Clonidine blocked the effect of piribedil on AD, OD and FD. These data suggest a differential involvement of α(2) adrenergic receptors in the action of piribedil on different subclasses of L-DOPA-induced dyskinesias.
Full Text Available When faced with visual uncertainty during motor performance, humans rely more on predictive forward models and proprioception and attribute lesser importance to the ambiguous visual feedback. Though disrupted predictive control is typical of patients with cerebellar disease, sensorimotor deficits associated with the involuntary and often unconscious nature of L-dopa-induced dyskinesias in Parkinson’s disease (PD suggests dyskinetic subjects may also demonstrate impaired predictive motor control. Methods: We investigated the motor performance of 9 dyskinetic and 10 non-dyskinetic PD subjects on and off L-dopa, and of 10 age-matched control subjects, during a large-amplitude, overlearned, visually-guided tracking task. Ambiguous visual feedback was introduced by adding ‘jitter’ to a moving target that followed a Lissajous pattern. Root mean square (RMS tracking error was calculated, and ANOVA, robust multivariate linear regression and linear dynamical system analyses were used to determine the contribution of speed and ambiguity to tracking performance. Results: Increasing target ambiguity and speed contributed significantly more to the RMS error of dyskinetic subjects off medication. L-dopa improved the RMS tracking performance of both PD groups. At higher speeds, controls and PDs without dyskinesia were able to effectively de-weight ambiguous visual information. Conclusions: PDs’ visually-guided motor performance degrades with visual jitter and speed of movement to a greater degree compared to age-matched controls. However, there are fundamental differences in PDs with and without dyskinesia: subjects without dyskinesia are generally slow, and less responsive to dynamic changes in motor task requirements but, PDs with dyskinesia there was a trade-off between overall performance and inappropriate reliance on ambiguous visual feedback. This is likely associated with functional changes in posterior parietal-ponto-cerebellar pathways.
Full Text Available Lu Song,1,* Zhanzhao Zhang,2,* Rongguo Hu,1 Jie Cheng,1 Lin Li,1 Qinyi Fan,1 Na Wu,1 Jing Gan,1 Mingzhu Zhou,1 Zhenguo Liu11Department of Neurology, Xinhua Hospital, 2Department of Plastic and Reconstructive Surgery, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workAbstract: L-3,4-dihydroxyphenylalanine (L-dopa remains the most effective therapy for Parkinson’s disease (PD, but its long-term administration is associated with the development of debilitating motor complications known as L-dopa-induced dyskinesia (LID. Enhanced function of dopamine D1 receptor (D1R and N-methyl-d-aspartate receptor (NMDAR is believed to participate in the pathogenesis of LID. Given the existence of physical and functional interactions between D1R and NMDAR, we explored the effects of uncoupling D1R and NMDA GluN1 (GluN1 interaction on LID by using the Tat-conjugated interfering peptide (Tat-D1-t2. In this study, we demonstrated in 6-hydroxydopamine (6-OHDA-lesioned PD rat model that intrastriatal injection of Tat-D1-t2 alleviated dyskinetic behaviors and downregulated the phosphorylation of DARPP-32 at Thr34 induced by levodopa. Moreover, we also showed intrastriatal administration of Tat-D1-t2 elicited alterations in membranous GluN1 and D1R expression. These findings indicate that D1R/GluN1 complexes may be a molecular target with therapeutic potential for the treatment of dyskinesia in Parkinson’s patients.Keywords: 6-hydroxydopamine, Parkinson’s disease, dyskinesia, L-dopa, D1 receptor, NMDA, protein–protein interaction
Full Text Available Bradykinesia (slowness of movement and other characteristic motor manifestations of Parkinson’s disease (PD are alleviated by treatment with L-dihydroxyphenylalanine (L-DOPA. Long-term L-DOPA treatment, however, is associated with complications such as motor fluctuations and dyskinesia that severely impair the quality of life. It is unclear whether the effect of L-DOPA on spontaneous motor activity and its dyskinesia-inducing effect share a common mechanism. To investigate the possible connection between these two effects, we analyzed the spontaneous locomotor activity of parkinsonian rats before surgery (unilateral injection of 6-OHDA in the right medial forebrain bundle, before treatment with L-DOPA, during L-DOPA treatment (the ON phase, and after the end of L-DOPA treatment (the OFF phase. We correlated the severity of dyskinesia (AIM scores with locomotor responses in the ON/OFF phases of chronic L-DOPA treatment at two different doses. We treated three groups of parkinsonian animals with chronic injections of 8 mg/kg L-DOPA, 6 mg/kg L-DOPA, and saline solution and one group of non-lesioned animals with 8 mg/kg L-DOPA. At the end of the experiment, tyrosine hydroxylase (TH immunoreactivity was analyzed in the striatum of all parkinsonian rats. We found no correlation between the severity of dyskinesia and spontaneous locomotor activity in the ON or OFF phase of L-DOPA treatment. The only observed correlation was between the pathological rotation induced by L-DOPA at the highest dose and locomotor activity in the ON phase of L-DOPA treatment. In addition, a L-DOPA withdrawal effect was observed, with worse motor performance in the OFF phase than before the start of L-DOPA treatment. These findings suggest that different neural mechanisms underlie the effect of L-DOPA on spontaneous motor activity and its dyskinesia-inducing effect, with a different dose-response relationship for each of these two effects.
Sebastianutto, Irene; Maslava, Natallia; Hopkins, Corey R; Cenci, M Angela
Rodent models of l-DOPA-induced dyskinesia (LID) are essential to investigate pathophysiological mechanisms and treatment options. Ratings of abnormal involuntary movements (AIMs) are used to capture both qualitative and quantitative features of dyskinetic behaviors. Thus far, validated rating scales for the mouse have anchored the definition of severity to the time during which AIMs are present. Here we have asked whether the severity of axial, limb, and orolingual AIMs can be objectively assessed with scores based on movement amplitude. Mice sustained 6-OHDA lesions in the medial forebrain bundle and were treated with l-DOPA (3-6mg/kg/day) until they developed stable AIMs scores. Two independent investigators rated AIM severity using both the validated time-based scale and a novel amplitude scale, evaluating the degree of deviation of dyskinetic body parts relative to their resting position. The amplitude scale yielded a high degree of consistency both within- and between raters. Thus, time-based scores, amplitude scores, and a combination of the two ('global AIM scores') were applied to compare antidyskinetic effects produced by amantadine and by the following subtype-specific DA receptor antagonists: SCH23390 (D1/D5), Raclopride (D2/D3), PG01037 (D3), L-745,870 (D4), and VU6004461 (D4). SCH23390 and Raclopride produced similarly robust reductions in both time-based scores and amplitude scores, while PG01037 and L-745,870 had more partial effects. Interestingly, a novel and highly brain penetrable D4 receptor antagonist (VU6004461) markedly attenuated both time-based and amplitude scores without diminishing the general motor stimulant effect of l-DOPA. In summary, our results show that a dyskinesia scale combining a time dimension with an amplitude dimension ('global AIMs') is more sensitive than unidimensional scales. Moreover, the antidyskinetic effects produced by two chemically distinct D4 antagonists identify the D4 receptor as a potential future target for
Wan, Ying; Wu, Na; Song, Lu; Wang, Xijin; Liu, Zhenguo; Yuan, Weien; Gan, Jing
Background: The long-term intermittent Levodopa (L-dopa) stimulation contributes to an aberrant activation of D1 receptor (D1R) mediated extracellular signal-regulated kinases1/2 (ERK1/2) in the striatal medium spiny neurons, resulting in the occurrence of L-dopa induced dyskinesia (LID). Recently, a novel signaling pathway, D1R/Shp-2/ERK1/2, was proposed to be required for the occurrence of LID. Here we designed the study in which two different methods of L-dopa delivery [continuous dopamine stimulation (CDS) vs. intermittent dopamine stimulation] were used to further identify: (1) the role of D1R/Shp-2/ERK1/2 signaling pathway in the occurrence of LID; (2) whether CDS alleviated LID though preventing the over-expression of the D1R/Shp-2/ERK1/2 signaling pathway. Methods: 6-OHDA-lesioned rat models of Parkinson's disease (PD) were randomly divided into two groups to receive intermittent L-dopa stimulation (L-dopa/benserazide standard group, LS group) or CDS (L-dopa/benserazide loaded microspheres, LBM group) for 21 days. Dyskinesia and anti-parkinsonian effect were compared between the two groups through the AIMs assessment and cylinder test. The critical protein changes in the D1R/Shp-2/ERK1/2 signaling pathway were compared between the two groups through Western blotting. Results: Intermittent L-dopa administration induced serious dyskinetic movements in the 6-OHDA-lesioned rats, and the anti-parkinsonian effect of L-dopa was gradually counteracted by the occurrence of dyskinesia. Intermittent L-dopa administration enhanced the expression of membrane D1R, and induced a robust increase of phosphorylation of Shp-2, Src, DARPP-32, and ERK1/2 in the 6-OHDA-lesioned striatum. In contrast, CDS played a dose-dependent anti-parkinsonian role, without inducing such apparent dyskinetic movements. Moreover, CDS induced no change of membrane D1R expression or phosphorylation of Shp-2, Src, DARPP-32, and ERK1/2 in the 6-OHDA-lesioned striatum. Conclusion: The aberrant
Ruiz de Diego, Irene
La enfermedad de Parkinson es una de las enfermedades neurodegenerativas más prevalentes en la actualidad. Se caracteriza por la muerte de las neuronas dopaminérgicas de la substantia nigra pars compacta, lo que conlleva la subsecuente depleción dopaminérgica a nivel estriatal. La L-DOPA constituye desde su descubrimiento a principio de la década de los sesenta el tratamiento de elección en la enfermedad de Parkinson, ya que es la terapia no invasiva más eficaz para combatir los síntomas de e...
Full Text Available Aggression is a major hallmark worldwide attributing negative traits in personality. Wide variety of antioxidants is used for the treatment of many ailments. The present study was conducted to evaluate the role of antioxidants such as ascorbic acid (15.42 and 30.84 mg/kg, beta carotene (1.02 and 2.05 mg/kg, vitamin E (2.5 and 5.0 mg/kg, and N-acetyl cysteine (102.85 and 205.70 mg/kg in the treatment of aggression. Two aggression models (isolation induced aggression model and L-DOPA induced aggression model were used in the study. Male albino mice (n = 330 were used in the study which were further subdivided into 11 groups (Group I-control, group II-diseased, group III-standard group, group IV–V treated with ascorbic, group VI–VII treated with beta carotene, group VIII–IX treated with vitamin E, group X–XI treated with N-acetyl cysteine for 14 consecutive days. Different biochemical markers (glutathione, superoxide dismutase, and catalase were determined to evaluate the antioxidant potential in oxidative stress. High dose of vitamin E (5.0 mg/kg was more effective to reduce the aggression in isolated animals while all other antioxidants produced dose-dependent anti-aggressive effect except N-acetyl cysteine which had marked anti-aggressive effect at low dose (102.75 mg/kg. Low doses of vitamin E (2.5 mg/kg and N-acetyl cysteine (102.75 mg/kg and high dose of beta carotene (2.05 mg/kg were effective to prevent all aggression parameters in acute anti-aggressive activity against L-DOPA induced aggression. However, all test antioxidants were equally effective in chronic anti-aggressive studies against L-DOPA induced aggression. It may be concluded that selected antioxidants can reverse the aggression which is a key symptom of many neurological disorder.
Dammann Andersen, Andreas; Binzer, Michael; Stenager, Egon
-dyskinetic PD patients and controls. Method: Cerebrospinal fluid (CSF) of 6 age-matched controls and 16 PD patients, (11 receiving levodopa, 6 dyskinetic and 6 not receiving levodopa), was analysed for catecholamines and metabolites by HPLC with electrochemical detection. Samples were collected after overnight...
F Hernández, Ledia; Castela, Ivan; Ruiz-DeDiego, Irene; Obeso, Jose A; Moratalla, Rosario
Long-term levodopa (l-dopa) treatment is associated with the development of l-dopa-induced dyskinesias in the majority of patients with Parkinson disease (PD). The etiopathogonesis and mechanisms underlying l-dopa-induced dyskinesias are not well understood. We used striatal optogenetic stimulation to induce dyskinesias in a hemiparkinsonian model of PD in rats. Striatal dopamine depletion was induced unilaterally by 6-hydroxydopamine injection into the medial forebrain bundle. For the optogenetic manipulation, we injected adeno-associated virus particles expressing channelrhodopsin to stimulate striatal medium spiny neurons with a laser source. Simultaneous optical activation of medium spiny neurons of the direct and indirect striatal pathways in the 6-hydroxydopamine lesion but l-dopa naïve rats induced involuntary movements similar to l-dopa-induced dyskinesias, labeled here as optodyskinesias. Noticeably, optodyskinesias were facilitated by l-dopa in animals that did not respond initially to the laser stimulation. In general, optodyskinesias lasted while the laser stimulus was applied, but in some instances remained ongoing for a few seconds after the laser was off. Postmortem tissue analysis revealed increased FosB expression, a molecular marker of l-dopa-induced dyskinesias, primarily in medium spiny neurons of the direct pathway in the dopamine-depleted hemisphere. Selective optogenetic activation of the dorsolateral striatum elicits dyskinesias in the 6-hydroxydopamine rat model of PD. This effect was associated with a preferential activation of the direct striato-nigral pathway. These results potentially open new avenues in the understanding of mechanisms involved in l-dopa-induced dyskinesias. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.
Astradsson, Arnar; Jenkins, Bruce G; Choi, Ji-Kyung
It has been suggested, based on rodent studies, that levodopa (L-dopa) induced dyskinesia is associated with a disrupted blood-brain barrier (BBB). We have investigated BBB integrity with in vivo neuroimaging techniques in six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned primates ...
Westin, Jenny E.; Lindgren, Hanna S.; Gardi, Jonathan Eyal
3,4-Dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia is associated with molecular and synaptic plasticity in the basal ganglia, but the occurrence of structural remodeling through cell genesis has not been explored. In this study, rats with 6-hydroxydopamine lesions received injections...
Navarrete, Roberto; Slawińska, Urszula; Vrbová, Gerta
In rats, hindlimb postural and locomotor functions mature during the first 3 postnatal weeks. Previous evidence indicates that maturation of descending monoaminergic pathways is important for the postnatal emergence of locomotion with adequate antigravity postural support. Here we have studied the effect of the monoamine precursor L-DOPA on locomotor activity in freely moving postnatal rats (7-9 days old) using electromyographic recordings from ankle extensor (soleus) and flexor (tibialis anterior or extensor digitorum longus) muscles. Before pharmacological treatment, both muscles were usually silent at rest, and during spontaneous movements there was a high degree of coactivation between the two antagonists. This was due to a longer electromyographic (EMG) burst duration in flexors, which partly overlapped with the extensor burst. L-DOPA administration (150 mg/kg) resulted in a marked increase in postural tonic EMG activity in extensors which appeared gradually within 10 min after injection and was sufficient for the pups to maintain a standing posture with the pelvis raised above ground. Thereafter, episodes of locomotion characterized by rhythmic reciprocal bursts of EMG activity in flexor and extensor muscles were seen. The L-DOPA-induced rhythmic EMG pattern was also seen in postnatal rats subjected to a midthoracic spinal cord transection, indicating that the effect of L-DOPA on motor coordination is exerted primarily at the level of the spinal pattern generator. Analysis of EMG burst characteristics showed that the pattern of L-DOPA-induced locomotion in both intact and spinalized postnatal rats resembled in some respects that observed in adults during spontaneous locomotion. The appearance of reciprocal activation during L-DOPA-induced locomotion in neonates was primarily due to a shortening of the EMG burst duration in flexors, which reduced the degree of antagonist coactivation. These results show that the spinal cord has the potential to produce
Morelli, Micaela; Blandini, Fabio; Simola, Nicola; Hauser, Robert A.
Dyskinesia, a major complication of treatment of Parkinson's disease (PD), involves two phases: induction, which is responsible for dyskinesia onset, and expression, which underlies its clinical manifestation. The unique cellular and regional distribution of adenosine A2A receptors in basal ganglia areas that are richly innervated by dopamine, and their antagonistic role towards dopamine receptor stimulation, have positioned A2A receptor antagonists as an attractive nondopaminergic target to improve the motor deficits that characterize PD. In this paper, we describe the biochemical characteristics of A2A receptors and the effects of adenosine A2A antagonists in rodent and primate models of PD on L-DOPA-induced dyskinesia, together with relevant biomarker studies. We also review clinical trials of A2A antagonists as adjuncts to L-DOPA in PD patients with motor fluctuations. These studies have generally demonstrated that the addition of an A2A antagonist to a stable L-DOPA regimen reduces OFF time and mildly increases dyskinesia. However, limited clinical data suggest that the addition of an A2A antagonist along with a reduction of L-DOPA might maintain anti-Parkinsonian benefit and reduce dyskinesia. Whether A2A antagonists might reduce the development of dyskinesia has not yet been tested clinically. PMID:22754707
Full Text Available L-dopa is the most effective, currently available treatment for Parkinson’s disease (PD, but it leads to the development of involuntary movements known as L-dopa-induced dyskinesia (LID in the majority of patients after long-term use. Both gene and cell therapy approaches are the subject of multiple ongoing studies as potential ways of relieving symptoms of PD without the complication of dyskinesia. However, the spectre of dyskinesia in the absence of L-dopa, the so-called “off-phase” or graft-induced dyskinesia (GID, remains a major obstacle particularly in the further development of cell therapy in PD, but it is also a concern for proponents of gene therapy approaches. LID results from nonphysiological dopamine release, supersensitivity of dopamine receptors, and consequent abnormal signalling through mechanisms of synaptic plasticity. Restoration of physiological circuitry within the basal ganglia loops is ultimately the aim of all cell and gene therapy approaches but each using distinctive strategies and accompanied by risks of exacerbation of LID or development of “off-phase”/GID. In this paper we discuss the details of what is understood regarding the development of dyskinesias with relevance to cell and gene therapy and potential strategies to minimize their occurrence.
Wictorin, K; Widner, H
The partial glutamate antagonist amantadine is currently used in clinical practice, to reduce dyskinesia developing as a side-effect of levodopa treatment in patients suffering from Parkinson's disease (PD). This study was aimed at evaluating the antidyskinetic effect of another glutamate antagonist, memantine. We performed a randomized, double-blind and placebo-controlled crossover clinical trial of memantine (20 mg), with a 3-week treatment period, and 15 patients completed the study. The primary outcome measure, a change in observed dyskinesia ratings, did not reach significance. Seven of the 15 patients reduced the L-dopa-induced dyskinesias by 32%, whereas for three patients, they increased by 33%, and for five patients, they did not change. Data from the self-administered diaries, as a secondary outcome measure, did show a significant 35% reduction in the percentage of time of the day spent with dyskinesia, from 25% (placebo) to 16% (memantine). Memantine was well tolerated, without any serious adverse events, or worsening in the parkinsonian motor score. The results suggest that memantine may be a useful antidyskinetic drug, and a larger clinical study is warranted. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Stockwell, K A; Scheller, D; Rose, S; Jackson, M J; Tayarani-Binazir, K; Iravani, M M; Smith, L A; Olanow, C W; Jenner, P
Rotigotine is a novel, non-ergoline dopamine D(3)/D(2)/D(1)-receptor agonist for the treatment of Parkinson's disease that can be continuously delivered by the transdermal route to provide stable plasma levels. Continuous drug delivery should reduce the risk of dyskinesia induction in comparison to pulsatile dopaminergic treatment. Thus the aim of the study was to compare the reversal of motor disability and induction of dyskinesia produced by continuous compared to pulsatile rotigotine administration in MPTP-treated common marmosets. The study also investigated whether pulsatile or continuous rotigotine administration in combination with l-DOPA prevented l-DOPA-induced dyskinesia. Animals were treated for 28 days with vehicle or pulsatile (twice daily) or continuous delivery of rotigotine (via an osmotic minipump). Subsequently, l-DOPA was then co-administered for a further 28 days. Animals were assessed for locomotor activity, motor disability and dyskinesia induction. The study showed that both continuous and pulsatile administration of rotigotine improved motor deficits and normalized motor function in MPTP-treated monkeys. However, continuous rotigotine delivery reduced dyskinesia expression compared to pulsatile treatment. Both pulsatile and continuous rotigotine administration produced less dyskinesia than administration of l-DOPA alone. The addition of l-DOPA to either pulsatile or continuous rotigotine treatment resulted in the induction of marked dyskinesia similar to that produced by treatment with l-DOPA alone. These data further support the hypothesis that continuous delivery of a dopaminergic agent reduces the risk of dyskinesia induction. However, continuous rotigotine administration did not prevent l-DOPA from inducing dyskinesia suggesting that l-DOPA may induce dyskinesia by mechanisms different from dopamine agonist drugs.
Mehta, Shyamal H; Morgan, John C; Sethi, Kapil D
Paroxysmal dyskinesias are a rare group of movement disorders affecting both adults and children. Based on the events that precipitate the abnormal movements, they are subdivided into paroxysmal kinesigenic dyskinesia (PKD), precipitated by sudden voluntary movements; paroxysmal nonkinesigenic dyskinesia (PNKD), which occurs at rest; paroxysmal exertion-induced dyskinesia (PED), occurring after prolonged exercise; and paroxysmal hypnogenic dyskinesia (PHD), which occurs in sleep. Paroxysmal dyskinesias can be sporadic, familial (autosomal dominant inheritance), or secondary to other disorders. Recent genetic discoveries may aid us in elucidating the pathophysiology of these disorders. PKD has been linked to the pericentromeric region of chromosome 16, PNKD is associated with mutations in the myofibrillogenesis regulator 1 (MR-1) gene on the long arm of chromosome 2 (2q32-36 locus), and PED is associated with mutations in the glucose transporter gene, GLUT1, responsible for glucose transport across the blood-brain barrier. Lifestyle modification to avoid precipitating factors is important in the management of paroxysmal dyskinesias. Medical therapies have not been examined in controlled trials. Nevertheless, anticonvulsants have been found to be extremely effective in treating PKD and are sometimes useful in other types, suggesting that these disorders may indeed represent forms of channelopathies. Drugs such as acetazolamide, anticholinergics, levodopa, and tetrabenazine have been inconsistently successful. In rare cases with medically refractory symptoms, deep brain stimulation has also been employed. Development of successful treatments for the different paroxysmal dyskinesias rests on elucidating the pathophysiology and targeting therapy to treat the underlying perturbation.
... prior to starting therapy. Other drugs such as benzodiazepines, clozapine, or botulinum toxin injections also may be tried. Prognosis Symptoms of tardive dyskinesia may remain long after discontinuation of neuroleptic drugs. In many cases, the symptoms ...
Reset Control Systems addresses the analysis for reset control treating both its basic form which requires only that the state of the controller be reinitialized to zero (the reset action) each time the tracking error crosses zero (the reset condition), and some useful variations of the reset action (partial reset with fixed or variable reset percentage) and of the reset condition (fixed or variable reset band and anticipative reset). The issues regarding reset control – concepts and motivation; analysis tools; and the application of design methodologies to real-world examples – are given comprehensive coverage. The text opens with an historical perspective which moves from the seminal work of the Clegg integrator and Horowitz FORE to more recent approaches based on impulsive/hybrid control systems and explains the motivation for reset compensation. Preliminary material dealing with notation, basic definitions and results, and with the definition of the control problem under study is also included. The fo...
Malmlöf, Torun; Rylander, Daniella; Alken, Rudolf-Giesbert; Schneider, Frank; Svensson, Torgny H; Cenci, M Angela; Schilström, Björn
Treatment of Parkinson's disease is complicated by a high incidence of L-DOPA-induced dyskinesias (LID). Strategies to prevent the development of LID aim at providing more stable dopaminergic stimulation. We have previously shown that deuterium substitutions in the L-DOPA molecule (D3-L-DOPA) yield dopamine that appears more resistant to enzymatic breakdown. We here investigated the effects of D3-L-DOPA on motor performance and development of dyskinesias in a rodent model of Parkinson's disease. Through acute experiments, monitoring rotational behavior, dose-effect curves were established for D3-L-DOPA and L-DOPA. The equipotent dose of D3-L-DOPA was estimated to be 60% of L-DOPA. Subsequently, animals were treated with either the equipotent dose of D3-L-DOPA (5 mg/kg), the equivalent dose of D3-L-DOPA (8 mg/kg), L-DOPA (8 mg/kg) or vehicle. The equivalent dose of D3-L-DOPA produced superior anti-akinetic effects compared to L-DOPA in the cylinder test (pdeuterium substitutions in the molecule. These results are of clinical interest since the occurrence of LID is related to the total L-DOPA dose administered. D3-L-DOPA may thus represent a novel strategy to reduce the total dose requirement and yet achieve an effective control of parkinsonian symptoms. Copyright © 2010 Elsevier Inc. All rights reserved.
Bagetta, Vincenza; Sgobio, Carmelo; Pendolino, Valentina; Del Papa, Giulia; Tozzi, Alessandro; Ghiglieri, Veronica; Giampà, Carmela; Zianni, Elisa; Gardoni, Fabrizio; Calabresi, Paolo; Picconi, Barbara
Dopamine replacement with levodopa (L-DOPA) represents the mainstay of Parkinson’s disease (PD) therapy. Nevertheless, this well established therapeutic intervention loses efficacy with the progression of the disease and patients develop invalidating side effects, known in their complex as L-DOPA-induced dyskinesia (LID). Unfortunately, existing therapies fail to prevent LID and very few drugs are available to lessen its severity, thus representing a major clinical problem inPDtreatment. D2-like receptor (D2R) agonists are a powerful clinical option as an alternative to L-DOPA, especially in the early stages of the disease, being associated to a reduced risk of dyskinesia development. D2R agonists also find considerable application in the advanced stages of PD, in conjunction with L-DOPA, which is used in this context at lower dosages, to delay the appearance and the extent of the motor complications. In advanced stages of PD, D2R agonists are often effective in delaying the appearance and the extent of motor complications. Despite the great attention paid to the family of D2R agonists, the main reasons underlying the reduced risk of dyskinesia have not yet been fully characterized. Here we show that the striatal NMDA/AMPAreceptor ratio and theAMPAreceptor subunit composition are altered in experimental parkinsonism in rats. Surprisingly, while L-DOPA fails to restore these critical synaptic alterations, chronic treatment with pramipexole is associated not only with a reduced risk of dyskinesia development but is also able to rebalance, in a dose-dependent fashion, the physiological synaptic parameters, thus providing new insights into the mechanisms of dyskinesia.
Nakawah, Mohammad Obadah; Lai, Eugene C
.... Post-stroke dyskinesias are involuntary hyperkinetic movements arising from cerebrovascular insults and often present with mixed phenotypes of hyperkinesia which can sometimes be difficult to classify...
Full Text Available BackgroundLong-term use of levodopa (l-dopa is inevitably complicated with highly disabling fluctuations and drug-induced dyskinesias, which pose major challenges to the existing drug therapy of Parkinson’s disease.MethodsIn this study, we conducted a systematic review and meta-analysis to assess the efficacy of A2A receptor antagonists on reducing l-dopa-induced dyskinesias (LID.ResultsNine studies with a total of 152 animals were included in this meta-analysis. Total abnormal involuntary movements (AIM score, locomotor activity, and motor disability were reported as outcome measures in 5, 5, and 3 studies, respectively. Combined standardized mean difference (SMD estimates were calculated using a random-effects model. We pooled the whole data and found that, when compared to l-dopa alone, A2A receptor antagonists plus l-dopa treatment showed no effect on locomotor activity (SMD −0.00, 95% confidence interval (CI: −2.52 to 2.52, p = 1.0, superiority in improvement of motor disability (SMD −5.06, 95% CI: −9.25 to −0.87, p = 0.02 and more effective in control of AIM (SMD −1.82, 95% CI: −3.38 to −0.25, p = 0.02.ConclusionTo sum up, these results demonstrated that A2A receptor antagonists appear to have efficacy in animal models of LID. However, large randomized clinical trials testing the effects of A2A receptor antagonists in LID patients are always warranted.
Full Text Available Mohammad Obadah Nakawah, Eugene C Lai Stanely H. Appel Department of Neurology, Houston Methodist Neurological Institute, Houston, TX, USA Abstract: Strokes, whether ischemic or hemorrhagic, are among the most common causes of secondary movement disorders in elderly patients. Stroke-related (vascular movement disorders, however, are uncommon complications of this relatively common disease. The spectrum of post-stroke movement disorders is broad and includes both hypo- and hyperkinetic syndromes. Post-stroke dyskinesias are involuntary hyperkinetic movements arising from cerebrovascular insults and often present with mixed phenotypes of hyperkinesia which can sometimes be difficult to classify. Nevertheless, identification of the most relevant motor phenotype, whenever possible, allows for a more specific phenomenological categorization of the dyskinesia and thus helps guide its treatment. Fortunately, post-stroke dyskinesias are usually self-limiting and resolve within 6 to 12 months of onset, but a short-term pharmacotherapy might sometimes be required for symptom control. Functional neurosurgical interventions targeting the motor thalamus or globus pallidus interna might be considered for patients with severe, disabling, and persistent dyskinesias (arbitrarily defined as duration longer than 12 months. Keywords: vascular dyskinesia, stroke, movement disorders
Andersen, Andreas Dammann; Blaabjerg, Morten; Binzer, Michael; Kamal, Akram; Thagesen, Helle; Kjaer, Troels Wesenberg; Stenager, Egon; Gramsbergen, Jan Bert Paul
Levodopa (l-DOPA, l-3,4-dihydroxyphenylalanine) is the most effective drug in the symptomatic treatment of Parkinson's disease (PD), but chronic use initiates a maladaptive process leading to l-DOPA-induced dyskinesia (LID). Risk factors for early onset LID include younger age, more severe disease at baseline and higher daily l-DOPA dose, but biomarkers to predict the risk of motor complications are not yet available. Here, we investigated whether CSF levels of catecholamines and its metabolites are altered in PD patients with LID [PD-LID, n = 8)] as compared to non-dyskinetic PD patients receiving l-DOPA (PD-L, n = 6), or not receiving l-DOPA (PD-N, n = 7) as well as non-PD controls (n = 16). PD patients were clinically assessed using the Unified Parkinson's Disease Rating Scale and Unified Dyskinesia Rating Scale and CSF was collected after overnight fasting and 1-2 h after oral intake of l-DOPA or other anti-Parkinson medication. CSF catecholamines and its metabolites were analyzed by HPLC with electrochemical detection. We observed (i) decreased levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid in PD patients not receiving l-DOPA (ii) higher dopamine (DA) levels in PD-LID as compared to controls (iii) higher DA/l-DOPA and lower DOPAC/DA ratio's in PD-LID as compared to PD-L and (iv) an age-dependent increase of DA and decrease of DOPAC/DA ratio in controls. These results suggest increased DA release from non-DA cells and deficient DA re-uptake in PD-LID. Monitoring DA and DOPAC in CSF of l-DOPA-treated PD patients may help identify patients at risk of developing LID. © 2017 International Society for Neurochemistry.
Sphincter of Oddi dyskinesia is a functional disorder of the papillary region which can lead to clinical symptoms due to functional obstruction of biliary and pancreatic outflow. Based on the severity of the clinical symptoms the disorder can be graded into three types (biliary and pancreatic types I-III). The manometric diagnosis of this disorder using sphincter of Oddi manometry is hampered by the relatively high risk of pancreatitis after endoscopic retrograde cholangiopancreatography. Although papillary manometry is often carried out in North America, in Europe this is the exception rather than the rule. Manometrically, sphincter of Oddi dyskinesia is characterized by an increased pressure in the biliary and/or the pancreatic sphincter segments and can be treated by endoscopic papillotomy. This overview counterbalances the arguments for primary invasive diagnostics and a pragmatic clinical approach, i.e. papillotomy should be directly carried out when a sphincter of Oddi dyskinesia is clinically suspected. For patients with biliary or pancreatic type I, endoscopic papillotomy is the treatment of choice. In biliary type II sphincter of Oddi manometry could be helpful for clinical decision-making; however, the exact risk-benefit ratio is still difficult to assess. In type III patient selection and the low predictive value of manometry for treatment success questions the clinical usefulness of sphincter of Oddi manometry.
Ivanova, S. A.; Loonen, A. J. M.; Pechlivanoglou, P.; Freidin, M. B.; Al Hadithy, A. F. Y.; Rudikov, E. V.; Zhukova, I. A.; Govorin, N. V.; Sorokina, V. A.; Fedorenko, O. Y.; Alifirova, V. M.; Semke, A. V.; Brouwers, J. R. B. J.; Wilffert, B.
Dyskinesias are involuntary muscle movements that occur spontaneously in Huntington's disease (HD) and after long-term treatments for Parkinson's disease (levodopa-induced dyskinesia; LID) or for schizophrenia (tardive dyskinesia, TD). Previous studies suggested that dyskinesias in these three
Tegeler, J; Wöller, W
Studies on the treatments for neuroleptic-induced tardive dyskinesia published in the literature are reviewed. The great number of different treatments and the controversial results of most studies show that there is as yet no specific and safe treatment for tardive dyskinesia. Suggestions for well-designed treatment studies are given: Placebo-controlled double-blind design, larger patient populations, clear diagnostic and standard observing and rating conditions using different assessment methods and videotapes, withdrawal of neuroleptics and antiparkinsonian drugs to discover reversible tardive dyskinesia. If this procedure is not feasible, neuroleptics and other drugs should be maintained at a stable dose level. Longer term studies of some months are necessary to study the prolonged efficacy of different drugs. The effect of dopamine-antagonists such as neuroleptics and of dopamine-depleting agents such as reserpine and oxypertine is of limited duration. Dopamine-agonists such as L-Dopa, bromocriptine and amantadine help only few patients and may even aggravate the symptoms of tardive dyskinesia. In some double-blind studies cholinergic drugs such as lecithin and deanol have improved tardive dyskinesia, but further controlled studies are needed. Anticholinergic drugs such as antiparkinsonian agents should not be prescribed because they may aggravate tardive dyskinesia. Some patients respond to GABA-ergic agents such as baclofen, sodium valproate and the benzodiazepines, but further studies are needed before the value of GABA-ergic agents in the treatment of tardive dyskinesia can be properly assessed. After withdrawal of neuroleptics the average of remission rates within a year is 20%-30%. Elderly patients are more likely to have persistent dyskinesias. A progressive stepwise diminution of the neuroleptic dose and of the antiparkinsonian agents is recommended. When a patient's psychosis is exacerbated after withdrawal of the neuroleptics and tardive dyskinesia
... ADCY5 -related dyskinesia typically appear as sudden (paroxysmal) jerks, twitches, tremors, muscle tensing (dystonia), or writhing (choreiform) ... OMIM (1 link) DYSKINESIA, FAMILIAL, WITH FACIAL MYOKYMIA Sources for This Page Carapito R, Paul N, Untrau ...
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Vijayakumar, Dhanya; Jankovic, Joseph
Dyskinesias encompass a variety of different hyperkinetic phenomenologies, particularly chorea, dystonia, stereotypies, and akathisia. Levodopa-induced dyskinesia (LID) is one of the main types of drug-induced dyskinesia, occurring in patients with Parkinson's disease (PD) who have been treated with levodopa for long time, but this side effect may be encountered even within a few weeks or months after initiation of levodopa therapy. Based on the temporal pattern in relationship to levodopa dosing, LIDs are divided into "peak-dose dyskinesia," "diphasic dyskinesia," and "wearing off" or "off-period" dyskinesia, of which peak-dose dyskinesia is the most common, followed by off-period, and then diphasic dyskinesia. Treatment strategy includes identifying the kind of dyskinesia and tailoring treatment accordingly. Peak-dose dyskinesia is treated mainly by reducing individual doses of levodopa and adding amantadine and dopamine agonists, whereas off-period dystonia often responds to baclofen and botulinum toxin injections. Diphasic dyskinesias, occurring particularly in patients with young-onset PD, are the most difficult to treat. While fractionation of levodopa dosage is the most frequently utilized strategy, many patients require deep brain stimulation to control their troublesome motor fluctuations and LIDs. A variety of emerging (experimental) drugs currently in development promise to provide better control of LIDs and other levodopa-related complications in the near future.
S.A. Ivanova; A.J.M. Loonen (Anton); P. Pechlivanoglu (Petros); M.B. Freidin (M.); A.F.Y. Al Hadithy (Asmar); E.V. Rudikov (E.); I.A. Zhukova (I.); N.V. Govorin (N.); V.A. Sorokina (V.); O. Fedorenko (Olga); V.M. Alifirova (V.); A. Semke; J.R.B.J. Brouwers (Koos); B. Wilffert (Bob)
textabstractDyskinesias are involuntary muscle movements that occur spontaneously in Huntington's disease (HD) and after long-term treatments for Parkinson's disease (levodopa-induced dyskinesia; LID) or for schizophrenia (tardive dyskinesia, TD). Previous studies suggested that dyskinesias in these
Mary Anne Kowal Olm
Full Text Available Primary ciliary dyskinesia (PCD is a genetic disorder of ciliary structure or function. It results in mucus accumulation and bacterial colonization of the respiratory tract which leads to chronic upper and lower airway infections, organ laterality defects, and fertility problems. We review the respiratory signs and symptoms of PCD, as well as the screening tests for and diagnostic investigation of the disease, together with details related to ciliary function, ciliary ultrastructure, and genetic studies. In addition, we describe the difficulties in diagnosing PCD by means of transmission electron microscopy, as well as describing patient follow-up procedures.
Pookala S Bhat
Full Text Available Tardive dyskinesia (TD, neuroleptic-induced delayed onset movement disorder, remains an enigmatic phenomenon and a therapeutic challenge. Only a few cases of dysphagia also have been reported in world literature and to the best knowledge of the authors no case of TD manifesting as isolated dysphagia has been reported so far from India. We report a case of TD consequent to prolonged exposure to typical neuroleptics, manifesting as isolated dysphagia who responded well to a combination of Quetiapine, Donepezil and Vit E.
Lee, Kyoung J.; Goldstein, Raymond E.; Cox, Edward C.
The mechanism by which spiral wave patterns appear in populations of Dictyostelium was probed experimentally by external chemical perturbation. Spiral waves, which often arise from the breakup of circular waves driven by pacemakers, typically entrain those pacemakers. We studied these processes by resetting the waves with a spatially uniform pulse of extrinsic cyclic AMP. A pattern of spirals reappeared if resetting was early in the signaling stage, but only targets emerged following late resetting, in a manner analogous to cardiac defibrillation. This supports recent hypotheses that wave pattern selection naturally occurs by slow temporal variation of the excitability of the cells.
Loonen, A. J. M.; Ivanova, S. A.; Pechlivanoglou, P.; Rudikov, E.; Zhukova, I.; Al Hadithy, A. F. Y.; Alifirova, V.; Brouwers, J. R. B. J.; Semke, A.; Wilffert, B.
Dyskinesia occurs as clinical feature of Huntington's Disease (HD) and as an adverse consequence of chronic exposure to levodopa in Parkinson's disease (levodopa-induced dyskinesia, LID) and to antipsychotic drugs in schizophrenia (tardive dyskinesia, TD). Arning et al. have reported that specific
Chadda, R.; Kulhara, P.
SUMMARY This study reports the results of an open trial of Sodium Valproate in tardive-dyskinesia. Fifteen patients identified having tardive dyskinesia by two psychiatrists independently were treated with Sodium Valproate in dosage of 1200 mg/day for 4 weeks. Assessments were made on abbreviated Dyskinesia Scale. There was statistically significant improvement after 2 and 4 weeks of treatment. Authors found Sodium Valproate quite effective in the management of tardive-dyskinesia.
Loonen, Anton J. M.; Ivanova, Svetlana A.
Dyskinesia is an extrapyramidal movement disorder characterized by involuntary, repetitive, irregular motions that affect the mouth and face and/or the limbs and trunk. Tardive dyskinesia (TD) is a well-known complication of long-term treatment with antipsychotic drugs. Dyskinesia is also induced
Evans, Martin R.; Majumdar, Satya N.
We consider diffusion in arbitrary spatial dimension d with the addition of a resetting process wherein the diffusive particle stochastically resets to a fixed position at a constant rate r. We compute the nonequilibrium stationary state which exhibits non-Gaussian behaviour. We then consider the presence of an absorbing target centred at the origin and compute the survival probability and mean time to absorption of the diffusive particle by the target. The mean absorption time is finite and has a minimum value at an optimal resetting rate r which depends on dimension. Finally we consider the problem of a finite density of diffusive particles, each resetting to its own initial position. While the typical survival probability of the target at the origin decays exponentially with time regardless of spatial dimension, the average survival probability decays asymptotically as exp ( - A(ln t)d) where A is a constant. We explain these findings using an interpretation as a renewal process and arguments invoking extreme value statistics.
Roy van Dalm
Like the Great Depression and the Long Depression before it, experts have viewed prolonged economic downturns as crises. In The Great Reset , bestselling author Richard Florida argues that we should instead see the recent recession as an opportunity to create entirely new ways of working and living
Werner, Claudius; Lablans, Martin; Ataian, Maximilian
Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder leading to chronic upper and lower airway disease. Fundamental data on epidemiology, clinical presentation, course and treatment strategies are lacking in PCD. We have established an international PCD registry to realise an u...
Full Text Available Marty Hinz,1 Alvin Stein,2 Ted Cole3 1Clinical Research, NeuroResearch Clinics, Cape Coral, FL, 2Stein Orthopedic Associates, Plantation, FL, 3Cole Center for Healing, Cincinnati, OH, USA Abstract: When ʟ-dopa use began in the early 1960s for the treatment of Parkinson's disease, nausea and reversible dyskinesias were experienced as continuing side effects. Carbidopa or benserazide was added to ʟ-dopa in 1975 solely to control nausea. Subsequent to the increasing use of carbidopa has been the recognition of irreversible dyskinesias, which have automatically been attributed to ʟ-dopa. The research into the etiology of these phenomena has identified the causative agent of the irreversible dyskinesias as carbidopa, not ʟ-dopa. The mechanism of action of the carbidopa and benserazide causes irreversible binding and inactivation of vitamin B6 throughout the body. The consequences of this action are enormous, interfering with over 300 enzyme and protein functions. This has the ability to induce previously undocumented profound antihistamine dyskinesias, which have been wrongly attributed to ʟ-dopa and may be perceived as irreversible if proper corrective action is not taken. Keywords: vitamin B6, PLP, irreversible, pyridoxal 5'-phosphate
Miguel E. Litvin
Full Text Available This study presents a novel design approach combining wave pipelining and self reset logic, which provides an elegant solution at high-speed data throughput with significant savings in power and area as compared with other dynamic CMOS logic implementations. To overcome some limitations in SRL art, we employ a new SRL family, namely, dual-rail self reset logic with input disable (DRSRL-ID. These gates depict fairly constant timing parameters, specially the width of the output pulse, for varying fan-out and logic depth, helping accommodate process, supply voltage, and temperature variations (PVT. These properties simplify the implementation of wave pipelined circuits. General timing analysis is provided and compared with previous implementations. Results of circuit implementation are presented together with conclusions and future work.
Full Text Available In this paper, we present a new reset tree-based scheme to protect cryptographic hardware against optical fault injection attacks. As one of the most powerful invasive attacks on cryptographic hardware, optical fault attacks cause semiconductors to misbehave by injecting high-energy light into a decapped integrated circuit. The contaminated result from the affected chip is then used to reveal secret information, such as a key, from the cryptographic hardware. Since the advent of such attacks, various countermeasures have been proposed. Although most of these countermeasures are strong, there is still the possibility of attack. In this paper, we present a novel optical fault detection scheme that utilizes the buffers on a circuit’s reset signal tree as a fault detection sensor. To evaluate our proposal, we model radiation-induced currents into circuit components and perform a SPICE simulation. The proposed scheme is expected to be used as a supplemental security tool.
OBJECTIVES: This is one of the first cases reported in the literature of paliperidone-palmitate-induced prolonged dyskinesia. METHOD: Case report. RESULTS: We report the case of a 49-year-old woman with paranoid schizophrenia who developed orofacial dyskinesia some 4 months after the commencement of paliperidone long-acting injection. CONCLUSION: This case serves as a clinical reminder that dyskinesia can occur with all antipsychotic medications.
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Full Text Available Nadirah Damseh,1 Nada Quercia,1,2 Nisreen Rumman,3 Sharon D Dell,4 Raymond H Kim5 1Division of Clinical and Metabolic Genetics, 2Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; 3Pediatric Department, Makassed Hospital, Jerusalem, Palestine; 4Division of Respiratory Medicine, Department of Pediatrics, Child Health Evaluative Sciences, Hospital for Sick Children, 5Fred A Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Department of Medicine, University of Toronto, Toronto, ON, Canada Abstract: Primary ciliary dyskinesia is a genetically heterogeneous disorder of motile cilia that is predominantly inherited in an autosomal-recessive fashion. It is associated with abnormal ciliary structure and/or function leading to chronic upper and lower respiratory tract infections, male infertility, and situs inversus. The estimated prevalence of primary ciliary dyskinesia is approximately one in 10,000–40,000 live births. Diagnosis depends on clinical presentation, nasal nitric oxide, high-speed video-microscopy analysis, transmission electron microscopy, genetic testing, and immunofluorescence. Here, we review its clinical features, diagnostic methods, molecular basis, and available therapies. Keywords: genetic testing, Kartagener’s syndrome, primary ciliary dyskinesia
Pérez Pérez, F M; Sánchez Salado, J
The Takotsubo syndrome, also called transient apical dyskinesia syndrome, was first described in Japan in the 1990s. It is a rare entity found in almost 1% of all patients with suspicion of acute coronary syndrome. It usually affects postmenopausal women with a few cardiovascular risk factors. It is characterized by angina-type chest pain, electrocardiographic changes, elevation of the enzymes of myocardial injury, absence of coronary obstruction on angiography, and a characteristic left ventricular anteroapical dyskinesia, which returns to normal within a few days. Severe emotional stress is the most common trigger for this syndrome. The aetiopathogenesis of this syndrome remains to be defined. This syndrome has been considered a clinical condition since 2001, when a series of 88 cases was published. It is a disease with a partially known mechanism, characterised by the morphology adopted by the left ventricle secondary to hypokinesis or dyskinesia of the apical segments, and hypercontractility of basal segments. Unlike acute coronary syndrome, patients with left ventricle dysfunction do not have atherothrombotic disease in the coronary arteries. In addition, the alterations described are reversible. Some clinical diagnostic criteria have been proposed, although they are still controversial, as well as in the complementary examinations required for diagnosis. Copyright © 2012 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.
Izumi, K; Tominaga, H; Koja, T; Nomoto, M; Shimizu, T; Sonoda, H; Imamura, K; Igata, A; Fukuda, T
Tardive dyskinesia seems to occur as a result of diminished cholinergic and enhanced dopaminergic activity in the striatum. Meclofenoxate has been shown to increase cerebral cholinergic activity. To ameliorate the tardive dyskinesia, meclofenoxate was given orally, 600-1200 mg/day, for 6-12 weeks. The effects of the drug were evaluated by scoring the degree of involuntary movement. Among 11 subjects with tardive dyskinesia or dystonia, 4 improved markedly, 1 moderately, 2 slightly, and there was no improvement in 4. One patient with subacute oral dyskinesia, induced by administration of neuroleptics for 1 month, improved markedly. The possibility that meclofenoxate may be effective in dealing with dyskinesias that are induced by neuroleptics warrants further attention.
Mapanao, Ratchaneegorn; Kuo, Hsin-Wei; Chang, Chin-Chuan; Liu, Kuan-Fu; Cheng, Winton
L-3,4-Dihydroxyphenylalanine (l-DOPA) is a precursor for dopamine (DA) synthesis. Assessments were conducted to analyze the effects of l-DOPA on mediating regulation of neuroendocrinological, immunological, and physiological parameters in the shrimp, Litopenaeus vannamei when they were individually injected with 0.01 N HCl or l-DOPA at 0.5 or 1.0 μmol shrimp -1 for 60, 120, and 240 min. For catecholamine synthesis evaluation, tyrosine hydroxylase (TH) and DA beta hydroxylase (DBH) activities, l-DOPA, DA, and norepinephrine (NE) levels in hemolymph were determined. The total hemocyte count (THC), differential hemocyte count (DHC), phenoloxidase (PO) activity, respiratory bursts (RBs), superoxide dismutase (SOD) activity, phagocytic activity, and clearance efficiency in response to the pathogen, Vibrio alginolyticus were assessed for immune responses, and plasma glucose and lactate levels were for physiological response. Results showed that the TH activity, THC, hyaline cells (HCs), and semigranular cells (SGCs) at 120 min, DA levels at 60-240 min, PO activity in hemocytes per 50 μL of hemolymph at 60-120 min, and PO activity per granulocyte (granular cells (GCs) + SGCs) at 60 min significantly increased, but TH activity, l-DOPA levels, GCs, SGCs, and respiratory bursts in hemocytes per 10 μL of hemolymph at 60 min, respiratory bursts per hemocyte and SOD activity at 120 min, phagocytic activity at 60-240 min, and the clearance efficiency at 60-120 min significantly decreased in shrimp injected with l-DOPA at 1.0 μmol shrimp -1 . In another experiment, 60 min after shrimp had received l-DOPA at 0.5 or 1.0 μmol shrimp -1 , they were challenged with an injection of V. alginolyticus at 2 × 10 5 colony-forming units (cfu) shrimp -1 . The injection of l-DOPA at 1.0 μmol shrimp -1 also significantly increased the cumulative mortality of shrimp by 16.7%, compared to the HCl-challenged control after 120 h. These results suggest that l-DOPA administration at 1.0 μmol shrimp -1 can mediate the transient regulation of neuroendocrinological, immunological, and physiologic responses resulting in immunosuppression, which in turn promoted the susceptibility of L. vannamei to V. alginolyticus. Copyright © 2018 Elsevier Ltd. All rights reserved.
Wu Tai Tsun; Wu, Tai Tsun; Yu, Ming Lun
A model is presented for the quantum memory, the content of which is a pure quantum state. In this model, the fundamental operations of writing on, reading, and resetting the memory are performed through scattering from the memory. The requirement that the quantum memory must remain in a pure state after scattering implies that the scattering is of a special type, and only certain incident waves are admissible. An example, based on the Fermi pseudo-potential in one dimension, is used to demonstrate that the requirements on the scattering process are consistent and can be satisfied. This model is compared with the commonly used model for the quantum memory; the most important difference is that the spatial dimensions and interference play a central role in the present model.
A nonce is a cryptographic input value which must never repeat within a given context. Nonces are important for the security of many cryptographic building blocks, such as stream ciphers, block cipher modes of operation, and message authentication codes. Nonetheless, the correct generation...... of nonces is rarely discussed in the cryptographic literature. In this paper, we collect a number of nonce generators and describe their cryptographic properties. In particular, we derive upper bounds on the nonce collision probabilities of nonces that involve a random component, and lower bounds...... current state. After describing this problem, we compare the resistance of the nonce generators described to nonce resets by again giving formal bounds on collision probabilities and nonce lengths. The main purpose of this paper is to provide a help for system designers who have to choose a suitable nonce...
Inada, T; Yagi, G
This article reviews current topics in tardive dyskinesia (TD), a movement disorder associated with the prolonged use of neuroleptic agents, especially therapeutic and preventive strategies which have been or are now being studied in Japan. Tardive dyskinesia has become a major problem in the clinical psychiatric field since the early 1970s in Japan, lagging behind Western countries by more than 10 years. The average prevalence rate of TD has been estimated as 7.7% in Japan, while it has been reported in the English literature at around 15 to 20%. Clinical trials of treatments for TD have been or are now being performed in Japan with a number of novel compounds, such as ceruletide, meclofenoxate, and rolipram; however, no effective treatment has yet been established and measures to prevent TD have therefore been emphasized. These include (i) the development of new antipsychotic drugs which are free from TD, (ii) the identification of risk factors from prospective longitudinal studies, and (iii) the investigation of genetic variations that could act as a marker to identify especially vulnerable patients within the whole population of patients who need neuroleptic therapy.
Harris, Rosemary J.; Touchette, Hugo
We study the large deviations of additive quantities, such as energy or current, in stochastic processes with intermittent reset. Via a mapping from a discrete-time reset process to the Poland-Scheraga model for DNA denaturation, we derive conditions for observing first-order or continuous dynamical phase transitions in the fluctuations of such quantities and confirm these conditions on simple random walk examples. These results apply to reset Markov processes, but also show more generally that subleading terms in generating functions can lead to non-analyticities in large deviation functions of ‘compound processes’ or ‘random evolutions’ switching stochastically between two or more subprocesses.
Andreoli, Daniel C; Whittier, William L
A reset osmostat as a cause of hyponatremia can be found in a variety of clinical settings, including pulmonary and neurologic diseases, as well as in physiologic circumstances such as pregnancy. This teaching case describes a 72-year-old white man with a long-standing history of self-medicating with desmopressin acetate (DDAVP) who presented with profound hyponatremia. On discontinuation of DDAVP treatment, he was found to have a reset osmostat. The mild hyponatremia persisted on follow-up. We theorize that the reset osmostat may have developed secondary to long-standing DDAVP use. Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
Approved for public release; distribution is unlimited. All mobile phones use internal flash memory to store information. The flash memory contains personal user data that can be extracted with the use of forensics tools. This information could be used to profile a user's daily activity. However, all smartphones provide a tool to erase (factory reset) the information from the flash memory. Twenty-one smartphones were used to evaluate the effectiveness of the factory-reset feature. A set of...
should be aware that notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply with a collection of...LIMITATION OF ABSTRACT Same as Report (SAR) 18. NUMBER OF PAGES 52 19a. NAME OF RESPONSIBLE PERSON a. REPORT unclassified b. ABSTRACT unclassified...summarizes budgetary information for Reset (Procurement) and forwards approved items (by BLIN ) Navy takes budgetary figures for Ground Reset and
existence and uniqueness of solutions, and in particular to the resetting times to be well defined and distinct. A sufficient condition is developed for a reset system to have well-posed resetting times, which is also a sufficient condition for avoiding Zeno solutions and, thus, for a reset control system to be well-posed.
Biliary dyskinesia is a functional gastrointestinal disorder of the gallbladder and sphincter of Oddi. Diagnosis is made on the basis of symptoms of biliary colic in the absence of cholelithiasis and gallbladder inflammation. Palpatory findings of tissue texture changes at midthoracic levels (T6-T9) may correspond to visceral dysfunction related to the biliary system. Osteopathic manipulative treatment (OMT) of the T6-T9 segments can remove the feedback related to the somatic component, thereby affecting nociceptive facilitation at the spinal level and allowing the body to restore autonomic balance. Few reports in the current literature provide examples of treatment for patients with biliary dyskinesia using OMT. The author describes the case of a 51-year-old woman who presented with symptoms consistent with biliary dyskinesia. Her biliary colic completely resolved after OMT. Osteopathic evaluation and OMT should be considered a safe and effective option for conservative management of biliary dyskinesia.
Swoboda, KJ; Soong, BW; McKenna, C; Brunt, ERP; Litt, M; Bale, JF; Ashizawa, T; Bennett, LB; Bowcock, AM; Roach, ES; Gerson, D; Matsuura, T; Heydemann, PT; Nespeca, MP; Jankovic, J; Leppert, M; Ptacek, LJ
Objective: To clinically characterize affected individuals in families with paroxysmal kinesigenic dyskinesia (PEM), examine the association with infantile convulsions, and confirm linkage to a pericentromeric chromosome 16 locus. Background: PKD is characterized by frequent, recurrent attacks of
Swoboda, KJ; Soong, BW; McKenna, C; Brunt, ERP; Litt, M; Bale, JF; Ashizawa, T; Bennett, LB; Bowcock, AM; Roach, ES; Gerson, D; Matsuura, T; Heydemann, PT; Nespeca, MP; Jankovic, J; Leppert, M; Ptacek, LJ
Objective: To clinically characterize affected individuals in families with paroxysmal kinesigenic dyskinesia (PKD), examine the association with infantile convulsions, and confirm linkage to a pericentromeric chromosome 16 locus. Background PKD is characterized by frequent, recurrent attacks of
Oliver, Brett D. (Inventor); Caltagirone, Joseph (Inventor); Brickner, Christopher (Inventor)
An apparatus comprises first and second modules configured to operate in a lockstep mode and a reset mode. Each of the first and second modules is configured to asynchronously enter the reset mode when a parent reset signal is asserted at the respective each module. Each of the first and second modules is configured to, in response to the asserted parent reset signal being negated at the respective each module, indicate to the respective other module that the respective each module is ready to exit the reset mode and exit the reset mode when the respective other module has also indicated that the respective other module is ready to exit the reset mode.
Full Text Available Primary ciliary dyskinesia (PCD is a rare, genetically heterogeneous disease, characterized by ciliary disfunction and impaired mucociliary clearance, resulting in a range of clinical manifestations such as chronic bronchitis, bronchiectasis, chronic rhino-sinusitis, chronic otitis media, situs viscerum inversus in almost 40-50% of cases and male infertility. The triad situs viscerum inversus, bronchiectasis and sinusitis is known as Kartagener syndrome. Up to now little is known about genetic, diagnostic and therapeutic aspects of primary motile ciliary diseases in children: for this reason, diagnosis is generally delayed and almost all treatments for PCD are not based on randomized studies but extrapolated from cystic fibrosis guidelines. The aim of this review is to propose to pediatricians a summary of current clinical and diagnostic evidence to obtain better knoledwge of this condition. The earlier diagnosis and the right treatment are both crucial to improve the prognosis of PCD.
Sawada, Hideyuki; Oeda, Tomoko; Kuno, Sadako; Nomoto, Masahiro; Yamamoto, Kenji; Yamamoto, Mitsutoshi; Hisanaga, Kinya; Kawamura, Takashi
Dyskinesias are some of the major motor complications that impair quality of life for patients with Parkinson's disease. The purpose of the present study was to investigate the efficacy of amantadine in Parkinson's disease patients suffering from dyskinesias. In this multi-center, double-blind, randomized, placebo-controlled, cross-over trial, 36 patients with Parkinson's disease and dyskinesias were randomized, and 62 interventions, which included amantadine (300 mg/day) or placebo treatment for 27 days, were analyzed. At 15 days after washout, the treatments were crossed over. The primary outcome measure was the changes in the Rush Dyskinesia Rating Scale (RDRS) during each treatment period. The secondary outcome measures were changes in the Unified Parkinson's Disease Rating Scale part IVa (UPDRS-IVa, dyskinesias), part IVb (motor fluctuations), and part III (motor function). RDRS improved in 64% and 16% of patients treated with amantadine or placebo, respectively, with significant differences between treatments. The adjusted odds-ratio for improvement by amantadine was 6.7 (95% confidence interval, 1.4 to 31.5). UPDRS-IVa was improved to a significantly greater degree in amantadine-treated patients [mean (SD) of 1.83 (1.56)] compared with placebo-treated patients [0.03 (1.51)]. However, there were no significant effects on UPDRS-IVb or III scores. Results from the present study demonstrated that amantadine exhibited efficacious effects against dyskinesias in 60-70% of patients. UMIN Clinical Trial Registry UMIN000000780.
M. AUGUSTA MONTENEGRO; ANNA ELISA SCOTONI; FERNANDO CENDES
Phenytoin is an effective antiepileptic drug, although, it can be associated with many side effects, including dyskinesia. OBJECTIVE: To describe the clinical characteristics of phenytoin induced dyskinesia. METHODS: We investigated the occurrence of involuntary movements in patients followed at our adult and pediatric epilepsy clinics during the period of one year. RESULTS: Three patients presented with phenytoin-induced dyskinesia: one adult with axial and orofacial dyskinesia, and two chil...
Kjøller, E; Køber, L; Jørgensen, S
the nine segment model, scoring 3 for hyperkinesia, 2 for normokinesia, 1 for hypokinesia, 0 for akinesia, and -1 for dyskinesia. Calculation of WMI either included information on dyskinesia or excluded this information by giving dyskinesia the same score as akinesia. MAIN OUTCOME MEASURES: Long term...
Full Text Available Dystonia is defined as a neurological syndrome characterized by involuntary sustained or intermittent muscle contractions causing twisting, often repetitive movements and postures. Paroxysmal dyskinesias are episodic movement disorders encompassing dystonia, chorea, athetosis and ballism in conscious individuals. Several decades of research have enhanced the understanding of the etiology of human dystonia and dyskinesias that are associated with dystonia, but the pathophysiology remains largely unknown. The spontaneous occurrence of hereditary dystonia and paroxysmal dyskinesia is well documented in rodents used as animal models in basic dystonia research. Several hyperkinetic movement disorders, described in dogs, horses and cattle, show similarities to these human movement disorders. Although dystonia is regarded as the third most common movement disorder in humans, it is often misdiagnosed because of the heterogeneity of etiology and clinical presentation. Since these conditions are poorly known in veterinary practice, their prevalence may be underestimated in veterinary medicine. In order to attract attention to these movement disorders, i.e. dystonia and paroxysmal dyskinesias associated with dystonia, and to enhance interest in translational research, this review gives a brief overview of the current literature regarding dystonia/paroxysmal dyskinesia in humans, and summarizes similar hereditary movement disorders reported in domestic animals.
Daniel M. Williams
Full Text Available Paroxysmal hypnogenic dyskinesia is a rare clinical entity characterized by intermittent dystonia and choreoathetoid movements that begin exclusively during sleep, often with consciousness preserved once the patient is awakened during the episodes. They occur almost every night and are often misdiagnosed as sleeping disorders. Paroxysmal hypnogenic dyskinesia is currently known to be a form of frontal lobe epilepsy, but not in all cases. We present a 19-year-old male patient with paroxysmal hypnogenic dyskinesia who responded to antihistamines. This supports an alternative theory from 1977 (before the cases had been adequately described that the disorder lies in dysregulation in the basal ganglia. This description now appears similar to acute dystonic reactions such as extrapyramidal symptoms from antipsychotic medications, which also respond to antihistamines.
Full Text Available BACKGROUND: Dyskinesias are some of the major motor complications that impair quality of life for patients with Parkinson's disease. The purpose of the present study was to investigate the efficacy of amantadine in Parkinson's disease patients suffering from dyskinesias. METHODS: In this multi-center, double-blind, randomized, placebo-controlled, cross-over trial, 36 patients with Parkinson's disease and dyskinesias were randomized, and 62 interventions, which included amantadine (300 mg/day or placebo treatment for 27 days, were analyzed. At 15 days after washout, the treatments were crossed over. The primary outcome measure was the changes in the Rush Dyskinesia Rating Scale (RDRS during each treatment period. The secondary outcome measures were changes in the Unified Parkinson's Disease Rating Scale part IVa (UPDRS-IVa, dyskinesias, part IVb (motor fluctuations, and part III (motor function. RESULTS: RDRS improved in 64% and 16% of patients treated with amantadine or placebo, respectively, with significant differences between treatments. The adjusted odds-ratio for improvement by amantadine was 6.7 (95% confidence interval, 1.4 to 31.5. UPDRS-IVa was improved to a significantly greater degree in amantadine-treated patients [mean (SD of 1.83 (1.56] compared with placebo-treated patients [0.03 (1.51]. However, there were no significant effects on UPDRS-IVb or III scores. CONCLUSIONS: Results from the present study demonstrated that amantadine exhibited efficacious effects against dyskinesias in 60-70% of patients. TRIAL REGISTRATION: UMIN Clinical Trial Registry UMIN000000780.
Porkolab, F L; Alpert, B L; Scheinman, M M
A patient with a right atriofascicular (Mahaim) tachycardia was found to have inducible antidromic supraventricular tachycardia, but atrial premature beats from the right atrial free wall failed to reset the tachycardia. An interesting transition from AV nodal reentry tachycardia to Mahaim tachycardia is also presented.
Polenkova, Svetlana; Polderman, Jan W.; Langerak, Romanus
In this work we perform a stability analysis for a class of switched linear systems, modeled as hybrid automata. We deal with a switched linear planar system, modeled by a hybrid automaton with one discrete state. We assume the guard on the transition is a line in the state space and the reset map
Full Text Available This exploratory study assessed the pattern of closed-loop baroreflex resetting using multi-logistic-curve analysis. Operating point gain and ranges of RR-interval (RRI and systolic blood pressure (SBP are derived to examine how these relate to sympathetic activation. Sustained low-intensity isometric handgrip exercise, with a period of post-exercise circulatory occlusion (PECO, provided a model to study baroreflex resetting because the progression toward fatigue at constant tension induces a continuous increase in volitional contribution to neuro-cardiovascular control. Continuous measurements of muscle sympathetic nerve activity (MSNA, blood pressure, and RRI were made simultaneously throughout the experimental session. Spontaneous sequence analysis was used to detect episodes of baroreflex “engagements”, but the results are examined with a view to the fundamental difference between experimental conditions that isolate the carotid sinus (open-loop and intact physiological conditions (closed-loop. While baroreflex function under open-loop conditions can be described in terms of a single logistic curve, intact physiologic conditions require a family of logistic curves. The results suggest that the baroreflex is in a “floating” state whereby it is continuously resetting during the timeline of the experiment but with minute-by-minute average values that mimic the less complex step-wise resetting pattern reported under open-loop conditions. Furthermore, the results indicate that baroreflex function and resetting of the operating point gain is reflected not in terms of change in the values of blood pressure or RR-interval but in terms of change in the range of values of these variables prevailing under different experimental conditions.
Lai, Sarah W; Rothenberg, Steven S; Kay, Saundra M; Shipman, Kristin E; Slater, Bethany J
To determine the outcomes of laparoscopic cholecystectomy as a treatment for biliary dyskinesia in children. With ethics approval, a retrospective chart review was performed on children (resolution. Laparoscopic cholecystectomy was performed in 215 children with biliary dyskinesia (156/215 [72.6%] female, age 13.8 ± 3.4 years, body mass index [BMI] 22.3 ± 6.3 kg/m 2 ). 181/206 (87.9%) had EF 181 (89.5%). Chronic cholecystitis was found in 183/213 (85.9%) and unexpected cholelithiasis in 4/213 (1.9%) on pathology. Postoperatively, 6/181 (3.3%) had wound infections and 8/181 (4.4%) required common bile duct stents for the following indications: 6 sphincter of Oddi dysfunction, 1 choledocholithiasis, and 1 stricture. Virgin abdomen (odds ratio [OR] 4.03, confidence interval [95% CI] 1.12-14.53, P = .0460) and follow-up resolution for biliary dyskinesia in children. Virgin abdomen and follow-up <6 months were associated with better outcomes. Prospective long-term studies comparing surgical and nonoperative management of biliary dyskinesia are required to determine the utility of cholecystectomy.
Dooley, Joseph M; Brna, Paula M
Familial paroxysmal nonkinesigenic dyskinesia (Mount and Reback syndrome) is characterized by episodes of dystonia and chorea, which are precipitated by fatigue, emotional stress, alcohol, or foods. We report two children from a large kindred with this condition who responded to sublingual lorazepam.
Purpose: To determine the risk factors involved in the onset of dyskinesias in patients suffering from Parkinson's disease in South Africa. Methods: A questionnaire survey and medical record review were conducted. A total of 43 patients with Parkinson's disease in two metropolitan areas were included in the study. Results: ...
Renato Puppi Munhoz
Full Text Available One of the main indications for stereotactic surgery in Parkinson’s disease (PD is the control of levodopa induced dyskinesia. This can be achieved by by pallidotomy and globus pallidus internus (GPi deep brain stimulation (DBS or by subthalamotomy and subthalamic nucleus (STN DBS, which usually allow for a cut down in the dosage of levodopa. DBS has assumed a pivotal role in stereotactic surgical treatment of PD and, in fact, ablative procedures are currently considered surrogates, particularly when bilateral procedures are required, as DBS does not produce a brain lesion and the stimulator can be programmed to induce better therapeutic effects while minimizing adverse effects. Interventions in either the STN and the GPi seem to be similar in controlling most of the other motor aspects of PD, nonetheless, GPi surgery seems to induce a more particular and direct effect on dyskinesia, while the antidyskinetic effect of STN interventions is mostly dependent on a reduction of dopaminergic drug dosages. Hence, the si ne qua non condition for a reduction of dyskinesia when STN interventions are intended is their ability to allow for a reduction of levodopa dosage. Pallidal surgery is indicated when dyskinesia is a dose-limiting factor for maintaining or introducing higher adequate levels of dopaminergic therapy. Also medications used for the treatment of PD may be useful for the improvement of several non-motor aspects of the disease, including sleep, psychiatric, and cognitive domains, therefore, dose reduction of medication withdrawal are not always a fruitful objective.
Background: Primary ciliary dyskinesia is a genetically heterogeneous autosomal recessive disorder with variable clinical manifestations, including chronic rhinosinusitis, otitis media, bronchitis, pneumonia, bronchiectasis, situs inversus totalis, reduced fertility in female patients and male infertility. The condition occurs as a ...
van Strien, Teun W.; van Rootselaar, Anne-Fleur; Hilgevoord, Anthony A. J.; Linssen, Wim H. J. P.; Groffen, Alexander J. A.; Tijssen, Marina A. J.
Paroxysmal kinesigenic dyskinesia (PKD) is characterized by involuntary dystonia and/or chorea triggered by a sudden movement. Cases are usually familial with an autosomal dominant inheritance. Hypotheses regarding the pathogenesis of PKD focus on the controversy whether PKD has a cortical or
Paszkowski, Jerzy; Grossniklaus, Ueli
Transgenerational epigenetic inheritance (TEI), which is the inheritance of expression states and thus traits that are not determined by the DNA sequence, is often postulated but the molecular mechanisms involved are only rarely verified. This especially applies to the heritability of environmentally induced traits, which have gained interest over the last years. Here we will discuss selected examples of epigenetic inheritance in plants and artificially divide them according to the occurrence of inter-generational resetting. The decision which epigenetic marks are reset and which ones are not is crucial for the understanding of TEI. We will consider examples of epialleles found in natural populations and epialleles induced by genetic and/or environmental factors used in experimental setups. Copyright © 2011 Elsevier Ltd. All rights reserved.
Full Text Available Mobile devices usually provide a “factory-reset” tool to erase user-specific data from the main secondary storage. 9 Apple iPhones, 10 Android devices, and 2 BlackBerry devices were tested in the first systematic evaluation of the effectiveness of factory resets. Tests used the Cellebrite UME-36 Pro with the UFED Physical Analyzer, the Bulk Extractor open-source tool, and our own programs for extracting metadata, classifying file paths, and comparing them between images. Two phones were subjected to more detailed analysis. Results showed that many kinds of data were removed by the resets, but much user-specific configuration data was left. Android devices did poorly at removing user documents and media, and occasional surprising user data was left on all devices including photo images, audio, documents, phone numbers, email addresses, geolocation data, configuration data, and keys. A conclusion is that reset devices can still provide some useful information to a forensic investigation.
Nomura, Taishin; Kawa, Kazuyoshi; Suzuki, Yasuyuki; Nakanishi, Masao; Yamasaki, Taiga
Dynamic stability during periodic biped gait in humans and in a humanoid robot is considered. Here gait systems of human neuromusculoskeletal system and a humanoid are simply modeled while keeping their mechanical properties plausible. We prescribe periodic gait trajectories in terms of joint angles of the models as a function of time. The equations of motion of the models are then constrained by one of the prescribed gait trajectories to obtain types of periodically forced nonlinear dynamical systems. Simulated gait of the models may or may not fall down during gait, since the constraints are made only for joint angles of limbs but not for the motion of the body trunk. The equations of motion can exhibit a limit cycle solution (or an oscillatory solution that can be considered as a limit cycle practically) for each selected gait trajectory, if an initial condition is set appropriately. We analyze the stability of the limit cycle in terms of Poincaré maps and the basin of attraction of the limit cycle in order to examine how the stability depends on the prescribed trajectory. Moreover, the phase resetting of gait rhythm in response to external force perturbation is modeled. Since we always prescribe a gait trajectory in this study, reacting gait trajectories during the phase resetting are also prescribed. We show that an optimally prescribed reacting gait trajectory with an appropriate amount of the phase resetting can increase the gait stability. Neural mechanisms for generation and modulation of the gait trajectories are discussed.
Full Text Available During human aging there is an increase in the activity of inflammatory, cancer promoting, and tissue destructive genes plus a decrease in the activity of regenerative and reparative genes. The human blood tripeptide GHK possesses many positive effects but declines with age. It improves wound healing and tissue regeneration (skin, hair follicles, stomach and intestinal linings, and boney tissue, increases collagen and glycosaminoglycans, stimulates synthesis of decorin, increases angiogenesis, and nerve outgrowth, possesses antioxidant and anti-inflammatory effects, and increases cellular stemness and the secretion of trophic factors by mesenchymal stem cells. Recently, GHK has been found to reset genes of diseased cells from patients with cancer or COPD to a more healthy state. Cancer cells reset their programmed cell death system while COPD patients’ cells shut down tissue destructive genes and stimulate repair and remodeling activities. In this paper, we discuss GHK’s effect on genes that suppress fibrinogen synthesis, the insulin/insulin-like system, and cancer growth plus activation of genes that increase the ubiquitin-proteasome system, DNA repair, antioxidant systems, and healing by the TGF beta superfamily. A variety of methods and dosages to effectively use GHK to reset genes to a healthier state are also discussed.
Full Text Available Background Paroxysmal kinesigenic dyskinesia (PKD is a disorder characterized by recurrent and brief dystonic or choreoathetoid attacks that are induced by sudden voluntary movement with highly clinical and genetic heterogeneity. We aimed to investigate the clinical features of PKD in a large Chinese population. Methods One hundred and ninety five patients diagnosed as primary PKD were recruited. For all of the participants, neurological examinations were conducted and clinical manifestations were recorded and summarized in self - made uniform registration form for PKD patients. Clinical characteristics were statistically analyzed and compared between familial and sporadic PKD patients. Results Among all of the 195 PKD patients in the present study, the gender ratio was 4.42∶1 (male∶ female. The average age of onset was (12.32 ± 3.49 years. There were 162 patients (83.08% manifestated with pure form and 33 (16.92% with complicated form of PKD. Among them 16 patients (8.21% had essential tremor (ET, and 144 patients (73.85% had premonitory symptom. The percentage of patients manifested as dystonia, chorea and mixed form during episodic attacks were 68.72% (134/195, 4.10% (8/195 and 27.18% (53/195 repectively. There were 134 cases (68.72% had facial involvement. It was recorded that 115 (58.97%, 54 (27.69% and 26 (13.33% patients had frequency of attack < 10 times/d, 10-20 times/d and > 20-30 times/d respectively. The percentages of patients whose duration of attack <10 s, 10-30 s and > 30-60 s were 60% (117/195, 29.74% (58/195 and 10.26% (20/195 respectively. There were 64 patietns (32.82% with family history of PKD and 131 (67.18% were sporadic PKD patients. Up to 40% (78/195 of patients did not require/take medications, as they had minor clinical manifestations or concerns about the side effects of anticonvulsants. Among 117 patients (60% prescribed with anticonvulsants, 114 patients showed a good response, including complete control (N
Haagensen, Brian N.; Nielsen, Silas H.; Madsen, Kristoffer H.; Løkkegaard, Annemette; Siebner, Hartwig R.
ABSTRACT Background Levodopa‐induced dyskinesias are a common side effect of dopaminergic therapy in PD, but their neural correlates remain poorly understood. Objectives This study examines whether dyskinesias are associated with abnormal dopaminergic modulation of resting‐state cortico‐striatal connectivity. Methods Twelve PD patients with peak‐of‐dose dyskinesias and 12 patients without dyskinesias were withdrawn from dopaminergic medication. All patients received a single dose of fast‐acting soluble levodopa and then underwent resting‐state functional magnetic resonance imaging before any dyskinesias emerged. Levodopa‐induced modulation of cortico‐striatal resting‐state connectivity was assessed between the putamen and the following 3 cortical regions of interest: supplementary motor area, primary sensorimotor cortex, and right inferior frontal gyrus. These functional connectivity measures were entered into a linear support vector classifier to predict whether an individual patient would develop dyskinesias after levodopa intake. Linear regression analysis was applied to test which connectivity measures would predict dyskinesia severity. Results Dopaminergic modulation of resting‐state connectivity between the putamen and primary sensorimotor cortex in the most affected hemisphere predicted whether patients would develop dyskinesias with a specificity of 100% and a sensitivity of 91% (P resting‐state connectivity between the supplementary motor area and putamen predicted interindividual differences in dyskinesia severity (R 2 = 0.627, P = .004). Resting‐state connectivity between the right inferior frontal gyrus and putamen neither predicted dyskinesia status nor dyskinesia severity. Conclusions The results corroborate the notion that altered dopaminergic modulation of cortico‐striatal connectivity plays a key role in the pathophysiology of dyskinesias in PD. © 2016 International Parkinson and Movement Disorder Society PMID:26954295
Kong, Min; Ba, Maowen; Ren, Chao; YU Ling; Dong, Shengjie; Yu, Guoping; Liang, Hui
In recent years, a few of randomized controlled trials (RCTs) about amantadine for treating dyskinesia in Parkinson's disease (PD) were completed. Here, we conducted a systematic literature review about the clinical research to provide the updated evidence for treating dyskinesia. Electronic search of Medline, PubMed, Cochrane Library, and other databases up to May 2016 for relevant studies was performed. We selected the Unified Parkinson's Disease Rating Scale IV (UPDRS IV) and Dyskinesia Ra...
Quintela, Cátia; Meireles, Cláudia; Bettencourt, Maria João; Ribeirinho, Augusto; Bentes, Teresa
Primary ciliary dyskinesia is an autosomal recessive disease with a clinical history of upper and lowers respiratory infections, rhinosinusitis and bronquitis associated with complete or partial situs inversus. The authors present a 78 -year -old male caucasian patient with rhinosinusitis, lower respiratory tract infection and dyspnea, chronic otitis with hearing deficit and infertility followed in Gastroenterology for dyspepsia and constipation. The radiological studies revealed agenesis of right frontal sinus; bronchial wall thickening; bronchiectasis; cecum and ascending colon located on the left and small bowel occupies right side of abdomen. He had no immunodeficiency, allergies, cystic fibrosis and others. We concluded primary ciliary dyskinesia with heterotaxy. For the rarity of this case we decided to present it.
Full Text Available Gastroesophageal reflux (GER disease is a significant comorbidity of neuromuscular disorders. It may present as paroxysmal dyskinesia, an entity known as Sandifer syndrome. A 6-week-old neonate presented with very frequent paroxysms of generalized stiffening and opisthotonic posture since day 22 of life. These were initially diagnosed as seizures and he was started on multiple antiepileptics which did not show any response. After a normal video electroencephalogram (VEEG was documented, possibility of dyskinesia was kept. However, when he did not respond to symptomatic therapy, Sandifer syndrome was thought of and GER scan was done, which revealed severe GER. After his symptoms got reduced to some extent, a detailed clinical examination revealed abnormal facies with flaccid quadriparesis. Muscle biopsy confirmed the diagnosis of a specific congenital myopathy. On antireflux measures, those episodic paroxysms reduced to some extent. Partial response to therapy in GER should prompt search for an underlying secondary etiology.
Full Text Available Tardive dyskinesia (TD from long-term neuroleptic treatment may be irreversible; therefore prevention has become a major concern. A controversial issue with regard to the clinical use of neuroleptic drugs is the possible influence on the development of TD of drug holidays. The major characteristics of kindling, theories of TD and the role of multiplicity in the development of TD are described. Some clinical studies point to interruption of neuroleptic therapy being a risk factor for development of irreversible TD. Induction of dyskinesia in non-human primates has been demonstrated after repeated administration of haloperidol. Rodent studies have not been conclusive. Several experimental results link TD with kindling: both conditions involve repeated stimulations, both seem to involve increased receptor responsiveness and in both conditions does depression in GABA transmission in SNR (substantia nigra; pars reticulata play an important role. It is concluded that the kindling hypothesis is relevant to the investigation of TD.
Alimi, M.; Gaillard, P; Camus, V.; El-Hage, W.
Background and Objectives: Tardive dyskinesia (TD) is a frequent and incapacitating side effect of first-generation antipsychotics. Although second-generation antipsychotics (SGAs) seem to be associated with a decreased risk of TD, it remains a severe, unresolved iatrogenic condition. Moreover, there is no commonly accepted effective treatment for TD. We conducted a systematic review of the literature to assess evidence regarding the effectiveness of different therapeutic interventions for TD...
Boomershine, K H; Shelton, P S; Boomershine, J E
To review the efficacy of vitamin E in the treatment of tardive dyskinesia (TD). Published articles and abstracts in English were identified from January 1986 to March 1999 by MEDLINE and International Pharmaceutical Abstracts searches using the terms vitamin E, alpha-tocopherol, and tardive dyskinesia. Additional articles were identified from the references of the retrieved articles and cross- referencing selected articles. All clinical trials evaluating the use of vitamin E in human subjects with TD were reviewed. Selected articles also included those considered to be helpful in providing a basic introduction to TD pathophysiology and management. TD occurs in approximately 20% of patients treated with neuroleptics. The resulting dyskinesias can be irreversible and are often psychologically and physically debilitating. Recent research suggests that TD may be a result of neuronal damage inflicted by free radicals generated from increased neurotransmitter turnover and metabolism. Vitamin E as a naturally occurring free radical scavenger has been evaluated in the treatment of TD. Eighteen completed trials are available either in completed or abstract form. Twelve of these trials have produced positive results with vitamin E in the treatment of TD. Patients who have had TD for less than five years appear to respond better than patients with long-standing TD. Research suggests that vitamin E offers benefit in the management of a subgroup of patients with TD. Further investigation is needed to ascertain continued efficacy with long-term use as well as the role of vitamin E in TD prophylaxis.
Marthin, June K; Petersen, Nadia; Skovgaard, Lene T
Early diagnosis and treatment is considered important to prevent lung damage in primary ciliary dyskinesia (PCD).......Early diagnosis and treatment is considered important to prevent lung damage in primary ciliary dyskinesia (PCD)....
Circuit measures constant or slowly-varying unidirectional electrical current using flux-reset transformer coupling. Measurement nonintrusive in sense that no need for direct contact with wire that carries load current to be measured, and no need to install series resistive element in load-current path. Toroidal magnetic core wrapped with coil of wire placed around load-current-carrying wire, acts as transformer core, load-current-carrying wire acts as primary winding of transformer, and coil wrapped on core acts as secondary winding.
Riqui Schwamm; Rowe, Neil C.
Mobile devices usually provide a “factory-reset” tool to erase user-specific data from the main secondary storage. 9 Apple iPhones, 10 Android devices, and 2 BlackBerry devices were tested in the first systematic evaluation of the effectiveness of factory resets. Tests used the Cellebrite UME-36 Pro with the UFED Physical Analyzer, the Bulk Extractor open-source tool, and our own programs for extracting metadata, classifying file paths, and comparing them between images. Two phones were subje...
Biundo, Roberta; Weis, Luca; Abbruzzese, Giovanni; Calandra-Buonaura, Giovanna; Cortelli, Pietro; Jori, Maria Cristina; Lopiano, Leonardo; Marconi, Roberto; Matinella, Angela; Morgante, Francesca; Nicoletti, Alessandra; Tamburini, Tiziano; Tinazzi, Michele; Zappia, Mario; Vorovenci, Ruxandra Julia; Antonini, Angelo
Impulse control disorders and dyskinesia are common and disabling complications of dopaminergic treatment in Parkinson's disease. They may coexist and are possibly related. The objectives of this study were to assess the frequency and severity of impulse control disorders in Parkinson's disease patients with dyskinesia. The ALTHEA study enrolled 251 Parkinson's disease patients with various degrees of dyskinesia severity from 11 movement disorders centers in Italy. Each patient underwent a comprehensive assessment including Unified Dyskinesia Rating Scale and the Questionnaire for Impulsive Compulsive Disorders in Parkinson Disease-Rating Scale. There was an overall 55% frequency of impulse control disorder and related behaviors (36% were clinically significant). The positive patients were younger at disease diagnosis and onset and had higher Unified Dyskinesia Rating Scale historical and total score (P = 0.001 and P = 0.02, respectively, vs negative). There was an increased frequency of clinically significant impulse control disorders in patients with severe dyskinesia (P = 0.013), a positive correlation between the questionnaire total score and dopamine agonist dose (P = 0.018), and a trend with levodopa dose. More than half of Parkinson's disease patients with dyskinesia have impulse control disorders and related behaviors, which are frequently clinically significant. Dopaminergic therapy total dose is associated with their severity. Clinicians should carefully assess patients with maladaptive behaviors and dyskinesia because they do not properly evaluate their motor and nonmotor status. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.
Groffen, Alexander J. A.; Klapwijk, Thom; van Rootselaar, Anne-Fleur; Groen, Justus L.; Tijssen, Marina A. J.
Paroxysmal dyskinesia (PxD) is a group of movement disorders characterized by recurrent episodes of involuntary movements. Familial paroxysmal kinesigenic dyskinesia (PKD) is caused by PRRT2 mutations, but a distinct etiology has been suggested for sporadic PKD. Here we describe a cohort of patients
Herz, Damian M.; Haagensen, Brian N.; Nielsen, Silas H.
Background: Levodopa-induced dyskinesias are a common side effect of dopaminergic therapy in PD, but their neural correlates remain poorly understood. Objectives: This study examines whether dyskinesias are associated with abnormal dopaminergic modulation of resting-state cortico-striatal connect...
Verhagen Metman, L.; del Dotto, P.; van den Munckhof, P.; Fang, J.; Mouradian, M. M.; Chase, T. N.
To determine the effects of the N-methyl-D-aspartate (NMDA) antagonist amantadine on levodopa-associated dyskinesias and motor fluctuations in Parkinson's disease (PD). NMDA receptor blockade can ameliorate levodopa-induced dyskinesias in primates and PD patients. Amantadine, a well-tolerated and
Ren, Chao; Yu, Ling; Dong, Shengjie; Yu, Guoping; Liang, Hui
In recent years, a few of randomized controlled trials (RCTs) about amantadine for treating dyskinesia in Parkinson's disease (PD) were completed. Here, we conducted a systematic literature review about the clinical research to provide the updated evidence for treating dyskinesia. Electronic search of Medline, PubMed, Cochrane Library, and other databases up to May 2016 for relevant studies was performed. We selected the Unified Parkinson's Disease Rating Scale IV (UPDRS IV) and Dyskinesia Rating Scales (DRS) as efficacy outcomes of amantadine on dyskinesia. Pooled data from included studies was then used to carry out meta-analysis. A total of eleven eligible RCTs that involved 356 PD patients with existing dyskinesia were included in the present study. The results of meta-analysis showed that amantadine significantly improved UPDRS IV (P Parkinson's Disease Rating Scale III after amantadine treatment in advanced PD patients with dyskinesia (P = 0.01) compared with placebo. High dosage of amantadine obviously improved existing dyskinesia in PD, yet at the expense of the increased adverse events. It was necessary to detect the optimal therapeutic efficacy to balance the incidence of adverse events when we used amantadine to treat existing dyskinesia in PD patients. PMID:28915672
Packer, R A; Patterson, E E; Taylor, J F; Coates, J R; Schnabel, R D; O'Brien, D P
Paroxysmal dyskinesias are episodes of abnormal, involuntary movement or muscle tone, distinguished from seizures by the character of the episode and lack of seizure activity on ictal EEG. Paroxysmal dyskinesia is an inherited, autosomal recessive disorder in Chinook dogs. Families of Chinook dogs with paroxysmal dyskinesia. Pedigrees and medical histories were reviewed for 299 Chinook dogs. A family of 51 dogs was used for analysis. Episodes were classified as seizures, paroxysmal dyskinesia, or unknown, and segregation analysis was performed. Paroxysmal dyskinesia was identified in 16 of 51 dogs and characterized by an inability to stand or ambulate, head tremors, and involuntary flexion of 1 or multiple limbs, without autonomic signs or loss of consciousness. Episode duration varied from minutes to an hour. Inter-ictal EEGs recorded on 2 dogs with dyskinesia were normal. Three dogs with dyskinesia also had generalized tonic-clonic seizures. One of 51 dogs had episodes of undetermined type. Phenotype was unknown for 6 of 51 dogs, and 28 dogs were unaffected. Segregation was consistent with an autosomal recessive trait. This movement disorder is prevalent in the Chinook breed, and consistent with a partially penetrant autosomal recessive or polygenic trait. Insufficient evidence exists for definitive localization; episodes may be of basal nuclear origin, but atypical seizures and muscle membrane disorders remain possible etiologies. The generalized seizures may be a variant phenotype of the same mutation that results in dyskinesia, or the 2 syndromes may be independent. Copyright © 2010 by the American College of Veterinary Internal Medicine.
Keijsers, N.L.W.; Horstink, M.W.I.M.; Gielen, C.C.A.M.
It is well known that long-term use of levodopa by patients with Parkinson's disease causes dyskinesia. Several methods have been proposed for the automatic, unsupervised detection and classification of levodopa induced dyskinesia. Recently, we have demonstrated that neural networks are highly
Convertino, V. A.; Ludwig, D. A.; Elliott, J. J.; Wade, C. E.
In the early phase of the Space Shuttle program, NASA flight surgeons implemented a fluid-loading countermeasure in which astronauts were instructed to ingest eight 1-g salt tablets with 960 ml of water approximately 2 hours prior to reentry from space. This fluid loading regimen was intended to enhance orthostatic tolerance by replacing circulating plasma volume reduced during the space mission. Unfortunately, fluid loading failed to replace plasma volume in groundbased experiments and has proven minimally effective as a countermeasure against post-spaceflight orthostatic intolerance. In addition to the reduction of plasma volume, central venous pressure (CVP) is reduced during exposure to actual and groundbased analogs of microgravity. In the present study, we hypothesized that the reduction in CVP due to exposure to microgravity represents a resetting of the CVP operating point to a lower threshold. A lower CVP 'setpoint' might explain the failure of fluid loading to restore plasma volume. In order to test this hypothesis, we conducted an investigation in which we administered an acute volume load (stimulus) and measured responses in CVP, plasma volume and renal functions. If our hypothesis is true, we would expect the elevation in CVP induced by saline infusion to return to its pre-infusion levels in both HDT and upright control conditions despite lower vascular volume during HDT. In contrast to previous experiments, our approach is novel in that it provides information on alterations in CVP and vascular volume during HDT that are necessary for interpretation of the proposed CVP operating point resetting hypothesis.
Roldán, Édgar; Gupta, Shamik
We study the dynamics of overdamped Brownian particles diffusing in conservative force fields and undergoing stochastic resetting to a given location at a generic space-dependent rate of resetting. We present a systematic approach involving path integrals and elements of renewal theory that allows us to derive analytical expressions for a variety of statistics of the dynamics such as (i) the propagator prior to first reset, (ii) the distribution of the first-reset time, and (iii) the spatial distribution of the particle at long times. We apply our approach to several representative and hitherto unexplored examples of resetting dynamics. A particularly interesting example for which we find analytical expressions for the statistics of resetting is that of a Brownian particle trapped in a harmonic potential with a rate of resetting that depends on the instantaneous energy of the particle. We find that using energy-dependent resetting processes is more effective in achieving spatial confinement of Brownian particles on a faster time scale than performing quenches of parameters of the harmonic potential.
USA president Barack Obama on avaldanud soovi vajutada USA-Vene suhetes reset-nuppu. Eesti president Toomas Hendrik Ilves ütles NATO tippkohtumise eelõhtul kuivalt, et arvutil reset-nuppu vajutades ei kustu mällu salvestatud failid siiski ära. President T. H. Ilvese teravast sõnavõtust president Lennart Meri konverentsi avamisel Tallinnas
Uller, Tobias; English, Sinead; Pen, Ido
Resetting of epigenetic marks, such as DNA methylation, in germ cells or early embryos is not always complete. Epigenetic states may therefore persist, decay or accumulate across generations. In spite of mounting empirical evidence for incomplete resetting, it is currently poorly understood whether
Norton, K H; Boushel, Robert Christopher; Andersen, Line Strange
Recent investigations have demonstrated that at the onset of low-to-moderate-intensity leg cycling exercise (L) the carotid baroreflex (CBR) was classically reset in direct relation to the intensity of exercise. On the basis of these data, we proposed that the CBR would also be classically reset ...
Green, Kent; Buchvald, Frederik F; Marthin, June Kehlet
damage in children with cystic fibrosis, which shares features with primary ciliary dyskinesia (PCD). Normalised phase III slope indices S(cond) and S(acin) reflect function of the small conducting and acinar airways, respectively. The involvement of the peripheral airways assessed by MBW tests has......The lung clearance index (LCI) derived from the multiple breath inert gas washout (MBW) test reflects global ventilation distribution inhomogeneity. It is more sensitive than forced expiratory volume in 1 s (FEV(1)) for detecting abnormal airway function and correlates closely with structural lung...
Sohbati, Reza; Murray, Andrew S.; Jain, Mayank
There are many examples of buried rock surfaces whose age is of interest to geologists and archaeologists. Luminescence dating is a potential method which can be applied to dating such surfaces; as part of a research project which aims to develop such an approach, the degree of resetting of OSL...... signals in grains and slices from five different cobbles/boulders collected from a modern beach is investigated. All the rock surfaces are presumed to have been exposed to daylight for a prolonged period of time (weeks to years). Feldspar was identified as the preferred dosimeter because quartz extracts...... were insensitive. Dose recovery tests using solar simulator and IR diodes on both K-feldspar grains and solid slices taken from the inner parts of the rocks are discussed. Preheat plateau results using surface grains and slices show that significant thermal transfer in naturally bleached samples can...
Koppel, Barbara S
Cannabis has been used for many medicinal purposes, including management of spasms, dystonia, and dyskinesias, with variable success. Its use for tetanus was described in the second century BCE, but the literature continues to include more case reports and surveys of its beneficial effects in managing symptoms of hyperkinetic movement disorders than randomized controlled trials, making evidence-based recommendations difficult. This paper reviews clinical research using various formulations of cannabis (botanical products, oral preparations containing ∆(9)-tetrahydrocannabinol and/or cannabidiol) and currently available preparations in the USA (nabilone and dronabinol). This has been expanded from a recent systematic review of cannabis use in several neurologic conditions to include case reports and case series and results of anonymous surveys of patients using cannabis outside of medical settings, with the original evidence classifications marked for those papers that followed research protocols. Despite overlap in some patients, dyskinesias will be treated separately from dystonia and chorea; benefit was not established beyond individual patients for these conditions. Tics, usually due to Tourettes, did respond to cannabis preparations. Side effects reported in the trials will be reviewed but those due to recreational use, including the dystonia that can be secondary to synthetic marijuana preparations, are outside the scope of this paper.
Full Text Available Abdul Qayyum Rana,1–4 Zishan M Chaudry,5 Pierre J Blanchet6 1Parkinson's Clinic of Eastern Toronto and Movement Disorders Centre, Toronto, ON, Canada; 2Scarborough Memory Program, Toronto, ON, Canada; 3Journal of Parkinsonism and RLS, Toronto, ON, Canada; 4Bulletin of World Parkinson's Program, Toronto, ON, Canada; 5Saba University School of Medicine, The Bottom, Saba, Dutch Caribbean; 6Department of Stomatology, University of Montreal, Montreal, QC, Canada Abstract: The aim of this review is to assess new, emerging, and experimental treatment options for tardive dyskinesia (TD. The methods to obtain relevant studies for review included a MEDLINE search and a review of studies in English, along with checking reference lists of articles. The leading explanatory models of TD development include dopamine receptor supersensitivity, GABA depletion, cholinergic deficiency, neurotoxicity, oxidative stress, changes in synaptic plasticity, and defective neuroadaptive signaling. As such, a wide range of treatment options are available. To provide a complete summary of choices we review atypical antipsychotics along with resveratrol, botulinum toxin, Ginkgo biloba, tetrabenazine, clonazepam, melatonin, essential fatty acids, zonisamide, levetiracetam, branched-chain amino acids, drug combinations, and invasive surgical treatments. There is currently no US Food and Drug Administration-approved treatment for TD; however, prudent use of atypical antipsychotics with routine monitoring remain the cornerstone of therapy, with experimental treatment options available for further management. Keywords: tardive dyskinesia, first-generation antipsychotics, motor symptoms, schizophrenia, Parkinson's, atypical antipsychotics
Hauptmann, Christian; Ströbel, Armin; Williams, Mark; Patel, Nitesh; Wurzer, Hannes; von Stackelberg, Tatjana; Brinkmann, Uwe; Langguth, Berthold; Tass, Peter A.
Purpose. Primary tinnitus has a severe negative influence on the quality of life of a significant portion of the general population. Acoustic coordinated reset neuromodulation is designed to induce a long-lasting reduction of tinnitus symptoms. To test acoustic coordinated reset neuromodulation as a treatment for chronic, tonal tinnitus under real life conditions, an outpatient study “RESET Real Life” was commissioned by ANM GmbH. Herein we present the results of this study. Methods. In a prospective, open-label, nonrandomized, noncontrolled multicenter clinical study with 200 chronic tinnitus patients, tinnitus questionnaire TBF-12 and Global Clinical Improvement-Impression Scale (CGI-I7) are used to study the safety and efficacy of acoustic coordinated reset neuromodulation. 189 patients completed the last 12-month visit, 11 patients dropped out (8 because of nontreatment related reasons; 2 because tinnitus did not change; and 1 because tinnitus got louder). Results. Acoustic coordinated reset neuromodulation caused a statistically and clinically significant decrease in TBF-12 scores as well as in CGI-I7 after 12 months of therapy under real life conditions. There were no persistent adverse events reported that were related to the therapy. Conclusion. The field study “RESET Real Life” provides evidence for safety and efficacy of acoustic coordinated reset neuromodulation in a prospective, open-label, real life setting. PMID:26568958
Full Text Available Purpose. Primary tinnitus has a severe negative influence on the quality of life of a significant portion of the general population. Acoustic coordinated reset neuromodulation is designed to induce a long-lasting reduction of tinnitus symptoms. To test acoustic coordinated reset neuromodulation as a treatment for chronic, tonal tinnitus under real life conditions, an outpatient study “RESET Real Life” was commissioned by ANM GmbH. Herein we present the results of this study. Methods. In a prospective, open-label, nonrandomized, noncontrolled multicenter clinical study with 200 chronic tinnitus patients, tinnitus questionnaire TBF-12 and Global Clinical Improvement-Impression Scale (CGI-I7 are used to study the safety and efficacy of acoustic coordinated reset neuromodulation. 189 patients completed the last 12-month visit, 11 patients dropped out (8 because of nontreatment related reasons; 2 because tinnitus did not change; and 1 because tinnitus got louder. Results. Acoustic coordinated reset neuromodulation caused a statistically and clinically significant decrease in TBF-12 scores as well as in CGI-I7 after 12 months of therapy under real life conditions. There were no persistent adverse events reported that were related to the therapy. Conclusion. The field study “RESET Real Life” provides evidence for safety and efficacy of acoustic coordinated reset neuromodulation in a prospective, open-label, real life setting.
Daneault, Jean-François; Carignan, Benoit; Sadikot, Abbas F; Panisset, Michel; Duval, Christian
Dyskinesia, a major complication in the treatment of Parkinson's disease (PD), can require prolonged monitoring and complex medical management. The current paper proposes a new way to view the management of dyskinesia in an integrated fashion. We suggest that dyskinesia be considered as a factor in a signal-to-noise ratio (SNR) equation where the signal is the voluntary movement and the noise is PD symptomatology, including dyskinesia. The goal of clinicians should be to ensure a high SNR in order to maintain or enhance the motor repertoire of patients. To understand why such an approach would be beneficial, we first review mechanisms of dyskinesia, as well as their impact on the quality of life of patients and on the health-care system. Theoretical and practical bases for the SNR approach are then discussed. Clinicians should not only consider the level of motor symptomatology when assessing the efficacy of their treatment strategy, but also breadth of the motor repertoire available to patients.
Versek, Brian E; Carpenedo, Carolyn M; Rosenwasser, Beth J; Dugosh, Karen Leggett; Bresani, Elena; Kirby, Kimberly C
Voucher-based reinforcement therapy (VBRT) is an efficacious contingency management intervention for substance use disorders that provides escalating voucher values to reinforce continuous abstinence and typically resets escalated values to the initial low level upon detection of drug use. The objective of this study involving 130 methadone-maintained outpatients receiving VBRT was to investigate whether resets (a) increase risk for adverse events (AEs) and (b) delay return to abstinence in relation to magnitude of voucher reset. Weeks following resets were examined for increased likelihood of AEs using a Poisson regression. A Cox proportional hazards model was used to determine if higher resets increased the number of days until a negative urine specimen. Results showed that resets did not increase the likelihood of AEs nor were higher resets related to an increased delay to abstinence. Research involving larger samples is needed to produce sufficient data directly addressing safety concerns of various treatment stakeholders. Copyright 2010. Published by Elsevier Inc.
Yeh, Jia-Yin; Tu, Kun-Yu; Tseng, Ping-Tao; Lee, Yu; Lin, Pao-Yen
Belly dancer syndrome, also called belly dance syndrome or belly dancer dyskinesia, is a kind of abdominal dyskinesia with painful sensation. Its etiology is still unclear and there are few studies reporting its association with antipsychotics. Quetiapine is an atypical antipsychotic that causes lower risk of extrapyramidal symptoms than typical antipsychotics. Here, we presented the first case of belly dancer syndrome in a 71-year-old woman with major depressive disorder after short-term use of quetiapine.
Dumont, Grégory; Ermentrout, G. Bard; Gutkin, Boris
The study of brain rhythms is an open-ended, and challenging, subject of interest in neuroscience. One of the best tools for the understanding of oscillations at the single neuron level is the phase-resetting curve (PRC). Synchronization in networks of neurons, effects of noise on the rhythms, effects of transient stimuli on the ongoing rhythmic activity, and many other features can be understood by the PRC. However, most macroscopic brain rhythms are generated by large populations of neurons, and so far it has been unclear how the PRC formulation can be extended to these more common rhythms. In this paper, we describe a framework to determine a macroscopic PRC (mPRC) for a network of spiking excitatory and inhibitory neurons that generate a macroscopic rhythm. We take advantage of a thermodynamic approach combined with a reduction method to simplify the network description to a small number of ordinary differential equations. From this simplified but exact reduction, we can compute the mPRC via the standard adjoint method. Our theoretical findings are illustrated with and supported by numerical simulations of the full spiking network. Notably our mPRC framework allows us to predict the difference between effects of transient inputs to the excitatory versus the inhibitory neurons in the network.
Núñez-Gil, Iván J; Feltes, Gisela I; Mejía-Rentería, Hernán D; Biagioni, Corina; De Agustín, J Alberto; Vivas, David; Fernández-Ortiz, Antonio
Transient apical dyskinesia syndromes present features similar to acute coronary syndromes, but with normal coronary arteries and rapid complete resolution of wall motion alterations. We report the case of a 73-year-old woman who was admitted to hospital because of typical chest pain at rest after her brother's death. She had had a pacemaker implanted in 2001. Troponin levels were elevated and apical hypokinesia was shown by ventriculography and echocardiography, with normal coronary arteries. Evolving ECG alterations were observed in spite of the continued pacing rhythm. All these alterations were fully resolved after discharge. This case shows that, even in the presence of a pacemaker, evolving ECG alterations can be observed in Takotsubo syndrome. Copyright © 2014 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.
Full Text Available Tardive dyskinesia (TD, characterized by oro‐buccal‐lingual stereotypy, can manifest in the form of akathisia, dystonia, tics, tremor, chorea, or as a combination of different types of abnormal movements. In addition to movement disorders (including involuntary vocalizations, patients with TD may have a variety of sensory symptoms, such as urge to move (as in akathisia, paresthesias, and pain. TD is a form of tardive syndrome—a group of iatrogenic hyperkinetic and hypokinetic movement disorders caused by dopamine receptor‐blocking agents. The pathophysiology of TD remains poorly understood, and treatment of this condition is often challenging. In this update, we provide the most current information on the history, nomenclature, etiology, pathophysiology, epidemiology, phenomenology, differential diagnosis, and treatment of TD.
Waln, Olga; Jankovic, Joseph
Tardive dyskinesia (TD), characterized by oro-buccal-lingual stereotypy, can manifest in the form of akathisia, dystonia, tics, tremor, chorea, or as a combination of different types of abnormal movements. In addition to movement disorders (including involuntary vocalizations), patients with TD may have a variety of sensory symptoms, such as urge to move (as in akathisia), paresthesias, and pain. TD is a form of tardive syndrome—a group of iatrogenic hyperkinetic and hypokinetic movement disorders caused by dopamine receptor-blocking agents. The pathophysiology of TD remains poorly understood, and treatment of this condition is often challenging. In this update, we provide the most current information on the history, nomenclature, etiology, pathophysiology, epidemiology, phenomenology, differential diagnosis, and treatment of TD. PMID:23858394
M KAR AHMADI
Full Text Available Introduction. Expresssion of tardive dyskinesia as one of the side effects of antipsychotic drugs causes various problems in psychotic patients. It is the main cause of patient"s drug incompliance.Vitamine E with it"s antioxidants properties might be an effective treatment for tardive dyskinesia. Methods. In a randomized double blind clinical trial, thirty inpatients of the psychiatric hospital in Isfahan were studied. Patients were stratified according to their age, psychiatric disorder and duration, intensity of tardive dyskinesia and antipsychotic dosage. Then they were asssigned randomly into two groups. Vitamine E (600 mg/day was administered to interventional group (15 patients. Another group received placebo (15 patients. Treatment durated for 6 weeks. Abnormal Involuntary Movment Scale (AIMS was used to measure tardive dyskinesia intensity. Results. Average of disorder intensity in those who received vit. E, dropped down from 8.33/10 (befor treatment to 6.13/10 (after treatment. It means 26.3 percent reduction of tardive dyskinesia intensity. This difference was only 7.3 percent in control group. There were no statistical diffrence between two groups after treatment (P>0.05. Discussion. There is no statistical efficacy for vitamine E in the management of tardive dyskinesia. But it is recommended to make another study with more samples.
Muramatsu, S; Yoshida, M; Nakamura, S
The neuronal mechanism of dyskinesia of the contralateral forelimb produced by microinjection of picrotoxin (PTX), a GABA antagonist, into the caudoputaminal unit (CPU) was analyzed electrophysiologically. PTX injection resulted in production of sharp, negative field potentials with or without preceding or succeeding positivity in the CPU and cerebral cortex (CX). These spike potentials first appeared in the CPU, thereafter within the CX, and were finally accompanied by dyskinesia indicated by electromyogram activity of the forelimb in association with fully developed CX spike potentials. Dyskinesia disappeared reversibly by cooling, and irreversibly by ablation, of the CX, indicating the crucial participation of the CX in the manifestation of dyskinesia. CPU spike potentials remained even after isolation of the CPU from its major afferents. Grouped discharges of extracellularly recorded single-unit spikes were observed in the CPU in association with the development of CPU spike potentials. Single-unit spikes of the pars reticulata of the substantia nigra were inhibited, and those of the ventromedial nucleus (VM) of the thalamus were excited in association with CPU spike potentials. We therefore propose that the primary origin of the dyskinesia is the CPU and that the inhibitory CPU efferent, as well as the nigrothalamic, pathway plays a basic role in the manifestation of the dyskinesia.
Gałecki, Piotr; Pietras, Tadeusz; Florkowki, Antoni
Central nervous system diseases are connected with the production of an increased amount of reactive oxygen species. Decreased antioxidant activity is considered as one of the causes of tardive dyskinesia (TD) in schizophrenic patients in a prolonged neuroleptic treatment course. Evaluation of superoxide dismutase, catalase, glutathione peroxidase activity as well as lipid peroxidation by TBARS saturation in blood platelets in schizophrenic patients with or without tardive dyskinesia symptoms. 84 paranoid schizophrenic patients took part in the study, 40 of them with TD symptoms. The groups were comparative in clinical and demographic terms. Indication of TBARS in blood platelets was performed by the Placed and coop method. GSH-Px activity was indicated by the Little and O'Brien method. CAT activity was indicated according to the Beers and coop method. CuZnSOD activity in blood platelets was indicated by the Mirsa and Fridovich method. CuZnSOD activity in schizophrenic patients without TD is 820.23 and accordingly 710.75 U/g in TD symptoms patients and it is statistical essential. TBARS for patients with TD is 1.06 and accordingly without TD it is 0.92 micromol/10(9)), the difference is statistically essential. For groups with and without TD CAT activity is accordingly 19.87 and 17.93 Ub/g. For groups with and without TD GSH-Px is accordingly 32.30 and 30.48 U/g. schizophrenic patients with TD symptoms have lower CuZnSOD activity and higher concentration of TBARS in platelets than patients without TD. CAT activity is higher in patients with TD symptoms. CuZnSOD activity and concentration of TBARS are in correlation with age in both studied groups.
JOSÉ WELLINGTON ALVES DOS SANTOS
Full Text Available Discinesia ciliar primária é uma doença autossômica recessiva caracterizada pela história de infecções repetidas do trato respiratório superior e inferior, otite média, bronquite e rinossinusite, associada a situs inversus na metade dos casos. O diagnóstico é estabelecido pela análise ciliar ultra-estrutural de espécimes respiratórios, após a exclusão inicial de outras doenças, como fibrose cística, deficiência de alfa-1-antitripsina, imunodeficiências (IgG, neutrófilos e complemento e síndrome de Young. O propósito deste artigo é revisar os achados clínicos, o diagnóstico e o manejo da discinesia ciliar primária, incluindo um fluxograma diagnóstico.Primary ciliary dyskinesia is an autosomal recessive disorder characterized by a history of recurrent upper and lower respiratory tract infections with chronic otitis media, bronchitis and rhinosinusitis, associated with situs inversus in 50% of cases. The diagnosis is established by ciliary ultrastructural analysis of respiratory specimens, after ruling out some disorders as cystic fibrosis, alpha-1 anti-trypsin deficiency, immune deficiencies (IgG, neutrophils and complement and Young's syndrome. The purpose of this paper is to review the clinical features, diagnosis and management of primary ciliary dyskinesia, including a diagnostic algorithm.
MODIFICATIONS NEUROCHIMIQUES INDUITES PAR LA STIMULATION HAUTE FREQUENCE DU NOYAU SOUS-THALAMIQUE AU SEIN DES RESEAUX NEURONAUX IMPLIQUES DANS LES CIRCUITS MOTEURS ET LEURS INTERACTIONS AVEC UN TRAITEMENT A LA L-DOPA
Etude par microdialyse intracérébrale chez le rat sain et hémiparkinsonien.
High frequency stimulation (HFS) of the subthalamic nucleus (STN) counteracts the motor symptoms of Parkinson's disease (PD), but also diminishes dramatically the L-Dopa-induced dyskinesia (LID) following an important, or even total reduction of L-Dopa doses in stimulated patients. However, the precise mechanisms underlying the therapeutic effectiveness of deep brain stimulation are not elucidated yet. In particular, the possible interactions existing between the effects of both STN HFS and L...
Nandhakumar, Amar; Silverman, Gregory L
We present the case of a parturient diagnosed with primary ciliary dyskinesia with secondary bronchiectasis who developed significant hypoxemia following administration of intravenous oxytocin during...
Becker, H.; Gawronski, T.; Wang, Z.
Among long-lived geochronometers, the Re-Os decay system is unique in that it permits to obtain direct age information on past melt extraction events in the mantle. Some studies have discovered ancient melting residues in oceanic peridotites emplaced on young seafloor [1-3]. Other work indicates that melt transport and reactive infiltration may affect the Re-Os systematics of both depleted and fertile peridotites to variable extent [4-6]. Open system polybaric melting of depleted lherzolites and harzburgites should lead to removal of basaltic components and at the same time partial or complete equilibration with infiltrating magma. If such magma carries radiogenic Os, it will lead to partial or complete resetting of the Re-Os clock. This is what may have occurred in many abyssal peridotites [e.g. 2, 7], although, the parameters that control isotopic resetting, the timing, extent and controls on equilibration with melts carrying radiogenic Os are still incompletely understood. Studies of well-characterized Phanerozoic peridotite massifs that represent former ocean-continent transitions and analogues of modern slow spreading environments do offer some additional insight. Re-Os data on the Ligurian peridotite massifs [8,9], the Lanzo peridotite , and peridotites from the Ivrea zone [10,11] suggest addition of radiogenic Os to some, but not all, harzburgites and depleted lherzolites. The source of the radiogenic Os may have been either local (melting of pyroxenites) or external. Fertile lherzolites in these massifs often display petrological and geochemical evidence for refertilization, but the timing of magmatic processes is not always clear. In the Ivrea zone, Sm-Nd dates obtained on clinopyroxenes from peridotites are Paleozoic , as are some Os model ages of peridotites [10, 11], however, the spectrum of Re-Os (primitive mantle) model ages ranges between 0.2 and 1.6 Ga (median 0.5 Ga). Hence, it is likely that extensive magmatic re-equilibration occurred in
Seigneurie, A-S; Sauvanaud, F; Limosin, F
Tardive dyskinesia (TD) is a movement disorder of tongue, jawbone, trunk and/or limbs that may appear after a prolonged use of dopamine receptor blocking agents (after 3 months of treatment or after 1 month for patients over 60), and that are present during at least four consecutive weeks. TD is a frequent side effect of both classical neuroleptics and new generation antipsychotic drugs. The prevalence of iatrogenic TD is between 24 and 32 % after treatment with classical neuroleptics and about 13 % after treatment with a new generation antipsychotic. This paper presents an updated literature review of data on diagnosis, prevention and treatment of TD. We conducted a review of literature using the Medline Browser tool, screening studies from 1950 to 2013 in English or French with keywords « tardive dyskinesia », « tardive dystonia », and « abnormal movements caused by antipsychotic drugs ». We first describe and define semeiological features of TD: dystonia, tremor, myoclonus, acathisie, chorea, ballism and athetosia. Secondarily, we resume the main differential diagnoses to exclude when confronted with this kind of movement disorders. Differential diagnoses for dyskinesia can be classified between primary (Parkinson and Huntington diseases) and secondary (Wilson disease, intoxication, metabolic abnormality, cerebrovascular accident) abnormal movements. Psychogenic TD can be evocated if previous pathologies are excluded in case of atypical clinical presentation. We detail the risk factors for TD. Endogenous risk factors are related to the patient's age, underlying psychiatric disease (bipolar disorder or Alzheimer dementia), addiction to alcohol or cocaine, female gender, or neurodevelopmental vulnerability. Iatrogenic risk factors are high doses of antipsychotics, long or intermittent administration, and particular pharmaceutical classes or associations of antipsychotics. As a comprehensive tool, we review the main physiopathological hypotheses to
Nobukawa, Sou; Nishimura, Haruhiko; Yamanishi, Teruya
Several hybrid spiking neuron models combining continuous spike generation mechanisms and discontinuous resetting processes following spiking have been proposed. The Izhikevich neuron model, for example, can reproduce many spiking patterns. This model clearly possesses various types of bifurcations and routes to chaos under the effect of a state-dependent jump in the resetting process. In this study, we focus further on the relation between chaotic behaviour and the state-dependent jump, approaching the subject by comparing spiking neuron model versions with and without the resetting process. We first adopt a continuous two-dimensional spiking neuron model in which the orbit in the spiking state does not exhibit divergent behaviour. We then insert the resetting process into the model. An evaluation using the Lyapunov exponent with a saltation matrix and a characteristic multiplier of the Poincar'e map reveals that two types of chaotic behaviour (i.e. bursting chaotic spikes and near-period-two chaotic spikes) are induced by the resetting process. In addition, we confirm that this chaotic bursting state is generated from the periodic spiking state because of the slow- and fast-scale dynamics that arise when jumping to the hyperpolarization and depolarization regions, respectively.
Bortolanza, Mariza; Bariotto-Dos-Santos, Keila D; Dos-Santos-Pereira, Maurício; da-Silva, Célia Aparecida; Del-Bel, Elaine
Amantadine is the noncompetitive antagonist of N-methyl-D-aspartate, receptor activated by the excitatory neurotransmitter glutamate. It is the only effective medication used to alleviate dyskinesia induced by L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease patients. Unfortunately, adverse effects as abnormal involuntary movements (AIMs) known as L-DOPA-induced dyskinesia limit its clinical utility. Combined effective symptomatic treatment modalities may lessen the liability to undesirable events. Likewise drugs known to interfere with nitrergic system reduce AIMs in animal models of Parkinson's disease. We aimed to analyze an interaction between amantadine, neuronal nitric oxide synthase inhibitor (7-nitroindazole, 7NI), and nitric oxide donor (sodium nitroprusside, SNP) in 6-hydroxydopamine-(6-OHDA)-lesioned rats (microinjection in the medial forebrain bundle) presenting L-DOPA-induced dyskinesia (20 mg/kg, gavage, during 21 days). We confirm that 7NI-30 mg/kg, SNP-2/4 mg/kg and amantadine-40 mg/kg, individually reduced AIMs. Our results revealed that co-administration of sub-effective dose of amantadine (10 mg/kg) plus sub-effective dose of 7NI (20 mg/kg) potentiates the effect of reducing AIMs scores when compared to the effect of the drugs individually. No superior benefit on L-DOPA-induced AIMs was observed with the combination of amantadine and SNP. The results revealed that combination of ineffective doses of amantadine and 7NI represents a new strategy to increase antidyskinetic effect in L-DOPA-induced AIMs. It may provide additional therapeutic benefits to Parkinson's disease patients from these disabling complications at lower and thus safer and more tolerable doses than required when either drug is used alone. To close, we discuss the paradox of both nitric oxide synthase inhibitor and/or donor produced AIMs reduction by targeting nitric oxide synthase.
Full Text Available We have measured the transition process from the high to low resistivity states, i.e., the reset process of resistive switching based memristors based on Ni/HfO2/Si-n+ structures, and have also developed an analytical model for their electrical characteristics. When the characteristic curves are plotted in the current-voltage (I-V domain a high variability is observed. In spite of that, when the same curves are plotted in the charge-flux domain (Q-phi, they can be described by a simple model containing only three parameters: the charge (Qrst and the flux (rst at the reset point, and an exponent, n, relating the charge and the flux before the reset transition. The three parameters can be easily extracted from the Q-phi plots. There is a strong correlation between these three parameters, the origin of which is still under study.
Boutin, Samuel; Andersen, Christian Kraglund; Venkatraman, Jayameenakshi; Ferris, Andrew J.; Blais, Alexandre
We study an implementation of the open GRAPE (gradient ascent pulse engineering) algorithm well suited for large open quantum systems. While typical implementations of optimal control algorithms for open quantum systems rely on explicit matrix exponential calculations, our implementation avoids these operations, leading to a polynomial speedup of the open GRAPE algorithm in cases of interest. This speedup, as well as the reduced memory requirements of our implementation, are illustrated by comparison to a standard implementation of open GRAPE. As a practical example, we apply this open-system optimization method to active reset of a readout resonator in circuit QED. In this problem, the shape of a microwave pulse is optimized such as to empty the cavity from measurement photons as fast as possible. Using our open GRAPE implementation, we obtain pulse shapes, leading to a reset time over 4 times faster than passive reset.
Pahwa, Rajesh; Tanner, Caroline M; Hauser, Robert A; Sethi, Kapil; Isaacson, Stuart; Truong, Daniel; Struck, Lynn; Ruby, April E; McClure, Natalie L; Went, Gregory T; Stempien, Mary Jean
ADS-5102 is a long-acting, extended-release capsule formulation of amantadine HCl administered once daily at bedtime. This study investigated the safety, efficacy, and tolerability of ADS-5102 in Parkinson's disease (PD) patients with levodopa-induced dyskinesia. This was a randomized, double-blind, placebo-controlled, parallel-group study of 83 PD patients with troublesome dyskinesia assigned to placebo or one of three doses of ADS-5102 (260 mg, 340 mg, 420 mg) administered daily at bedtime for 8 weeks. The primary efficacy analysis compared change from baseline to week 8 in Unified Dyskinesia Rating Scale (UDysRS) total score for 340 mg ADS-5102 versus placebo. Secondary outcome measures included change in UDysRS for 260 mg, 420 mg, Fatigue Severity Scale (FSS), Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), patient diary, Clinician's Global Impression of Change, and Parkinson's Disease Questionnaire (PDQ-39). ADS-5102 340 mg significantly reduced dyskinesia versus placebo (27% reduction in UDysRS, P = 0.005). In addition, ADS-5102 significantly increased ON time without troublesome dyskinesia, as assessed by PD patient diaries, at 260 mg (P = 0.004), 340 mg (P = 0.008) and 420 mg (P = 0.018). Adverse events (AEs) were reported for 82%, 80%, 95%, and 90% of patients in the placebo, 260-mg, 340-mg, and 420-mg groups, respectively. Constipation, hallucinations, dizziness, and dry mouth were the most frequent AEs. Study withdrawal rates were 9%, 15%, 14%, and 40% for the placebo, 260-mg, 340-mg, and 420-mg groups, respectively. All study withdrawals in the active treatment groups were attributable to AEs. ADS-5102 was generally well tolerated and resulted in significant and dose-dependent improvements in dyskinesia in PD patients. © 2015 Adamas Pharmaceuticals, Inc. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Xu, Linhai; Chen, Xiaogang; Song, Zhitang; Chen, Yifeng; Liu, Bo; Chen, Houpeng; Yang, Zuoya; Wu, Guanping; Cai, Daolin; Feng, Gaoming; Li, Ying
Resistance distributions of the crystalline (SET) state and amorphous (RESET) state for phase change memory (PCM) are experimentally investigated at the array level. The RESET distribution shows a low resistance tail, which potentially affects the reading margin of the chip. These tail cells are divided into two types by resistance programming current (R-IP) and current voltage (I-V) characteristics. Finally, approaches of improving the integration process to remove the Type-1 tail cells and optimizing the programming operation to repair the Type-2 tail cells are proposed.
Jalloul, Nahed; Porée, Fabienne; Viardot, Geoffrey; L'Hostis, Philippe; Carrault, Guy
In this paper, we present an activity classification-based algorithm for the automatic detection of Levodopa Induced Dyskinesia in Parkinson's Disease (PD) patients. Two PD patients experiencing motor fluctuations related to chronic Levodopa therapy performed a protocol of simple daily life activities on at least two different occasions. A Random Forest classifier was able to classify the performed activities by the patients with an overall accuracy of 86%. Based on the detected activity, a K Nearest Neighbor classifier detected the presence of dyskinesia with accuracy ranging from 75% to 88%.
Olanow, C Warren; Gracies, Jean-Michel; Goetz, Christopher G; Stoessl, A Jon; Freeman, Thomas; Kordower, Jeffrey H; Godbold, James; Obeso, Jose A
The objective of this study is to assess dyskinesias in 34 Parkinson's disease patients randomized to receive bilateral fetal nigral transplantation with 4 donors per side (12), 1 donor per side (11), or placebo (11). Videotape recordings were performed at the baseline, 3, 6, 12, 18, and 24 month visits during the "practically defined off" (12 hours after last evening dopaminergic therapy) and "best on" (best response following morning dopaminergic therapy) states. Videotapes were analyzed in random order by a blinded investigator. Dyskinesias during "best on" (on-medication dyskinesia) were observed in all, but 1 patient at baseline, and in all patients at each subsequent visit. There were no differences between groups. No patient had dyskinesia at baseline in "practically-defined off" ("off-medication" dyskinesia). Following transplantation, off-medication dyskinesia was observed in 13 of 23 patients, but not in any patient in the placebo group (P = 0.019). There was no difference in dyskinesia score between patients in the 1 and 4 donor groups. On-medication dyskinesias were typically generalized and choreiform, whereas off-medication dyskinesias were usually repetitive, stereotypic movements in the lower extremities with residual Parkinsonism in other body regions. Off-medication dyskinesias are common following transplantation and may represent a prolonged form of diphasic dyskinesias. (c) 2008 Movement Disorder Society.
Yakovlev, Volodya; Amit, Yali; Hochstein, Shaul
The Delay-Match-to-Sample (DMS) task has been used in countless studies of memory, undergoing numerous modifications, making the task more and more challenging to participants. The physiological correlate of memory is modified neural activity during the cue-to-match delay period reflecting reverberating attractor activity in multiple interconnected cells. DMS tasks may use a fixed set of well-practiced stimulus images-allowing for creation of attractors-or unlimited novel images, for which no attractor exists. Using well-learned stimuli requires that participants determine if a remembered image was seen in the same or a preceding trial, only responding to the former. Thus, trial-to-trial transitions must include a "reset" mechanism to mark old images as such. We test two groups of monkeys on a delay-match-to-multiple-images task, one with well-trained and one with novel images. Only the first developed a reset mechanism. We then switched tasks between the groups. We find that introducing fixed images initiates development of reset, and once established, switching to novel images does not disable its use. Without reset, memory decays slowly, leaving ~40% recognizable after a minute. Here, presence of reward further enhances memory of previously-seen images.
Madsen, P L; Hasselbalch, S G; Hagemann, L P
showed that the activation-induced resetting of the relation between CMRglc and CMRO2 persisted virtually unaltered for > or = 40 min after the mental activation task was terminated. The activation-induced increase in cerebral lactate efflux measured over the same time period accounted for only a small...
Balan, Ranjini; Suraishkumar, G K
We report for the first time that the endogenous, pseudo-steady-state, specific intracellular levels of the hydroxyl radical (si-OH) oscillate in an ultradian fashion (model system: the microalga, Chlorella vulgaris), and also characterize the various rhythm parameters. The ultradian rhythm in the endogenous levels of the si-OH occurred with an approximately 6 h period in the daily cycle of light and darkness. Further, we expected that the rhythm reset to a shorter period could rapidly switch the cellular redox states that could favor lipid accumulation. We reset the endogenous rhythm through entrainment with UVA radiation, and generated two new ultradian rhythms with periods of approximately 2.97 h and 3.8 h in the light phase and dark phase, respectively. The reset increased the window of maximum lipid accumulation from 6 h to 12 h concomitant with the onset of the ultradian rhythms. Further, the saturated fatty acid content increased approximately to 80% of total lipid content, corresponding to the peak maxima of the hydroxyl radical levels in the reset rhythm. © 2014 American Institute of Chemical Engineers.
Burke, Lisa A.; Ray, Ruth
Evidence suggests that college students' concentration levels are limited and hard to maintain. Even though relevant in higher education, scant empirical research exists on interventions to "re-set" their concentration during a college lecture. Using a within-subjects design, four active learning interventions are administered across two…
Barbato, A.; Frischer, T.; Kuehni, C. E.; Snijders, D.; Azevedo, I.; Baktai, G.; Bartoloni, L.; Eber, E.; Escribano, A.; Haarman, E.; Hesselmar, B.; Hogg, C.; Jorissen, M.; Lucas, J.; Nielsen, K. G.; O'Callaghan, C.; Omran, H.; Pohunek, P.; Strippoli, M.-P. F.; Bush, A.
Primary ciliary dyskinesia (PCD) is associated with abnormal ciliary structure and function, which results in retention of mucus and bacteria in the respiratory tract, leading to chronic oto-sino-pulmonary disease, situs abnormalities and abnormal sperm motility. The diagnosis of PCD requires the
Pozhidaev, Ivan V; Alifirova, V. M.; Freidin, Maxim B.; Zhukova, I.A.; Fedorenko, Olga Yu; Osmanova, Diana Z; Mironova, Y.S.; Wilffert, Berend; Ivanova, Svetlana A.; Loonen, Antonius
Dopamine receptors genes polymorphisms in Parkinson patients with levodopa-induced dyskinesia I. Pozhidaev(1), V.M. Alifirova(2), M.B. Freidin(3), I.A. Zhukova(2), O.Y. Fedorenko(1), D.Z. Osmanova(1), Y.S. Mironova(2), B. Wilffert(4), S.A. Ivanova(1), A.J.M. Loonen(5) (1)Mental Health Research
Pozzi, Marco; Piccinini, Luigi; Giordano, Flavio; Carnovale, Carla; Perrone, Valentina; Pellegrino, Paolo; Antoniazzi, Stefania; Turconi, Anna Carla; Radice, Sonia; Clementi, Emilio
To report on the first case of ziconotide-induced dyskinesia. Ziconotide, a synthetic peptide analogue of the ω-conotoxin MVIIA that blocks selectively N-type voltage-sensitive calcium channels, has been used in intrathecal administration for 30 years. Ziconotide is a drug of choice for chronic pain because of its efficacy and flexibility because it can substitute or complement other intrathecal therapies including morphine or baclofen. Whereas substantial information is available regarding its efficacy, systematic data regarding the safety of ziconotide remain scant. The adverse reactions to ziconotide described so far regard only the coordination and execution of intentional movements. A 15-year-old male patient developed dyskinesia affecting the head and upper limbs 2 days after administration of ziconotide as an add-on therapy to an established regimen of treatment with baclofen. The strict temporal relationship between ziconotide administration and dyskinesia, together with the absence of any other clinical alteration, led to the hypothesis of a possible adverse drug reaction. Ziconotide was thus withdrawn, and the symptoms disappeared within 2 days. An analysis of the signaling pathways of baclofen and ziconotide revealed a possible drug interaction that allowed ziconotide to trigger dyskinesia.
Ivanova, S. A.; Al Hadithy, A. F. Y.; Pechlivanoglou, P.; Semke, A. V.; Fedorenko, O. Y.; Levchuk, L. A.; Kornetova, E. G.; Brouwers, J. R. B. J.; Bruggeman, R.; Loonen, A. J. M.
Tardive dyskinesia (TD) is a severe and potentially irreversible antipsychotic-induced movement disorder that has been and continues to be a significant problem associated with long-term use of antipsychotics . About 30% of patients chronically exposed to neuroleptics may exhibit tardive
Lundervold, Duane A.; Pahwa, Rajesh; Lyons, Kelly E.
Effects of brief Behavioral Relaxation Training (BRT) on anxiety and dyskinesia of a 57-year-old female, with an 11-year history of Parkinson's disease (PD) and 18-months post-deep brain stimulation of the subthalamic nucleus, were evaluated. Multiple process and outcome measures were used including the Clinical Anxiety Scale (CAS), Subjective…
Ivanova, S.A.; Alifirova, V.M.; Freidin, M.B.; Pozhidaev, I.V.; Fedorenko, O.Y.; Bokhan, N.A.; Zhukova, I.A.; Zhukova, N.G.; Wilffert, B.; Loonen, A.J.M.
Parkinson's disease (PD), a common neurodegenerative disorder caused by the loss of the dopaminergic input to the basal ganglia, is commonly treated with levodopa (L-DOPA). The use of this drug, however, is severely limited by adverse effects. Levodopa-induced dyskinesia (LID) is one of these and
Pozhidaev, I.; Alifirova, V.M.; Freidin, M.B.; Zhukova, I.A.; Fedorenko, O.Y.; Osmanova, D.Z.; Mironova, Y.S.; Wilffert, B.; Ivanova, S.A.; Loonen, A.J.M.
Introduction: Long-term levodopa treatment of Parkinson's disease (PD) is frequently complicated by spontaneously occur ring involuntary muscle movements called levodopa-induced dyskinesia (LID). LID are a substantial barrier to effective symptomatic management of Parkinson's disease (PD), as up to
Zariwala, Maimoona A; Gee, Heon Yung; Kurkowiak, Małgorzata
Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the ...
Andersen, Tobias Nicolai; Alanin, Mikkel Christian; von Buchwald, Christian
INTRODUCTION: Primary ciliary dyskinesia (PCD) is an autosomal recessive genetic disease, which primarily manifests with oto-sino-pulmonary symptoms. Otitis media with effusion (OME) is common from early childhood. The existing literature on OME management in PCD is conflicting. The goals of the ...
Geremek, Maciej; Bruinenberg, Marcel; Zietkiewicz, Ewa; Pogorzelski, Andrzej; Wijmenga, Cisca; Witt, Michal
Cilia are small cellular projections that either act as sensors (primary cilia) or propel fluid over the epithelia of various organs (motile cilia). The organellum has gained much attention lately because of its involvement in a group of human diseases called ciliopathies. Primary ciliary dyskinesia
Herz, Damian M.; Haagensen, Brian N.; Christensen, Mark S.
In Parkinson disease (PD), long‐term treatment with the dopamine precursor levodopa gradually induces involuntary “dyskinesia” movements. The neural mechanisms underlying the emergence of levodopa‐induced dyskinesias in vivo are still poorly understood. Here, we applied functional magnetic...
De Lau, L.M.L.; Verbaan, D.; Marinus, J.; Heutink, P.; van Hilten, J.J.
Background:: The A-allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with decreased enzymatic activity and higher dopamine availability. Methods:: We studied 219 patients with PD who were free of dyskinesias at baseline and underwent thorough annual examinations.
Maglione, Marco; Bush, Andrew; Nielsen, Kim G
BACKGROUND: No studies longitudinally, simultaneously assessed body mass index (BMI) and spirometry in primary ciliary dyskinesia (PCD). METHODS: We determined BMI and spirometry in 158 PCD children and adolescents from London, UK (n = 75), Naples, Italy (n = 23) and Copenhagen, Denmark (n = 60) ...
Lee, Hsien-Yang; Huang, Yong; Bruneau, Nadine; Roll, Patrice; Roberson, Elisha D. O.; Hermann, Mark; Quinn, Emily; Maas, James; Edwards, Robert; Ashizawa, Tetsuo; Baykan, Betul; Bhatia, Kailash; Bressman, Susan; Bruno, Michiko K.; Brunt, Ewout R.; Caraballo, Roberto; Echenne, Bernard; Fejerman, Natalio; Frucht, Steve; Gurnett, Christina A.; Hirsch, Edouard; Houlden, Henry; Jankovic, Joseph; Lee, Wei-Ling; Lynch, David R.; Mohammed, Shehla; Mueller, Ulrich; Nespeca, Mark P.; Renner, David; Rochette, Jacques; Rudolf, Gabrielle; Saiki, Shinji; Soong, Bing-Wen; Swoboda, Kathryn J.; Tucker, Sam; Wood, Nicholas; Hanna, Michael; Bowcock, Anne M.; Szepetowski, Pierre; Fu, Ying-Hui; Ptacek, Louis J.
Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) is an episodic movement disorder with autosomal-dominant inheritance and high penetrance, but the causative genetic mutation is unknown. We have now identified four truncating mutations involving the gene PRRT2 in the vast
Thakur, Kuldeep Singh; Prakash, Atish; Bisht, Rohit; Bansal, Puneet Kumar
Tardive dyskinesia is a serious motor disorder of the orofacial region, resulting from chronic neuroleptic treatment of schizophrenia. Candesartan (AT1 antagonist) and lisinopril (ACE inhibitor) has been reported to possess antioxidant and neuroprotective effects. The present study is designed to investigate the effect of candesartan and lisinopril on haloperidol-induced orofacial dyskinesia and oxidative damage in rats. Tardive dyskinesia was induced by administering haloperidol (1 mg/kg i.p.) and concomitantly treated with candesartan (3 and 5 mg/kg p.o.) and lisinopril (10 and 15 mg/kg p.o.) for 3 weeks in male Wistar rats. Various behavioral parameters were assessed on days 0, 7, 14 and 21 and biochemical parameters were estimated at day 22. Chronic administration of haloperidol significantly increased stereotypic behaviors in rats, which were significantly improved by administration of candesartan and lisinopril. Chronic administration of haloperidol significantly increased oxidative stress and neuro-inflammation in the striatum region of the rat's brain. Co-administration of candesartan and lisinopril significantly attenuated the oxidative damage and neuro-inflammation in the haloperidol-treated rat. The present study supports the therapeutic use of candesartan and lisinopril in the treatment of typical antipsychotic-induced orofacial dyskinesia and possible antioxidant and neuro-inflammatory mechanisms. © The Author(s) 2014.
Full Text Available Guiyun Cui,1,* Xinxin Yang,1,* Xiaoying Wang,2,* Zunsheng Zhang,1 Xuanye Yue,1 Hongjuan Shi,1 Xia Shen11Department of Neurology, 2Department of Ultrasound, the Affiliated Hospital of Xuzhou Medical College, Jiangsu, People’s Republic of China *These authors contributed equally to this workBackground: Chronic administration of levodopa in Parkinson’s disease leads to debilitating involuntary movements, termed levodopa-induced dyskinesia (LID. The pathogenesis of LID is poorly understood. Previous research has shown that histamine H2 receptors are highly expressed in the input (striatum and output (globus pallidus, substantia nigra regions of the basal ganglia, particularly in the GABAergic striatopallidal and striatonigral pathways. Therefore, a histamine H2 receptor antagonist could be used to reduce LID. In the present work, we investigated whether ranitidine has the potential to diminish LID in rats with dyskinesia and explored the underlying mechanisms involved.Methods: A rat model of PD was induced by 6-hydroxydopamine. Valid PD rats were then treated with levodopa (25 mg/kg, intraperitoneally and benserazide (12.5 mg/kg, intraperitoneally for 21 days to induce a rat model of LID. The acute and chronic effects of administration of ranitidine at different doses (5 mg/kg, 10 mg/kg, and 20 mg/kg on abnormal involuntary movements, levodopa-induced rotations, and the forelimb adjusting steps test were investigated in LID rats. The chronic effect of ranitidine (10 mg/kg on the expression of Arc and proenkephalin was also evaluated.Results: Levodopa elicited increased dyskinesia in PD rats. Acute ranitidine treatment had no effect on LID, but chronic ranitidine administration (10 mg/kg, 20 mg/kg reduced LID in rats with dyskinesia. Importantly, levodopa-induced rotations were not affected by chronic treatment with ranitidine. In addition, chronic ranitidine (10 mg/kg, 20 mg/kg significantly improved stepping of the lesioned forepaw. Real
Full Text Available Abstract Since the 1980 s, when cell transplantation into the brain as a cure for Parkinson's disease hit the headlines, several patients with Parkinson's disease have received transplantation of cells from aborted fetuses with the aim of replacing the dopamine cells destroyed by the disease. The results in human studies were unpredictable and raised controversy. Some patients showed remarkable improvement, but many of the patients who underwent transplantation experienced serious disabling adverse reactions, putting an end to human trials since the late 1990 s. These side effects consisted of patients' developing troublesome involuntary, uncontrolled movements in the absence of dopaminergic medication, so-called off-phase, graft-induced dyskinesias. Notwithstanding the several mechanisms having been proposed, the pathogenesis of this type of dyskinesias remained unclear and there was no effective treatment. It has been suggested that graft-induced dyskinesias could be related to fiber outgrowth from the graft causing increased dopamine release, that could be related to the failure of grafts to restore a precise distribution of dopaminergic synaptic contacts on host neurons or may also be induced by inflammatory and immune responses around the graft. A recent study, however, hypothesized that an important factor for the development of graft-induced dyskinesias could include the composition of the cell suspension and specifically that a high proportion of serotonergic neurons cografted in these transplants engage in nonphysiological properties such as false transmitter release. The findings from this study showed serotonergic hyperinnervation in the grafted striatum of two patients with Parkinson's disease who exhibited major motor recovery after transplantation with fetal mesencephalic tissue but later developed graft-induced dyskinesias. Moreover, the dyskinesias were significantly attenuated by administration of a serotonin agonist, which
Datta, Swati; Jamwal, Sumit; Deshmukh, Rahul; Kumar, Puneet
Tardive Dyskinesia is a severe side effect of chronic neuroleptic treatment consisting of abnormal involuntary movements, characterized by orofacial dyskinesia. The study was designed to investigate the protective effect of lycopene against haloperidol induced orofacial dyskinesia possibly by neurochemical and neuroinflammatory modulation in rats. Rats were administered with haloperidol (1mg/kg, i.p for 21 days) to induce orofacial dyskinesia. Lycopene (5 and 10mg/kg, p.o) was given daily 1hour before haloperidol treatment for 21 days. Behavioral observations (vacuous chewing movements, tongue protrusions, facial jerking, rotarod activity, grip strength, narrow beam walking) were assessed on 0th, 7th(,) 14th(,) 21st day after haloperidol treatment. On 22nd day, animals were killed and striatum was excised for estimation of biochemical parameters (malondialdehyde, nitrite and endogenous enzyme (GSH), pro-inflammatory cytokines [Tumor necrosis factor, Interleukin 1β, Interleukin 6] and neurotransmitters level (dopamine, serotonin, nor epinephrine, 5-Hydroxyindole acetic acid (5-HIAA), Homovanillic acid, 3,4- dihydroxyphenylacetic acid. Haloperidol treatment for 21 days impaired muscle co-ordination, motor activity and grip strength with an increased in orofacial dyskinetic movements. Further free radical generation increases MDA and nitrite levels, decreasing GSH levels in striatum. Neuroinflammatory markers were significantly increased with decrease in neurotransmitters levels. Lycopene (5 and 10mg/kg, p.o) treatment along with haloperidol significantly attenuated impairment in behavioral, biochemical, neurochemical and neuroinflammatory markers. Results of the present study attributed the therapeutic potential of lycopene in the treatment (prevented or delayed) of typical antipsychotic induced orofacial dyskinesia. Copyright © 2015 Elsevier B.V. All rights reserved.
Patil, Rupali; Dhawale, Kiran; Gound, Hanmant; Gadakh, Rajendra
Murraya koenigii L. (Rutaceae), commonly known as curry leaf tree, closely associated with south India where the word "curry" originates from the Tamil "kari" for spiced sauces. Curry leaves are a rich source of carbazole alkaloids which possess various biological activities such as antitumor, antioxidant and anti-inflammatory. Curry leaf has a potential role in the treatment of diabetes. Reserpine-induced orofacial dyskinesia in rats is an animal model of tardive dyskinesia that has been linked with free radical generation and oxidative stress. In this study, neuroprotective potential and in-vivo antioxidant status of methanol extract of the leaves of Murraya koenigii (MEMK) in reserpine-induced orofacial dyskinesia are investigated. Reserpine was used to induce orofacial dyskinesia. The effect of MEMK on locomotion and catalepsy was studied using Open-field apparatus and Bar-test, respectively. The effect of MEMK on the levels of protective anti-oxidant enzymes i.e. superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSH) and inhibited lipid peroxidation (LPO) in forebrain region were investigated in reserpine-treated animals. Results demonstrated that the MEMK significantly inhibited the reserpine-induced vacuous chewing movements (VCM), tongue protrusion (TP), orofacial burst (OB) and catalepsy. MEMK significantly increased the number of squares traversed and rearing in open field apparatus. Treatment with MEMK significantly restored the levels of protective anti-oxidant enzymes i.e. SOD, CAT, GSH and inhibited LPO in forebrain region when compared with reserpine. It also inhibited haloperidol-induced catalepsy. The present study concludes that the oxidative stress might play an important role in reserpine-induced abnormal oral movements, and Murraya koenigii may have great potential in the treatment of neuroleptic-induced orofacial dyskinesia.
Full Text Available The study of synchronization in biological systems is essential for the understanding of the rhythmic phenomena of living organisms at both molecular and cellular levels. In this paper, by using simple dynamical systems theory, we present a novel mechanism, named transient resetting, for the synchronization of uncoupled biological oscillators with stimuli. This mechanism not only can unify and extend many existing results on (deterministic and stochastic stimulus-induced synchrony, but also may actually play an important role in biological rhythms. We argue that transient resetting is a possible mechanism for the synchronization in many biological organisms, which might also be further used in the medical therapy of rhythmic disorders. Examples of the synchronization of neural and circadian oscillators as well as a chaotic neuron model are presented to verify our hypothesis.
Gaudin, M. [Electricite de France (EDF), Direction des Etudes et Recherches, 92 - Clamart (France)
Resetting models is applied to electricity generating plant pipework systems. A frequency approach to the problem is made in an original way thanks to the use of precise dynamic rigidity matrices. The method assumes two kinds of unknown: the usually processed mechanical characteristics (Young`s Modulus, density etc.) and new resetting parameters acting on the dynamic behaviour of unknown connections. As the latter have a very wide range of possible variation, they benefit from a change of variable which allows the assumptions formulated to be complied with. The minimized cost function is based on a error in load. The frequencies required for building it are automatically selected thanks to different tests on measurements. Minimization uses a sensitivity technique linked with a method of least standard squares. The method has been programmed in Fortran 90 within the CIRCUS code and tried out on various examples which were simulated and sound effects cases as well as an actual case. (author). 128 refs.
Kobylecki, Christopher; Hill, Michael P; Crossman, Alan R; Ravenscroft, Paula
L-Dopa-induced dyskinesia in patients with Parkinson's disease can be alleviated by amantadine, an antagonist at N-methyl-D-aspartate glutamate receptors. The antiepileptic drug topiramate, which blocks α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, has also been shown to reduce dyskinesia. The purpose of this study was to examine the behavioral pharmacology of topiramate alone and in combination with amantadine in animal models of PD and L-dopa-induced dyskinesia. The effects of topiramate (5-20 mg/kg) and amantadine (5-20 mg/kg) on abnormal involuntary movements (the rat homologue of dyskinesia) and Rotarod performance were assessed alone and in combination in the 6-hydroxydopamine-lesioned rat following chronic L-dopa treatment. Dyskinesia, parkinsonian disability, and "on-time" were assessed in the MPTP-lesioned nonhuman primate following administration of topiramate (5-20 mg/kg) and amantadine (0.1-1.0 mg/kg) alone and in combination. Topiramate and amantadine dose-dependently reduced dyskinesia in the 6-hydroxydopamine-lesioned rat, whereas topiramate reduced Rotarod performance; there was no effect on parkinsonian disability in the MPTP-lesioned nonhuman primate, in which both drugs reduced dyskinesia. Topiramate and amantadine exhibited differential antidyskinetic effects on dyskinesia elicited by the dopamine D1 receptor agonist SKF 38393 (2 mg/kg). Subthreshold doses of both drugs in combination had a synergistic effect on dyskinesia in the 6-hydroxydopamine-lesioned rat, with no worsening of motor performance; this effect was confirmed in the MPTP-lesioned nonhuman primate, with a selective reduction in "bad on-time." These data confirm the antidyskinetic potential of topiramate and suggest that combination with low-dose amantadine may allow better reduction of dyskinesia with no adverse motor effects. Copyright © 2011 Movement Disorder Society.
Full Text Available Light is a crucial input for circadian clocks. In Drosophila, short light exposure can robustly shift the phase of circadian behavior. The model for this resetting posits that circadian photoreception is cell autonomous: CRYPTOCHROME senses light, binds to TIMELESS (TIM, and promotes its degradation, which is mediated by JETLAG (JET. However, it was recently proposed that interactions between circadian neurons are also required for phase resetting. We identify two groups of neurons critical for circadian photoreception: the morning (M and the evening (E oscillators. These neurons work synergistically to reset rhythmic behavior. JET promotes acute TIM degradation cell autonomously in M and E oscillators but also nonautonomously in E oscillators when expressed in M oscillators. Thus, upon light exposure, the M oscillators communicate with the E oscillators. Because the M oscillators drive circadian behavior, they must also receive inputs from the E oscillators. Hence, although photic TIM degradation is largely cell autonomous, neural cooperation between M and E oscillators is critical for circadian behavioral photoresponses.
Full Text Available The mono-stereo controller using audio mute clock is used at the International Broadcasting Bureau (IBB FM 106.6 MHz transmitter in Ulaan Baatar, Mongolia since 2010. The major problem of the FM broadcast station was from the frozen Programmable Logic Controller, PLC, which must be manually reset and the report by the VOA listeners. Then, the PLC auto power reset circuit is proposed and built in mono-stereo controller to monitor the operation of the PLC. The circuit is also used to restart the PLC whenever, it is frozen. The cloud router and Transmission Control Protocol/Internet Protocol (TCP/IP to Recommended Standard number 232 (RS-232 converter are used to synchronize the PLC time. From the results, this circuit can improve the transmitter availability and quality of the 24 hours/day broadcast program without affection to the listeners. The reliability of the cloud router is acceptable with low delay of data transfer via the internet connection between Thailand to Mongolia. The cloud router which the IBB leases cloud service from the provider that offers high speed internet up to 1000 Mb/s, via the remote terminal is used for the schedule program and the time synchronization of the PLC correctly. The proposed system is very stable and there is no problem of the frozen PLC whether it connects to the internet or not. Hence, the designed PLC auto power reset circuit can be used to eliminate the frozen PLC problem.
EW-201408) Demonstration of Energy Savings in Commercial Buildings for Tiered Trim and Respond Method in Resetting Static Pressure for VAV...2014 – February 2017 4. TITLE AND SUBTITLE Demonstration of Energy Savings in Commercial Buildings for Tiered Trim and Respond Method in Resetting...facilities to show energy savings compared to Fixed Pressure Control method. Comparisons were made by alternating static pressure control modes every two
Versek, Brian E.; Carpenedo, Carolyn M; Rosenwasser, Beth J; Dugosh, Karen Leggett; Bresani, Elena; Kirby, Kimberly C.
Voucher-based reinforcement therapy (VBRT) is an efficacious contingency management intervention for substance use disorders that provides escalating voucher values to reinforce continuous abstinence and typically resets escalated values to the initial low level upon detection of drug use. The objective of this study involving 130 methadone-maintained outpatients receiving VBRT was to investigate whether resets 1) increase risk for adverse events (AEs) and 2) delay return to abstinence in rel...
Ellerman, A; Bisgaard, H
patients entering as children (forced vital capacity (FVC) 70 versus 85% predicted; forced expiratory volume in one second (FEV1) 59 versus 72% pred). The lung damage did not relate to the type of ciliary dyskinesia. During the subsequent surveillance of the groups for a median of 14 and 7 yrs......Patients with primary ciliary dyskinesia (PCD) have pronounced stasis of their respiratory secretions and therefore recurrent lower airway infections, which raises concerns for the development of lung function. Twenty four patients with PCD have been studied prospectively with a standardized regime...... in our clinic for 2-16 yrs with clinic visits, including spirometry 2-4 times per year, daily physiotherapy and monthly sputum cultures with subsequent specific antibiotic treatment. Lung function was significantly lower in the 12 PCD patients entering the cohort as adults when compared to the PCD...
Herz, Damian M.; Haagensen, Brian N.; Christensen, Mark S.
Dopaminergic signalling in the striatum contributes to reinforcement of actions and motivational enhancement of motor vigour. Parkinson's disease leads to progressive dopaminergic denervation of the striatum, impairing the function of cortico-basal ganglia networks. While levodopa therapy......-cortical connectivity as a neural signature of levodopa-induced dyskinesias in humans. We argue that excessive striato-cortical connectivity in response to levodopa produces an aberrant reinforcement signal producing an abnormal motor drive that ultimately triggers involuntary movements....
Shapiro, Adam J; Weck, Karen E; Chao, Kay C; Rosenfeld, Margaret; Nygren, Anders O H; Knowles, Michael R; Leigh, Margaret W; Zariwala, Maimoona A
Cri du chat syndrome (CdCS) and primary ciliary dyskinesia (PCD) are rare diseases that present with frequent respiratory symptoms. PCD can be caused by hemizygous DNAH5 mutation in combination with a 5p segmental deletion attributable to CdCS on the opposite chromosome. Chronic oto-sino-pulmonary symptoms or organ laterality defects in CdCS should prompt an evaluation for PCD. Copyright © 2014 Elsevier Inc. All rights reserved.
Ivanova, Svetlana A.; Alifirova, V. M.; Freidin, Maxim B.; Pozhidaev, Ivan V; Fedorenko, Olga Yu; Bokhan, Nikolay A.; Zhukova, I. A.; Zhukova, Natalia G; Wilffert, Berend; Loonen, Antonius
Predictive genetic model for levodopa-induced dyskinesia in patients with Parkinson's disease S.A. Ivanova(1), V.M. Alifirova(2), M.B. Freidin(3), I.V. Pozhidaev(4), O.Y. Fedorenko(4), N.A. Bokhan(4), I.A. Zhukova(5), N.G. Zhukova(5), B. Wilffert(6), A.J.M. Loonen(6) (1)Mental Health Research
Tawde, Pooja; Dabadghav, Rachana; Bedekar, Nilima; Shyam, Ashok; Sancheti, Parag
Playing the violin can lead to asymmetric postures which can affect the cervical range of motion, cervical core strength and scapular stability. The objective of the study was to assess the cervical range of motion, cervical core strength and scapular dyskinesia in violin players and non-players of the same age group. An inclinometer was used to assess the cervical range of motion, pressure biofeedback was used to assess cervical core strength and scapular dyskinesia was also assessed in 30 professional violin players (18-40 years) compared with 30 age-matched non-players. Analysis was done using an unpaired t test. Significant change was seen with respect to extension (p = 0.051), cervical core strength (p = 0.005), right (Rt) superior angle 0° (p = 0.004), Rt superior angle 45° (p = 0.015) and Rt inferior angle 90° (p = 0.013). This study shows a significant difference in extension range of motion and cervical core strength of violin players. Also, there was scapular dyskinesia seen at 0° and 45° right-side superior angle of the scapula and 90° right-side inferior angle of the scapula.
Full Text Available Despite recent progress in defining the ciliome, the genetic basis for many cases of primary ciliary dyskinesia (PCD remains elusive. We evaluated five children from two unrelated, consanguineous Palestinian families who had PCD with typical clinical features, reduced nasal nitric oxide concentrations, and absent dynein arms. Linkage analyses revealed a single common homozygous region on chromosome 8 and one candidate was conserved in organisms with motile cilia. Sequencing revealed a single novel mutation in LRRC6 (Leucine-rich repeat containing protein 6 that fit the model of autosomal recessive genetic transmission, leading to a change of a highly conserved amino acid from aspartic acid to histidine (Asp146His. LRRC6 was localized to the cytoplasm and was up-regulated during ciliogenesis in human airway epithelial cells in a Foxj1-dependent fashion. Nasal epithelial cells isolated from affected individuals and shRNA-mediated silencing in human airway epithelial cells, showed reduced LRRC6 expression, absent dynein arms, and slowed cilia beat frequency. Dynein arm proteins were either absent or mislocalized to the cytoplasm in airway epithelial cells from a primary ciliary dyskinesia subject. These findings suggest that LRRC6 plays a role in dynein arm assembly or trafficking and when mutated leads to primary ciliary dyskinesia with laterality defects.
Brumberg, Joachim; Küsters, Sebastian; Al-Momani, Ehab; Marotta, Giorgio; Cosgrove, Kelly P; van Dyck, Christopher H; Herrmann, Ken; Homola, György A; Pezzoli, Gianni; Buck, Andreas K; Volkmann, Jens; Samnick, Samuel; Isaias, Ioannis U
To investigate the association between levodopa-induced dyskinesias and striatal cholinergic activity in patients with Parkinson's disease. This study included 13 Parkinson's disease patients with peak-of-dose levodopa-induced dyskinesias, 12 nondyskinetic patients, and 12 healthy controls. Participants underwent 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine single-photon emission computed tomography, a marker of nicotinic acetylcholine receptors, [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single-photon emission computed tomography, to measure dopamine reuptake transporter density and 2-[18F]fluoro-2-deoxyglucose positron emission tomography to assess regional cerebral metabolic activity. Striatal binding potentials, uptake values at basal ganglia structures, and correlations with clinical variables were analyzed. Density of nicotinic acetylcholine receptors in the caudate nucleus of dyskinetic subjects was similar to that of healthy controls and significantly higher to that of nondyskinetic patients, in particular, contralaterally to the clinically most affected side. Our findings support the hypothesis that the expression of dyskinesia may be related to cholinergic neuronal excitability in a dopaminergic-depleted striatum. Cholinergic signaling would play a role in maintaining striatal dopaminergic responsiveness, possibly defining disease phenotype and progression.
M. AUGUSTA MONTENEGRO
Full Text Available Phenytoin is an effective antiepileptic drug, although, it can be associated with many side effects, including dyskinesia. OBJECTIVE: To describe the clinical characteristics of phenytoin induced dyskinesia. METHODS: We investigated the occurrence of involuntary movements in patients followed at our adult and pediatric epilepsy clinics during the period of one year. RESULTS: Three patients presented with phenytoin-induced dyskinesia: one adult with axial and orofacial dyskinesia, and two children with choreoathetosis. They did not have other signs of phenytoin intoxication and had complete recovery after phenytoin withdrawal. CONCLUSION: Phenytoin induced dyskinesia may occur during either chronic or initial treatment and with normal serum phenytoin levels. However, it occurs most often in patients on polytherapy, usually after increasing dosage and with toxic serum levels. Other signs of phenytoin intoxication may be present in these patients, but often the dyskinesia is the only side effect, which may delay the diagnosis and treatment. The clinical characteristics of the involuntary movements vary and may be focal or generalized, most often characterized by choreoathetosis and dyskinesias. These may last for hours, days or even years, but frequently disappear completely after phenytoin withdrawal.Fenitoína é droga anti-epiléptica eficaz, mas pode estar associada a vários efeitos colaterais, inclusive discinesia. OBJETIVO: Descrever as características clínicas da discinesia induzida por fenitoína. MÉTODO: Avaliamos a ocorrência de movimentos involuntários em pacientes seguidos nos ambulatórios de epilepsia durante o período de um ano. RESULTADOS: Três pacientes apresentaram discinesia induzida por fenitoína: um adulto com discinesia orofacial e duas crianças com coreoatetose. Eles não tinham outros sinais de intoxicação por fenitoína e apresentaram recuperação completa após a retirada da fenitoína. CONCLUSÃO: Discinesia
Kim, Sungjun; Park, Byung-Gook
A study on the bipolar-resistive switching of an Ni/SiN/Si-based resistive random-access memory (RRAM) device shows that the influences of the reset power and the resistance value of the low-resistance state (LRS) on the reset-switching transitions are strong. For a low LRS with a large conducting path, the sharp reset switching, which requires a high reset power (>7 mW), was observed, whereas for a high LRS with small multiple-conducting paths, the step-by-step reset switching with a low reset power (device, which are not too strong and not too weak, offer considerable potential for the realization of low-power and high-density crossbar-array applications.
Walsh, Kenneth K.
Earthquakes have the potential to cause large-scale destruction of civil infrastructure often leading to significant economic losses or even the loss of human life. Therefore, it is vital to protect civil infrastructure during these events. Structural vibration control provides a method for mitigating the damage to civil infrastructure during earthquakes by absorbing seismic energy from the structure. Semi-active control has emerged as an attractive form of structural control due to its effectiveness, inherent stability, and reliability. One semi-active control device particularly effective in reducing the response of civil structures subject to near-field earthquakes is the resetting semi-active stiffness damper (RSASD). Substantial research has been conducted to develop the RSASD and demonstrate its control performance. However, like other semi-active control technologies, the RSASD relies on a multi-component feedback control system that is subject to reliability issues. The purpose of the proposed research is to develop a novel resettable stiffness system that is capable of achieving a similar control performance to the RSASD, but with fewer feedback components. The resulting device, the resetting semi-passive stiffness damper (RSPSD), will offer increased reliability without compromising effectiveness. The objective of the present work is to present the concept for the RSPSD, develop a mathematical model describing its resetting, identify critical design parameters, and then evaluate its control performance for single-degree-of-freedom structures subject to an earthquake ground motion. Numerical results indicate that the RSPSD is capable of comparable control performance to the RSASD for the structures and earthquake ground motion considered.
Full Text Available Initiating an eye movement towards a suddenly appearing visual target is faster when an accessory auditory stimulus occurs in close spatiotemporal vicinity. Such facilitation of saccadic reaction time (SRT is well-documented, but the exact neural mechanisms underlying the crossmodal effect remain to be elucidated. From EEG/MEG studies it has been hypothesized that coupled oscillatory activity in primary sensory cortices regulates multisensory processing. Specifically, it is assumed that the phase of an ongoing neural oscillation is shifted due to the occurrence of a sensory stimulus so that, across trials, phase values become highly consistent (phase reset. If one can identify the phase an oscillation is reset to, it is possible to predict when temporal windows of high and low excitability will occur. However, in behavioral experiments the pre-stimulus phase will be different on successive repetitions of the experimental trial, and average performance over many trials will show no signs of the modulation. Here we circumvent this problem by repeatedly presenting an auditory accessory stimulus followed by a visual target stimulus with a temporal delay varied in steps of 2 ms. Performing a discrete time series analysis on SRT as a function of the delay, we provide statistical evidence for the existence of distinct peak spectral components in the power spectrum. These frequencies, although varying across participants, fall within the beta and gamma range (20 to 40 Hz of neural oscillatory activity observed in neurophysiological studies of multisensory integration. Some evidence for high-theta/alpha activity was found as well. Our results are consistent with the phase reset hypothesis and demonstrate that it is amenable to testing by purely psychophysical methods. Thus, any theory of multisensory processes that connects specific brain states with patterns of saccadic responses should be able to account for traces of oscillatory activity in observable
Lam, T J G M; Jansen, J; Wessels, R J
Prudent use of antibiotics is important to prevent antibiotic resistance in humans and in animals. For this reason politicians demanded a decrease of total antibiotic use and of use of critically important antibiotics in animal husbandry in the Netherlands. In the dairy sector the use of antibiotics almost halved in the years 2009-2015, with a decrease of the use of critically important antibiotics to very low levels. To realize a sustainable decrease in antibiotic usage, the mindset towards the subject was considered crucial. Based on several models from social psychology, the RESET Mindset Model was used. This model contains the most important cues to change human behaviour, being Rules and regulations, Education and information, Social pressure, Economics, and Tools. To change behaviour of groups in order to reach a tipping point, it is of utmost importance to not choose among the different cues, but to use them all. In order to decrease antibiotic usage in dairy cattle in the Netherlands several actions, obliged as well as voluntary, were undertaken. An independent veterinary medicine authority was founded that became active for all animal sectors. In the dairy sector a national database on antibiotic usage called MediRund was developed, which made transparency and benchmarking on antibiotic usage at the national and the herd level possible. Several other activities are described, such as herd health and treatment plans, selective dry cow therapy, and the strong limitation on the use of critically important antibiotics. Antibiotic usage at the herd level, referred to as the 'antibiotic number', became an important and socially accepted herd level parameter. The actions undertaken worked through different cues, all part of the RESET Mindset Model. As such, different types of dairy farmers sensitive to different types of cues were motivated to change their behaviour. Antibiotic usage in dairy cattle in the Netherlands decreased significantly by intense
RESEt (Research and Education Svalbard Experience www.resetsvalbard.it) is an ongoing educational project focusing mainly on polar and climate system topics. It started in 2014 and will end in 2017 with the high school diploma of the 22 students (16 y. o.) making the participant class. This class attend a school (Liceo Filzi, Rovereto, Trento. Italy) with a primary focus on disciplines like philosophy and education, rather then STEM (Science, Technology, Engineering, and Mathematics). Nevertheless their science curricula include climate topics that are rather challenging to grasp and, at the same time, crucial for their scientific citizenship. Some questions arise: How to foster their interest in geosciences topics? How to engage them in authentic scientific knowledge? How to increase their interest in scientific university courses during their post-secondary career? RESEt project will attempt to answer these questions through the development of integrated activities distributed over the last three years of their high school cycle. The most important moment will be an educational scientific expedition at the Svalbard, an archipelago located in the Arctic. The expedition be entirely organized, planned, and directed by students. In Svalbard, students will visit the main scientific facilities devoted to climate studies including those of Italian CNR (National Research Council) and they will perform some environmental measurement using data-loggers. Students are even involved in the fundraising process to raise more than ten thousand Euros needed to for travel expenses. This work is aimed mainly at presenting some of the preliminary data collected during the RESEt project, including the fundraising aspects. The management of the RESEt project strongly relies on the experience and network gained by the abstract author during the participation to the Education and Public Outreach (EPO) program of International Polar Year (IPY) 2007-2009 as well as the support of Polar
Pastötter, Bernhard; Kliegl, Oliver; Bäuml, Karl-Heinz T
In list-method directed forgetting (LMDF), people are cued to forget a previously studied item list (List 1) and to learn a new list of items (List 2) instead. Such cuing typically enhances memory for the List 2 items, in both recall and (sometimes) item-recognition testing. It has recently been hypothesized that the enhancement effect for List 2 items (partly) reflects the result of a reset-of-encoding process. The proposal is that encoding efficacy decreases with an increase in study material, but the forget cue can reset the encoding process to make the encoding of early List 2 items as effective as the encoding of early List 1 items. An experiment is reported that examined the reset-of-encoding hypothesis with item-recognition testing, examining influences of items' serial learning position on the effects of the forget cue. Item-recognition tests were conducted separately for the two lists. Consistent with the reset-of-encoding hypothesis, the results showed strong enhancement effects for early List 2 items, but hardly any enhancement effects for middle and late List 2 items. Like in previous item-recognition studies, no cuing effects were found for List 1 items. The results support two-mechanism accounts of LMDF, which assume a critical role for a reset-of-encoding process for List 2 enhancement.
Full Text Available In order to improve the performance of traditional particle swarm optimization, this paper introduces the principle of Levy flight and cross-border reset mechanism. In the proposed particle swarm optimization, the dynamic variation of parameters meets the power-law distribution and the pattern of particles transition conforms to the Levy flight in the process of algorithm optimization. It means the particles make long distance movements in the search space with a small probability and make short distance movements with a large probability. Therefore, the particles can jump out of local optimum more easily and coordinate the global search and local search of particle swarm optimization. This paper also designs the cross-border reset mechanism to make particles regain optimization ability when stranding on the border of search space after a long distance movement. The simulation results demonstrate the proposed algorithms are easier to jump out of local optimum and have higher accuracy when compared with the existing similar algorithms based on benchmark test functions and handwriting character recognition system.
Full Text Available The objective vividly defines a new low-power and high-speed logic family; named Self Resetting Logic with Gate Diffusion Input (SRLGDI. This logic family resolves the issues in dynamic circuits like charge sharing, charge leakage, short circuit power dissipation, monotonicity requirement and low output voltage. In the proposed design structure of SRLGDI, the pull down tree is implemented with Gate Diffusion Input (GDI with level restoration which apparently eliminated the conductance overlap between nMOS and pMOS devices, thereby reducing the short circuit power dissipation and providing High Output Voltage VoH. The output stage of SRLGDI has been incorporated with an inverter to produce both true and complementary output function. The Resistance Capacitance (RC delay model has been proposed to obtain the total delay of the circuit during precharge and evaluation phases. Using SRLGDI, the primitive cells and 3 different full adder circuits were designed and simulated in a 0.250 μm Complementary Metal Oxide Semiconductor (CMOS process technology. The simulated result demonstrates that the proposed SRLGDI logic family is superior in terms of speed and power consumption with respect to other logic families like Dynamic logic (DY, CMOS, Self Resetting CMOS (SRCMOS and GDI.
Maes, Christian; Thiery, Thimothée
We consider a probe linearly coupled to the center of mass of a nonequilibrium bath. We study the induced motion on the probe for a model where a resetting mechanism is added to an overdamped bath dynamics with quadratic potentials. The fact that each bath particle is at random times reset to a fixed position is known for optimizing diffusive search strategies, but here stands for the nonequilibrium aspect of the bath. In the large bath scaling limit the probe is governed by an effective Langevin equation. Depending on the value of the parameters, there appear three regimes: (i) an equilibrium-like regime but with a reduced friction and an increased effective temperature; (ii) a regime where the noise felt by the probe is continuous but non-Gaussian and exhibits fat-tails; (iii) a regime with a non-Gaussian noise exhibiting power-law distributed jumps. The model thus represents an exactly solvable case for the origin of nonequilibrium probe dynamics.
Full Text Available Other than tremor, movement disorders are uncommon in multiple sclerosis. Among these uncommon clinical manifestations, paroxysmal kinesigenic dyskinesia is the most frequently reported. It is characterized by episodic attacks of involuntary movements that are induced by repetitive or sudden movements, startling noise or hyperventilation. The diagnosis is essentially clinical and based on a good observation of the attacks. It is very easy to misdiagnose it. We describe the case of a young female patient who presented paroxysmal kinesigenic dyskinesia as the first and only clinical manifestation of multiple sclerosis, with no recurrence of attacks nor any other neurologic symptom after eighteen months of follow-up.
Voon, Valerie; Napier, T Celeste; Frank, Michael J; Sgambato-Faure, Veronique; Grace, Anthony A; Rodriguez-Oroz, Maria; Obeso, Jose; Bezard, Erwan; Fernagut, Pierre-Olivier
Dopaminergic medications used in the treatment of patients with Parkinson's disease are associated with motor and non-motor behavioural side-effects, such as dyskinesias and impulse control disorders also known as behavioural addictions. Levodopa-induced dyskinesias occur in up to 80% of patients with Parkinson's after a few years of chronic treatment. Impulse control disorders, including gambling disorder, binge eating disorder, compulsive sexual behaviour, and compulsive shopping occur in about 17% of patients with Parkinson's disease on dopamine agonists. These behaviours reflect the interactions of the dopaminergic medications with the individual's susceptibility, and the underlying neurobiology of Parkinson's disease. Parkinsonian rodent models show enhanced reinforcing effects of chronic dopaminergic medication, and a potential role for individual susceptibility. In patients with Parkinson's disease and impulse control disorders, impairments are observed across subtypes of decisional impulsivity, possibly reflecting uncertainty and the relative balance of rewards and losses. Impairments appear to be more specific to decisional than motor impulsivity, which might reflect differences in ventral and dorsal striatal engagement. Emerging evidence suggests impulse control disorder subtypes have dissociable correlates, which indicate that individual susceptibility predisposes towards the expression of different behavioural subtypes and neurobiological substrates. Therapeutic interventions to treat patients with Parkinson's disease and impulse control disorders have shown efficacy in randomised controlled trials. Large-scale studies are warranted to identify individual risk factors and novel therapeutic targets for these diseases. Mechanisms underlying impulse control disorders and dyskinesias could provide crucial insights into other behavioural symptoms in Parkinson's disease and addictions in the general population. Copyright © 2017 Elsevier Ltd. All rights
Rose, J Bart; Fields, Ryan C; Strasberg, Steven M
Twenty percent of cholecystectomies in the US are performed for a diagnosis of biliary dyskinesia. Diagnosis is made by measuring gallbladder ejection fraction (GbEF) using hepatobiliary scintigraphy. Our purpose was to evaluate the reproducibility of GbEF measurements. This is a retrospective review of patients referred for cholecystectomy, from 2010 to 2016, with a diagnosis of biliary dyskinesia based on a GbEF test, who then underwent a repeat GbEF test. Thirty consecutive patients were identified by hospital records. Re-testing of GbEF was performed at least 6 weeks after the initial test using Tc-99m and slow injection of sincalide at 0.02 mcg/kg. On re-testing, 16 of 30 patients (53%) patients had a normal GbEF of >35%, ie the initial test result was not reproducible in them. Age, sex, days between testing, and initial GbEF did not differ between groups. The 14 patients who re-tested positive for biliary dyskinesia with reduced GbEF were significantly more likely to have episodic pain than steady pain. Re-testing frequently resulted in change in management in that most patients who re-tested in the normal range were not offered cholecystectomy. Hepatobiliary scintigraphy with GbEF is a poorly reproducible test. Re-testing resulted in a change in management in many patients who then avoided cholecystectomy. Strong consideration should be given to repeating hepatobiliary scintigraphy with GbEF before cholecystectomy in patients with an initial positive test. Copyright © 2017 American College of Surgeons. Published by Elsevier Inc. All rights reserved.
Frau, Roberto; Savoia, Paola; Fanni, Silvia; Fiorentini, Chiara; Fidalgo, Camino; Tronci, Elisabetta; Stancampiano, Roberto; Meloni, Mario; Cannas, Antonino; Marrosu, Francesco; Bortolato, Marco; Devoto, Paola; Missale, Cristina; Carta, Manolo
Levodopa-induced dyskinesia (LID) is a disabling motor complication occurring in Parkinson's disease patients (PD) after long-term l-DOPA treatment. Although its etiology remains unclear, there is accumulating evidence that LID relies on an excessive dopamine receptor transmission, particularly at the downstream signaling of D1 receptors. We previously reported that the pharmacological blockade of 5-alpha reductase (5AR), the rate limiting enzyme in neurosteroids synthesis, rescued a number of behavioral aberrations induced by D1 receptor-selective and non-selective agonists, without inducing extrapyramidal symptoms. Thus, the present study was designed to verify whether the 5AR inhibitor finasteride (FIN) may counteract the dyskinesias induced by dopaminergic agonists in 6-hydroxydopamine (6-OHDA)-lesioned rats. First, we assessed the acute and chronic effect of different doses of FIN (30-60mg/kg) on LID, in male 6-OHDA-lesioned dyskinetic rats. Thereafter, to fully characterize the therapeutic potential of FIN on LID and its impact on l-DOPA efficacy, we assessed abnormal involuntary movements and forelimb use in hemiparkinsonian male rats chronically injected with FIN (30-60mg/kg/24days) either prior to- or concomitant with l-DOPA administration. In addition, to investigate whether the impact of FIN on LID may be ascribed to a modulation of the D1- or D2/D3-receptor function, dyskinesias were assessed in l-DOPA-primed 6-OHDA-lesioned rats that received FIN in combination with selective direct dopaminergic agonists. Finally, we set to investigate whether FIN may produce similar effect in female hemiparkinsonian rats, as seen in males. The results indicated that FIN administrations significantly dampened LID in all tested treatment regimens, without interfering with the ability of l-DOPA to ameliorate forelimb use in the stepping test. The antidyskinetic effect appears to be due to modulation of both D1- and D2/D3-receptor function, as FIN also reduced abnormal
Full Text Available Paroxysmal kinesigenic dyskinesia (PKD is a disorder characterized by recurrent and brief attacks that are induced by sudden voluntary movement with highly clinical and genetic heterogeneity. Familial PKD are mostly autosomal dominant inherited and proline-rich transmembrare protein 2 (PRRT2 gene has been identified as the causative gene for PKD. So far 56 mutations have been documented and most of them are nonsense ones. No obvious genotype-phenotype correlation has been observed and the function of PRRT2 is still unclear, but the interaction between PRRT2 and synaptosomal-associated protein 25 (SNAP25 will shed the light on the research of PKD mechanism.
Gardella, Elena; Becker, Felicitas; Moller, Rikke S.
Objective: Benign familial infantile seizures (BFIS), paroxysmal kinesigenic dyskinesia (PKD), and their combination-known as infantile convulsions and paroxysmal choreoathetosis (ICCA)-are related autosomal dominant diseases. PRRT2 (proline-rich transmembrane protein 2 gene) has been identified...... at school age. All patients stayed otherwise seizure-free, most without medication. Interictal electroencephalogram (EEG) was normal in all cases but 2. Five of 16 patients developed additional brief paroxysmal episodes in puberty, either dystonic/dyskinetic or "shivering" attacks, triggered by stretching...
Paydarfar, D; Gilbert, R J; Poppel, C S; Nassab, P F
1. Relationships between the timing of respiration and deglutition were studied in thirty awake healthy subjects at rest. Deglutition was monitored by submental electromyography, pharyngeal manometry and videofluoroscopy. Respiration was recorded by measurement of oronasal airflow and chest wall movement. Three types of deglutition were studied: injected bolus swallows, spontaneous swallows, and visually cued swallows of boluses previously placed in the mouth. 2. The effect of each swallow on respiratory rhythm was characterized by measurement of cophase, defined as the interval between the onset of deglutitive submental EMG activity to the onset of subsequent rescheduled inspirations. Cophase was determined for swallows initiated at different phases of the respiratory cycle. In all subjects deglutition caused phase resetting of respiratory rhythm. Cophase was largest for swallows initiated near the the inspiratory-expiratory (E-I) transition and smallest for swallows initiated near the expiratory-inspiratory (E-I) transition. The pattern of respiratory resetting by deglutition was topologically classified as type 0. This pattern was shown for swallows induced by bolus injection or visual cue, and for spontaneous swallows. 3. The incidence of spontaneous deglutition was influenced by the position of the swallow in the respiratory cycle. Few spontaneous swallows were initiated near the E-I transition whereas most occurred from late inspiration to mid-expiration. 4. Deglutition caused an abrupt decrease in airflow leading to an interval of apnoea, followed by a period of expiration. The duration of deglutition apnoea for spontaneous swallows was shorter than that for 5 ml bolus swallows, and was unaffected by the respiratory phase of swallow initiation. The period of expiration after swallowing was longest for swallows initiated at the I-E transition, and shortest for E-I swallows. 5. The intervals between bolus injection and the onset of deglutition apnoea, and the
Panizzi, Jennifer R.; Becker-Heck, Anita; Castleman, Victoria H.; Al-Mutairi, Dalal; Liu, Yan; Loges, Niki T.; Pathak, Narendra; Austin-Tse, Christina; Sheridan, Eamonn; Schmidts, Miriam; Olbrich, Heike; Werner, Claudius; Häffner, Karsten; Hellman, Nathan; Chodhari, Rahul; Gupta, Amar; Kramer-Zucker, Albrecht; Olale, Felix; Burdine, Rebecca D.; Schier, Alexander F.; O’Callaghan, Christopher; Chung, Eddie MK; Reinhardt, Richard; Mitchison, Hannah M.; King, Stephen M.; Omran, Heymut; Drummond, Iain A.
Cilia are essential for fertilization, respiratory clearance, cerebrospinal fluid circulation, and to establish laterality1. Cilia motility defects cause Primary Ciliary Dyskinesia (PCD, MIM 242650), a disorder affecting 1:15-30,000 births. Cilia motility requires the assembly of multisubunit dynein arms that drive cilia bending2. Despite progress in understanding the genetic basis of PCD, mutations remain to be identified for several PCD linked loci3. Here we show that the zebrafish cilia paralysis mutant schmalhanstn222 (smh) mutant encodes the coiled-coil domain containing 103 protein (Ccdc103), a foxj1a regulated gene. Screening 146 unrelated PCD families identified patients in six families with reduced outer dynein arms, carrying mutations in CCDC103. Dynein arm assembly in smh mutant zebrafish was rescued by wild-type but not mutant human CCDC103. Chlamydomonas Ccdc103 functions as a tightly bound, axoneme-associated protein. The results identify Ccdc103 as a novel dynein arm attachment factor that when mutated causes Primary Ciliary Dyskinesia. PMID:22581229
Wang, Mao-Hsien; Lin, Rui-Feng; Tseng, Hsiang-Chien; Soung, Hung-Sheng; Chang, Kuo-Chi; Tsai, Cheng-Chia
Reserpine-induced orofacial dyskinesia (OD) has been used for decades as an animal model for human tardive dyskinesia (TD) because both of them have pathophysiology strongly associated with striatal oxidative stress. Green tea catechins, especially (-) epigallocatechin-3-gallate (EGCG), have potent antioxidative effects and are able to protect against various oxidative injuries. In this study, we examined the potential protective effects of EGCG on reserpine-induced behavioral and neurochemical dysfunction in rats. Reserpine treatment (1mg/kgs.c. one injection every other day, three injections total) induced significant increases (p<0.001) in the frequency of vacuous chewing movement (VCM) and tongue protrusion (TP) as well as the duration of facial twitching (FT). EGCG treatment (100mg/kgi.p. for 11days, starting 7days before the reserpine injections) was able to prevent most of the reserpine-induced OD. Also, EGCG treatment was able to reduce the reserpine-induced lipid peroxidation (LPO) production, and enhances the antioxidation power in the striatum of reserpine-treated rats. The above results indicate that EGCG has a protective role against reserpine-induced OD, probably via its powerful antioxidative properties. Thus, EGCG may possible have a clinically relevant therapeutic effect in preventing, delaying or even treating TD. Copyright © 2015. Published by Elsevier Inc.
Lucas, Jane S.
Key points Primary ciliary dyskinesia (PCD) is a genetically and clinically heterogeneous disease characterised by abnormal motile ciliary function. There is no “gold standard” diagnostic test for PCD. The European Respiratory Society (ERS) Task Force Guidelines for diagnosing PCD recommend that patients should be referred for diagnostic testing if they have several of the following features: persistent wet cough; situs anomalies; congenital cardiac defects; persistent rhinitis; chronic middle ear disease with or without hearing loss; or a history, in term infants, of neonatal upper and lower respiratory symptoms or neonatal intensive care admission. The ERS Task Force recommends that patients should be investigated in a specialist PCD centre with access to a range of complementary tests: nasal nitric oxide, high-speed video microscopy analysis and transmission electron microscopy. Additional tests including immunofluorescence labelling of ciliary proteins and genetic testing may also help determine the diagnosis. Educational aims This article is intended for primary and secondary care physicians interested in primary ciliary dyskinesia (PCD), i.e. those who identify patients for testing, and those involved in diagnosing and managing PCD patients. It aims: to inform readers about the new European Respiratory Society Task Force Guidelines for diagnosing patients with PCDto enable primary and secondary care physicians to: identify patients who need diagnostic testing; understand the diagnostic tests that their patients will undergo, the results of the tests and their limitations; and ensure that appropriate care is subsequently delivered. PMID:28894478
Li, Michael H; Mestre, Tiago A; Fox, Susan H; Taati, Babak
Levodopa is the gold standard therapy for Parkinson's disease (PD), but its prolonged usage leads to additional motor complications, namely levodopa-induced dyskinesia (LID). To assess LID and adjust drug regimens for optimal relief, patients attend regular clinic visits. However, the intermittent nature of these visits can fail to capture important changes in a person's condition. With the recent emergence of deep learning achieving impressive results in a wide array of fields including computer vision, there is an opportunity for video analysis to be used for automated assessment of LID. Deep learning for pose estimation was studied as a viable means of extracting body movements from PD assessment videos. Movement features were computed from joint trajectories. Results show that features derived from vision-based analysis have moderate to good correlation with clinician ratings of dyskinesia severity. This study presents the first application of deep learning to video analysis in PD, and demonstrates promise for future development of a non-contact system for objective PD assessment.
Full Text Available Norio Yasui-Furukori,1 Atsuhiro Kikuchi,1 Hiroshi Katagai,1,2 Sunao Kaneko11Department of Neuropsychiatry, Hirosaki University School of Medicine, 2Department of Neuropsychiatry, Hirosaki-Aiseikai Hospital, Hirosaki, JapanBackground: Tardive dystonia and dyskinesia are potentially irreversible neurological syndromes. Successful electroconvulsive treatment (ECT has been reported by multiple sources; however, the existing retrospective reviews and open prospective trials provide little information on the response rate.Methods: Eighteen consecutive patients with tardive dystonia or dyskinesia received a standard course of ECT to treat abnormal movement. The severity of the tardive dystonia and dyskinesia was evaluated using the Abnormal Involuntary Movement Scale (AIMS before and after the course of ECT. The patients who displayed a greater than 50% improvement in the AIMS score were classified as the responders.Results: The mean AIMS score decreased from 19.1±4.7 to 9.6±4.2. There were seven responders among the 18 patients, which yielded a 39% response rate. Conclusion: ECT has a moderate but significant effect on tardive dystonia and dyskinesia. Keywords: tardive dystonia, tardive diskinesia, ECT, medication
Papapetropoulos, S; Mash, D C
Treatment-related motor fluctuations (MFs) and dyskinesias are considered one of the most important problems in the long-term management of Parkinson's disease (PD). However, only a few studies have focused on their characteristics during advanced and end stages of the disease. We therefore assessed MFs and dyskinesias in a cohort of 61 late/end stage patients with a clinical and pathological diagnosis of PD and investigated the influence of disease- and treatment-related variables on their occurrence. A total of 62.3% of our patients experienced "wearing-off" phenomena, 68.9% "on-off" motor fluctuations and 60.7% dyskinesias at advanced/end stage disease. Age at disease onset and disease duration were significantly associated with dyskinesias. A substantial number of patients experienced spontaneous resolution of their motor complications during the last two years of their disease without treatment modifications. The clinical heterogeneity of treatment-related motor complications in PD points towards a complex mechanism for their etiopathogenesis. Although advanced disease and L-dopa administration are closely tied to their development, other mechanisms involving synaptic aging, altered neuronal plasticity and post-synaptic degeneration may be involved.
Olcese, C.; Patel, M.P.; Shoemark, A.; Kiviluoto, S.; Legendre, M.; Williams, H.J.; Vaughan, C.K.; Hayward, J.; Goldenberg, A.; Emes, R.D.; Munye, M.M.; Dyer, L.; Cahill, T.; Bevillard, J.; Gehrig, C.; Guipponi, M.; Chantot, S.; Duquesnoy, P.; Thomas, L.; Jeanson, L.; Copin, B.; Tamalet, A.; Thauvin-Robinet, C.; Papon, J.F.; Garin, A.; Pin, I.; Vera, G.; Aurora, P.; Fassad, M.R.; Jenkins, L.; Boustred, C.; Cullup, T.; Dixon, M.; Onoufriadis, A.; Bush, A.; Chung, E.M.; Antonarakis, S.E.; Loebinger, M.R.; Wilson, R.; Armengot, M.; Escudier, E.; Hogg, C.; Amselem, S.; Sun, Z.; Bartoloni, L.; Blouin, J.L.; Mitchison, H.M.; Schmidts, M.; et al.,
By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of
Ivanova, Svetlana A.; Fedorenko, Olga Yu; Freidin, Maxim B.; Alifirova, Valentina M.; Zhukova, Natalia G.; Zhukova, Irina A.; Al Hadithy, Asmar F Y; Brouwers, Jacobus R B J; Bokhan, Nikolay A.; Wilffert, Bob; Loonen, Anton J M
Introduction: Long-term levodopa treatment of Parkinson’s disease (PD) is frequently complicated by spontaneously occurring involuntary muscle movements called dyskinesia. The exact pathological mechanism of this complication has not yet been elucidated. We have previously demonstrated that in PD
Benvegnú, Dalila Moter; Roversi, Katiane; Barcelos, Raquel Cristine Silva; Trevizol, Fabíola; Pase, Camila Simonetti; Segat, Hecson Jesser; Dias, Verônica Tironi; Savian, Ana Luiza; Piccoli, Bruna Lopes; Piccolo, Jaqueline; Dutra-Filho, Carlos Severo; Emanuelli, Tatiana; de Bona da Silva, Cristiane; Beck, Ruy Carlos Ruver; Burger, Marilise Escobar
Haloperidol is a widely used antipsychotic, despite the severe motor side effects associated with its chronic use. This study was carried out to compare oral dyskinesia induced by different formulations of haloperidol-loaded nanocapsules containing caprylic/capric triglycerides, fish oil or grape seed oil (GSO) as core, as well as free haloperidol. Haloperidol-loaded lipid-core nanocapsules formulations were prepared, physicochemical characterized and administered (0.5 mg kg -1 -ip) to rats for 28 days. Oral dyskinesia was evaluated acutely and subchronically and after that cell viability and free radical generation in cortex and substantia nigra. All formulations presented satisfactory physicochemical parameters. Acutely, all formulations were able to prevent oral dyskinesia development in comparison to free haloperidol, except haloperidol-loaded nanocapsules containing GSO, whose effect was only partial. After subchronic treatment, all haloperidol-loaded nanocapsules formulations prevented oral dyskinesia in relation to free drug. Also, haloperidol-loaded nanocapsules containing fish oil and GSO were more effective than caprylic/capric triglycerides nanocapsules and free haloperidol in cell viability preservation and control of free radical generation. Our findings showed that fish oil formulation may be considered as the best formulation of haloperidol-loaded lipid-core nanocapsules, being able to prevent motor side effects associated with chronic use of antipsychotic drugs, as haloperidol.
Hjeij, Rim; Onoufriadis, Alexandros; Watson, Christopher M
, produced and preassembled in the cytosol, are transported to the ciliary or flagellar compartment and anchored into the axonemal microtubular scaffold via the ODA docking complex (ODA-DC) system. In humans, defects in ODA assembly are the major cause of primary ciliary dyskinesia (PCD), an inherited...
Ivanova, S.A.; Alifirova, V.M.; Pozhidaev, I.V.; Fedorenko, O.Y.; Osmanova, D.Z.; Tiguntsev, V.V.; Bokhan, N.A.; Zhukova, I.A.; Wilffert, B.; Loonen, A.J.M.
Parkinson's disease (PD), a common neurodegenerative disorder caused by the loss of the dopaminergic input to the basal ganglia, is commonly treated with levodopa (L-DOPA). Use of this drug, however, is severely limited by the development of side effect. Levodopa-induced dyskinesias (LID) are
OA, Andreassen; Weber, Christine; HA, Jorgensen
dyskinesias in rats, a putative analogue to human TD, could be prevented by the antioxidant coenzyme Q10 (CoQ10). Rats received 16 weeks of treatment with haloperidol decanoate (HAL) IM alone or together with orally administered CoQ10, and the behavior was recorded during and after treatment. HAL......, no increase of either CoQ10 or coenzyme Q9 was detected in the brain. These results suggest that cotreatment with CoQ10 does not inhibit the development of HAL-induced oral dyskinesias in rats, and that further studies seem to be needed in order to clarify the pharmakokinetics of CoQ10 in rats...... significantly increased the level of oral dyskinesias, and the increase persisted for 12 weeks after drug withdrawal. Cotreatment with CoQ10 did not attenuate the development of HAL-induced oral dyskinesia. Despite adequate absorption of orally administered CoQ10, shown by the increased serum levels of CoQ10...
Al Hadithy, A. F. Y.; Ivanova, S. A.; Pechlivanoglou, P.; Semke, A.; Fedorenko, O.; Kornetova, E.; Ryadovaya, L.; Brouwers, J. R. B. J.; Bruggeman, R.; Loonen, A. J. M.
Tardive dyskinesia (TD) is a potentially irreversible motor sideeffect occurring in about 30% of patients chronically exposed to neuroleptics. Genetic polymorphisms of dopamine D3 (DRD3), serotonin 2A (HTR2A) and 2C (HTR2C) receptors have been associated with TD. Currently, there are no
Boivin, D. B.; Czeisler, C. A.
The present study was designed to investigate whether a weak photic stimulus can reset the endogenous circadian rhythms of plasma melatonin and plasma cortisol in human subjects. A stimulus consisting of three cycles of 5 h exposures to ordinary room light (approximately 180 lux), centered 1.5 h after the endogenous temperature nadir, significantly phase-advanced the plasma melatonin rhythm in eight healthy young men compared with the phase delays observed in eight control subjects who underwent the same protocol but were exposed to darkness (p melatonin and plasma cortisol maintained stable temporal relationships with the endogenous core body temperature cycle, consistent with the conclusion that exposure to ordinary indoor room light had shifted a master circadian pacemaker.
Boivin, D. B.; Czeisler, C. A.
The present study was designed to investigate whether a weak photic stimulus can reset the endogenous circadian rhythms of plasma melatonin and plasma cortisol in human subjects. A stimulus consisting of three cycles of 5 h exposures to ordinary room light (approximately 180 lux), centered 1.5 h after the endogenous temperature nadir, significantly phase-advanced the plasma melatonin rhythm in eight healthy young men compared with the phase delays observed in eight control subjects who underwent the same protocol but were exposed to darkness (p rhythms of plasma melatonin and plasma cortisol maintained stable temporal relationships with the endogenous core body temperature cycle, consistent with the conclusion that exposure to ordinary indoor room light had shifted a master circadian pacemaker.
Sampietro, M; Fasoli, L
We present a circuit solution to provide DC feedback and signal reset in charge amplifiers that overcomes the difficulty to integrate high value resistors in VLSI technology. The feedback resistor is substituted by a MOSFET current conveyor that re-direct to the input node the current already available at the output follower. The lower noise of this 'active resistor' with respect to a physical resistor of equal value makes possible a first shaping within the preamplifier. The circuit has been implemented for a fast shaping time system (20 ns peaking time) using a BJT as input transistor for best noise performance. The circuit has been powered with single supply as low as 1.6 V with a total power consumption down to 220 mu W/ch and has shown a measured noise of 660 electrons rms, in accordance with the theoretical expectation.
Thorne, Philippa M; Ruta, Marcello; Benton, Michael J
Ichthyosaurs were important marine predators in the Early Jurassic, and an abundant and diverse component of Mesozoic marine ecosystems. Despite their ecological importance, however, the Early Jurassic species represent a reduced remnant of their former significance in the Triassic. Ichthyosaurs passed through an evolutionary bottleneck at, or close to, the Triassic-Jurassic boundary, which reduced their diversity to as few as three or four lineages. Diversity bounced back to some extent in the aftermath of the end-Triassic mass extinction, but disparity remained at less than one-tenth of pre-extinction levels, and never recovered. The group remained at low diversity and disparity for its final 100 Myr. The end-Triassic mass extinction had a previously unsuspected profound effect in resetting the evolution of apex marine predators of the Mesozoic.
Lu, Bei; Wu, Fen; Kim, SungWan
In flight control, the design objective and the aircraft dynamics may be different in low and high angle of attack regions. This paper presents a systematic switching Linear Parameter-varying LPV method to determine if it is practical to use for flight control designs over a wide angle of attack region. The approach is based on multiple parameter-dependent Lyapunov functions a family of LPV controllers are designed, and each of them is suitable for a specific parameter subspace. The state of the controller is reset to guarantee the stability requirement of the Lyapunov function when the switching event occurs. Two parameter-dependent switching logics, hysteresis switching and switching with average dwell times are examined. The proposed switching LPV control scheme is applied to an F-16 aircraft model with different design objectives and aircraft dynamics in low and high angle of attack regions. The nonlinear simulating results using both switching logics are compared.
Yasuo, Shinobu; Iwamoto, Ayaka; Lee, Sang-Il; Ochiai, Shotaro; Hitachi, Rina; Shibata, Satomi; Uotsu, Nobuo; Tarumizu, Chie; Matsuoka, Sayuri; Furuse, Mitsuhiro; Higuchi, Shigekazu
Background: The circadian clock is modulated by the timing of ingestion or food composition, but the effects of specific nutrients are poorly understood.Objective: We aimed to identify the amino acids that modulate the circadian clock and reset the light-induced circadian phase in mice and humans.Methods: Male CBA/N mice were orally administered 1 of 20 l-amino acids, and the circadian and light-induced phase shifts of wheel-running activity were analyzed. Antagonists of several neurotransmitter pathways were injected before l-serine administration, and light-induced phase shifts were analyzed. In addition, the effect of l-serine on the light-induced phase advance was investigated in healthy male students (mean ± SD age 22.2 ± 1.8 y) by using dim-light melatonin onset (DLMO) determined by saliva samples as an index of the circadian phase.Results: l-Serine administration enhanced light-induced phase shifts in mice (1.86-fold; P light-dark cycle by 6 h, l-serine administration slightly accelerated re-entrainment to the shifted cycle. In humans, l-serine ingestion before bedtime induced significantly larger phase advances of DLMO after bright-light exposure during the morning (means ± SEMs-l-serine: 25.9 ± 6.6 min; placebo: 12.1 ± 7.0 min; P light-induced phase resetting in mice and humans, and it may be useful for treating circadian disturbances. © 2017 American Society for Nutrition.
Zeitzer, J. M.; Dijk, D. J.; Kronauer, R.; Brown, E.; Czeisler, C.
Ocular exposure to early morning room light can significantly advance the timing of the human circadian pacemaker. The resetting response to such light has a non-linear relationship to illuminance. The dose-response relationship of the human circadian pacemaker to late evening light of dim to moderate intensity has not been well established. Twenty-three healthy young male and female volunteers took part in a 9 day protocol in which a single experimental light exposure6.5 h in duration was given in the early biological night. The effects of the light exposure on the endogenous circadian phase of the melatonin rhythm and the acute effects of the light exposure on plasma melatonin concentration were calculated. We demonstrate that humans are highly responsive to the phase-delaying effects of light during the early biological night and that both the phase resetting response to light and the acute suppressive effects of light on plasma melatonin follow a logistic dose-response curve, as do many circadian responses to light in mammals. Contrary to expectations, we found that half of the maximal phase-delaying response achieved in response to a single episode of evening bright light ( approximately 9000 lux (lx)) can be obtained with just over 1 % of this light (dim room light of approximately 100 lx). The same held true for the acute suppressive effects of light on plasma melatonin concentrations. This indicates that even small changes in ordinary light exposure during the late evening hours can significantly affect both plasma melatonin concentrations and the entrained phase of the human circadian pacemaker.
Full Text Available This article addresses different duct static pressure control strategies which could be implemented in variable air volume air-conditioning systems (VAV. Two pressure reset control strategies are compared to the commonly used control solution based on the “Constant static pressure” method. First pressure reset control strategy, known as PID Control, uses signals from VAV boxes controllers to reset duct static pressure in a way that one of the VAV dampers is maintained almost entirely open. Second strategy decreases static pressure setpoint until an adjustable number of pressure requests occur. As a response to the certain amount of requests, static pressure setpoint is increased. This strategy is called Trim & Respond. Both static pressure reset control strategies described in this paper are considered to have more significant potential for energy savings than the “Constant static pressure” method. In order to validate this potential, several simulations for different control strategies were carried out and the obtained results are compared and analysed. The theoretical limit of the energy savings - set of the optimal control actions, was estimated with Nelder-Mead algorithm and also presented in this article. General description of the static pressure control strategies "Constant static pressure", PID Control and Trim & Respond is given.
Nahimi, Adjmal; Høltzermann, Mette; Landau, Anne M.
Recent studies suggest that l-3,4 dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a severe complication of conventional L-DOPA therapy of Parkinson's disease, may be caused by dopamine (DA) release originating in serotonergic neurons. To evaluate the in vivo effect of a 5-HT(1A) agonist...... the severity of LID. The reversal of the effect of L-DOPA on [(11) C]raclopride binding, extracellular DA and LID by 5-HT agonist administration is consistent with the notion that part of the DA increase associated with LID originates in serotonergic neurons....
Ozünlü Pekyavaş, Nihan; Kunduracılar, Zuhal; Ersin, Aybüke; Ergüneş, Cengiz; Tonga, Eda; Karataş, Metin
To investigate the relationship between scapular dyskinesia, pain, and flexibility in patients with neck, shoulder, or both injuries. A total of 160 patients who came to Baskent University Hospital, Department of Physical Medicine and Rehabilitation with pathology and pain in the neck and shoulder regions were included to our study. Patients were divided into three groups; Neck group, shoulder group and neck+shoulder group. Visual Analog Scale (VAS) for pain intensity, goniometer for range of motion, and tape measurement for evaluation of flexibility was used. Lateral Scapular Slide Test (LSST) and Scapular Retraction Test (SRT) vs Skapular Assisstance Test (SAT) were used for evaluation of scapular dyskinesia. SRT (r=0.617, p=0.000) and SAT (r=0.565, p=0.000) positivity was found to be correlated with dominant and non-dominant sides in patients with neck pathology. Pain at night and during rest were found to correlate with pain during activity in patients with neck+shoulder pathology (r=0.572, p=0.002). No significant correlation was found between pain intensity and scapular dyskinesia in all groups. LSST values were found under 1.5 cm and therefore, scapular mobilization was considered as normal (LSST1=0.76±0.74; LSST2=0.68±0.81; LSST3=0.75±0.75). In addition to joint limitations and flexibility, scapular dyskinesia should also be evaluated in order to solve problems related to pain in patients with neck, shoulder and neck+shoulder pathology. In future studies, the classification of groups according to pathology may help to understand the impact of scapular dyskinesia on the pathology of shoulder and neck pain.
Alabed, Samer; Latifeh, Youssef; Mohammad, Husam Aldeen; Rifai, Abdullah
Chronic antipsychotic drug treatment may cause tardive dyskinesia (TD), a long-term movement disorder. Gamma-aminobutyric acid (GABA) agonist drugs, which have intense sedative properties and may exacerbate psychotic symptoms, have been used to treat TD. To determine the clinical effects of GABA agonist drugs (baclofen, gamma-vinyl-GABA, gamma-acetylenic-GABA, progabide, muscimol, sodium valproate and tetrahydroisoxazolopyridine (THIP) for people with schizophrenia or other chronic mental illnesses who also developed neuroleptic-induced tardive dyskinesia. We updated the previous Cochrane review by searching the Cochrane Schizophrenia Group Register (June 2010). We included reports if they were controlled trials dealing with people with neuroleptic-induced TD and schizophrenia or other chronic mental illness who had been randomly allocated to either non-benzodiazepine GABA agonist drugs with placebo or no intervention. Working independently, we selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate we calculated risk ratios (RR) and their 95% confidence intervals (CI) with the number needed to treat (NNT). For continuous data we calculated mean differences (MD). We identified eight small poorly reported studies for inclusion. For the outcome of 'no clinically important improvement in tardive dyskinesia' GABA agonist drugs were not clearly better than placebo (n = 108, 3 RCTs, RR 0.83 CI 0.6 to 1.1). Deterioration in mental state was more likely to occur in people receiving GABA medication (n = 95, 4 RCTs, RR 2.47 CI 1.1 to 5.4), but this effect was influenced by the decision to assign a negative outcome to those who left early before the end of the study. A greater proportion of people allocated GABA medication may fail to complete the trial compared with those allocated placebo (20% versus 9%), but this difference was not statistically significant (n = 136, 5 RCTs, RR 1.99 CI 0.8 to 4
Flamez, Anja; Cordenier, Ann; De Raedt, Sylvie; Michiels, Veronique; Smetcoren, Sara; Van Merhaegen-Wieleman, Annick; Parys, Eva; De Keyser, Jacques; Baeken, Chris
Background: In late stage Parkinson patients there is an unmet need for new treatments to adequately control motor complications, especially dyskinesias. In several preliminary studies, it has been suggested that applying unilateral low-frequency repetitive transcranial magnetic stimulation (LF
Madsen, Morten V; Peacock, Linda P; Werge, Thomas
Antipsychotic drugs may cause extrapyramidal symptoms (EPS), such as dyskinesia and dystonia. These effects are believed to involve dysfunctional striatal dopamine transmission. Patients with schizophrenia show increased prevalence of cannabis abuse and this has been linked to severity of EPS....... Endocannabinoids modulate striatal dopamine activity via type 1 cannabinoid (CB(1)) receptors, and studies in rats and humans suggest beneficial effects of CB(1) ligands on EPS. The present study explored the effects of CB(1) receptor ligands on oral dyskinesia induced by the dopamine D(1) receptor agonist SKF...... for oral dyskinesia or dystonia. SKF-induced oral dyskinesia was dose-dependently reduced by CP55,940, with no effect of SR141716A. Haloperidol-induced dystonia was not affected by either CP55,940 or SR141716A....
Full Text Available Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC is an episodic movement disorder with autosomal-dominant inheritance and high penetrance, but the causative genetic mutation is unknown. We have now identified four truncating mutations involving the gene PRRT2 in the vast majority (24/25 of well-characterized families with PKD/IC. PRRT2 truncating mutations were also detected in 28 of 78 additional families. PRRT2 encodes a proline-rich transmembrane protein of unknown function that has been reported to interact with the t-SNARE, SNAP25. PRRT2 localizes to axons but not to dendritic processes in primary neuronal culture, and mutants associated with PKD/IC lead to dramatically reduced PRRT2 levels, leading ultimately to neuronal hyperexcitability that manifests in vivo as PKD/IC.
Paton, D M
Deutetrabenazine is a derivative of tetrabenazine in which two trideuteromethoxy groups substitute two methoxy groups. The active metabolites of deutetrabenazine have a longer half-life than those of tetrabenazine, together with a greater overall absorption. However, the peak plasma concentrations are lower. Because of these pharmacokinetic differences, deutetrabenazine can be given twice daily, thus improving compliance. The lower peak concentrations may account for a lower incidence of some unwanted adverse effects. Unlike tetrabenazine, deutetrabenazine has no effect on the QT interval. Treatment with deutetrabenazine significantly improved chorea in Huntington's disease, the hyperkinetic features of tardive dyskinesia, and tics in Tourette syndrome. In all three conditions, deutetrabenazine produced an acceptable level of overall adverse effects without causing any severe adverse effects. Copyright 2017 Clarivate Analytics.
Full Text Available Background: Four cases of paroxysmal kinesigenic dyskinesia (PKD have been reported in individuals with proximal 16p11.2 microdeletions that include PRRT2. Case Report: We describe a fifth patient with PKD, features of Asperger’s syndrome, and mild language delays. Sanger sequencing of the PRRT2 gene did not identify any mutations implicated in PKD. However, microarray‐based comparative genomic hybridization (aCGH detected a 533.9‐kb deletion on chromosome 16, encompassing over 20 genes and transcripts. Discussion: This case underscores the importance of aCGH testing for individuals with PKD who do not have PRRT2 mutations, particularly when developmental delays, speech problems, intellectual disability, and/or autism spectrum disorder are present.
Full Text Available Huntington’s disease (HD is a neurodegenerative disorder characterized by a triad of choreoathetosis, dementia and dominant inheritance. The cause of HD is an expansion of CAG trinucleotide repeats in the HD gene. Typical age at onset of symptoms is in the 40s, but the disorder can manifest at any time. Late-onset (≥ 60 years HD is clinically different from other adult or juvenile onset HD and characterized by mild motor problem as the initial symptoms, shorter disease duration, frequent lack of family history, and relatively low CAG repeats expansion. We report a case of an 80-year-old female with oromandibular dyskinesia as an initial manifestation of HD and 40 CAG repeats.
A. A. Baranov
Full Text Available The article presents the most modern positions of healthcare delivery for children with primary ciliary dyskinesia. Symptoms of this pathology in clinical practice vary that is conditioned by genetic heterogeneity of the disease. The most common disease manifestation in children is frequent inflammatory diseases of the upper and lower respiratory tract. They are recorded in most patients, especially in young children, and the diagnosis is often determined untimely due to a low awareness of specialists about this nosology. Differential diagnostic approach is described in detail, peculiarities of treatment and management of children with this nosology are specified. The material is based on clinical guidelines developed and approved by the professional association «Union of Pediatricians of Russia».
Maglione, Marco; Bush, Andrew; Montella, Silvia; Mollica, Carmine; Manna, Angelo; Esposito, Antonietta; Santamaria, Francesca
Despite its extensive use, there is no evidence that spirometry is useful in the assessment of progression of lung disease in primary ciliary dyskinesia (PCD). We hypothesize that high-resolution computed tomography (HRCT) is a better indicator of PCD lung disease progression than spirometry. We retrospectively evaluated two paired spirometry and HRCT examinations from 20 PCD patients (age, 11.6 years; range, 6.5-27.5 years). The evaluations were performed in stable state and during unstable lung disease. HRCT scans were scored blind by two raters. Compared to the first assessment, at the second evaluation spirometry did not change while HRCT scores significantly worsened (P spirometry. In PCD, structural lung disease may worsen despite spirometry being stable. Copyright © 2011 Wiley Periodicals, Inc.
Morgan, Lucy C; Birman, Catherine S
Primary Ciliary Dyskinesia (PCD) is an autosomal recessive genetic condition affecting the function of motile cilia. The upper respiratory tract is lined with ciliated epithelium and hence a hallmark of PCD is the development, from the neonatal period onwards, of persisting secretion retention and suppurative infection in the middle ear, nose and facial sinuses . This review aims to remind the clinician involved in the care of a patient with PCD of the complexities of making the diagnosis of chronic rhinosinusitis (CRS) and chronic otitis media with effusion (ChOME), the morbidity associated with CRS and ChOME and of current evidence of best practice for the management of these conditions. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.
Storch, Alexander; Trenkwalder, Claudia; Oehlwein, Christian; Winkelmann, Juliane; Polzer, Ulrich; Hundemer, Hans-Peter; Schwarz, Johannes
Motor complications arising after long-term treatment with levodopa remain one of the main challenges in the treatment of patients with Parkinson's disease (PD). Monotherapy with dopamine agonists may delay the onset of motor complications or reduce their severity when added to levodopa treatment. Here, we retrospectively analyzed data from 62 patients with advanced PD who presented with moderate to severe response fluctuations in whom we increased the dose of oral treatment with pergolide beyond 4.5mg daily. Patients had been treated with levodopa for 10.7+/-4.8 years. Pergolide was increased to 8.2+/-4.3 mg per day over a median titration period of 13.5 weeks. Mean daily dose of levodopa prior to pergolide high-dose treatment was 733+/-468 mg and decreased to 348+/-186 mg after pergolide titration. The duration of OFF times decreased from 7.3+/-3.8 to 1.7+/-0.9 h per day (p patients' diaries. Dyskinesias, present for 5.0+/-3.3 h per day at baseline, were reduced to 1.4+/-0.8 h per day (p motor fluctuations (off-time duration plus dyskinesia duration) decreased from 10.5+/-7.0 to 2.8+/-2.2 h (p patients required concomitant treatment with domperidone. Seven patients developed hallucinations during the titration period, six patients required treatment with clozapine. Our data indicate that increasing the dose of pergolide above 5mg per day can dramatically reduce the need for levodopa, motor fluctuations and severity of clinical symptoms. Controlled trials are needed to further substantiate the efficacy and safety of this treatment strategy.
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Full Text Available Synchronization of populations of neurons is a hallmark of several brain diseases. Coordinated reset (CR stimulation is a model-based stimulation technique which specifically counteracts abnormal synchrony by desynchronization. Electrical CR stimulation, e.g. for the treatment of Parkinson’s disease (PD, is administered via depth electrodes. In order to get a deeper understanding of this technique, we extended the top-down approach of previous studies and constructed a large-scale computational model of the respective brain areas. Furthermore, we took into account the spatial anatomical properties of the simulated brain structures and incor- porated a detailed numerical representation of 2·104 simulated neurons. We simulated the subthalamic nucleus (STN and the globus pallidus externus (GPe. Connections within the STN were governed by spike-timing dependent plasticity (STDP. In this way, we modeled the physiological and pathological activity of the considered brain structures. In particular, we investigated how plasticity could be exploited and how the model could be shifted from strongly synchronized (pathological activity to strongly desynchronized (healthy activity of the neuronal populations via CR stimulation of the STN neurons. Furthermore, we investigated the impact of specific stimulation parameters especially the electrode position on the stimulation outcome. Our model provides a step forward towards a biophysically realistic model of the brain areas relevant to the emergence of pathological neuronal activity in PD. Furthermore, our model constitutes a test bench for the optimization of both stimulation parameters and novel electrode geometries for efficient CR stimulation.
Prasanna, G.; Jayapandian, J.; Sheela, O. K.; Amarendra, G.
A novel, cost effective pulse height digitization scheme for spectroscopy applications, utilizing a CMOS analog switch as reset element in the feedback of preamplifier stage is designed. The CMOS switch resistance is controlled by a signal generated from a firmware, run in parallel with a digitizer. While the very high open-state resistance of the switch reduces the thermal noise in the preamplifier output, eliminating the need for pulse shaping, it increases the probability of pulse pile-up. A state machine run in conjunction with the firmware eliminates the pile-up event error contribution by prompting the firmware to prevent the piled-up pulse levels from getting registered. The Pulse height digitization and pile up elimination functions are implemented on a single-chip Programmable System on Chip (PSoC) mixed signal platform from Cypress Semiconductor. The digitized pulse heights are communicated to a PC based virtual instrument graphical user interface developed using National Instruments Lab VIEW. The new scheme is functionally verified with Planar PIN diode detectors in obtaining alpha particle spectra.
Full Text Available Over time, organisms developed various strategies to adapt to their environment. Circadian clocks are thought to have evolved to adjust to the predictable rhythms of the light-dark cycle caused by the rotation of the Earth around its own axis. The rhythms these clocks generate persist even in the absence of environmental cues with a period of about 24 hours. To tick in time, they continuously synchronize themselves to the prevailing photoperiod by appropriate phase shifts. In this study, we disrupted two molecular components of the mammalian circadian oscillator, Rev-Erbalpha and Period1 (Per1. We found that mice lacking these genes displayed robust circadian rhythms with significantly shorter periods under constant darkness conditions. Strikingly, they showed high amplitude resetting in response to a brief light pulse at the end of their subjective night phase, which is rare in mammals. Surprisingly, Cry1, a clock component not inducible by light in mammals, became slightly inducible in these mice. Taken together, Rev-Erbalpha and Per1 may be part of a mechanism preventing drastic phase shifts in mammals.
Chandler, M P; Rodenbaugh, D W; DiCarlo, S E
We tested the hypothesis that postexercise reductions in arterial pressure and heart rate (HR) are mediated by a lowering of the operating point and a reduction in the gain of the arterial baroreflex. To test this hypothesis, spontaneous changes in arterial pressure and the reflex responses of HR were examined before and after a single bout of mild to moderate dynamic exercise in 19 spontaneously hypertensive rats (SHR, 10 male and 9 female). Eleven SHR subjected to sinoaortic denervation (SAD) (6 male, 5 female) were also studied. All rats were instrumented with an arterial catheter for the measurement of arterial pressure and HR. After exercise, arterial pressure and HR were reduced below preexercise levels. Furthermore, the operating point and spontaneous gain (G) of the arterial baroreflex were reduced. Specifically, after exercise, the spontaneous range of HR (P1, 50%), the pressure at the midpoint of the pressure range (P3, 13%) and the HR at the midpoint of the HR range (H3, 10%), the spontaneous minimum HR (P4, 8%) and maximum HR (10%), and G (76%) were significantly attenuated. SAD significantly attenuated the relationship between arterial pressure and HR by reducing G (males 94%, females 95%). These results demonstrate that acute exercise resulted in a postexercise resetting of the operating point and a reduction in the gain of the arterial baroreflex. Furthermore, these data suggest that postexercise reductions in arterial pressure and HR are mediated by a lowering of the operating point of the arterial baroreflex.
Tricker, Penny J
The transgenerational inheritance of stress-induced epigenetic modifications is still controversial. Despite several examples of defense "priming" and induced genetic rearrangements, the involvement and persistence of transgenerational epigenetic modifications is not known to be general. Here I argue that non-transmission of epigenetic marks through meiosis may be regarded as an epigenetic modification in itself, and that we should understand the implications for plant evolution in the context of both selection for and selection against transgenerational epigenetic memory. Recent data suggest that both epigenetic inheritance and resetting are mechanistically directed and targeted. Stress-induced epigenetic modifications may buffer against DNA sequence-based evolution to maintain plasticity, or may form part of plasticity's adaptive potential. To date we have tended to concentrate on the question of whether and for how long epigenetic memory persists. I argue that we should now re-direct our question to investigate the differences between where it persists and where it does not, to understand the higher order evolutionary methods in play and their contribution.
Full Text Available Primary tinnitus has a severe negative influence on the quality of life of a substantial portion of the general population. When acoustic coordinated reset (CR neuromodulation stimuli are delivered for several hours per day over several weeks a clinically significant symptom reduction in patients with primary tonal tinnitus has been reported by several clinical sites. Here, we reported the first case where CR neuromodulation was delivered through a hearing aid. A 52-year-old man with chronic primary tonal tinnitus was previously considered untreatable with sound therapy. He initially received the classic CR treatment protocol with signals delivered with the separate proprietary device with his hearing aids removed during treatment. He was subsequently treated with the therapy being deployed through a set of contemporary hearing aids. After 5 months of classic CR treatment with the separate custom device, the THI and VASL/A scores worsened by 57% and 13%/14%, respectively. Using the hearing aid without CR treatment for 5 months no change in tinnitus symptoms was observed. However, after three months of CR treatment delivered through the hearing aids, the THI and VASL/A scores were reduced by 70% and 32%/32%, respectively.
Penny J Tricker
Full Text Available The transgenerational inheritance of stress-induced epigenetic modifications is still controversial. Despite several examples of defence ‘priming’ and induced genetic rearrangements, the involvement and persistence of transgenerational epigenetic modifications is not known to be general. Here I argue that non-transmission of epigenetic marks through meiosis may be regarded as an epigenetic modification in itself, and that we should understand the implications for plant evolution in the context of both selection for and selection against transgenerational epigenetic memory. Recent data suggest that both epigenetic inheritance and resetting are mechanistically directed and targeted. Stress-induced epigenetic modifications may buffer against DNA sequence-based evolution to maintain plasticity, or may form part of plasticity’s adaptive potential. To date we have tended to concentrate on the question of whether and for how long epigenetic memory persists. I argue that we should now re-direct our question to investigate the differences between where it persists and where it does not, to understand the higher order evolutionary methods in play and their contribution.
Full Text Available Elderly patients are vulnerable to the adverse neurological effects of antipsychotics, particularly Parkinsonian symptoms and tardive dyskinesia. This vulnerability in the elderly becomes complex and unpredictable when aripiprazole is prescribed to replace other second-generation or first-generation antipsychotics. This report describes a 69-year-old female schizophrenic patient, who received aripiprazole after using a few antipsychotics, including the first- and second-generation ones. The tardive dyskinesia developed 6 weeks after switching to aripiprazole but subsided 4 weeks later when stopping the concurrent amantadine and decreasing the dosage of trihexyphenidyl. However, Parkinsonian symptoms developed insidiously thereafter, which remitted after the dosage of trihexyphenidyl was increased again. The possible mechanisms of the alternated adverse neurological events after a switch to aripiprazole in the chronic elderly psychosis are discussed.
Shin, Jihoon; Youn, Hong-Duk
In embryonic stem cells (ESCs), cell cycle regulation is deeply connected to pluripotency. Especially, core transcription factors (CTFs) which are essential to maintaining the pluripotency transcription programs should be reset during M/G1 transition. However, it remains unknown about how CTFs are governed during cell cycle progression. Here, we describe that the regulation of Oct4 by Aurora kinase b (Aurkb)/protein phosphatase 1 (PP1) axis during the cell cycle is important for resetting Oct4 to pluripotency and cell cycle related target genes in determining the identity of ESCs. Aurkb starts to phosphorylate Oct4(S229) at the onset of G2/M phase, inducing the dissociation of Oct4 from chromatin, whereas PP1 binds Oct4 and dephosphorylates Oct4(S229) during M/G1 transition, which resets Oct4-driven transcription for pluripotency and the cell cycle. Furthermore, Aurkb phosphormimetic and PP1 binding-deficient mutations in Oct4 disrupt the pluripotent cell cycle, lead to the loss of pluripotency in ESCs, and decrease the efficiency of somatic cell reprogramming. Based on our findings, we suggest that the cell cycle is directly linked to pluripotency programs in ESCs. [BMB Reports 2016; 49(10): 527-528].
Garcia, L. A.; Elhaddad, A.
Reliable estimates of evapotranspiration (ET) from vegetation are needed for many types of water-resource investigations. This presentation introduces an enhanced surface energy balance-based model, the Remote Sensing of Evapotranspiration or ReSET model, for estimating ET. ReSET is an ET estimation model that takes into consideration the spatial variability in weather parameters, which makes it particularly applicable for calculating regional scale ET. ReSET also has the capability of interpolating between the available weather stations in time and space. The model's accuracy at daily and seasonal time scales is evaluated in several case studies. A special application of the model to investigate the relationship between ET and soil salinity in agricultural areas is presented. The case study focuses on the impacts of salinity on ET in corn and alfalfa in the Lower Arkansas River Basin in Colorado during the period 1999 to 2007. Evapotranspiration values were regressed against the spatially corresponding soil salinity values to develop a relation between ET and soil salinity. The ET values correlate well with the soil salinity levels in the study region, with a correlation coefficient of up to 0.86.
Llinás, R R
The cerebellum can be viewed as supporting two distinct aspects of motor execution related to a) motor coordination and the sequence that imparts such movement temporal coherence and b) the reorganization of ongoing movement when a motor execution error occurs. The former has been referred to as "motor time binding" as it requires that the large numbers of motoneurons involved be precisely activated from a temporal perspective. By contrast, motor error correction requires the abrupt reorganization of ongoing motor sequences, on occasion sufficiently important to rescue the animal or person from potentially lethal situations. The olivo-cerebellar system plays an important role in both categories of motor control. In particular, the morphology and electrophysiology of inferior olivary neurons have been selected by evolution to execute a rather unique oscillatory pace-making function, one required for temporal sequencing and a unique oscillatory phase resetting dynamic for error correction. Thus, inferior olivary (IO) neurons are electrically coupled through gap junctions, generating synchronous subthreshold oscillations of their membrane potential at a frequency of 1-10 Hz and are capable of fast and reliable phase resetting. Here I propose to address the role of the olivocerebellar system in the context of motor timing and reset.
Differentiation of atrioventricular nodal reentrant tachycardia from orthodromic reciprocating tachycardia by the resetting response to ventricular extrastimuli: comparison to response to continuous ventricular pacing.
Javier García-Fernández, F; Almendral, Jesús; Marta Pachón; González-Torrecilla, Esteban; Martín, Javier; Gallardo, Rodrigo
The usefulness of ventricular entrainment to differentiate AV nodal reentrant tachycardia (AVNRT) from orthodromic reciprocating tachycardia (ORT) by substracting the corrected postpacing interval (cPPI) from the tachycardia cycle length (TCL) or the ventriculoatrial interval during stimulation (SA) from that during tachycardia (VA) have been widely validated. However, some tachycardias are interrupted by pacing trains but may not be so by ventricular extrastimuli resulting in resetting. To validate prospectively the diagnostic yield of cPPI-TCL and SA-VA measurements after resetting and to determine the proportion of AVNRT and ORT that can be entrained and/or reset from the right ventricular apex (RVA). 223 consecutive patients with inducible AVNRT or ORT underwent pacing trains and single extrastimulus (also double extrastimuli if singles did not reset tachycardia) at the RVA. We calculated cPPI-TCL and SA-VA during entrainment and resetting. Entrainment could not be achieved in 15.2% of tachycardias because of consistent tachycardia interruption by pacing; resetting was observed in 99.5%. Values of cPPI-TCL and SA-VA > 110 milliseconds after resetting identified AVNRT as accurately as after entrainment. Values for cPPI-TCL/ SA-VA were: sensitivity: 98/100%; specificity: 96/98%; positive predictive value: 98/99%; negative predictive value: 98/100%. Determinations of cPPI-TCL and SA-VA after resetting with single or double RVA extrastimuli are useful maneuvers to differentiate AVNRT from ORT and can be used for nearly every inducible AVNRT or ORT, even if they are interrupted by ventricular trains. © 2012 Wiley Periodicals, Inc.
Bishnoi, Mahendra; Chopra, Kanwaljit; Kulkarni, Shrinivas K
Tardive dyskinesia is considered to be the late onset adverse effect of prolonged administration of typical neuroleptic drugs. Adenosine is now widely accepted as the major inhibitory neuromodulators in the central nervous system besides GABA. Antagonists of A2A receptors are known to confer protection against neuronal damage caused by toxins and reactive oxygen species. The present study investigated the effect of adenosine receptor antagonist, theophylline (25 and 50 mg/kg, ip) in an animal model of tardive dyskinesia by using different behavioral (orofacial dyskinetic movements, stereotypy, locomotor activity, % retention), biochemical (lipid peroxidation, reduced glutathione levels, antioxidant enzyme levels (SOD and catalase)) and neurochemical (neurotransmitter levels) parameters. Chronic administration of haloperidol (1 mg/kg ip for 21 days) significantly increased vacuous chewing movements (VCMs), tongue protrusions, facial jerking in rats which was dose-dependently inhibited by theophylline. Chronic administration of haloperidol also resulted in the increased dopamine receptor sensitivity as evidenced by increased locomotor activity and stereotypic rearing. Further, it also decreased % retention time in elevated plus maze paradigm. Pretreatment with theophylline reversed these behavioral changes. Chronic administration of haloperidol also induced oxidative damage in all the brain regions which was prevented by theophylline, especially in the striatum. Chronic administration of haloperidol resulted in a decrease in dopamine levels which was reversed by treatment with theophylline (at higher doses). The findings of the present study suggested the involvement of adenosinergic receptor system in the development of tardive dyskinesia and possible therapeutic potential of theophylline in this disorder.
Shinkai, Takahiro; Müller, Daniel J; De Luca, Vincenzo; Shaikh, Sajid; Matsumoto, Chima; Hwang, Rudi; King, Nicole; Trakalo, Joseph; Potapova, Natalia; Zai, Gwyneth; Hori, Hiroko; Ohmori, Osamu; Meltzer, Herbert Y; Nakamura, Jun; Kennedy, James L
A possible involvement of oxidative stress in the pathophysiology of tardive dyskinesia (TD) has previously been proposed (reviewed in [Andreassen, O.A., Jorgensen, H.A., 2000. Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia? Progress in Neurobiology 61, 525-541.]). Long-term administration of neuroleptics alters dopaminergic turnover, which results in increased formation of reactive oxygen species (ROS). This is hypothesized to lead to TD through neuronal toxicity as a consequence of oxidative stress. In the present study, the relationship between TD and a possible functional polymorphism of the human glutathione peroxidase (GPX1) gene (an important antioxidant enzyme) was studied in 68 chronic treatment-refractory patients with schizophrenia. A proline (Pro) to leucine (Leu) substitution at codon 197 (Pro197Leu) in the GPX1 gene was genotyped. No significant difference in total Abnormal Involuntary Movements Scale (AIMS) scores was observed among patients in the three genotype groups. Moreover, no significant differences in genotype or allele frequencies were observed between subjects with and without TD. Our results suggest that the GPX1 gene polymorphism does not confer increased susceptibility to TD, although further studies are warranted before a conclusion can be drawn.
Moritz J Rossner
Full Text Available BACKGROUND: The circadian system provides the basis to anticipate and cope with daily recurrent challenges to maintain the organisms' homeostasis. De-synchronization of circadian feedback oscillators in humans causes 'jet lag', likely contributes to sleep-, psychiatric-, metabolic disorders and even cancer. However, the molecular mechanisms leading to the disintegration of tissue-specific clocks are complex and not well understood. METHODOLOGY/PRINCIPAL FINDINGS: Based on their circadian expression and cell culture experiments, the basic Helix-Loop-Helix (bHLH transcription factors SHARP-1(Dec2 and SHARP-2(Stra13/Dec1 were proposed as novel negative regulators of the molecular clock. To address their function in vivo, we generated Sharp-1 and Sharp-2 single and double mutant mice. Our experiments reveal critical roles for both factors in regulating period length, tissue-specific control of clock gene expression and entrainment to external cues. Light-pulse experiments and rapid delays of the light-dark cycle (experimental jet lag unravel complementary functions for SHARP-1 and SHARP-2 in controlling activity phase resetting kinetics. Moreover, we show that SHARP-1 and 2 can serve dual functions as repressors and co-activators of mammalian clock gene expression in a context-specific manner. This correlates with increased amplitudes of Per2 expression in the cortex and liver and a decrease in the suprachiasmatic nucleus (SCN of double mutant mice. CONCLUSIONS/SIGNIFICANCE: The existence of separate mechanisms regulating phase of entrainment, rhythm amplitude and period length has been postulated before. The differential effects of Sharp-deficiency on rhythmicity and behavioral re-entrainment, coupled to tissue-dependent regulatory functions, provide a new mechanistic basis to further understand the complex process of clock synchronizations.
Rossner, Moritz J; Oster, Henrik; Wichert, Sven P; Reinecke, Lisa; Wehr, Michael C; Reinecke, Johannes; Eichele, Gregor; Taneja, Reshma; Nave, Klaus-Armin
The circadian system provides the basis to anticipate and cope with daily recurrent challenges to maintain the organisms' homeostasis. De-synchronization of circadian feedback oscillators in humans causes 'jet lag', likely contributes to sleep-, psychiatric-, metabolic disorders and even cancer. However, the molecular mechanisms leading to the disintegration of tissue-specific clocks are complex and not well understood. Based on their circadian expression and cell culture experiments, the basic Helix-Loop-Helix (bHLH) transcription factors SHARP-1(Dec2) and SHARP-2(Stra13/Dec1) were proposed as novel negative regulators of the molecular clock. To address their function in vivo, we generated Sharp-1 and Sharp-2 single and double mutant mice. Our experiments reveal critical roles for both factors in regulating period length, tissue-specific control of clock gene expression and entrainment to external cues. Light-pulse experiments and rapid delays of the light-dark cycle (experimental jet lag) unravel complementary functions for SHARP-1 and SHARP-2 in controlling activity phase resetting kinetics. Moreover, we show that SHARP-1 and 2 can serve dual functions as repressors and co-activators of mammalian clock gene expression in a context-specific manner. This correlates with increased amplitudes of Per2 expression in the cortex and liver and a decrease in the suprachiasmatic nucleus (SCN) of double mutant mice. The existence of separate mechanisms regulating phase of entrainment, rhythm amplitude and period length has been postulated before. The differential effects of Sharp-deficiency on rhythmicity and behavioral re-entrainment, coupled to tissue-dependent regulatory functions, provide a new mechanistic basis to further understand the complex process of clock synchronizations.
Convertino, V. A.; Ludwig, D. A.; Elliott, J. J.; Wade, C. E.
We measured central venous pressure (CVP); plasma volume (PV); urine volume rate (UVR); renal excretion of sodium (UNa); and renal clearances of creatinine, sodium, and osmolality before and after acute volume infusion to test the hypothesis that exposure to microgravity causes resetting of the CVP operating point. Six rhesus monkeys underwent two experimental conditions in a crossover counterbalance design: 1) continuous exposure to 10 degrees head-down tilt (HDT) and 2) a control, defined as 16 h/day of 80 degrees head-up tilt and 8 h prone. After 48 h of exposure to either test condition, a 120-min course of continuous infusion of isotonic saline (0.4 ml. kg(-1). min(-1) iv) was administered. Baseline CVP was lower (P = 0.011) in HDT (2.3 +/- 0.3 mmHg) compared with the control (4.5 +/- 1.4 mmHg) condition. After 2 h of saline infusion, CVP was elevated (P = 0.002) to a similar magnitude (P = 0.485) in HDT (DeltaCVP = 2.7 +/- 0.8 mmHg) and control (DeltaCVP = 2.3 +/- 0.8 mmHg) conditions and returned to preinfusion levels 18 h postinfusion in both treatments. PV followed the same pattern as CVP. The response relationships between CVP and UVR and between CVP and UNa shifted to the left with HDT. The restoration of CVP and PV to lower preinfusion levels after volume loading in HDT compared with control supports the notion that lower CVP during HDT may reflect a new operating point about which vascular volume is regulated. These results may explain the ineffective fluid intake procedures currently employed to treat patients and astronauts.
Carbon, Maren; Hsieh, Cheng-Hsi; Kane, John M; Correll, Christoph U
Comparison of tardive dyskinesia (TD) prevalence during contemporaneous treatment with first-generation antipsychotics (FGAs) and/or second-generation antipsychotics (SGAs). PubMed/MEDLINE/Google Scholar search (January 1, 2000-September 30, 2015) without language restriction using (tardive dyskinesia OR tardive) AND (antipsychotic*) plus specific names of SGAs. Of 8,895 hits, we screened 203 full-text articles for cross-sectional, rating scale-based TD rates during SGA, FGA, or FGA+SGA treatment. Forty-one studies were used for random effects meta-analysis and meta-regression. Two authors independently extracted data on overall and antipsychotic class-wise TD rates and on TD moderators. The global mean TD prevalence was 25.3% (95% CI = 22.7%-28.1%) across all 41 studies (N = 11,493, mean age = 42.8 years, male = 66.4%, schizophrenia-spectrum disorders = 77.1%). TD prevalence varied greatly: Rates were lower with current SGA treatment (20.7%; 95% CI = 16.6%-25.4%, N = 5,103) vs current FGA treatment (30.0%; 95% CI = 26.4%-33.8%, N = 5,062; Q = 9.17, P = .002). This difference remained significant after controlling for moderators: higher age (Z = 2.85, P = .004; number of studies = 39 ) and region (39 studies; Asia vs Europe, Z = 1.55, P = .12; Asia lower than United States, Z = 2.6, P = .009; Asia lower than other regions, Z = 2.42, P = .015). Additional moderators of TD prevalence included longer illness duration (R² = 0.15; P = .03; 21 studies) and frequency of parkinsonism (R² = 0.23, P = .017; number of studies = 19). Particularly low TD prevalence (7.2%; number of studies = 4) was found in the treatment arms with FGA-naive subjects relative to SGA-treated cohorts with likely prior FGA exposure (23.4%; P Z = -2.55, P = .011) and FGA + SGA vs FGAs (risk ratio = 0.80, 95% CI = 0.71-0.90, Z = -3.56, P < .001). Reports on TD severity, provided by 10 studies, were of insufficient quality for meta-analysis. Rating scale-based TD remains highly prevalent, with
Full Text Available Usman Adam, Nusrat Husain, Peter M Haddad, Tariq Munshi, Fauzia Tariq, Farooq Naeem, Imran B ChaudhryBackground: Tardive dyskinesia (TD is a side effect of antipsychotic treatment that often only appears after months or years of treatment. A systematic review of randomized controlled trials lasting more than 1 year showed that second-generation antipsychotics (SGAs were associated with an approximately fivefold lower risk of TD compared to haloperidol in patients with chronic schizophrenia. In contrast, there is little research on the risk of TD with other first-generation antipsychotics (FGAs, and this applies especially to their use in the treatment of patients with first episode psychosis (FEP.Objectives: To determine the severity and point prevalence of TD in a naturalistic sample of patients with FEP in Pakistan treated with FGAs or SGAs.Methods: This was an observational study. TD was assessed by trained clinicians using the Abnormal Involuntary Movement Scale.Results: In the total sample (number =86 the mean age of patients was 26 years and the prevalence of TD (Schooler Kane criteria was 29% with no significant difference between those treated with FGAs and SGAs (31% FGAs versus 26% SGAs; P=0.805. The Abnormal Involuntary Movement Scale total score (items 1–7, a measure of the severity of TD, was significantly higher for patients treated with FGAs versus those treated with SGAs (P=0.033. Scores on specific items showed that this reflected higher scores for dyskinesia affecting the muscles of facial expression, as well as of the upper and lower limb, whereas scores did not differ significantly in other body areas. Conclusion: FGAs were associated with greater severity, though not prevalence, of TD than SGAs. The study highlights the relatively high rate of TD in Asian FEP patients and the need for clinicians to monitor for this and other potential antipsychotic side effects during treatment. Keywords: first-generation antipsychotic
Tian, Wo-Tu; Huang, Xiao-Jun; Liu, Xiao-Li; Shen, Jun-Yi; Liang, Gui-Ling; Zhu, Chen-Xi; Tang, Wei-Guo; Chen, Sheng-Di; Song, Yan-Yan; Cao, Li
Paroxysmal kinesigenic dyskinesia (PKD) is a rare movement disorder characterized by recurrent dystonic or choreoathetoid attacks triggered by sudden voluntary movements. Under the condition of psychological burden, some patients' attacks may get worsened with longer duration and higher frequency. This study aimed to assess nonmotor symptoms and quality of life of patients with PKD in a large population. We performed a cross-sectional survey in 165 primary PKD patients from August 2008 to October 2016 in Rui Jin Hospital, using Symptom Check List-90-Revised (SCL-90-R), World Health Organization Quality of Life-100 (WHOQoL-100), Self-Rating Depression Scale, and Self-Rating Anxiety Scale. We evaluated the differences of SCL-90-R and WHOQOL-100 scores in patients and Chinese normative data (taken from literature) by using the unpaired Student's t-test. We applied multivariate linear regression to analyze the relationships between motor manifestations, mental health, and quality of life among PKD patients. Compared with Chinese normative data taken from literature, patients with PKD exhibited significantly higher (worse) scores across all SCL-90-R subscales (somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism; P= 0.000 for all) and significantly lower (worse) scores of five domains in WHOQoL-100 (physical domain, psychological domain, independence domain, social relationship domain, and general quality of life; P= 0.000 for all). Nonremission of dyskinesia episodes (P = 0.011) and higher depression score (P = 0.000) were significantly associated with lower levels of quality of life. The rates of depression and anxiety in patients with PKD were 41.2% (68/165) and 26.7% (44/165), respectively. Depression, anxiety, and low levels of quality of life were prevalent in patients with PKD. Co-occurrence of depression and anxiety was common among these patients. Regular mental health
Chen, L L; Yang, Y G; Wu, J Z; Chen, X R
Objective: To review children's primary ciliary dyskinesia (PCD) in the pathogenesis, clinical manifestation, diagnosis and treatment. Method: To summarize and analyze the clinical data of a patient who was admitted to the first affiliated hospital of Xiamen University with primary ciliary dyskinesia in April 2014 while referring to related literature. Result: An 11 years old boy, weighting about 22 kg, had a course of more than 10 years with repeated cough, stuffy and runny nose shortly after the birth. Examinations after admission to hospital showed that he presented with visible clubbing, bilateral paranasal sinus area tenderness, pharynx posterior wall with visible yellow pussy stuff drip and bilateral lung had scattered wet rales. Auxiliary examination revealed bilateral maxillary sinus, ethmoid sinus inflammation and bronchitis with left lower lung bronchiectasis. Fiberoptic bronchoscopy discovered congestion and a lot of sputum; ciliary biopsy pathology displayed that cilia were sparse and partial cilia 9+ 2 microtubules structural abnormalities. Full sequence of exon gene sequencing revealed two mutations located at chromosome 16 chr16: 71061369 (non-coding regions) and chr16: 70993591 (coding). Two novel mutations m. 3362A>G(E20) and c. 6101G>A(E39) in exon 16 of the HYDIN gene were identified. With the" ciliary motility disorder, gene" as keywords , the CNKI, Wanfang digital knowledge service platform and PubMed were searched for relevant articles from the establishment to July 2016. The studies retrieved included 9 cases and these cases were summarized. Comprehensive analysis showed that HYDIN gene mutations related PCD patients had the typical PCD performance such as repeatedly wet cough, sinusitis, bronchiectasis, and otitis media. The majority of patients have a history of acute respiratory distress syndrome in infancy and no visceral dislocation was not found. Most of the patients had no obvious structural abnormalities in cilia electron microscopic
Full Text Available Yasuto Kunii,1,2 Nozomu Matsuda,3 Hirooki Yabe1 1Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan; 2Department of Neuropsychiatry, Aizu Medical Center, School of Medicine, Fukushima Medical University, Fukushima, Japan; 3Department of Neurology, Fukushima Medical University School of Medicine, Fukushima, Japan Background: Paroxysmal kinesigenic dyskinesia (PKD is a rare heritable neurologic disorder characterized by attacks of involuntary movement induced by sudden voluntary movements. No previous reports have described cases showing comorbidity with psychiatric disease or symptoms. In this case, we showed a patient with PKD who exhibited several manifestations of anxiety disorder.Case: A 35-year-old Japanese man with PKD had been maintained on carbamazepine since he was 16 years of age without any attacks. However, 10 years before this referral, he became aware of a feeling of breakdown in his overall physical functions. He had then avoided becoming familiar with people out of concern that his physical dysfunctions might be perceived in a negative light. One day he was referred by the neurologic department at our hospital to the Department of Psychiatry because of severe anxiety and hyperventilation triggered by carbamazepine. We treated with escitalopram, aripiprazole, and ethyl loflazepate. Both his subjective physical condition and objective expressions subsequently showed gradual improvement. At last, the feelings of chest compression and anxiety entirely disappeared. Accordingly, increases in plasma monoamine metabolite levels were observed, and the c.649dupC mutation, which has been found in most Japanese PKD families, was detected in his proline-rich transmembrane protein 2 gene.Conclusion: This is the first report to describe psychiatric comorbidities or symptoms in a PKD case. The efficacy of psychotropic medication used in this case, the resulting changes in plasma monoamine metabolite
Oertel, Wolfgang; Eggert, Karla; Pahwa, Rajesh; Tanner, Caroline M; Hauser, Robert A; Trenkwalder, Claudia; Ehret, Reinhard; Azulay, Jean Philippe; Isaacson, Stuart; Felt, Larissa; Stempien, Mary Jean
The treatment of levodopa-induced dyskinesia in Parkinson's disease (PD) is an unmet need with no approved drug therapy. The purpose of this study was to investigate the efficacy and safety of 274 mg ADS-5102 (amantadine) extended-release capsules (equivalent to 340-mg amantadine HCl) for levodopa-induced dyskinesia in a randomized controlled trial. PD patients with ≥1 hour of troublesome dyskinesia and at least mild functional impact were randomized to placebo or ADS-5102 once daily at bedtime for 13 weeks. The primary efficacy analysis was based on change from baseline to week 12 on the Unified Dyskinesia Rating Scale total score in the modified intent-to-treat population. OFF time was a key secondary measure. At week 12, least-squares mean change in the Unified Dyskinesia Rating Scale was -20.7 (standard error 2.2) for ADS-5102 (n = 37) and -6.3 (standard error 2.1) for placebo (n = 38; treatment difference -14.4, 95% confidence interval -20.4 to -8.3, P Parkinson and Movement Disorder Society. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Stefanova, N; Lundblad, M; Tison, F; Poewe, W; Cenci, M A; Wenning, G K
We examined the role of a striatal lesion in the development of L-DOPA-induced abnormal involuntary movements (AIMs) using the double lesion rat model of striatonigral degeneration (SND), the underlying neuropathological substrate of parkinsonism associated with multiple system atrophy (MSA-P), in comparison to a Parkinson's disease (PD) rat model. L-DOPA administration reliably induced AIMs in SND and PD rats in a dose-dependent fashion. AIMs occurred significantly earlier in SND compared to PD rats. There was a mild, but significant, transient increase of orolingual AIMs during the first week of low-dose L-DOPA treatment in SND. Whereas L-DOPA significantly improved contralateral forelimb akinesia in PD rats, there was no beneficial effect in SND rats. Striatal FosB/Delta FosB up-regulation in SND and PD rats correlated with the severity of L-DOPA-induced dyskinesias. Pulsatile L-DOPA administration in the double lesion SND rat model replicates salient features of the human disease MSA-P, including loss of the anti-akinetic L-DOPA response and induction of dyskinesias with transient orolingual predominance.
Noone Peadar G
Full Text Available Abstract Primary ciliary dyskinesia (PCD is a genetic disorder of abnormal ciliary structure and function that leads to defective mucociliary clearance, resulting in oto-sino-pulmonary disease, and infertility. The disease is currently under intense investigation by a number of research groups worldwide. At the recent American Thoracic Society meeting in San Francisco in May 2001, two sessions focused on PCD; a symposium session on May 21 with several featured expert speakers was followed by a mini-symposium on Tuesday May 22, with one featured speaker and presentation of nine abstracts covering a range of research topics. Mattias Salathe (University of Miami, USA and Stephen Brody (Washington University, St Louis, USA chaired the symposium session. Presentations focused on the clinical spectrum of PCD, the genetics of PCD, a proteomics approach to detail the structure of cilia, the role of cilia in the embryology of situs laterality, and airway epithelial cell biology. The mini-symposium was chaired by Peadar Noone (University of North Carolina, USA and Malcolm King (University of Alberta, USA and included presentations on the use of PCD as a human disease model, accurate definition of the phenotype using clinical and cell biologic markers, and molecular studies. The latter reports ranged from isolation of a protein involved in ciliary structure and function to genetic studies using linkage analysis and the candidate gene approach. Clinicians and scientists alike displayed considerable interest at both sessions, and there were several lively question–answer sessions.
Jiménez-Urbieta, Haritz; Gago, Belén; de la Riva, Patricia; Delgado-Alvarado, Manuel; Marin, Concepció; Rodriguez-Oroz, María C
Dopaminergic treatment in Parkinson's disease (PD) reduces the severity of motor symptoms of the disease. However, its chronic use is associated with disabling motor and behavioral side effects, among which levodopa-induced dyskinesias (LID) and impulse control disorders (ICD) are the most common. The underlying mechanisms and pathological substrate of these dopaminergic complications are not fully understood. Recently, the refinement of imaging techniques and the study of the genetics and molecular bases of LID and ICD indicate that, although different, they could share some features. In addition, animal models of parkinsonism with LID have provided important knowledge about mechanisms underlying such complications. In contrast, animal models of parkinsonism and abnormal impulsivity, although useful regarding some aspects of human ICD, do not fully resemble the clinical phenotype of ICD in patients with PD, and until now have provided limited information. Studies on animal models of addiction could complement the previous models and provide some insights into the background of these behavioral complications given that ICD are regarded as behavioral addictions. Here we review the most relevant advances in relation to imaging, genetics, biochemistry and pharmacological interventions to treat LID and ICD in patients with PD and in animal models with a view to better understand the overlapping and unique maladaptations to dopaminergic therapy that are associated with LID and ICD. Copyright © 2015 Elsevier Ltd. All rights reserved.
Full Text Available Abstract Background Primary ciliary dyskinesia (PCD is a rare genetically induced disorder of cilia inducing mainly respiratory diseases. Transmission electron microscopy (TEM analysis of ciliary ultrastructure is classically used for diagnosis. We report our experience of TEM investigations in a large series of patients. Methods TEM analysis performed of 742 biopsies from patients with suspected PCD was reviewed retrospectively. Ultrastructural defects were analysized further in 125 cases with changes typical for PCD. Results In 18.1% of patients diagnosis of PCD was made because of morphological alterations, in 68.2% secondary changes were seen. In 13.7% material was not feasible for analysis. Mostly defects of dynein arms were detected in PCD (96.8%. In particular defects of the inner arms (51.2% and combined dynein defects (37.6% were found. Total loss of dynein arms was dominant. Only in 3.2% deficiencies of central structures were found alone. Associated situs inversus or dextracardia was reported clinically in 21.4%. Conclusions TEM analysis is possible in most patients and a useful tool for diagnosis of PCD. Functional and genetic analysis should be done additionally. Registers should be installed to collect all available informations and push further research.
Ferkol, Thomas W.; Puffenberger, Erik G.; Lie, Hauw; Helms, Cynthia; Strauss, Kevin A.; Bowcock, Anne; Carson, John L.; Hazucha, Milan; Morton, D. Holmes; Patel, Anand C.; Leigh, Margaret W.; Knowles, Michael R.; Zariwala, Maimoona A.
Objective To determine whether individuals with primary ciliary dyskinesia (PCD) from unrelated Amish and Mennonite families harbor a single and unique founder mutation. Study design Subjects from Amish and Mennonite communities in several states were enrolled in the study. All subjects were clinically characterized, and nasal nitric oxide levels were measured. Nasal epithelial scrapings were collected from several subjects for ciliary ultrastructural analyses. DNA was isolated from patients with PCD and their unaffected first- and second-degree relatives. Genome-wide homozygosity mapping, linkage analyses, targeted mutation analyses, and exome sequencing were performed. Results All subjects from Old-Order Amish communities from Pennsylvania were homozygous for a nonsense mutant DNAH5 allele, c.4348C>T (p.Q1450X). Two affected siblings from an unrelated Mennonite family in Arkansas were homozygous for the same nonsense DNAH5 mutation. Children with PCD from an Amish family from Wisconsin had biallelic DNAH5 mutations, c.4348C>T (p.Q1450X) and c.10815delT (p.P3606HfsX23), and mutations in other genes associated with PCD were also identified in this community. Conclusion The Amish and Mennonite subjects from geographically dispersed and socially isolated communities had the same founder DNAH5 mutation, owing to the common heritage of these populations. However, disease-causing mutations in other PCD-associated genes were also found in affected individuals in these communities, illustrating the genetic heterogeneity in this consanguineous population. PMID:23477994
Daniels, M. Leigh Anne; Leigh, Margaret W.; Davis, Stephanie D.; Armstrong, Michael C.; Carson, Johnny L.; Hazucha, Milan; Dell, Sharon D.; Eriksson, Maria; Collins, Francis S.; Knowles, Michael R.; Zariwala, Maimoona A.
Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive, genetically heterogeneous disorder characterized by ciliary dysfunction resulting in chronic oto-sino-pulmonary disease, respiratory distress in term neonates, laterality (situs) defects, and bronchiectasis. Diagnosis has traditionally relied on ciliary ultrastructural abnormalities seen by electron microscopy. Mutations in radial spoke head proteins occur in PCD patients with central apparatus defects. Advances in genetic testing have been crucial in addressing the diagnostic challenge. Here, we describe a novel splice-site mutation (c.921+3_6delAAGT) in RSPH4A, which leads to a premature translation termination signal in nine subjects with PCD (seven families). Loss-of-function was confirmed with quantitative ciliary ultrastructural analysis, measurement of ciliary beat frequency and waveform, and transcript analysis. All nine individuals carrying c.921+3_6delAAGT splice-site mutation in RSPH4A were Hispanic with ancestry tracing to Puerto Rico. This mutation is a founder mutation and a common cause of PCD without situs abnormalities in patients of Puerto Rican descent. PMID:23798057
Full Text Available Panagiotis Bargiotas, Spyridon KonitsiotisDepartment of Neurology, University of Ioannina, Ioannina, GreeceAbstract: Parkinson’s disease therapy is still focused on the use of l-3,4-dihydroxyphenylalanine (levodopa or l-dopa for the symptomatic treatment of the main clinical features of the disease, despite intensive pharmacological research in the last few decades. However, regardless of its effectiveness, the long-term use of levodopa causes, in combination with disease progression, the development of motor complications termed levodopa-induced dyskinesias (LIDs. LIDs are the result of profound modifications in the functional organization of the basal ganglia circuitry, possibly related to the chronic and pulsatile stimulation of striatal dopaminergic receptors by levodopa. Hence, for decades the key feature of a potentially effective agent against LIDs has been its ability to ensure more continuous dopaminergic stimulation in the brain. The growing knowledge regarding the pathophysiology of LIDs and the increasing evidence on involvement of nondopaminergic systems raises the possibility of more promising therapeutic approaches in the future. In the current review, we focus on novel therapies for LIDs in Parkinson’s disease, based mainly on agents that interfere with glutamatergic, serotonergic, adenosine, adrenergic, and cholinergic neurotransmission that are currently in testing or clinical development.Keywords: motor fluctuations, dopaminergic/nondopaminergic systems, pharmacotherapy
Eggink, H; Kremer, D; Brouwer, O F; Contarino, M F; van Egmond, M E; Elema, A; Folmer, K; van Hoorn, J F; van de Pol, L A; Roelfsema, V; Tijssen, M A J
Cerebral palsy (CP) can be classified as spastic, dyskinetic, ataxic or combined. Correct classification is essential for symptom-targeted treatment. This study aimed to investigate agreement among professionals on the phenotype of children with CP based on standardized videos. In a prospective, observational pilot study, videos of fifteen CP patients (8 boys, mean age 11 ± 5 y) were rated by three pediatric neurologists, three rehabilitation physicians and three movement disorder specialists. They scored the presence and severity of spasticity, ataxia or dyskinesias/dystonia. Inter- and intraobserver agreement were calculated using Cohen's and Fleiss' kappa. We found a fair inter-observer (κ = 0.36) and moderate intra-observer agreement (κ = 0.51) for the predominant motor symptom. This only slightly differed within the three groups of specialists (κ = 0.33-0.55). A large variability in the phenotyping of CP children was detected, not only between but also within clinicians, calling for a discussing on the operational definitions of spasticity, dystonia and ataxia. In addition, the low agreement found in our study questions the reliability of use of videos to measure intervention outcomes, such as deep brain stimulation in dystonic CP. Future studies should include functional domains to assess the true impact of management options in this highly challenging patient population. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Diefenderfer, Lauren A; Nelson, Leigh Anne; Elliott, Ellie; Liu, Yifei; Iuppa, Courtney; Winans, Elizabeth; Sommi, Roger W
Tardive dyskinesia (TD) is a potentially irreversible, chronic syndrome related to antipsychotic medication use characterized by hyperkinetic abnormal involuntary movements. Various studies have shown that development of TD is possible with both first- and second-generation antipsychotics. Regular monitoring for emergence of TD symptoms is recommended in clinical practice for early recognition and intervention. This is a retrospective, single-center, observational study of the effectiveness of a pharmacist-driven monitoring database for TD assessment. Subjects were adult inpatients at a state psychiatric hospital who received antipsychotic treatment for at least 3 or 6 months between January 2006 and December 2011. The primary objective was to assess compliance rates with TD monitoring based on facility policy before and after implementation of the database at 3 and 6 months following initiation of antipsychotic therapy. A significant improvement in compliance with TD monitoring policy was seen after implementation of the database (2.9% vs 66.7%; P monitoring did not differ between classes of antipsychotic medication, hospital units, or age groups. The results of this study demonstrate that pharmacists can help improve compliance with TD assessment and that monitoring databases may be useful for similar extended or long-term care settings to ensure timely assessment of patients for the development or progression of TD.
Kipfer, Stefan; Stephan, Marianne A; Schüpbach, W M Michael; Ballinari, Pietro; Kaelin-Lang, Alain
It is unclear whether patients with different clinical subtypes of Parkinson disease (PD) differ in their risk of developing levodopa-induced dyskinesia (LID) and whether resting tremor is negatively correlated with this risk. To determine whether resting tremor as an initial manifestation of PD negatively correlated with subsequent occurrence and severity of LID and to study the correlations between LID and other epidemiological factors (eg, age at onset of PD and duration of PD). Logistic regression analysis was used to determine predictive factors of LID. Spearman rank correlations between LID and epidemiological factors and motor signs (including tremor) were calculated. Institutional tertiary referral center for movement disorders. Cohort of 85 patients with PD. Occurrence of LID according to the Unified Parkinson Disease Rating Scale part IV. Resting tremor as an initial manifestation of PD was associated with reduced risk of developing LID independent of other predictors of LID (duration of PD, axial signs, and levodopa dose). Resting tremor as an initial manifestation of PD predicts lower probability of developing LID under levodopa treatment.
Full Text Available Rationale: Primary ciliary dyskinesia (PCD is under diagnosed and underestimated. Most clinical research has used some form of questionnaires to capture data but none has been critically evaluated particularly with respect to its end-user feasibility and utility. Objective: To critically appraise a clinical data collection questionnaire for PCD used in a large national PCD consortium in order to apply conclusions in future PCD research. Methods: We describe the development, validation and revision process of a clinical questionnaire for PCD and its evaluation during a national clinical PCD study with respect to data collection and analysis, initial completion rates and user feedback. Results: 14 centers participating in the consortium successfully completed the revised version of the questionnaire for 173 patients with various completion rates for various items. While content and internal consistency analysis demonstrated validity, there were methodological deficiencies impacting completion rates and end-user utility. These deficiencies were addressed resulting in a more valid questionnaire. Conclusions: Our experience may be useful for future clinical research in PCD. Based on the feedback collected on the questionnaire through analysis of completion rates, judgmental analysis of the content, and feedback from experts and end users, we suggest a practicable framework for development of similar tools for various future PCD research.
Ferkol, Thomas W; Puffenberger, Erik G; Lie, Hauw; Helms, Cynthia; Strauss, Kevin A; Bowcock, Anne; Carson, John L; Hazucha, Milan; Morton, D Holmes; Patel, Anand C; Leigh, Margaret W; Knowles, Michael R; Zariwala, Maimoona A
To determine whether individuals with primary ciliary dyskinesia (PCD) from unrelated Amish and Mennonite families harbor a single and unique founder mutation. Subjects from Amish and Mennonite communities in several states were enrolled in the study. All subjects were clinically characterized, and nasal nitric oxide levels were measured. Nasal epithelial scrapings were collected from several subjects for ciliary ultrastructural analyses. DNA was isolated from patients with PCD and their unaffected first- and second-degree relatives. Genome-wide homozygosity mapping, linkage analyses, targeted mutation analyses, and exome sequencing were performed. All subjects from Old-Order Amish communities from Pennsylvania were homozygous for a nonsense mutant DNAH5 allele, c.4348C>T (p.Q1450X). Two affected siblings from an unrelated Mennonite family in Arkansas were homozygous for the same nonsense DNAH5 mutation. Children with PCD from an Amish family from Wisconsin had biallelic DNAH5 mutations, c.4348C>T (p.Q1450X) and c.10815delT (p.P3606HfsX23), and mutations in other genes associated with PCD were also identified in this community. The Amish and Mennonite subjects from geographically dispersed and socially isolated communities had the same founder DNAH5 mutation, owing to the common heritage of these populations. However, disease-causing mutations in other PCD-associated genes were also found in affected individuals in these communities, illustrating the genetic heterogeneity in this consanguineous population. Copyright © 2013 Mosby, Inc. All rights reserved.
Dudko, Yevgeni; Kruger, Estie; Tennant, Marc
been the subject of debate at the government level and, over the years, has seen an increase in allocation of public funds in an effort to address the policy needs. What does this paper add? This study calculates the actual number of people on the public dental waitlist, provides a detailed analysis of the distribution of the demand for the services and offers a cost model for resetting public dental waitlists across Australia. What are the implications for practitioners? This study carries no implications for individual practitioners at the clinical level. However, at the state and national levels, this model offers direction to a more cost-effective allocation of public funds and human resources.
MacDonald, L. H.; Wagenbrenner, J. W.; Robichaud, P. R.; Nelson, P. A.; Kampf, S. K.; Brogan, D. J.
High and moderate severity wildfires can reduce infiltration rates to less than 10 mm/hr, and the resulting surface runoff can increase small-scale peak flows by one or more orders of magnitude. Fires can increase hillslope erosion rates by several orders of magnitude, but this increase is less linear with rainfall intensity because it also depends on sediment supply and detachment processes as well as transport capacity. These localized and shorter-term effects have been relatively well documented, but there is much more uncertainty in how these fire-induced changes can lead to larger-scale and/or longer-term effects. The goal of this presentation is to provide a process-based analysis of how, where, and when wildfires can cause either longer-term or larger-scale changes, effectively resetting the system as opposed to a more transient "flash in the pan". An understanding of vegetation, climatic, and geomorphic dynamics are are critical for predicting larger-scale and longer-term effects. First is the potential for the vegetation to return to pre-fire conditions, and this depends on vegetation type, spatial extent of the fire, and if the pre-fire vegetation is marginalized by climate change, land use, or other factors. The trajectory of post-fire regrowth controls the duration of increased runoff and erosion as well as the size and severity of future fires, which then sets the scene for longer-term hydrologic and geomorphic change. Climate defines the dominant storm type and how they match up with the spatial extent of a fire. Historic data help estimate the extent and magnitude of post-fire rainfall, but there is a strong stochastic component and the more extreme events are of greatest concern. Geomorphic controls on larger-scale effects include the valley and drainage network characteristics that help govern the storage and delivery of water and sediment. Assessing each component involves multiple site factors, but the biggest problem is understanding their
Silchenko, Alexander N; Adamchic, Ilya; Hauptmann, Christian; Tass, Peter A
Chronic subjective tinnitus is an auditory phantom phenomenon characterized by abnormal neuronal synchrony in the central auditory system. As recently shown in a proof of concept clinical trial, acoustic coordinated reset (CR) neuromodulation causes a significant relief of tinnitus symptoms combined with a significant decrease of pathological oscillatory activity in a network comprising auditory and non-auditory brain areas. The objective of the present study was to analyze whether CR therapy caused an alteration of the effective connectivity in a tinnitus related network of localized EEG brain sources. To determine which connections matter, in a first step, we considered a larger network of brain sources previously associated with tinnitus. To that network we applied a data-driven approach, combining empirical mode decomposition and partial directed coherence analysis, in patients with bilateral tinnitus before and after 12 weeks of CR therapy as well as in healthy controls. To increase the signal-to-noise ratio, we focused on the good responders, classified by a reliable-change-index (RCI). Prior to CR therapy and compared to the healthy controls, the good responders showed a significantly increased connectivity between the left primary cortex auditory cortex and the posterior cingulate cortex in the gamma and delta bands together with a significantly decreased effective connectivity between the right primary auditory cortex and the dorsolateral prefrontal cortex in the alpha band. Intriguingly, after 12 weeks of CR therapy most of the pathological interactions were gone, so that the connectivity patterns of good responders and healthy controls became statistically indistinguishable. In addition, we used dynamic causal modeling (DCM) to examine the types of interactions which were altered by CR therapy. Our DCM results show that CR therapy specifically counteracted the imbalance of excitation and inhibition. CR significantly weakened the excitatory connection
Debono, Miguel; Harrison, Robert F; Chadarevian, Rita; Gueroult, Carole; Abitbol, Jean-Louis; Newell-Price, John
Adrenal incidentalomas (AIs) are found commonly on axial imaging. Around 30% exhibit autonomous cortisol secretion (ACS) associated with increased cardiovascular events and death. We hypothesized that AI/ACS patients have an abnormal cortisol rhythm that could be reversed by use of carefully timed short-acting cortisol synthesis blockade, with improvement in cardiovascular disease markers. In a phase 1/2a, prospective study (Eudract no. 2012-002586-35), we recruited six patients with AI/ACS and two control groups of six sex-, age-, and body mass index-matched individuals: (1) patients with AI and no ACS (AI/NoACS) and (2) healthy volunteers with no AI [healthy controls (HC)]. Twenty-four-hour circadian cortisol analysis was performed to determine any differences between groups and timing of intervention for cortisol lowering using the 11β-hydroxylase inhibitor metyrapone. Circadian profiles of serum interleukin-6 (IL-6) were assessed. Serum cortisol levels in group AI/ACS were significantly higher than both group AI/NoACS and group HC from 6 pm to 10 pm [area under the curve (AUC) difference: 0.81 nmol/L/h; P = 0.01] and from 10 pm to 2 am (AUC difference: 0.86 nmol/L/h; P cortisol rhythms were reassessed. Postintervention evening serum cortisol was lowered, similar to controls [6 pm to 10 pm (AUC difference: -0.06 nmol/L/h; P = 0.85); 10 pm to 2 am (AUC difference: 0.10 nmol/L/h; P = 0.76)]. Salivary cortisone showed analogous changes. IL-6 levels were elevated before treatment [10 pm to 2 pm (AUC difference: 0.42 pg/mL/h; P = 0.01)] and normalized post treatment. In AI/ACS, the evening and nocturnal cortisol exposure is increased. Use of timed evening doses of metyrapone resets the cortisol rhythm to normal. This unique treatment paradigm is associated with a reduction in the cardiovascular risk marker IL-6.
Maria Sheila G. Rocha
Full Text Available A ocorrência de discinesias dificulta consideravelmente o manuseio terapêutico dos pacientes parkinsonianos tratados com levodopa. Estudamos as características clínicas das discinesias em 176 pacientes com diagnóstico de doença de Parkinson e tratados com levodopa. As discinesias ocorreram, em média, após 6,2 anos de duração da doença e após 4,2 anos de tratamento com levodopa. A maioria dos pacientes (90% achava-se nos estágios II e III de Hoehn & Yahr por ocasião do início das discinesias. As discinesias mais frequentes foram as de "pico de dose" e "contínua". Movimento do tipo distônico ocorreu em 40% dos casos e predominou nas discinesias de "fim de dose" e "bifásica". Distonia matinal correspondeu a 35% dos casos de distonia. Movimentos coreiformes se manifestaram de forma generalizada em 43,2% dos casos. Movimentos distônicos predominaram nos membros inferiores. A discinesia, quando unilateral, ocorreu mais frequüentemente no hemicorpo mais comprometido pela doença de Parkinson. A discinesia orofacial, quando isolada, foi mais frequente nos pacientes mais idosos.Dyskinesias are frequently observed in parkinsonian patients during levodopa treatment. The occurrence of these movement disorders usually makes the therapeutic management of the patients very difficult. The clinical characteristics of 176 patients with dyskinesias were retrospectively studied. Dyskinesias occurred, on average, after 6,2 years of duration of Parkinson's disease and after 4.2 years on treatment with levodopa. Patients were more likely to have dyskinesias during more advanced stages (measured by Hoehn and Yahr scale. Peak of dose and square wave were the types of dyskinesia more frequently described and were associated with choreic movements in most cases. Dystonia occurred in 40% of the cases and was predominant in end of dose and diphasic dyskinesias. Thirty-five percent of dystonia cases presented as "early morning dystonia". Chorea was the
Full Text Available Tardive dyskinesia (TD is a disfiguring side-effect of antipsychotic medications that is potentially irreversible in affected patients. Newer atypical antipsychotics are felt by many to have a lower risk of TD. As a result, many clinicians may have developed a false sense of security when prescribing these medications. We report five cases of patients taking atypical antipsychotics who developed TD, review the risk of TD, its potential etiologic mechanisms, and treatment options available. The goal of this paper is to alert the reader to continue to be diligent in obtaining informed consent and monitoring for the onset of TD in patients taking atypical antipsychotics.
Full Text Available The structural dynamics of chromatin have been implicated in the regulation of fundamental eukaryotic processes, such as DNA transcription, replication and repair. Although previous studies have revealed that the chromatin landscape, nucleosome remodeling and histone modification events are intimately tied into cellular energetics and redox state, few studies undertake defined time-resolved measurements of these state variables. Here, we use metabolically synchronous, continuously-grown yeast cultures to measure DNA occupancy and track global patterns with respect to the metabolic state of the culture. Combined with transcriptome analyses and ChIP-qPCR experiments, these paint an intriguing picture where genome-wide nucleosome focusing occurs during the recovery of energy charge, followed by clearance of the promoter regions and global transcriptional slow-down, thus indicating a nucleosome-mediated “reset point” for the cycle. The reset begins at the end of the catabolic and stress-response transcriptional programs and ends prior to the start of the anabolic and cell-growth transcriptional program, and the histones on genes from both the catabolic and anabolic superclusters are deacetylated.
Full Text Available BACKGROUND: Primary ciliary dyskinesia (PCD is a genetic disorder characterized by impaired ciliary function, leading to chronic sinopulmonary disease. The genetic causes of PCD are still evolving, while the diagnosis is often dependent on finding a ciliary ultrastructural abnormality and immotile cilia. Here we report a novel gene associated with PCD but without ciliary ultrastructural abnormalities evident by transmission electron microscopy, but with dyskinetic cilia beating. METHODS: Genetic linkage analysis was performed in a family with a PCD subject. Gene expression was studied in Chlamydomonas reinhardtii and human airway epithelial cells, using RNA assays and immunostaining. The phenotypic effects of candidate gene mutations were determined in primary culture human tracheobronchial epithelial cells transduced with gene targeted shRNA sequences. Video-microscopy was used to evaluate cilia motion. RESULTS: A single novel mutation in CCDC65, which created a termination codon at position 293, was identified in a subject with typical clinical features of PCD. CCDC65, an orthologue of the Chlamydomonas nexin-dynein regulatory complex protein DRC2, was localized to the cilia of normal nasal epithelial cells but was absent in those from the proband. CCDC65 expression was up-regulated during ciliogenesis in cultured airway epithelial cells, as was DRC2 in C. reinhardtii following deflagellation. Nasal epithelial cells from the affected individual and CCDC65-specific shRNA transduced normal airway epithelial cells had stiff and dyskinetic cilia beating patterns compared to control cells. Moreover, Gas8, a nexin-dynein regulatory complex component previously identified to associate with CCDC65, was absent in airway cells from the PCD subject and CCDC65-silenced cells. CONCLUSION: Mutation in CCDC65, a nexin-dynein regulatory complex member, resulted in a frameshift mutation and PCD. The affected individual had altered cilia beating patterns, and
Djakow, Jana; Kramná, Lenka; Dušátková, Lenka; Uhlík, Jiří; Pursiheimo, Juha-Pekka; Svobodová, Tamara; Pohunek, Petr; Cinek, Ondřej
Primary ciliary dyskinesia (PCD) is a multigenic autosomal recessive condition affecting respiratory tract and other organs where ciliary motility is required. The extent of its genetic heterogeneity is remarkable. The aim of the study was to develop a cost-effective pipeline for genetic diagnostics using a combination of Sanger and next generation sequencing (NGS). Data and samples of 33 families with 38 affected subjects with PCD diagnosed in childhood were collected over the territory of the Czech Republic. A panel of 18 PCD causative or candidate genes was implemented into an Illumina TruSeq Custom Amplicon NGS assay, and three ancestral mutations in SPAG1 were screened by conventional Sanger sequencing, which was also used for the confirmation of the NGS results and for the analysis of familial segregation. The causative gene was DNAH5 in 11/33 (33%) probands, SPAG1 in 8/33 (24%), and DNAI1, CCDC40, LRRC6 in one family each. If the high proportion of subjects with bi-allelic ancestral mutations in SPAG1 is corroborated in other Caucasian populations, a simple Sanger sequencing test for these three mutations may serve as an effective pre-screening step, being followed by an NGS panel for other, much larger, PCD genes. We present a combination of Sanger sequencing with an NGS panel for known and candidate PCD genes, implemented in a moderate-size national collection of patients. This strategy has proven to be cost-effective, rapid and reliable, and was able to detect the causative gene in two thirds of our PCD patients. © 2015 Wiley Periodicals, Inc.
Gardiner, Alice R; Bhatia, Kailash P; Stamelou, Maria; Dale, Russell C; Kurian, Manju A; Schneider, Susanne A; Wali, G M; Counihan, Tim; Schapira, Anthony H; Spacey, Sian D; Valente, Enza-Maria; Silveira-Moriyama, Laura; Teive, Hélio A G; Raskin, Salmo; Sander, Josemir W; Lees, Andrew; Warner, Tom; Kullmann, Dimitri M; Wood, Nicholas W; Hanna, Michael; Houlden, Henry
The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM). The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders.
Patil, Rupali; Hiray, Yogesh; Shinde, Sandesh; Langade, Padmaja
Orofacial dyskinesia (OD) is a late complication of prolonged neuroleptic treatment characterized by involuntary movements of the oral region. Chronic treatment with neuroleptics leads to development of vacuous chewing movements (VCMs). VCMs in rats are widely accepted as an animal model of OD. To study the effect of Murraya koenigii L. (Rutaceae) leaves on haloperidol-induced OD. Effect of alcohol extract of M. koenigii leaves (EEMK) and its alkaloid fraction (AMK) on body weight, locomotor activity, behavioral parameters, such as VCMs, tongue protrusions (TPs), orofacial bursts (OBs), and biochemical parameters such as antioxidant defense enzymes levels [superoxide dismutase (SOD) and catalase (CAT)], glutathione (GSH) levels, and lipid peroxidation (LPO) in the forebrain region was studied in haloperidol-treated rats. Rats chronically treated with haloperidol (1 mg/kg, i.p., 21 days) significantly decreased locomotion and developed VCMs, OBs, and TPs. Biochemical analysis reveals that chronic haloperidol-treated rats also showed decreased levels of SOD and CAT. Chronic haloperidol treatment significantly induced LPO and decreased the forebrain GSH levels in the rats. Co-administration of EEMK (100 and 300 mg/kg, p.o.) and AMK (30 and 100 mg/kg, p.o.) along with haloperidol significantly reversed the effect on locomotion. EEMK and AMK significantly reversed the haloperidol-induced decrease in forebrain SOD and CAT levels in rats and significantly reduced the LPO and restored the decreased GSH levels by chronic haloperidol treatment. The study concludes that M. koenigii could be screened as a potential drug for the prevention or treatment of neuroleptic-induced OD.
Full Text Available The exact mechanisms that generate levodopa-induced dyskinesias (LID during chronic levodopa therapy for Parkinson’s disease (PD are not yet fully established. The most widely accepted theories incriminate the non-physiological synthesis, release and reuptake of dopamine generated by exogenously administered levodopa in the striatum, and the aberrant plasticity in the corticostriatal loops. However, normal motor performance requires the correct recruitment of motor maps. This depends on a high level of synergy within the primary motor cortex (M1 as well as between M1 and other cortical and subcortical areas, for which dopamine is necessary. The plastic mechanisms within M1 which are crucial for the maintenance of this synergy are disrupted both during OFF and dyskinetic states in PD. When tested without levodopa, dyskinetic patients show loss of treatment benefits on long-term potentiation and long-term depression-like plasticity of the intracortical circuits. When tested with the regular pulsatile levodopa doses, they show further impairment of the M1 plasticity, such as inability to depotentiate an already facilitated synapse and paradoxical facilitation in response to afferent input aimed at synaptic inhibition. Dyskinetic patients have also severe impairment of the associative, sensorimotor plasticity of M1 attributed to deficient cerebellar modulation of sensory afferents to M1. Here we review the anatomical and functional studies, including the recently described bidirectional connections between the cerebellum and the basal ganglia that support a key role of the cerebellum in the generation of LID. This model stipulates that aberrant neuronal synchrony in PD with LID may propagate from the sub thalamic nucleus to the cerebellum and lock the cerebellar cortex in a hyperactive state. This could affect critical cerebellar functions such as the dynamic and discrete modulation of M1 plasticity and the matching of motor commands with sensory
Full Text Available Paroxysmal kinesigenic dyskinesia (PKD is a monogenic movement disorder with autosomal dominant inheritance. We previously identified the proline-rich transmembrane protein 2 (PRRT2 as a causative gene of PKD. However, the pathogenesis of PKD remains largely unknown so far. In addition, applicable modeling tools to investigate the underlying mechanisms of PKD are still lacking. The combination of disease-specific human induced pluripotent stem cells (iPSCs and directed cell differentiation offers an ideal platform for disease modeling. In this study, we generated two iPSC lines from the renal epithelial cells of one PKD patient with the hotspot c.649dupC mutation (PKD-iPSCs. These cell lines were positive for alkaline phosphatase Nanog, Tra-1-80, Tra-1-60, SSEA-3 and SSEA-4. Teratomas with three blastoderms including ectoderm, mesoderm, and endoderm were obtained two months after injection of PKD-iPSCs into NOD/SCID mice. The expression of PRRT2 mRNA was decreased in PKD-iPSCs compared with that of the control iPSCs. Furthermore, PKD-iPSCs possessed the differentiation potential of functional glutamatergic, dopaminergic and motor neurons in vitro. Electrophysiological examinations revealed that the current densities of fast activated and deactivated sodium channels as well as voltage gated potassium channels were not different between the neurons from PKD-iPSCs and control iPSCs. Thus, PKD-iPSCs are a feasible modeling tool to investigate the pathogenic mechanisms of PKD.
Rajan, Tess Maria; Bharadwaj, Balaji; Rajkumar, Ravi Philip; Adole, Prashant Shankarrao
Patients with Bipolar Disorder (BD) may have higher risk of Tardive Dyskinesia (TD). Theories for TD include inflammatory or oxidative stress and altered iron metabolism. The current frequency and clinical and biochemical correlates of TD in BD needs exploration. To assess: (1) the frequency of TD in BD; (2) clinical correlates of TD in BD; (3) oxidative stress markers, inflammatory markers and hepcidin in TD in BD. In this cross-sectional study, 170 patients with BD were assessed for clinical characteristics using structured assessments. Inflammatory and oxidative markers like Interleukin-6 (IL-6), high sensitivity C-Reactive Protein (hsCRP), malondialdehyde (MDA), Total Antioxidant Status (TAS) and hepcidin were assessed by ELISA. Frequency of TD was 10.6% (95%C.I.=6.4%-16.2%). Compared to patients without TD, patients with TD were older (F=0.340;p=0.000), had more episodes of illness (U=962.5;p=0.044) higher rates of medical comorbidity (X2=6.924; p=0.009*), antipsychotic exposure (U=592.5;p=0.000), typical antipsychotic exposure (U=756.5;p=0.001) and cognitive deficits (F=1.129;p=0.001). The biomarkers levels did not differ between the groups. Hepcidin levels correlated with Abnormal involuntary Movements scale (AIMS) score (r=0.213;p=0.006). Patients treated with lithium were more likely to have TD, but also had greater exposure to antipsychotics than patients on valproate. About one-tenth of patients with BD-I have TD. The presence of TD is associated several clinical characteristics such as age, exposure to typical antipsychotics and chronicity of illness. Hepcidin was associated with greater severity of dyskinetic movements and needs further exploration. Copyright © 2017 Elsevier B.V. All rights reserved.
Resetting criteria during ventricular overdrive pacing successfully differentiate orthodromic reentrant tachycardia from atrioventricular nodal reentrant tachycardia despite interobserver disagreement concerning QRS fusion.
Rosman, Jonathan Z; John, Roy M; Stevenson, William G; Epstein, Laurence M; Tedrow, Usha B; Koplan, Bruce A; Albert, Christine M; Michaud, Gregory F
The beginning of ventricular overdrive pacing (VOP) during supraventricular tachycardia (SVT) accurately distinguishes orthodromic reentrant tachycardia (ORT) from atrioventricular nodal reentrant tachycardia (AVNRT) even when pacing terminates tachycardia. Tachycardia resetting most often occurs during this transition zone (TZ) of QRS fusion in ORT and after this TZ in AVNRT. The end of the TZ is marked by the first beat with a stable QRS morphology but is a subjective assessment. Disagreement concerning this beat may change tachycardia diagnosis. The purpose of this study was to assess interobserver agreement for identifying the TZ and whether disagreement affected diagnosis. Seventy-nine consecutive patients with inducible ORT and AVNRT were included. Resetting of tachycardia was evaluated by (1) atrial timing perturbation and (2) fixed stimulation-atrial activation timing (SA). Two blinded observers identified the end of the TZ and used the two resetting criteria to establish a diagnosis. Diagnostic results were compared with standard criteria for SVT diagnosis. The diagnosis was considered correct if both electrophysiologists' TZ assessment resulted in a correct diagnosis. Agreement on the TZ occurred in 80% (148/186) of VOP trains. In ORT patients, tachycardia resetting occurred during the TZ and correctly diagnosed ORT based on atrial timing perturbation and fixed SA in 91% and 98% of VOP trains, respectively. In AVNRT patients, tachycardia resetting occurred after the TZ and correctly diagnosed AVNRT based on atrial timing perturbation and fixed SA in 93% and 94% of VOP trains, respectively. Resetting criteria used during the VOP TZ accurately differentiate between ORT and AVNRT despite interobserver disagreement concerning identification of the TZ. Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
Srinivasa Rao Gunti
Full Text Available A new phase-change memory material, in bulk, has been prepared by melt-quenching technique, which has a better glass forming ability. This sample is set and resettable relatively easily for several cycles at 2mA SET and RESET input currents, and is likely to be a suitable material for phase-change memory applications. Raman scattering studies have been undertaken during the SET and RESET operations to elucidate the local structural transformations that occur during these operations.
Svetlana A. Ivanova
Full Text Available A serendipitous pharmacogenetic finding links the vulnerability to developing levodopa-induced dyskinesia to the age of onset of Huntington’s disease. Huntington’s disease is caused by a polyglutamate expansion of the protein huntingtin. Aberrant huntingtin is less capable of binding to a member of membrane-associated guanylate kinase family (MAGUKs: postsynaptic density- (PSD- 95. This leaves more PSD-95 available to stabilize NR2B subunit carrying NMDA receptors in the synaptic membrane. This results in increased excitotoxicity for which particularly striatal medium spiny neurons from the indirect extrapyramidal pathway are sensitive. In Parkinson’s disease the sensitivity for excitotoxicity is related to increased oxidative stress due to genetically determined abnormal metabolism of dopamine or related products. This probably also increases the sensitivity of medium spiny neurons for exogenous levodopa. Particularly the combination of increased oxidative stress due to aberrant dopamine metabolism, increased vulnerability to NMDA induced excitotoxicity, and the particular sensitivity of indirect pathway medium spiny neurons for this excitotoxicity may explain the observed increased prevalence of levodopa-induced dyskinesia.
Kasper, Siegfried; Lowry, Amanda J; Hodge, Andrew; Bitter, Istvan; Dossenbach, Martin
The point prevalence of Tardive Dyskinesia (TD) in schizophrenia outpatients (n=6981) participating in a study of health outcomes was 8.9%. Duration of diagnosis, age, and prior use of typical antipsychotics were diagnostic indicators of TD in this population, with male sex further increasing risk. This study provides new data in a non-Western population with a unique regional geography comparison.
Sharma, S; Paladino, P; Gabriele, J; Saeedi, H; Henry, P; Chang, M; Mishra, R K; Johnson, R L
In the present experimental paradigm, we examine the effect of L-prolyl-L-leucyl-glycinamide (PLG) co-administration with haloperidol on vacuous chewing movements (VCM) in rats-a model of tardive dyskinesia (TD) in humans. We examined the dose dependent induction of VCM through both injected and orally administered PLG (MIF-1). Our results show significant levels of VCM attenuation (PTD.
Mentzel, Charlotte L.; Tenback, Diederik E.; Tijssen, Marina A. J.; Visser-Vandewalle, Veerle E. R. M.; van Harten, Peter N.
Background: Tardive dyskinesia and dystonia (TDD) are severe side effects of dopamine-blocking agents, particularly antipsychotics. While deep brain stimulation (DBS) has proven effective in the treatment of TDD, little is known about the possible psychiatric complications of DBS in psychiatric
Al Hadithy, A. F. Y.; Ivanova, S. A.; Pechlivanoglou, P.; Wilffert, B.; Semke, A.; Fedorenko, O.; Kornetova, E.; Ryadovaya, L.; Brouwers, J. R. B. J.; Loonen, A. J. M.
Neuronal degeneration due to oxidative stress (OS) has been proposed as a mechanism for tardive dyskinesia (TD) pathogenesis. Cellular defense mechanisms against OS may involve detoxification enzymes (e.g., glutathione peroxidase-1, GPX1; superoxide dismutase-2, SOD2 [also commonly known as MnSOD];
Marthin, June Kehlet; Nielsen, Kim Gjerum
BACKGROUND: Nasal nitric oxide (nNO) measurement is an established first line test in the work-up for primary ciliary dyskinesia (PCD). Tidal breathing nNO (TB-nNO) measurements require minimal cooperation and are potentially useful even in young children. Hand-held NO devices are becoming increa...
Ivanova, S.A.; Alifirova, V.M.; Fedorenko, O.Y.; Freidin, M.B.; Bokhan, N.A.; Zhukova, I.; Al Hadithy, A.F.Y.; Brouwers, J.R.B.J.; Wilffert, B.; Loonen, A.J.M.
Levodopa-induced dyskinesias (LID) are involuntary muscle movements that occur as a consequence of chronic levodopa (L-DOPA) treatment. LID are a substantial barrier to effective symptomatic management of Parkinson's disease (PD), up to 45% of L-DOPA users develop LID within 5 years . Clinical
Loonen, A.J.M.; Verwey, H.A.; Roels, P.R.; Van Bavel, L.P.; Doorschot, C.H.
Calcium channel blockers, antiarrhythmic drugs, such as verapamil and diltiazem, may decrease the symptoms of tardive dyskinesia. The efficacy and safety of administering 60 mg diltiazem hydrochloride, four times daily for a period of 3 weeks, was studied in a random, double-blind, crossover trial
van Harten, Peter N.; Hoek, Hans W.; Matroos, Glenn E.; van Os, Jim
Objective: Tardive dyskinesia (TD) and tardive dystonia (TDt) syndromes represent severe side effects of first-generation antipsychotics (FGAs). Although second-generation antipsychotics (SGAs) confer a lower risk for tardive syndromes, many patients continue to use FGAs alone or in combination with
Gong, Yue-Feng; Ling, Yun; Song, Zhi-Tang; Feng, Song-Lin
A three-dimensional finite element models for phase change random access memory (PCRAM) is established to simulate thermal and electrical behaviours during RESET operation. The RESET behaviours of the conventional structure (CS) and the ring-type contact in bottom electrode (RIB) are compared with each other. The simulation results indicate that the RIB cell has advantages of high heat efficiency for melting phase change material in cell, reduction of contact area and lower RESET current with maintaining good resistance contrast. The RESET current decreases from 1.26mA to 1.2mA and the heat consumption in GST material during programming increases from 12% to 37% in RIB structure. Thus the RIB structure PCRAM cell is suitable for future device with high heat efficiency and smaller RESET current.
Full Text Available BACKGROUND: Although aerobic fitness is regarded as an overall prognostic measure of morbidity and mortality, its evaluation in the chronic progressive sinopulmonary disease primary ciliary dyskinesia (PCD has been infrequently and inconsistently reported. Here we assessed peak oxygen uptake (VO2peak in a large well-characterized cohort of PCD patients, and explored whether VO2peak was associated with parameters of pulmonary function, self-reported physical limitations, and physical activity level. METHODS: VO2peak, spirometry, diffusing capacity, whole-body plethysmography, and nitrogen multiple breath inert gas washout (N2 MBW were assessed in a cross-sectional, single-occasion study of clinically stable children and young adults with PCD. We used a questionnaire including self-reported physical limitations in everyday life or in vigorous activities, and estimation of weekly hours of strenuous physical activity. VO2peak in PCD patients was compared with that in matched, healthy control subjects and a national reference. RESULTS: Forty-four PCD patients aged 6-29 years exhibited reduced VO2peak compared to healthy controls (P<0.001 and the national reference. VO2peak was abnormal (z-score <-1.96 in 34% of PCD patients. Spirometric values, RV/TLC, and indices of N2 MBW were significantly abnormal, but VO2peak only correlated with FEV1 and DLCO/VA. VO2peak correlated with complaints of moderate or significant limitations in vigorous activities (P = 0.0001, exhibited by 39% of PCD patients. CONCLUSION: One-third of PCD patients exhibited substantially lower aerobic fitness than healthy subjects. Aerobic fitness correlated with FEV1, DLCO/VA and self-reported complaints of limitations in vigorous physical activity. These findings are most likely explained by PCD pulmonary disease and its impact on pulmonary function and physical ability. Considering fitness as an important outcome and including regular strenuous physical activity in PCD
Full Text Available Primary ciliary dyskinesia (PCD is an orphan disease (MIM 244400, autosomal recessive inherited, characterized by motile ciliary dysfunction. The estimated prevalence of PCD is 1:10,000 to 1:20,000 live-born children, but true prevalence could be even higher. PCD is characterized by chronic upper and lower respiratory tract disease, infertility/ectopic pregnancy, and situs anomalies, that occur in ≈50% of PCD patients (Kartagener syndrome, and these may be associated with congenital heart abnormalities. Most patients report a daily year-round wet cough or nose congestion starting in the first year of life. Daily wet cough, associated with recurrent infections exacerbations, results in the development of chronic suppurative lung disease, with localized-to-diffuse bronchiectasis. No diagnostic test is perfect for confirming PCD. Diagnosis can be challenging and relies on a combination of clinical data, nasal nitric oxide levels plus cilia ultrastructure and function analysis. Adjunctive tests include genetic analysis and repeated tests in ciliary culture specimens. There are currently 33 known genes associated with PCD and correlations between genotype and ultrastructural defects have been increasingly demonstrated. Comprehensive genetic testing may hopefully screen young infants before symptoms occur, thus improving survival. Recent surprising advances in PCD genetic designed a novel approach called “gene editing” to restore gene function and normalize ciliary motility, opening up new avenues for treating PCD. Currently, there are no data from randomized clinical trials to support any specific treatment, thus, management strategies are usually extrapolated from cystic fibrosis. The goal of treatment is to prevent exacerbations, slowing the progression of lung disease. The therapeutic mainstay includes airway clearance maneuvers mainly with nebulized hypertonic saline and chest physiotherapy, and prompt and aggressive administration of
Terkildsen, Søren; Svendsen, Svend
The control strategy for mechanical ventilation systems has significant impact on the performance of the system, in terms of energy consumption and correct air distribution. This paper presents a static pressure reset control system employing a new type of flow damper with lower pressure loss...... shows that the droplet shaped damper resulted in an airflow of 234 L/s at 30 Pa pressure loss, more than twice the airflow past a flat-plate damper at the same pressure loss (114 L/s). Also the droplet shaped damper could operate precisely down to 5 Pa pressure loss. The programmed control algorithm...... significant fan power saving compared to a fixed static pressure control. A maximum static pressure of 15 Pa is a reduction of more than 50% compared to flat-plate dampers that required at least 30 Pa to operate precisely; this is expected to yield fan energy savings in practice....
Seluzicki, Adam; Flourakis, Matthieu; Kula-Eversole, Elzbieta; Zhang, Luoying; Kilman, Valerie; Allada, Ravi
Molecular circadian clocks are interconnected via neural networks. In Drosophila, PIGMENT-DISPERSING FACTOR (PDF) acts as a master network regulator with dual functions in synchronizing molecular oscillations between disparate PDF(+) and PDF(-) circadian pacemaker neurons and controlling pacemaker neuron output. Yet the mechanisms by which PDF functions are not clear. We demonstrate that genetic inhibition of protein kinase A (PKA) in PDF(-) clock neurons can phenocopy PDF mutants while activated PKA can partially rescue PDF receptor mutants. PKA subunit transcripts are also under clock control in non-PDF DN1p neurons. To address the core clock target of PDF, we rescued per in PDF neurons of arrhythmic per⁰¹ mutants. PDF neuron rescue induced high amplitude rhythms in the clock component TIMELESS (TIM) in per-less DN1p neurons. Complete loss of PDF or PKA inhibition also results in reduced TIM levels in non-PDF neurons of per⁰¹ flies. To address how PDF impacts pacemaker neuron output, we focally applied PDF to DN1p neurons and found that it acutely depolarizes and increases firing rates of DN1p neurons. Surprisingly, these effects are reduced in the presence of an adenylate cyclase inhibitor, yet persist in the presence of PKA inhibition. We have provided evidence for a signaling mechanism (PKA) and a molecular target (TIM) by which PDF resets and synchronizes clocks and demonstrates an acute direct excitatory effect of PDF on target neurons to control neuronal output. The identification of TIM as a target of PDF signaling suggests it is a multimodal integrator of cell autonomous clock, environmental light, and neural network signaling. Moreover, these data reveal a bifurcation of PKA-dependent clock effects and PKA-independent output effects. Taken together, our results provide a molecular and cellular basis for the dual functions of PDF in clock resetting and pacemaker output.
Jos H T Rohling
Full Text Available The circadian pacemaker of the suprachiasmatic nuclei (SCN contains a major pacemaker for 24 h rhythms that is synchronized to the external light-dark cycle. In response to a shift in the external cycle, neurons of the SCN resynchronize with different pace. We performed electrical activity recordings of the SCN of rats in vitro following a 6 hour delay of the light-dark cycle and observed a bimodal electrical activity pattern with a shifted and an unshifted component. The shifted component was relatively narrow as compared to the unshifted component (2.2 h and 5.7 h, respectively. Curve fitting and simulations predicted that less than 30% of the neurons contribute to the shifted component and that their phase distribution is small. This prediction was confirmed by electrophysiological recordings of neuronal subpopulations. Only 25% of the neurons exhibited an immediate shift in the phase of the electrical activity rhythms, and the phases of the shifted subpopulations appeared significantly more synchronized as compared to the phases of the unshifted subpopulations (p<0.05. We also performed electrical activity recordings of the SCN following a 9 hour advance of the light-dark cycle. The phase advances induced a large desynchrony among the neurons, but consistent with the delays, only 19% of the neurons peaked at the mid of the new light phase. The data suggest that resetting of the central circadian pacemaker to both delays and advances is brought about by an initial shift of a relatively small group of neurons that becomes highly synchronized following a shift in the external cycle. The high degree of synchronization of the shifted neurons may add to the ability of this group to reset the pacemaker. The large desynchronization observed following advances may contribute to the relative difficulty of the circadian system to respond to advanced light cycles.
Ruslan M. Yatsiuk
Full Text Available The synchronization of neurons in cortical column for ascending information flow is considered. Graphics of the synchronization coefficient dependence on different variations of Izhikevich model parameters of after-spike reset were constructed. The raster plots were constructed for visual study of synchronization. Corresponding diagrams were plotted for the opportunity to compare the synchronization coefficient on different layers of cortical column
Alanin, Mikkel Christian
The respiratory tract is lined with motile cilia that transport respiratory mucus. Primary ciliary dyskinesia (PCD) is a chronic genetic disease caused by mutations in genes responsible for ciliary structure and function. Non-functional airway cilia impair the mucociliary clearance (MCC), causing...... mucostasis, lung infections and destruction, chronic rhinosinusitis (CRS) and hearing impairment. It is of paramount importance to postpone chronic lung infection mainly with Gram-negative bacteria (GNB) in patients with an impaired MCC. When successful, lung function can be stabilized and quality of life...... airway cultures and better lung function; approximately one out of four operated patients, in search of an infectious focus, remained free of lung colonization with P. aeruginosa during follow-up for at least six months. Based on these results, it is tempting to speculate that ESS with adjuvant therapy...
Joensen, Odin; Paff, Tamara; Haarman, Eric G
The current diagnostic work-up and monitoring of pulmonary infections may be perceived as invasive, is time consuming and expensive. In this explorative study, we investigated whether or not a non-invasive exhaled breath analysis using an electronic nose would discriminate between cystic fibrosis...... (CF) and primary ciliary dyskinesia (PCD) with or without various well characterized chronic pulmonary infections. We recruited 64 patients with CF and 21 with PCD based on known chronic infection status. 21 healthy volunteers served as controls. An electronic nose was employed to analyze exhaled......, this method significantly discriminates CF patients suffering from a chronic pulmonary P. aeruginosa (PA) infection from CF patients without a chronic pulmonary infection. Further studies are needed for verification and to investigate the role of electronic nose technology in the very early diagnostic workup...
Kane, John M; Correll, Christoph U; Liang, Grace S; Burke, Joshua; O'Brien, Christopher F
Valbenazine (VBZ, NBI-98854) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia (TD). The KINECT 3 study (NCT02274558) evaluated the effects of VBZ on TD in subjects with schizophrenia/schizoaffective disorder (SCHZ) or mood disorder (mood disorder presented separately) who received up to 48 weeks of treatment. KINECT 3 included: 6-week, double-blind, placebo (PBO)-controlled (DBPC) period (205 completers); 42-week VBZ extension (VE) period (124 completers): 4-week washout period (121 completers). Subjects entering the DBPC were randomized 1:1:1 to once-daily VBZ 80 mg, VBZ 40 mg, or PBO; stable concomitant antipsychotic medication regimens were allowed. Subjects completing the DBPC and entering the VE period were re-randomized (blinded) 1:1 from PBO to VBZ (80 or 40 mg) or continued VBZ treatment at the same dose. Efficacy assessments included: mean changes from baseline in Abnormal Involuntary Movement Scale (AIMS) total score (items 1-7); mean Clinical Global Impression of Change (CGI-TD) scores; AIMS responders (subjects with ≥50% score reduction from baseline): and CGI-TD responders (subjects with score ≤2 ["much improved" or "very much improved"]). Treatment effect sizes (Cohen's d) and numbers needed to treat (NNTs) were analyzed for DBPC outcomes. Efficacy analyses were conducted in 148 subjects (DBPC) and 125 subjects (VE) with SCHZ. At Week 6 (end of DBPC), AIMS mean score improvements were greater in the VBZ groups (in a dose-related pattern) than in the PBO group (80 mg, -2.9, d = 0.88; 40 mg, -1.6, d = 0.52; PBO, +0.3). AIMS score changes at Week 48 (end of VE) showed continued TD improvement during long-term VBZ treatment (80 mg, -4.2; 40 mg, -2.5). By Week 52 (end of washout), AIMS scores were returning toward baseline levels, indicating re-emergence of TD. CGI-TD mean scores were as follows: Week 6 (80 mg, 3.0, d = 0.11; 40 mg, 2.9, d = 0.23; PBO, 3.2), Week 48 (80 mg, 2.2; 40 mg, 2
Hu, Zhongya; Hu, Wenxuan; Wang, Xiaomin; Lu, Yizhou; Wang, Lichao; Liao, Zhiwei; Li, Weiqiang
Magnesium isotopes are an emerging tool to study the geological processes recorded in carbonates. Calcite, due to its ubiquitous occurrence and the large Mg isotope fractionation associated with the mineral, has attracted great interests in applications of Mg isotope geochemistry. However, the fidelity of Mg isotopes in geological records of carbonate minerals (e.g., calcite and dolomite) against burial metamorphism remains poorly constrained. Here we report our investigation on the Mg isotope systematics of a dolomitized Middle Triassic Geshan carbonate section in eastern China. Magnesium isotope analysis was complemented by analyses of Sr-C-O isotopic compositions, major and trace element concentrations, and petrographic and mineralogical features. Multiple lines of evidence consistently indicated that post-depositional diagenesis of carbonate minerals occurred to the carbonate rocks. Magnesium isotope compositions of the carbonate rocks closely follow a mixing trend between a high δ26Mg dolomite end member and a low δ26Mg calcite end member, irrespective of sample positions in the section and calcite/dolomite ratio in the samples. By fitting the measured Mg isotope data using a two-end member mixing model, an inter-mineral Δ26Mgdolomite-calcite fractionation of 0.72‰ was obtained. Based on the experimentally derived Mg isotope fractionation factors for dolomite and calcite, a temperature of 150-190 °C was calculated to correspond to the 0.72‰ Δ26Mgdolomite-calcite fractionation. Such temperature range matches with the burial-thermal history of the local strata, making a successful case of Mg isotope geothermometry. Our results indicate that both calcite and dolomite had been re-equilibrated during burial metamorphism, and based on isotope mass balance of Mg, the system was buffered by dolomite in the section. Therefore, burial metamorphism may reset Mg isotope signature of calcite, and Mg isotope compositions in calcite should be dealt with caution in
Oparin, A G; Demerchian, T I; Korenovskiĭ, I P; Chonka, V Iu; Iakovenko, E L; Pandeĭ, I
Mucous barrier resistance was studied in 232 duodenal ulcer patients with signs of exacerbation as shown by PAS-positive substances and acid mucopolysaccharides in antral mucosa of the stomach and duodenum as well as by gastric juice levels of gastromucoproteins, fucose and sialic acids. In addition, measurements were performed of biliary motility. The tests indicated that half of the ulcer patients developed biliary dyskinesia manifesting as hyperkinesia or hypokinesia. The resultant decrease in gastric mucins requires individual correction.
Bandyopadhyay, Promode R.; Hellum, Aren M.
Many slow-moving biological systems like seashells and zebrafish that do not contend with wall turbulence have somewhat organized pigmentation patterns flush with their outer surfaces that are formed by underlying autonomous reaction-diffusion (RD) mechanisms. In contrast, sharks and dolphins contend with wall turbulence, are fast swimmers, and have more organized skin patterns that are proud and sometimes vibrate. A nonlinear spatiotemporal analytical model is not available that explains the mechanism underlying control of flow with such proud patterns, despite the fact that shark and dolphin skins are major targets of reverse engineering mechanisms of drag and noise reduction. Comparable to RD, a minimal self-regulation model is given for wall turbulence regeneration in the transitional regime--laterally coupled, diffusively--which, although restricted to pre-breakdown durations and to a plane close and parallel to the wall, correctly reproduces many experimentally observed spatiotemporal organizations of vorticity in both laminar-to-turbulence transitioning and very low Reynolds number but turbulent regions. We further show that the onset of vorticity disorganization is delayed if the skin organization is treated as a spatiotemporal template of olivo-cerebellar phase reset mechanism. The model shows that the adaptation mechanisms of sharks and dolphins to their fluid environment have much in common.
de Araújo, Dayane Pessoa; Camboim, Thaisa Gracielle Martins; Silva, Ana Patrícia Magalhães; Silva, Caio da Fonseca; de Sousa, Rebeca Canuto; Barbosa, Mabson Delâno Alves; Oliveira, Lucidio Clebeson; Cavalcanti, José Rodolfo Lopes de Paiva; Lucena, Eudes Euler de Souza; Guzen, Fausto Pierdoná
Tardive dyskinesia (TD) is characterized by involuntary movements of the lower portion of the face being related to typical antipsychotic therapy. TD is associated with the oxidative imbalance in the basal ganglia. Lipoic acid (LA) and omega-3 (ω-3) are antioxidants acting as enzyme cofactors, regenerating antioxidant enzymes. This study aimed to investigate behavioral and neurochemical effects of supplementation with LA (100 mg/kg) and ω-3 (1 g/kg) in the treatment of TD induced by chronic use of haloperidol (HAL) (1 mg/kg) in rats. Wistar male rats were used, weighing between 180-200 g. The animals were treated chronically (31 days) with LA alone or associated with HAL or ω-3. Motor behavior was assessed by open-field test, the catalepsy test, and evaluation of orofacial dyskinesia. Oxidative stress was accessed by determination of lipid peroxidation and concentration of nitrite. LA and ω-3 alone or associated caused an improvement in motor performance by increasing locomotor activity in the open-field test and decreased the permanence time on the bar in the catalepsy test and decreased the orofacial dyskinesia. LA and ω-3 showed antioxidant effects, decreasing lipid peroxidation and nitrite levels. Thus, the use of LA associated with ω-3 reduced the extrapyramidal effects produced by chronic use of HAL.
Waddington, J L; Youssef, H A; Dolphin, C; Kinsella, A
Little is known of factors that, on an individual basis, confer vulnerability to the emergence of involuntary movements (tardive dyskinesia) during long-term neuroleptic treatment. In this study of 88 chronic schizophrenic inpatients, 22 variables (four demographic, 14 medication history, and four features of illness) were compared for any association(s) with the presence, by differing topographies and criteria of abnormality, and severity of involuntary movements. Irrespective of the criterion used, the presence of marked cognitive dysfunction-muteness bore a consistent and highly significant primary association with both the presence and the overall severity of orofacial dyskinesia; no such association was found in relation to the presence of limb-truncal dyskinesia. Flattening of affect was the only other variable consistently associated with the presence of orofacial movements. The reliability and prominence of the association between the presence of orofacial, but not of limb-truncal, movements and cognitive dysfunction-negative symptoms suggest that these varying topographies may not constitute a unitary syndrome. This strong association, not with indexes of neuroleptic exposure but rather with features of the illness for which that treatment was prescribed, suggests some neurologic process, more subtle than may previously have been appreciated, as a vulnerability factor of some importance. In schizophrenia it appears to be intimately related to the disease process.
prepared two datasets, each integrating serial number–level data from multiple sources. The first dataset (hereafter called the “ SDC dataset”) included...vehicle usage, location, and field maintenance records from the Army Materiel Systems Analysis Activity (AMSAA) Sample Data Collection ( SDC ) program...vehicle manufacture dates from both SDC and the Logistics Integrated Database (LIDB); and reset dates and costs from Tank-automotive and Armaments
Nagano, Mamoru; Adachi, Akihito; Masumoto, Koh-hei; Meyer-Bernstein, Elizabeth; Shigeyoshi, Yasufumi
Photic resetting of a biological clock is one of the fundamental characteristics of circadian systems and allows living organisms to adjust to a particular environment. Nocturnal light induces the Per1 and Per2 genes, which leads to a resetting of the circadian clock in the suprachiasmatic nucleus (SCN), the mammalian circadian center. In our present study, we investigated whether light differentially induces the rat Per1 (rPer1) and Per2 (rPer2) genes to enable resetting of their circadian clocks. In a 24-hour LD cycle (12 h light:12 h dark), which is shorter than the normal free-running period for rats, Per1 alone showed strong induction in the ventrolateral region of the SCN (VLSCN) during the early day. In contrast, in a 25 hour LD cycle (12.5 h light:12.5 h dark), which is longer than the free running period for these animals, rPer2 alone was strongly induced in the VLSCN, at the end of the light phase and during the early dark periods. Our current findings therefore suggest that Per1 and Per2 are differentially regulated for daily entrainment to the LD cycle.
Pahwa, Rajesh; Tanner, Caroline M; Hauser, Robert A; Isaacson, Stuart H; Nausieda, Paul A; Truong, Daniel D; Agarwal, Pinky; Hull, Keith L; Lyons, Kelly E; Johnson, Reed; Stempien, Mary Jean
Medical treatment of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) is an unmet need. To evaluate the efficacy and safety of ADS-5102 (amantadine) extended-release 274-mg capsules for treatment of LID in patients with PD. A randomized, double-blind, placebo-controlled clinical trial was conducted between May 7, 2014, and July 22, 2015, at 44 North American sites among patients with PD treated with levodopa who experienced at least 1 hour of troublesome dyskinesia per day with at least mild functional impact. Patients were randomized to receive placebo or 274 mg of ADS-5102 administered orally at bedtime for up to 25 weeks. The primary efficacy analysis was the change from baseline to week 12 in the Unified Dyskinesia Rating Scale total score for ADS-5102 vs placebo in the modified intent-to-treat population. OFF time (amount of time the PD medication is not controlling motor symptoms) was a key secondary end point. Safety analyses included all patients who received the study drug (ADS-5102 or placebo). A total of 189 patients were screened, and 126 were randomized; the modified intent-to-treat population included 121 patients (51 women and 70 men; mean [SD] age, 64.7 [9.1] years). At week 12, the least-squares mean (SE) change in the Unified Dyskinesia Rating Scale score was -15.9 (1.6) for ADS-5102 (n = 63) and -8.0 (1.6) for placebo (n = 58) (treatment difference, -7.9; 95% CI, -12.5 to -3.3; P < .001). OFF time decreased by a mean (SE) of 0.6 (0.3) hours for ADS-5102 and increased by 0.3 (0.3) hours for placebo (treatment difference, -0.9 hours; 95% CI, -1.6 to -0.2; P = .02). Common adverse events for ADS-5102 vs placebo included visual hallucinations (15 [23.8%] vs 1 [1.7%]), peripheral edema (15 [23.8%] vs 0), and dizziness (14 [22.2%] vs 0). Adverse events led to treatment discontinuation for 13 patients receiving ADS-5102 (20.6%) vs 4 patients receiving placebo (6.9%). ADS-5102, 274 mg at bedtime, may be an effective treatment
Full Text Available Xinxin Yang, Na Wu, Lu Song, Zhenguo Liu Department of Neurology, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China Background: Levodopa remains the most effective drug for the treatment of Parkinson’s disease (PD. However, long-term levodopa treatment is associated with the emergence of levodopa-induced dyskinesia (LID, which has hampered its use for PD treatment. The mechanisms of LID are only partially understood. A previous study showed that KN-93, a Ca2+/calmodulin-dependent protein kinase II (CaMKII inhibitor, could be used to ameliorate LID in rats. However, the precise mechanisms by which KN-93 acts as an antidyskinetic are not fully understood. Methods: In the present study, a rat model of PD was induced by 6-hydroxydopamine (OHDA injections. Then, the successfully lesioned rats were intrastriatally administered with a different dose of KN-93 (1 µg, 2 µg, or 5 µg prior to levodopa treatment. Abnormal involuntary movements (AIMs scores and apomorphine-induced rotations were measured in PD rats. Phosphorylated levels of GluR1 at Serine-845 (pGluR1S845 levels were determined by western blot. Arc and Penk levels were measured by real-time polymerase chain reaction (PCR. Results: We found that both 2 µg and 5 µg KN-93 treatment lowered AIMs scores in levodopa priming PD rats without affecting the antiparkinsonian effect of levodopa. In agreement with behavioral analysis, KN-93 treatment (2 µg reduced pGluR1S845 levels in PD rats. Moreover, KN-93 treatment (2 µg reduced the expression of Gad1 and Nur77 in PD rats. Conclusion: These data indicated that intrastriatal injections of KN-93 were beneficial in reducing the expression of LID by lowering the expression of pGluR1S845 via suppressing the activation of CaMKII in PD rats. Decreased expression of pGluR1S845 further reduced the expression of Gad1 and Nur77 in PD rats. Keywords: Parkinson’s disease, levodopa
Noguchi, Takako; Ikeda, Masaaki; Ohmiya, Yoshihiro; Nakajima, Yoshihiro
In mammals, circadian rhythms of various organs and tissues are synchronized by pacemaker neurons in the suprachiasmatic nucleus (SCN) of the hypothalamus. Glucocorticoids released from the adrenal glands can synchronize circadian rhythms in other tissues. Many hormones show circadian rhythms in their plasma concentrations; however, whether organs outside the SCN can serve as master synchronizers to entrain circadian rhythms in target tissues is not well understood. To further delineate the function of the adrenal glands and the interactions of circadian rhythms in putative master synchronizing organs and their target tissues, here we report a simple co-culture system using a dual-color luciferase assay to monitor circadian rhythms separately in various explanted tissues and fibroblasts. In this system, circadian rhythms of organs and target cells were simultaneously tracked by the green-emitting beetle luciferase from Pyrearinus termitilluminans (ELuc) and the red-emitting beetle luciferase from Phrixothrix hirtus (SLR), respectively. We obtained tissues from the adrenal glands, thyroid glands, and lungs of transgenic mice that expressed ELuc under control of the promoter from a canonical clock gene, mBmal1. The tissues were co-cultured with Rat-1 fibroblasts as representative target cells expressing SLR under control of the mBmal1 promoter. Amplitudes of the circadian rhythms of Rat-1 fibroblasts were potentiated when the fibroblasts were co-cultured with adrenal gland tissue, but not when co-cultured with thyroid gland or lung tissue. The phases of Rat-1 fibroblasts were reset by application of adrenal gland tissue, whereas the phases of adrenal gland tissue were not influenced by Rat-1 fibroblasts. Furthermore, the effect of the adrenal gland tissue on the fibroblasts was blocked by application of a glucocorticoid receptor (GR) antagonist. These results demonstrate that glucocorticoids are strong circadian synchronizers for fibroblasts and that this co
Use of condensing boilers in residential heating systems offers the potential for significant improvements in efficiency. For these to operate in a condensing mode the return water temperature needs to be about 10 degrees below the saturation temperature for the flue gas water vapor. This saturation temperature depends on fuel type and excess air and ranges from about 110 F to 135 F. Conventional baseboard hydronic distribution systems are most common and these are designed for water temperatures in the 180 F range, well above the saturation temperature. Operating strategies which may allow these systems to operate in a condensing mode have been considered in the past. In this study an approach to achieving this for a significant part of the heating season has been tested in an instrumented home. The approach involves use of an outdoor reset control which reduces the temperature of the water circulating in the hydronic loop when the outdoor temperature is higher than the design point for the region. Results showed that this strategy allows the boiler to operate in the condensing region for 80% of the winter heating season with oil, 90% with propane, and 95% with gas, based on cumulative degree days. The heating system as tested combines space heating and domestic hot water loads using an indirect, 40 gallon tank with an internal heat exchanger. Tests conducted during the summer months showed that the return water temperature from the domestic hot water tank heat exchanger is always below a temperature which will provide condensing operation of the boiler. In the field tests both the condensing boiler and the conventional, non-condensing boiler were in the test home and each was operated periodically to provide a direct performance comparison.
Ehrenpreis, Eli D; Deepak, Parakkal; Sifuentes, Humberto; Devi, Radha; Du, Hongyan; Leikin, Jerrold B
We examined the effects of the black box warning about the risk of tardive dyskinesia (TD) with chronic use of metoclopramide on management of gastroparesis within a single clinical practice, and on reporting of adverse events. Medical records of gastroparesis patients were evaluated for physician management choices. The FDA Adverse Event Reporting System (FAERS) was analyzed for event reports, and for lawyer-initiated reports, with metoclopramide from 2004 to 2010. Google Scholar was searched for court opinions against metoclopramide manufacturers. Before the black box warning, 69.8% of patients received metoclopramide for gastroparesis, compared with 23.7% after the warning. Gastroenterologists prescribed domperidone more often after than before the warning. Metoclopramide prescriptions decreased after 2008. Adverse event reporting increased after the warning. Only 3.6% of all FAERS reports but 70% of TD reports were filed by lawyers, suggesting a distortion in signal. Forty-seven legal opinions were identified, 33 from 2009-2010. The black box warning for metoclopramide has decreased its usage and increased its rate of adverse event reporting. Lawyer-initiated reports of TD hinder pharmacovigilance.
Hui, Li; Han, Mei; Yin, Guang Zhong; Zhang, Yingyang; Huang, Xu Feng; Qian, Zheng Kang; Gu, Wei Guo; Gu, Xiao Chu; Zhu, Xiao Min; Soares, Jair C; Ning, Yuping; Zheng, Yingjun; Du, Xiang Dong; Zhang, Xiang Yang
Long-term antipsychotic treatment for schizophrenia is associated with the development of tardive dyskinesia (TD), which is involved in increased cognitive impairment. Dopamine beta-hydroxylase (DBH) gene associated with dopamine and norepinephrine systems influences cognition. Schizophrenia with TD have higher DBH activity than those without TD. This study examined whether DBH5'-insertion/deletion (-Ins/Del) polymorphism could influence cognitive function in schizophrenia with and without TD. The presence of DBH5'-Ins/Del polymorphism was determined in 345 schizophrenia with TD and 397 schizophrenia without TD. The Abnormal Involuntary Movement Scale and Repeatable Battery for Assessment of Neuropsychological Status (RBANS) were used to assess TD severity and cognition. The allele and genotype frequencies of DBH5'-Ins/Del polymorphism did not differ between patients with and without TD (both p>0.05). RBANS total score and subscales did not differ by DBH5'-Ins/Del genotype groups in patients with TD (all p>0.05). However, attention score significantly differed by DBH5'-Ins/Del genotype groups in those without TD (pschizophrenia with TD, but it may influence cognitive function in schizophrenia with non-TD. Moreover, schizophrenia with TD experienced greater cognitive deficits than those with non-TD, especially in immediate memory and attention. Copyright © 2016 Elsevier B.V. All rights reserved.
Pase, Camila Simonetti; Teixeira, Angélica Martelli; Dias, Verônica Tironi; Quatrin, Andréia; Emanuelli, Tatiana; Bürger, Marilise Escobar
Polyunsaturated fatty acids (FAs) are cell membrane components involved in brain functions. We hypothesized that long-term trans fat consumption is able to modify the membrane FAs composition impairing behavioral parameters related to aging. In this study, a comparison of behavioral parameters at 10 and 15 months of trans fat consumption by male Wistar rats was made. Animals were fed for 10 and 15 months from weaning with diets containing either 20% w/w soybean oil (SO), rich in n-6 PUFA, hydrogenated vegetable fat (HVF), rich in trans FAs, or a standard diet (control - C). At both evaluation times, HVF-fed rats showed progressively increased parameters of orofacial dyskinesia, fear and anxiety-like symptoms. The HVF diet reduced locomotor and exploratory activities progressively over 10 and 15 months of supplementation, while the standard and SO diets did not. In this study, we showed that chronic trans FAs consumption from weaning is able to favor the development of neuromotor and neuropsychiatric diseases, whose intensity was time dependent.
Goutaki, Myrofora; Halbeisen, Florian S; Spycher, Ben D; Maurer, Elisabeth; Belle, Fabiën; Amirav, Israel; Behan, Laura; Boon, Mieke; Carr, Siobhan; Casaulta, Carmen; Clement, Annick; Crowley, Suzanne; Dell, Sharon; Ferkol, Thomas; Haarman, Eric G; Karadag, Bulent; Knowles, Michael; Koerner-Rettberg, Cordula; Leigh, Margaret W; Loebinger, Michael R; Mazurek, Henryk; Morgan, Lucy; Nielsen, Kim G; Phillipsen, Maria; Sagel, Scott D; Santamaria, Francesca; Schwerk, Nicolaus; Yiallouros, Panayiotis; Lucas, Jane S; Kuehni, Claudia E
Chronic respiratory disease can affect growth and nutrition, which can influence lung function. We investigated height, body mass index (BMI), and lung function in patients with primary ciliary dyskinesia (PCD).In this study, based on the international PCD (iPCD) Cohort, we calculated z-scores for height and BMI using World Health Organization (WHO) and national growth references, and assessed associations with age, sex, country, diagnostic certainty, age at diagnosis, organ laterality and lung function in multilevel regression models that accounted for repeated measurements.We analysed 6402 measurements from 1609 iPCD Cohort patients. Height was reduced compared to WHO (z-score -0.12, 95% CI -0.17 to -0.06) and national references (z-score -0.27, 95% CI -0.33 to -0.21) in male and female patients in all age groups, with variation between countries. Height and BMI were higher in patients diagnosed earlier in life (p=0.026 and pnutrition are affected adversely in PCD patients from early life and are both strongly associated with lung function. If supported by longitudinal studies, these findings suggest that early diagnosis with multidisciplinary management and nutritional advice could improve growth and delay disease progression and lung function impairment in PCD. Copyright ©ERS 2017.
Full Text Available The role of Ras-ERK signaling in behavioral plasticity is well established. Inhibition studies using the blood-brain barrier permeable drug SL327 have conclusively demonstrated that this neuronal cell signaling cascade is a crucial component of the synaptic machinery implicated in the formation of various forms of long-term memory, from spatial learning to fear and operant conditioning. However, abnormal Ras-ERK signaling has also been linked to a number of neuropsychiatric conditions, including mental retardation syndromes (RASopathies, drug addiction and L-DOPA induced Dyskinesia (LID. The work recently done on these brain disorders has pointed to previously underappreciated roles of Ras-ERK in specific subsets of neurons, like GABAergic interneurons of the hippocampus or the cortex, as well as in the medium spiny neurons of the striatum. Here we will highlight the open questions related to Ras-ERK signaling in these behavioral manifestations and propose crucial experiments for the future.
Kim, Young-Cho; Alberico, Stephanie L; Emmons, Eric; Narayanan, Nandakumar S
The neurotransmitter dopamine acts via two major classes of receptors, D1-type and D2-type. D1 receptors are highly expressed in the striatum and can also be found in the cerebral cortex. Here we review the role of D1 dopamine signaling in two major domains: L-DOPA-induced dyskinesias in Parkinson's disease and cognition in neuropsychiatric disorders. While there are many drugs targeting D2-type receptors, there are no drugs that specifically target D1 receptors. It has been difficult to use selective D1-receptor agonists for clinical applications due to issues with bioavailability, binding affinity, pharmacological kinetics, and side effects. We propose potential therapies that selectively modulate D1 dopamine signaling by targeting second messengers downstream of D1 receptors, allosteric modulators, or by making targeted modifications to D1-receptor machinery. The development of therapies specific to D1-receptor signaling could be a new frontier in the treatment of neurological and psychiatric disorders.
Full Text Available The Ukrainian crisis provoked a serious and dangerous deterioration of relations between Russia and the West. However the relations between Russia and the West should not be reduced to the current Ukrainian crisis. The rational interpretation requires getting rid of Cold war prejudices and facing the systemic disfunctionality of the current international system routed in the failure to adjust it to post Cold war realities. To “reboot” this dangerous system “freeze” it’s important to reformulate the international agenda and political frameworks to encourage transformative leadership. The new architecture should provide an integrated agenda for progress on security, energy, and economic cooperation as well as coordinated efforts to address frozen conflicts. And most urgently, joint and concerted efforts are needed to take Ukraine out of a condition of social and state breakdown, and turn it into a hub of cooperation rather than a prize drawn from East-West competition.
Krishnan, Giri P.; Bazhenov, Maxim; Pikovsky, Arkady
In this paper, we introduce and study systematically, in terms of phase response curves, the effect of dual-pulse excitation on the dynamics of an autonomous oscillator. Specifically, we test the deviations from linear summation of phase advances resulting from two small perturbations. We analytically derive a correction term, which generally appears for oscillators whose intrinsic dimensionality is >1. The nonlinear correction term is found to be proportional to the square of the perturbatio...
Patty C Kandalepas
Full Text Available Melatonin is released from the pineal gland into the circulatory system at night in the absence of light, acting as "hormone of darkness" to the brain and body. Melatonin also can regulate circadian phasing of the suprachiasmatic nucleus (SCN. During the day-to-night transition, melatonin exposure advances intrinsic SCN neural activity rhythms via the melatonin type-2 (MT2 receptor and downstream activation of protein kinase C (PKC. The effects of melatonin on SCN phasing have not been linked to daily changes in the expression of core genes that constitute the molecular framework of the circadian clock. Using real-time RT-PCR, we found that melatonin induces an increase in the expression of two clock genes, Period 1 (Per1 and Period 2 (Per2. This effect occurs at CT 10, when melatonin advances SCN phase, but not at CT 6, when it does not. Using anti-sense oligodeoxynucleotides (α ODNs to Per 1 and Per 2, as well as to E-box enhancer sequences in the promoters of these genes, we show that their specific induction is necessary for the phase-altering effects of melatonin on SCN neural activity rhythms in the rat. These effects of melatonin on Per1 and Per2 were mediated by PKC. This is unlike day-active non-photic signals that reset the SCN clock by non-PCK signal transduction mechanisms and by decreasing Per1 expression. Rather, this finding extends roles for Per1 and Per2, which are critical to photic phase-resetting, to a nonphotic zeitgeber, melatonin, and suggest that the regulation of these clock gene transcripts is required for clock resetting by diverse regulatory cues.
Jha, Pawan Kumar; Bouâouda, Hanan; Gourmelen, Sylviane; Dumont, Stephanie; Fuchs, Fanny; Goumon, Yannick; Bourgin, Patrice; Kalsbeek, Andries; Challet, Etienne
Circadian rhythms in nocturnal and diurnal mammals are primarily synchronized to local time by the light/dark cycle. However, nonphotic factors, such as behavioral arousal and metabolic cues, can also phase shift the master clock in the suprachiasmatic nuclei (SCNs) and/or reduce the synchronizing effects of light in nocturnal rodents. In diurnal rodents, the role of arousal or insufficient sleep in these functions is still poorly understood. In the present study, diurnal Sudanian grass rats, Arvicanthis ansorgei, were aroused at night by sleep deprivation (gentle handling) or caffeine treatment that both prevented sleep. Phase shifts of locomotor activity were analyzed in grass rats transferred from a light/dark cycle to constant darkness and aroused in early night or late night. Early night, but not late night, sleep deprivation induced a significant phase shift. Caffeine on its own induced no phase shifts. Both sleep deprivation and caffeine treatment potentiated light-induced phase delays and phase advances in response to a 30 min light pulse, respectively. Sleep deprivation in early night, but not late night, potentiated light-induced c-Fos expression in the ventral SCN. Caffeine treatment in midnight triggered c-Fos expression in dorsal SCN. Both sleep deprivation and caffeine treatment potentiated light-induced c-Fos expression in calbindin-containing cells of the ventral SCN in early and late night. These findings indicate that, in contrast to nocturnal rodents, behavioral arousal induced either by sleep deprivation or caffeine during the sleeping period potentiates light resetting of the master circadian clock in diurnal rodents, and activation of calbindin-containing suprachiasmatic cells may be involved in this effect.SIGNIFICANCE STATEMENT Arousing stimuli have the ability to regulate circadian rhythms in mammals. Behavioral arousal in the sleeping period phase shifts the master clock in the suprachiasmatic nuclei and/or slows down the photic
Lockley, Steven W; Dressman, Marlene A; Licamele, Louis; Xiao, Changfu; Fisher, Dennis M; Flynn-Evans, Erin E; Hull, Joseph T; Torres, Rosarelis; Lavedan, Christian; Polymeropoulos, Mihael H
Most totally blind people have non-24-hour sleep-wake disorder (non-24), a rare circadian rhythm disorder caused by an inability of light to reset their circadian pacemaker. In two consecutive placebo-controlled trials (SET and RESET), we assessed safety and efficacy (in terms of circadian entrainment and maintenance) of once-daily tasimelteon, a novel dual-melatonin receptor agonist. We undertook the placebo-controlled, randomised, double-masked trials in 27 US and six German clinical research centres and sleep centres. We screened totally blind adults (18-75 years of age), who were eligible for the randomisation phase of SET if they had a non-24-hour circadian period (τ) of 24·25 h or longer (95% CI greater than 24·0 and up to 24·9 h), as calculated from measurements of urinary 6-sulphatoxymelatonin rhythms. For SET, we used block randomisation to assign patients (1:1) to receive tasimelteon (20 mg) or placebo every 24 h at a fixed clock time 1 h before target bedtime for 26 weeks. Patients who entered the open-label group receiving tasimelteon in SET or who did not meet the SET inclusion criteria but did meet the RESET inclusion criteria were screened for RESET. A subset of the patients who entered the open-label group before the RESET study and who had eligible τ values were screened for RESET after completing the open-label treatment. In RESET, we withdrew tasimelteon in a randomised manner (1:1) in patients who responded (ie, entrained) after a tasimelteon run-in period. Entrainment was defined as having τ of 24·1 h or less and a 95% CI that included 24·0 h. In SET, the primary endpoint was the proportion of entrained patients, assessed in the intention-to-treat population. The planned step-down primary endpoint assessed the proportion of patients who had a clinical response (entrainment at month 1 or month 7 plus clinical improvement, measured by the Non-24 Clinical Response Scale). In RESET, the primary endpoint was the proportion of non
Moore, Daniel J; Onoufriadis, Alexandros; Shoemark, Amelia
Primary ciliary dyskinesia (PCD) is a ciliopathy characterized by airway disease, infertility, and laterality defects, often caused by dual loss of the inner dynein arms (IDAs) and outer dynein arms (ODAs), which power cilia and flagella beating. Using whole-exome and candidate-gene Sanger...... neurons and sperm. In these cells, P-element-mediated gene silencing caused IDA and ODA defects, proprioception deficits, and sterility due to immotile sperm. Drosophila Zmynd10 with an equivalent c.47T>G (p.Val16Gly) missense change rescued mutant male sterility less than the wild-type did. Tagged...
Casey, Jillian P
Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterised by abnormal ciliary motion and impaired mucociliary clearance, leading to recurrent respiratory infections, sinusitis, otitis media and male infertility. Some patients also have laterality defects. We recently reported the identification of three disease-causing PCD genes in the Irish Traveller population; RSPH4A, DYX1C1 and CCNO. We have since assessed an additional Irish Traveller family with a complex phenotype involving PCD who did not have any of the previously identified PCD mutations.
Full Text Available BACKGROUND: Benign infantile convulsions and paroxysmal dyskinesia are episodic cerebral disorders that can share common genetic bases. They can be co-inherited as one single autosomal dominant trait (ICCA syndrome; the disease ICCA gene maps at chromosome 16p12-q12. Despite intensive and conventional mutation screening, the ICCA gene remains unknown to date. The critical area displays highly complicated genomic architecture and is the site of deletions and duplications associated with various diseases. The possibility that the ICCA syndrome is related to the existence of large-scale genomic alterations was addressed in the present study. METHODOLOGY/PRINCIPAL FINDINGS: A combination of whole genome and dedicated oligonucleotide array comparative genomic hybridization coupled with quantitative polymerase chain reaction was used. Low copy number of a region corresponding to a genomic variant (Variation_7105 located at 16p11 nearby the centromere was detected with statistical significance at much higher frequency in patients from ICCA families than in ethnically matched controls. The genomic variant showed no apparent difference in size and copy number between patients and controls, making it very unlikely that the genomic alteration detected here is ICCA-specific. Furthermore, no other genomic alteration that would directly cause the ICCA syndrome in those nine families was detected in the ICCA critical area. CONCLUSIONS/SIGNIFICANCE: Our data excluded that inherited genomic deletion or duplication events directly cause the ICCA syndrome; rather, they help narrowing down the critical ICCA region dramatically and indicate that the disease ICCA genetic defect lies very close to or within Variation_7105 and hence should now be searched in the corresponding genomic area and its surrounding regions.
Full Text Available Background: Forward head posture (FHP, the most common deviation from the normal curvature in cervical spine. Craniocervical flexor muscle strengthening is frequently used treatment for FHP. Scapular dykinesia (SD is the alteration in the normal static or dynamic motion of the scapula during coupled scapulohumeral movements. Shoulder stabilization exercises are an effective treatment for SD. As both FHP and SD are related to each other, the objective of the study was to find and compare the effect of FHP correction and shoulder stabilization exercises on SD and shoulder proprioception. Methods: 40 athletes (18-30yrs were recruited. Subjects were randomly allocated into two groups. Group A received deep neck flexor strengthening and anterior scalene stretch, group B received shoulder stabilizing exercises. Paired t test and chi-square test were used to judge the statistical significant difference. The level of significance was set at p <0.05. All data was analyzed using SPSS program version 12. Result: No statistical significant difference was found between the groups for the 4 outcome variables, but significant improvement was seen within the groups. Shoulder proprioception was found to be significant between the groups where group B (p =<0.001 showed better improvement than group A (p = <0.017. Conclusion: Both FHP correction as well as shoulder stabilization exercises were equally effective in correction of scapular dyskinesia and shoulder proprioception. Shoulder stabilization exercises showed slightly better improvement than FHP correction group in reducing proprioception errors. Also neck strength values were found to be clinically significant for deep neck strengthening group.
Quartarone, Angelo; Classen, Joseph; Morgante, Francesca; Rosenkranz, Karin; Hallett, Mark
Plasticity includes the ability of the nervous system to optimize neuronal activity at a cellular and system level according to the needs imposed by the environment. Neuroplasticity phenomena within sensorimotor cortex are crucial to enhance function to increase skillfulness. Such plasticity may be termed "adaptive" to indicate its ecologically beneficial role. In professional musicians, enhanced adaptive plasticity is associated with one of the highest level of motor skill a human being can achieve and the amount of these changes is even dependent on the age at which instrumental playing was started. In addition, adaptive neuroplastic changes occur when nervous system try to repair itself thus compensating dysfunctions. However, when these adaptive phenomena are pushed to an extreme, they can produce a maladaptive sensorimotor reorganization that interferes with motor performance rather than improving it. The model we discuss here is focal hand dystonia I which an intrinsic abnormality of neural plasticity, in some predisposed individuals, may lead to abnormal sensorimotor integration and to the appearance of a characteristic movement disorder. Deficient homeostatic control might be an important mechanism triggering this maladaptive reorganization, and future behavioral studies are needed to confirm this hypothesis. In the second part of this consensus paper, we will critically discuss as a second model, the hypothesis that levodopa-induced dyskinesia correlate with an aberrant form of plasticity in the human primary motor cortex, possibly because of abnormal oscillations within the basal ganglia loop. Disorders of cortical plasticity have not in the past been considered as possible causes of human clinical states. The recognition that this can occur, together with a speculative mechanism, generates an important and provocative hypothesis for future research at the clinical-scientific interface.
Gu, Chengzhi; Li, Jia; Zhu, Lianhai; Lu, Zhenhui; Huang, Huaiyu
We aimed to analyze the mutation site and frequency of catechol-O-methyltransferase (COMT) gene, to explore the relationship between COMT genotype and phenotype, and to find new pathogenic genes for paroxysmal kinesigenic dyskinesia (PKD). PKD patients who were treated from December 2011 to January 2014 were selected and subjected to genetic testing in the exon region of COMT. Two patients and one intrafamilial healthy control were subjected to exome sequencing using whole exome capture in combination with high-throughput sequencing to find candidate pathogenic gene sites. The results were verified by Sanger sequencing. A total of 11 familial PKD patients from 4 families and 9 sporadic patients without family history were included. Pathogenic c.634dupC(p.P220fsX7) mutation of COMT gene was found in 7 familial PKD patients and3 sporadic patients. Mutated COMT gene carriers suffered from PKD earlier (average age of onset: 11.61 ± 2.33 vs 16.21 ± 2.58, P = 0.001) with symmetric symptoms in most cases, while the mutation-negative group only showed unilateral symptoms (P = 0.001). The mutation-positive group also had more daily attacks (P = 0.038). Carbamazepine worked for all mutation-positive patients (10/10, 100%), but only for a part of mutation-negative patients (3/10, 30.0%). About 90000 single nucleotide polymorphisms and 2000 insertion-deletion polymorphisms were detected in each of the three samples. c.737C → T(p.T246 M) mutation of POC1B gene was a new pathogenic site for a selected family. COMT gene mutation, which was the pathogenesis of most familial PKD patients and a part of sporadic patients, predicted the response to carbamazepine. POC1B may be a novel pathogenic gene for PKD.
Yang, P., E-mail: email@example.com [Central China Normal University, Wuhan (China); Aglieri, G.; Cavicchioli, C. [CERN, 1210 Geneva 23 (Switzerland); Chalmet, P.L. [MIND, Archamps (France); Chanlek, N. [Suranaree University of Technology, Nakhon Ratchasima (Thailand); Collu, A. [University of Cagliari, Cagliari (Italy); INFN (Italy); Gao, C. [Central China Normal University, Wuhan (China); Hillemanns, H.; Junique, A. [CERN, 1210 Geneva 23 (Switzerland); Kofarago, M. [CERN, 1210 Geneva 23 (Switzerland); University of Utrecht, Utrecht (Netherlands); Keil, M.; Kugathasan, T. [CERN, 1210 Geneva 23 (Switzerland); Kim, D. [Dongguk and Yonsei University, Seoul (Korea, Republic of); Kim, J. [Pusan National University, Busan (Korea, Republic of); Lattuca, A. [University of Torino, Torino (Italy); INFN (Italy); Marin Tobon, C.A. [CERN, 1210 Geneva 23 (Switzerland); Marras, D. [University of Cagliari, Cagliari (Italy); INFN (Italy); Mager, M.; Martinengo, P. [CERN, 1210 Geneva 23 (Switzerland); Mazza, G. [University of Torino, Torino (Italy); INFN (Italy); and others
Active Pixel Sensors used in High Energy Particle Physics require low power consumption to reduce the detector material budget, low integration time to reduce the possibilities of pile-up and fast readout to improve the detector data capability. To satisfy these requirements, a novel Address-Encoder and Reset-Decoder (AERD) asynchronous circuit for a fast readout of a pixel matrix has been developed. The AERD data-driven readout architecture operates the address encoding and reset decoding based on an arbitration tree, and allows us to readout only the hit pixels. Compared to the traditional readout structure of the rolling shutter scheme in Monolithic Active Pixel Sensors (MAPS), AERD can achieve a low readout time and a low power consumption especially for low hit occupancies. The readout is controlled at the chip periphery with a signal synchronous with the clock, allows a good digital and analogue signal separation in the matrix and a reduction of the power consumption. The AERD circuit has been implemented in the TowerJazz 180 nm CMOS Imaging Sensor (CIS) process with full complementary CMOS logic in the pixel. It works at 10 MHz with a matrix height of 15 mm. The energy consumed to read out one pixel is around 72 pJ. A scheme to boost the readout speed to 40 MHz is also discussed. The sensor chip equipped with AERD has been produced and characterised. Test results including electrical beam measurement are presented.
Barbara J. O'Riley
Full Text Available One-Day cricket's eternal problem is how to fairly account for an interruption that occurs during a team's innings. Several methods have been applied in the past, some more successfully than others. Numerous articles have been written about different target resetting methods applicable in one-day international cricket and how they "favour" one team over another. In this paper we use an alternative approach looking at the psychic ability of four target resetting methods and compare how well they predict the final score based on the present state of the first innings. We attempt to convert each of methods we investigate into a ball-by-ball predictive tool. We introduce a terminal interruption to the first innings at every ball and compute the predicted final score. We ascribe a nominal value to the difference between the final achieved score and the prediction given by each method. We compute our own 'Psychic Metric' to enable a comparison between the four methods. We also develop a computer package to manipulate the data from matches in which the first innings was completed
Soderstrom, Katherine E.; O’Malley, Jennifer A.; Levine, Nathan D.; Sortwell, Caryl E.; Collier, Timothy J.; Steece-Collier, Kathy
Dopamine deficiency associated with Parkinson’s disease (PD) results in numerous changes in striatal transmitter function and neuron morphology. Specifically, there is marked atrophy of dendrites and dendritic spines on striatal medium spiny neurons (MSN), primary targets of inputs from nigral dopamine and cortical glutamate neurons, in advanced PD and rodent models of severe dopamine depletion. Dendritic spine loss occurs via dysregulation of intraspine Cav1.3 L-type Ca2+ channels and can be prevented, in animal models, by administration of the calcium channel antagonist, nimodipine. The impact of MSN dendritic spine loss in the parkinsonian striatum on dopamine neuron graft therapy remains unexamined. Using unilaterally parkinsonian Sprague Dawley rats, we tested the hypothesis that MSN dendritic spine preservation through administration of nimodipine would result in improved therapeutic benefit and diminished graft-induced behavioral abnormalities in rats grafted with embryonic ventral midbrain cells. Analysis of rotational asymmetry and spontaneous forelimb use in the cylinder task found no significant effect of dendritic spine preservation in grafted rats. However, analyses of vibrissae-induced forelimb use, levodopa-induced dyskinesias, and graft-induced dyskinesias showed significant improvement in rats with dopamine grafts associated with preserved striatal dendritic spine density. Nimodipine treatment in this model did not impact dopamine graft survival but allowed for increased graft reinnervation of striatum. Taken together, these results demonstrate that even with grafting suboptimal numbers of cells, maintaining normal spine density on target MSNs results in overall superior behavioral efficacy of dopamine grafts. PMID:20105237
Wu, Zhe; Zhang, Gang; Park, Youngwook; Kang, Stephen D.; Lyeo, Ho-Ki; Seok Jeong, Doo; Jeong, Jeung-hyun; No, Kwangsoo; Cheong, Byung-ki
An investigation was conducted to examine the high RESET-current (IRESET) problem of phase-change memory (PCM) using a fast growth-dominated Ge-doped SbTe (GeST). By examining material and device characteristics of GeST with varying Sb-to-Te ratio from 1.80 to 3.82, the growth rate of crystallization was found to play an important role in determining IRESET and SET speed of the device. Lower IRESET obtained with decreasing Sb-to-Te ratio was ascribed to lower growth rate leading to smaller degree of recrystallization during melt-quenching. With shrinkage of device dimensions, GeST-PCM of a lower Sb-to-Te ratio may become increasingly promising due to its lower IRESET and scaled SET speed.
Guenthner, W.; Reiners, P. W.; DeCelles, P. G.; Kendall, J. J.
Low-temperature thermochronology has become an established tool for deciphering the time-temperature (t-T) histories of sedimentary units involved in basin burial and thrust-belt exhumation. However, thermochronologic datasets from detrital samples can be complex and difficult to interpret if these samples contain grains with different pre-depositional t-T histories that are only partially reset. Here, we present an approach for interpreting complex detrital zircon (U-TH)/He datasets to constrain the maximum foreland basin burial temperatures and timing of thrust-belt related exhumation in the Sevier belt of central Utah. Using forward modeling of t-T paths, we combine the radiation-damage based kinetic model for He diffusion in zircon with a series of pre-depositional He ages to construct "inheritance envelopes" that encompass a wide range of age variation. A forward model is successful if an inheritance envelope captures or bounds the observed age variation in a given dataset. We highlight this approach with two datasets collected from sedimentary units in the Oquirrh Mountains and Wasatch Range near Provo, UT. For the Oquirrh Mtns. dataset, large observed age variation is modeled using a maximum burial temperature of ~173 °C, and an initial Sevier-belt related exhumation event at 110 Ma. The Wasatch Range samples are more straight-forward, with a lack of partially reset ages but some observed variation caused by radiation damage effects. For these samples, our model results constrain a maximum burial temperature of ~230 °C, with a subsequent exhumation event at 100 Ma. Combined, these results suggest a steady eastward migration of exhumation in the Sevier belt during the Late Cretaceous and demonstrate that our inheritance envelope approach is most sensitive to maximum burial temperatures and the timing of initial exhumation.
Urbizu, Aintzane; Cuenca-León, Ester; Raspall-Chaure, Miquel; Gratacòs, Margarida; Conill, Joan; Redecillas, Susana; Roig-Quilis, Manuel; Macaya, Alfons
We report two monochorionic twins that progressively developed, between ages 5 and 10, a combination of episodic neurological disorders including paroxysmal exercise-induced dyskinesia, migraine without or with aura, absence seizures and writer's cramp. CSF/serum glucose ratio was moderately decreased in both patients. Mutational analysis of SLC2A1 gene identified a de novo heterozygous missense mutation in exon 4. This novel mutation has been previously showed to disrupt glucose transport in vitro. Both patients showed immediate and near-complete response to ketogenic diet. This clinical observation suggests that a high index of suspicion for GLUT1 deficiency syndrome is warranted in evaluating patients with multiple neurological paroxysmal events. Copyright (c) 2010 Elsevier B.V. All rights reserved.
Hopkins, M.D.; Mojzsis, S.J.; Bottke, W.F.; Abramov, Oleg
Meteoritic zircons are rare, but some are documented to occur in asteroidal meteorites, including those of the howardite–eucrite–diogenite (HED) achondrite clan (Rubin, A. . Meteorit. Planet. Sci. 32, 231–247). The HEDs are widely considered to originate from the Asteroid 4 Vesta. Vesta and the other large main belt asteroids record an early bombardment history. To explore this record, we describe sub-micrometer distributions of trace elements (U, Th) and 235,238U–207,206Pb ages from four zircons (>7–40 μm ∅) separated from bulk samples of the brecciated eucrite Millbillillie. Ultra-high resolution (∼100 nm) ion microprobe depth profiles reveal different zircon age domains correlative to mineral chemistry and to possible impact scenarios. Our new U–Pb zircon geochronology shows that Vesta’s crust solidified within a few million years of Solar System formation (4561 ± 13 Ma), in good agreement with previous work (e.g. Carlson, R.W., Lugmair, G.W. . Timescales of planetesimal formation and differentiation based on extinct and extant radioisotopes. In: Canup, R., Righter, K. (Eds.), Origin of the Earth and Moon. University of Arizona Press, Tucson, pp. 25–44). Younger zircon age domains (ca. 4530 Ma) also record crustal processes, but these are interpreted to be exogenous because they are well after the effective extinction of 26Al (t1/2 = 0.72 Myr). An origin via impact-resetting was evaluated with a suite of analytical impact models. Output shows that if a single impactor was responsible for the ca. 4530 Ma zircon ages, it had to have been ⩾10 km in diameter and at high enough velocity (>5 km s−1) to account for the thermal field required to re-set U–Pb ages. Such an impact would have penetrated at least 10 km into Vesta’s crust. Later events at ca. 4200 Ma are documented in HED apatite 235,238U–207,206Pb ages (Zhou, Q. et al. . Early basaltic volcanism and Late Heavy Bombardment on Vesta: U–Pb ages of small
Full Text Available Primary ciliary dyskinesia (PCD is a genetic disease associated with abnormalities in ciliary structure and function. Although recurrent respiratory infection associated with ciliary dysfunction is a common clinical feature, there is no standardized treatment or management of respiratory infection in PCD patients. Here, we report that respiratory infection with PCD and intralobar sequestration (ILS were treated successfully with clarithromycin before the surgical resection of ILS. A 15-year-old non-smoking Japanese woman was admitted for productive cough and dyspnea on exertion. Chest CT scan on admission showed complex cystic LESIONS with air-fluid level in the right lower lobe, and diffuse nodular shadows in the whole lobe of the lung. On flexible bronchoscopy examination, sputum and bronchiolar fluid cultures revealed Staphylococcus aureus (S. aureus. An electron microscopic examination of the cilia showed inner dynein arm deficiency. Administration of clarithromycin improved the lower respiratory tract infection associated with S. aureus. CT angiography after clarithromycin treatment demonstrated an aberrant systemic artery arising from the celiac trunk and supplying the cystic mass lesions that were incorporated into the normal pulmonary parenchyma without their own pleural covering. Based on these results, the patient was diagnosed with PCD and ILS. Because of the clarithromycin treatment, resection of the ILS was performed safely without any complications. Although further observation of clarithromycin treatment is needed, we believe that clarithromycin may be considered one of the agents for treating PCD.
Full Text Available Levodopa-induced dyskinesias (LIDs are major complications in the pharmacological management of Parkinson’s disease (PD. Abnormal glutamatergic transmission in the striatum is considered a key factor in the development of LIDs. This work aims at i. characterizing NMDA receptor GluN2A/GluN2B subunit ratio as a common synaptic trait in rat and primate models of LIDs and in dyskinetic PD patients, and ii. validating the potential therapeutic effect of a cell-permeable peptide interfering with GluN2A synaptic localization on the dyskinetic behavior of these experimental models of LIDs. Here we demonstrate an altered ratio of synaptic GluN2A/GluN2B-containing NMDA receptors in the striatum of levodopa-treated dyskinetic rats and monkeys as well as in post-mortem tissue from dyskinetic PD patients. The modulation of synaptic NMDA receptor composition by a cell-permeable peptide interfering with GluN2A subunit interaction with the scaffolding protein PSD-95 leads to a reduction in the dyskinetic motor behavior in the two animal models of LIDs. Our results indicate that targeting synaptic NMDA receptor subunit composition may represent an intriguing therapeutic approach aimed at ameliorating levodopa motor side effects.
Full Text Available Kartagener's syndrome (KS is an autosomal recessive genetic disease accounting for approximately 50% of the cases of primary ciliary dyskinesia (PCD. As it is accompanied by many complications, PCD/KS severely affects the patient's quality of life. Therapeutic approaches for PCD/KS aim to enhance prevention, facilitate rapid definitive diagnosis, avoid misdiagnosis, maintain active treatment, control infection and postpone the development of lesions. In male patients, sperm flagella may show impairment in or complete absence of the ability to swing, which ultimately results in male infertility. Assisted reproductive technology will certainly benefit such patients. For PCD/KS patients with completely immotile sperm, intracytoplasmic sperm injection may be very important and even indispensable. Considering the number of PCD/KS susceptibility genes and mutations that are being identified, more extensive genetic screening is indispensable in patients with these diseases. Moreover, further studies into the potential molecular mechanisms of these diseases are required. In this review, we summarize the available information on various aspects of this disease in order to delineate the therapeutic objectives more clearly, and clarify the efficacy of assisted reproductive technology as a means of treatment for patients with PCD/KS-associated infertility.
Jain, K. [Department of Radiology, Royal Brompton and Harefield NHS Trust, London (United Kingdom); Padley, S.P.G. [Department of Radiology, Royal Brompton and Harefield NHS Trust, London (United Kingdom)], E-mail: firstname.lastname@example.org; Goldstraw, E.J.; Kidd, S.J. [Department of Radiology, Royal Brompton and Harefield NHS Trust, London (United Kingdom); Hogg, C.; Biggart, E.; Bush, A. [Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Trust, London (United Kingdom)
Aim: To investigate the clinical range and severity of radiological findings in a cohort of patients with primary ciliary dyskinesia (PCD) receiving tertiary care. Materials and methods: The case notes and clinical test results of 89 children attending the paediatric respiratory disease clinic at our institution were retrospectively analysed. Demographic details including age at diagnosis and common presenting signs and symptoms were studied. Results of chest radiographs, microscopy, and high-resolution computed tomography (HRCT) for quantification of lung damage were analysed. Results: In a cohort of 89 children with PCD, a presentation chest radiograph was available in 62% of patients (n = 55), with all but one demonstrating changes of bronchial wall thickening. HRCT of the lungs, available in 26 patients, were scored using the system described by Brody et al. analysing five specific features of lung disease, including bronchiectasis, mucus plugging, peribronchial thickening, parenchymal changes of consolidation, and ground-glass density, and focal air-trapping in each lobe. Peribronchial thickening was observed using HRCT in 25 patients, while 20 patients had bronchiectasis. Severity scores were highest for the middle and the lingular lobes. Conclusion: The radiographic findings of the largest reported cohort of patients with PCD are presented, with associated clinical findings. Dextrocardia remains the commonest finding on chest radiography. HRCT demonstrates peribronchial thickening and bronchiectasis, which is most marked in the lower zones. Radiological scoring techniques developed for assessment of cystic fibrosis can also be applied for the assessment of disease severity in this patient population.
Full Text Available Attention capture by potentially relevant environmental stimuli is critical for human survival, yet it varies considerably among individuals. A large series of studies has suggested that attention capture may depend on the cognitive balance between maintenance and manipulation of mental representations and the flexible switch between goal-directed representations and potentially relevant stimuli outside the focus of attention; a balance that seems modulated by a prefrontostriatal dopamine pathway. Here, we examined inter-individual differences in the cognitive control of attention through studying the effects of two single nucleotide polymorphisms regulating dopamine at the prefrontal cortex and the striatum (i.e., COMTMet108/158Val and ANKK1/DRD2TaqIA on stimulus-driven attention capture. Healthy adult participants (N = 40 were assigned to different groups according to the combination of the polymorphisms COMTMet108/158Val and ANKK1/DRD2TaqIA, and were instructed to perform on a well-established distraction protocol. Performance in individuals with a balance between prefrontal dopamine display and striatal receptor density was slowed down by the occurrence of unexpected distracting events, while those with a rather unbalanced dopamine activity were able maintain task performance with no time delay, yet at the expense of a slightly lower accuracy. This advantage, associated to their distinct genetic profiles, was paralleled by an electrophysiological mechanism of phase-resetting of gamma neural oscillation to the novel, distracting events. Taken together, the current results suggest that the epistatic interaction between COMTVal108/158Met and ANKK1/DRD2 TaqIa genetic polymorphisms lies at the basis of stimulus-driven attention capture.
Kim, Yoon Sik; Kim, Young-Beom; Kim, Woong Bin; Lee, Seung Won; Oh, Seog Bae; Han, Hee-Chul; Lee, C Justin; Colwell, Christopher S; Kim, Yang In
Recent evidence indicates that histamine, acting on histamine 1 receptor (H1R), resets the circadian clock in the mouse suprachiasmatic nucleus (SCN) by increasing intracellular Ca(2+) concentration ([Ca(2+)]i) through the activation of CaV1.3 L-type Ca(2+) channels and Ca(2+)-induced Ca(2+) release from ryanodine receptor-mediated internal stores. In the current study, we explored the underlying mechanisms with various techniques including Ca(2+)- and Cl(-)-imaging and extracellular single-unit recording. Our hypothesis was that histamine causes Cl(-) efflux through cystic fibrosis transmembrane conductance regulator (CFTR) to elicit membrane depolarization needed for the activation of CaV1.3 Ca(2+) channels in SCN neurons. We found that histamine elicited Cl(-) efflux and increased [Ca(2+)]i in dissociated mouse SCN cells. Both of these events were suppressed by bumetanide [Na(+)-K(+)-2Cl(-) cotransporter isotype 1 (NKCC1) blocker], CFTRinh-172 (CFTR inhibitor), gallein (Gβγ protein inhibitor) and H89 [protein kinase A (PKA) inhibitor]. By itself, H1R activation with 2-pyridylethylamine increased the level of cAMP in the SCN and this regulation was prevented by gallein. Finally, histamine-evoked phase shifts of the circadian neural activity rhythm in the mouse SCN slice were blocked by bumetanide, CFTRinh-172, gallein or H89 and were not observed in NKCC1 or CFTR KO mice. Taken together, these results indicate that histamine recruits the H1R-Gβγ-cAMP/PKA pathway in the SCN neurons to activate CaV1.3 channels through CFTR-mediated Cl(-) efflux and ultimately to phase-shift the circadian clock. This pathway and NKCC1 may well be potential targets for agents designed to treat problems resulting from the disturbance of the circadian system.
Full Text Available The link between the anti-Parkinsonian drug L-3,4-dihydroxyphenylalanine (L-DOPA and the serotonergic (5-HT system has been long established and has received increased attention during the last decade. Most studies have focused on the fact that L-DOPA can be transformed into dopamine (DA and released from 5-HT terminals, which is especially important for the management of L-DOPA-induced dyskinesia. In patients, treatment using L-DOPA also impacts 5-HT neurotransmission; however, few studies have investigated the mechanisms of this effect. The purpose of this review is to summarize the electrophysiological and neurochemical data concerning the effects of L-DOPA on 5-HT cell function. This review will argue that L-DOPA disrupts the link between the electrical activity of 5-HT neurons and 5-HT release as well as that between 5-HT release and extracellular 5-HT levels. These effects are caused by the actions of L-DOPA and DA in 5-HT neurons, which affect 5-HT neurotransmission from the biosynthesis of 5-HT to the impairment of the 5-HT transporter. The interaction between L-DOPA and 5-HT transmission is especially relevant in those Parkinson’s disease (PD patients that suffer dyskinesia, comorbid anxiety or depression, since the efficacy of antidepressants or 5-HT compounds may be affected.
Full Text Available In 2009 the U.S. Food and Drug Administration (FDA placed a black box warning on metoclopramide (MCP due to the increased risks and prevalence of tardive dyskinesia (TD. In this study, we developed a multi-step biomedical informatics screening (MSBIS approach leveraging publicly available bioactivity and drug safety data to identify concomitant drugs that mitigate the risks of MCP-induced TD. MSBIS includes (1 TargetSearch (http://dxulab.org/software bioinformatics scoring for drug anticholinergic activity using CHEMBL bioactivity data; (2 unadjusted odds ratio (UOR scoring for indications of TD-mitigating effects using the FDA Adverse Event Reporting System (FAERS; (3 adjusted odds ratio (AOR re-scoring by removing the effect of cofounding factors (age, gender, reporting year; (4 logistic regression (LR coefficient scoring for confirming the best TD-mitigating drug candidates. Drugs with increasing TD protective potential and statistical significance were obtained at each screening step. Fentanyl is identified as the most promising drug against MCP-induced TD (coefficient: −2.68; p-value < 0.01. The discovery is supported by clinical reports that patients fully recovered from MCP-induced TD after fentanyl-induced general anesthesia. Loperamide is identified as a potent mitigating drug against a broader range of drug-induced movement disorders through pharmacokinetic modifications. Using drug-induced TD as an example, we demonstrated that MSBIS is an efficient in silico tool for unknown drug-drug interaction detection, drug repurposing, and combination therapy design.
Full Text Available Background: Levodopa therapy alleviates the symptoms of Parkinson's disease (PD, but long-term treatment often leads to motor complications such as levodopa-induced dyskinesia (LID. Aim: To explore the neuronal activity in the basal ganglia nuclei in patients with PD and LID. Methods: Thirty patients with idiopathic PD (age, 55.1±11.0 years; disease duration, 8.7±5.6 years were enrolled between August 2006 and August 2013 at the Xuanwu Hospital, Capital Medical University, China. Their Hoehn and Yahr scores ranged from 2 to 4 and their UPDRS III scores were 28.5±5.2. Fifteen of them had severe LID (UPDRS IV scores of 6.7±1.6. Microelectrode recording was performed in the globus pallidus internus (GPi and subthalamic nucleus (STN during pallidotomy (n=12 or STN deep brain stimulation (DBS; bilateral, n=12; unilateral, n=6. The firing patterns and frequencies of various cell types were analyzed by assessing single cell interspike intervals (ISIs and the corresponding coefficient of variation (CV. Results: A total of 295 neurons were identified from the GPi (n=12 and STN (n=18. These included 26 (8.8% highly grouped discharge, 30 (10.2% low frequency firing, 78 (26.4% rapid tonic discharge, 103 (34.9% irregular activity, and 58 (19.7% tremor-related activity. There were significant differences between the two groups (P<0.05 for neurons with irregular firing, highly irregular cluster-like firing, and low-frequency firing. Conclusion: Altered neuronal activity was observed in the basal ganglia nucleus of GPi and STN, and may play important roles in the pathophysiology of PD and LID.
Full Text Available Abstract Background Primary ciliary dyskinesia (PCD is associated with pulmonary involvement that requires periodical assessment. Chest high-resolution computed tomography (HRCT has become the method of choice to evaluate chronic lung disease, but entails exposure to ionizing radiation. Magnetic resonance imaging (MRI has been proposed as a potential radiation-free technique in several chest disorders. Aim of our study is to evaluate whether high-field MRI is as effective as HRCT in identifying PCD pulmonary abnormalities. We also analyzed the relationships between the severity and extension of lung disease, and functional data. Methods Thirteen PCD patients (8 children/5 adults; median age, 15.2 yrs underwent chest HRCT and high-field 3T MRI, spirometry, and deep throat or sputum culture. Images were scored using a modified version of the Helbich system. Results HRCT and MRI total scores were 12 (range, 6–20 and 12 (range, 5–17, respectively. Agreement between HRCT and MRI scores was good or excellent (r > 0.8. HRCT and MRI total scores were significantly related to forced vital capacity (r = -0.5, p = 0.05; and r = -0.7, p = 0.009, respectively and forced expiratory volume at 1 second (r = -0.6, p = 0.03; and r = -0.7, p = 0.009, respectively. Conclusion Chest high-field 3T MRI appears to be as effective as HRCT in assessing the extent and severity of lung abnormalities in PCD. MRI scores might be used for longitudinal assessment and be an outcome surrogate in future studies.
Zhao, L; Verhagen-Metman, L; Kim, J H; Liu, C C; Lenz, F A
The nature of electromyogram (EMG) activity and its relationship to neuronal activity in the internal globus pallidus (GPi) have not previously been studied in hyperkinetic movement disorders. We now test the hypothesis that GPi spike trains are cross-correlated with EMG activity during apomorphine-induced dyskinesias of Parkinson's disease (AID), and Hemiballism. We have recorded these two signals during awake stereotactic pallidal surgeries and analyzed them by cross-correlation of the raw signals and of peaks of activity occurring in those signals. EMG signals in Hemiballism usually consist of 'sharp' activity characterized by peaks of activity with low levels of activity between peaks, and by co-contraction between antagonistic muscles. Less commonly, EMG in Hemiballism shows 'non-sharp' EMG activity with substantial EMG activity between peaks; 'non-sharp' EMG activity is more common in AID. Therefore, these hyperkinetic disorders show substantial differences in peripheral (EMG) activity, although both kinds of activity can occur in both disorders. Since GPi spike×EMG spectral and time domain functions demonstrated inconsistent cross-correlation in both disorders, we studied peaks of activity in GPi neuronal and in EMG signals. The peaks of GPi activity commonly show prolonged cross-correlation with peaks of EMG activity, which suggests that GPi peaks are related to the occurrence of EMG peaks, perhaps by transmission of GPi activity to the periphery. In Hemiballism, the presence of direct GPi peak×EMG peak cross-correlations at the site where lesions relieve these disorders is evidence that gradual changes in peak GPi neuronal activity are directly involved in Hemiballism. Copyright © 2015. Published by Elsevier B.V.
Paul C. Langley
Full Text Available The recently released value assessment of vesicular monoamine transporter 2 (VMAT2 inhibitors in tardive dyskinesia by the Institute for Clinical and Economic Review (ICER relies upon a long-term modeling exercise to support recommendations for what the ICER sees as the appropriate pricing for these products if prices are to be judged ‘cost-effective’. In this case, the recommendations are for a substantive price reduction of some 90% over WAC. Needless to say, this recommendation is unlikely to be welcomed with open arms by the respective manufacturers of valbenazine and deutetrabenazine. Unfortunately, as has been argued in a number of commentaries published over the past 18 months in INNOVATIONS in Pharmacy, the ICER endorsed health technology assessment methodology that underpins this exercise in building a modeled imaginary world to justify product pricing recommendations is fatally flawed: it does not meet the standards of normal science. Rather than addressing the issue of claims validation for VMAT2 products, the question of generating modeled evaluable claims, among others, for clinical, quality of life and resource utilization outcomes, the analysis focuses on claims that are neither credible nor evaluable and, of course, non-replicable. A more positive and useful approach would be for ICER to focus on a framework where claims could be assessed in the short term to provide feedback to health system decision makers, physicians and patients. Instead, we are asked to believe that we can model 20 or 30 years into the future to establish non-evaluable claims for pricing and, ultimately, access. Conflict of Interest: None Type: Commentary
de Jong, K.; Timmerman, M. J.; Cliff, R. A.; Wijbrans, J. R.; Daly, J. S.; Balagansky, V. V.
We present isotope data from amphiboles from the 2.6--2.8 Ga Murmansk Terrane in the northern foreland of the 1.9 Ga Lapland-Kola Orogen of northern Fennoscandia. Most amphiboles are zoned with tschermakitic cores that progressively change to actinolite in 5--10 μm wide areas in rims, defect zones or adjacent to biotite. Biotite chiefly occurs along cleavages, fractures and grain boundaries of amphibole, showing that its hydration and fluid ingress are confined to lattice imperfections. Furnace step heating of hornblende separate MT-11 gave spectra with increasing apparent ages and Ca/K ratios (a proxy for 37ArCa/39Ar_K). Hornblende is intergrown with biotite that also occurs in the matrix. Yet, laser step heating of single hornblende grain MT-11 yielded flat spectra with Neoarchaean apparent ages and constant Ca/K ratios. This suggests that the hornblende grain that was drilled from a thin section and which was not affected by biotite growth retained its Neoarchaean age. In contrast, the hornblende separate with intergrown biotite from this sample has a partially reset Neoarchaean isotope system. Hornblende MT-27 has Neoarchaean apparent ages and lacks low Ca/K ratios in both single grain and mineral separate spectra; it is not affected by biotite growth and this mineral is also absent from the matrix. Age spectra of other hornblende separates have increasing apparent ages to 2.56--2.65 Ga during final 39Ar release; their Ca/K ratio spectra similarly increase. Low Ca/K ratios for gas release below 950^oC imply degassing of included biotite. Apparent ages of the first heating increments may be as young as 1.8 Ga, comparable to the K-Ar and 40Ar/39Ar ages of the youngest biotites. Hornblende-plagioclase pairs from aliquots used for 40Ar/39Ar furnace step heating yielded sharply discordant Rb-Sr ages. MT-11 yielded an 1881 ± 23 Ma Rb-Sr age that compares well with the K-Ar and 40Ar/39Ar ages of biotite in the sample. In contrast, hornblende of sample MT-27 has a
Andringa, G; Stoof, J C; Cools, A R
SKF 83959 acts as a D(1) antagonist in vitro but has been claimed to induce anti-parkinsonian effects after acute administration in MPTP-treated marmosets. The aim of the present study was to evaluate the therapeutic and undesired effects of sub-chronic administration of SKF 83959 in bilaterally MPTP-treated rhesus monkeys and to compare these effects with the effects of l-dopa and the dopamine agonist SKF 82958. MPTP was given in the left carotid artery (2.5 mg) and 6 weeks later, the right carotid artery (1.25 mg). The monkeys (n = 4) had previously been treated chronically with l-dopa (22 days, 10 mg/kg) and SKF 82958 (22 days, 1 mg/kg). Three months after the last administration of SKF 82958, SKF 83959 was given in a dose of 0.5 mg/kg from day 1 to day 15 and in a dose of 1.0 mg/kg from day 16 to day 18. SKF 83959 increased goal-directed limb movements in all animals, including those unresponsive to l-dopa. This therapeutic effect did not diminish during treatment. With respect to body displacement and undesired effects, a large variation in the response to SKF 83959 was found: a large increase in body displacement co-occurred with oro-facial dyskinesia (n = 2), whereas a small increase in body displacement co-occurred with dystonia (n = 2). In contrast to the undesired effects of l-dopa, the dyskinetic effects of SKF 83959 were primarily limited to the first treatment day. Unlike l-dopa and SKF 82958, SKF 83959 did not induce epileptoid behaviour. Sub-chronic administration of SKF 83959 induced both clear-cut therapeutic effects that remained stable in time, and a limited number of dyskinetic effects that wore off during the treatment. The dopamine D(1) antagonist SKF 83959 may be considered as an alternative treatment in Parkinson's disease, especially in those patients who do not respond to L-dopa.
Effect of Tianqi antitremor granules on behavioral manifestations and expression of G protein-coupled receptor kinase 6 and β-arrestin1 in levodopa-induced dyskinesia in a rat model of Parkinson's disease
Full Text Available Na Wu,1 Xinxin Yang,1 Lu Song,1 Jianglei Wei,2 Zhenguo Liu1 1Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 2Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China Background: Recent studies have shown that expression of G protein-coupled receptor kinase 6 (GRK6 and β-arrestin1 in the striatum is closely associated with hyperactive dopamine receptors in rats with levodopa-induced dyskinesia (LID. Our research group has shown that Tianqi antitremor granules have a significant effect on the motor complications of Parkinson's disease (PD. However, whether Tianqi antitremor granules have an effect on the behavioral manifestations and expression of GRK6 and β-arrestin1 in rats with LID is unknown. Methods: Rats with PD received twice daily intraperitoneal injections of levodopa for 4 weeks to induce dyskinesia. Rats with LID were randomly divided into five groups: an LID-control group, an LID group, a levodopa plus Tianqi antitremor granules as traditional Chinese medicine (TCM-low group, a levodopa plus TCM-medium group, and levodopa plus TCM-high group. Peak intensity of rotations was measured. GRK6 and β-arrestin1 expression in the striatum of the dyskinetic rats was observed by immunohistochemistry and Western blotting. Results: Pulsatile treatment with levodopa induced abnormal involuntary movements in rats with PD similar to LID in patients with PD. We found that repeated levodopa administration increased peak rotations in dyskinetic rats. However, peak rotations were decreased in rats given levodopa plus the different doses of Tianqi antitremor granules. In accordance with changed behavior, GRK6 and β-arrestin1 expression was decreased in rats with PD and was persistently low in rats with LID, but this decrease was prevented by coadministration of levodopa and Tianqi antitremor granules. Conclusion: Tianqi antitremor granules ameliorated
Morissette, Marc; Di Paolo, Thérèse
Non-human primate (NHP) models of Parkinson disease show many similarities with the human disease. They are very useful to test novel pharmacotherapies as reviewed here. The various NHP models of this disease are described with their characteristics including the macaque, the marmoset, and the squirrel monkey models. Lesion-induced and genetic models are described. There is no drug to slow, delay, stop, or cure Parkinson disease; available treatments are symptomatic. The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-Dopa) still remains the gold standard symptomatic treatment of Parkinson. However, involuntary movements termed L-Dopa-induced dyskinesias appear in most patients after chronic treatment and may become disabling. Dyskinesias are very difficult to manage and there is only amantadine approved providing only a modest benefit. In this respect, NHP models have been useful to seek new drug targets, since they reproduce motor complications observed in parkinsonian patients. Therapies to treat motor symptoms in NHP models are reviewed with a discussion of their translational value to humans. Disease-modifying treatments tested in NHP are reviewed as well as surgical treatments. Many biochemical changes in the brain of post-mortem Parkinson disease patients with dyskinesias are reviewed and compare well with those observed in NHP models. Non-motor symptoms can be categorized into psychiatric, autonomic, and sensory symptoms. These symptoms are present in most parkinsonian patients and are already installed many years before the pre-motor phase of the disease. The translational usefulness of NHP models of Parkinson is discussed for non-motor symptoms.
Coelho, Miguel; Abreu, Daisy; Correia-Guedes, Leonor; Lobo, Patricia Pita; Fabbri, Margherita; Godinho, Catarina; Domingos, Josefa; Albuquerque, Luisa; Freitas, Vanda; Pereira, João Miguel; Cattoni, Begona; Carvalho, Herculano; Reimão, Sofia; Rosa, Mário M; Ferreira, António Gonalves; Ferreira, Joaquim J
There is scarce data on the level of handicap in Parkinson's disease (PD) and none in advanced stage PD. To assess the handicap in advanced stage PD patients with disabling levodopa-induced motor complications selected to deep brain stimulation (DBS). Data was prospectively recorded during routine evaluation for DBS. Handicap was measured using London Handicap Scale (LHS) (0 = maximal handicap; 1 = no handicap). Disease severity was evaluated using the Hoehn & Yahr scale and the UPDRS/MDS-UPDRS, during off and on after a supra-maximal dose of levodopa. Schwab and England Scale (S&E) was scored in off and on. Dyskinesias were scored using the modified Abnormal Involuntary Movement Scale (mAIMS). Results concern cross-sectional assessment before DBS. 100 PD patients (mean age 61 (±7.6); mean disease duration 12.20 (±4.6) years) were included. Median score of motor MDS-UPDRS was 54 in off and 25 in on. Mean total LHS score was 0.56 (±0.14). Patients were handicapped in several domains with a wide range of severity. Physical Independence and Social Integration were the most affected domains. Determinants of total LHS score were MDS-UPDRS part II off (β= -0.271; p = 0.020), S&E on (β= 0.264; p = 0.005) and off (β= 0.226; p = 0.020), and mAIMS on (β= -0.183; p = 0.042) scores (R2 = 29.6%). We were able to use handicap to measure overall health condition in advanced stage PD. Patients were moderately to highly handicapped and this was strongly determined by disability in ADL and dyskinesias. Change in handicap may be a good patient-centred outcome to assess efficiency of DBS.
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Full Text Available L-3,4-dihydroxypheylalanine (L-dopa-induced dyskinesia represent a debilitating complication of therapy for Parkinson's disease (PD that result from a progressive sensitization through repeated L-dopa exposures. The MPTP macaque model was used to study the proteome in dopamine-depleted striatum with and without subsequent acute and chronic L-dopa treatment using two-dimensional difference in-gel electrophoresis (2D-DIGE and mass spectrometry. The present data suggest that the dopamine-depleted striatum is so sensitive to de novo L-dopa treatment that the first ever administration alone would be able (i to induce rapid post-translational modification-based proteomic changes that are specific to this first exposure and (ii, possibly, lead to irreversible protein level changes that would be not further modified by chronic L-dopa treatment. The apparent equivalence between first and chronic L-dopa administration suggests that priming would be the direct consequence of dopamine loss, the first L-dopa administrations only exacerbating the sensitization process but not inducing it.
Kishore Kumar, S Narasimhan; Deepthy, Jayakumar; Saraswathi, Uthamaraman; Thangarajeswari, Mohan; Yogesh Kanna, Sathyamoorthy; Ezhil, Pannerselvam; Kalaiselvi, Periandavan
Parkinson disease (PD) is a neurodegenerative disorder affecting mainly the motor system, as a result of death of dopaminergic neurons in the substantia nigra pars compacta. The present scenario of research in PD is directed to identify novel molecules that can be administered individually or co-administered with L-Dopa to prevent the L-Dopa-Induced Dyskinesia (LID) like states that arise during chronic L-Dopa administration. Hence, in this study, we investigated whether Morinda citrifolia has therapeutic effects in rotenone-induced Parkinson's disease (PD) with special reference to mitochondrial dysfunction mediated intrinsic apoptosis. Male Sprague-Dawley rats were stereotaxically infused with rotenone (3 µg in both SNPc and VTA) and co-treated with the ethyl acetate extract of Morinda citrifolia and levodopa. The results revealed that rotenone-induced cell death was reduced by MCE treatment as measured by decline in the levels of pro-apoptotic proteins. Moreover, MCE treatment significantly augmented the levels of anti-apoptotic Bcl2 and blocks the release of cytochrome c, thereby alleviating the rotenone-induced dopaminergic neuronal loss, as evidenced by tyrosine hydroxylase (TH) immunostaining in the striatum. Taken together, the results suggest that Morinda citrifolia may be beneficial for the treatment of neurodegenerative diseases like PD.
Paquette, Melanie A.; Martinez, Alex A.; Macheda, Teresa; Meshul, Charles K.; Johnson, Steven W.; Berger, S. Paul; Giuffrida, Andrea
Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson’s disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT1A receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT1A agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT1A antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT1A agonism. Combined with previous work from our group, our results support the investigation of 5-HT1A agonists as pharmacotherapies for LID in PD patients. PMID:22861201
Ossola, Bernardino; Schendzielorz, Nadia; Chen, Shih-Heng; Bird, Gary S; Tuominen, Raimo K; Männistö, Pekka T; Hong, Jau-Shyong
Amantadine is commonly given to alleviate L-DOPA-induced dyskinesia of Parkinson's disease (PD) patients. Animal and human evidence showed that amantadine may also exert neuroprotection in several neurological disorders. Additionally, it is generally believed that this neuroprotection results from the ability of amantadine to inhibit glutamatergic NMDA receptor. However, several lines of evidence questioned the neuroprotective capacity of NMDA receptor antagonists in animal models of PD. Thus the cellular and molecular mechanism of neuroprotection of amantadine remains unclear. Using primary cultures with different composition of neurons, microglia, and astroglia we investigated the direct role of these glial cell types in the neuroprotective effect of amantadine. First, amantadine protected rat midbrain cultures from either MPP(+) or lipopolysaccharide (LPS), two toxins commonly used as PD models. Second, our studies revealed that amantadine reduced both LPS- and MPP(+)-induced toxicity of dopamine neurons through 1) the inhibition of the release of microglial pro-inflammatory factors, 2) an increase in expression of neurotrophic factors such as GDNF from astroglia. Lastly, differently from the general view on amantadine's action, we provided evidence suggesting that NMDA receptor inhibition was not crucial for the neuroprotective effect of amantadine. In conclusion, we report that amantadine protected dopamine neurons in two PD models through a novel dual mechanism, namely reducing the release of pro-inflammatory factors from activated microglia and increasing the expression of GNDF in astroglia. Published by Elsevier Ltd.
Ossola, Bernardino; Schendzielorz, Nadia; Chen, Shih-Heng; Bird, Gary S.; Tuominen, Raimo K.; Männistö, Pekka T.; Hong, Jau-Shyong
Amantadine is commonly given to alleviate L-DOPA-induced dyskinesia of Parkinson’s disease (PD) patients. Animal and human evidence showed that amantadine may also exert neuroprotection in several neurological disorders. Additionally, it is generally believed that this neuroprotection results from the ability of amantadine to inhibit glutamatergic NMDA receptor. However, several lines of evidence questioned the neuroprotection capacity of NMDA receptor antagonists in animal models of PD. Thus the cellular and molecular mechanism of neuroprotection of amantadine remains unclear. Using primary cultures with different composition of neurons, microglia, and astroglia we investigated the direct role of these different glial cell types in the neuroprotective effect of amantadine. First, amantadine protected rat midbrain cultures from either MPP+ or lipopolysaccharide (LPS), two toxins commonly used PD models. Second, our studies revealed that amantadine reduced both LPS- and MPP+ -induced toxicity of dopamine neuron through 1) the inhibition of the release of microglial pro-inflammatory factors, 2) an increase in expression of neurotrophic factor such as GDNF from astroglia. Lastly, differently from the general view on amantadine´s action, we provided evidence suggesting that NMDA receptor inhibition was not crucial for the neuroprotective effect of amantadine. In conclusion, we report that amantadine protected dopamine neurons in two PD models through a novel dual mechanism, namely reducing the release of pro-inflammatory factors from activated microglia and increasing the expression of GNDF in astroglia. PMID:21586298
Anthony R West
Full Text Available Striatal nitric oxide (NO-producing interneurons play an important role in the regulation of corticostriatal synaptic transmission and motor behavior. Striatal NO synthesis is driven by concurrent activation of NMDA and dopamine (DA D1 receptors. NO diffuses into the dendrites of medium-sized spiny neurons (MSNs which contain high levels of NO receptors called soluble guanylyl cyclases (sGC. NO-mediated activation of sGC leads to the synthesis of the second messenger cGMP. In the intact striatum, transient elevations in intracellular cGMP primarily act to increase neuronal excitability and to facilitate glutamatergic corticostriatal transmission. NO-cGMP signaling also functionally opposes the inhibitory effects of DA D2 receptor activation on corticostriatal transmission. Not surprisingly, abnormal striatal NO-sGC-cGMP signaling becomes apparent following striatal DA depletion, an alteration thought to contribute to pathophysiological changes observed in basal ganglia circuits in Parkinson’s disease (PD. Here, we discuss recent developments in the field which have shed light on the role of NO-sGC-cGMP signaling pathways in basal ganglia dysfunction and motor symptoms associated with PD and L-DOPA-induced dyskinesias.
Mary Anne K. Olm
Full Text Available OBJETIVO: Revisar a discinesia ciliar primária (DCP quanto aos seus aspectos ultra-estruturais, discriminar os defeitos ciliares primários dos secundários, descrever o quadro clínico, os testes laboratoriais de triagem e de diagnóstico disponíveis, bem como seu manejo clínico. FONTE DE DADOS: Pesquisa nas bases de dados Medline, Lilacs e SciELO, no período de 1980 a 2007. SÍNTESE DOS DADOS: A DCP é uma doença autossômica recessiva que compromete a estrutura e/ou a função ciliar e, conseqüentemente, o transporte mucociliar. As manifestações clínicas envolvem o trato respiratório superior e inferior, com infecções recorrentes do ouvido médio, seios paranasais e pulmonares, que podem evoluir para bronquiectasias. Outras manifestações incluem situs inversus totalis e infertilidade masculina. O diagnóstico deve ser suspeitado pelos pediatras em várias situações: recém-nascidos de termo com desconforto respiratório sem causa aparente; neonatos portadores de dextrocardia; lactentes com tosse persistente e/ou infecções otorrinolaringológicas de repetição, excluindo-se as imunodeficiências e a fibrose cística; crianças com asma atípica e as com bronquiectasias sem causa definida. Os testes de triagem diagnóstica são os da sacarina e do óxido nítrico nasal. As avaliações do defeito ultra-estrutural e funcional exigem análise por microscopia eletrônica e da freqüência e formato da onda de batimento ciliar. CONCLUSÕES: A DCP, apesar da baixa prevalência, é pouco diagnosticada pelas dificuldades de estabelecer o diagnóstico definitivo do defeito ciliar devido à complexidade da investigação laboratorial e pela falta de reconhecimento da doença pelos médicos. A suspeita clínica e o diagnóstico precoce são fundamentais para reduzir a morbidade e prevenir o desenvolvimento de complicações.OBJECTIVE: To review primary ciliary dyskinesia (PCD and its ultrastructural aspects, to differentiate primary
Hauser, Robert A.; Pahwa, Rajesh; Tanner, Caroline M.; Oertel, Wolfgang; Isaacson, Stuart H.; Johnson, Reed; Felt, Larissa; Stempien, Mary Jean
Background: Medical treatment of levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD) is an unmet need. ADS-5102 (amantadine) extended-release capsules is being developed for the treatment of LID in patients with PD. Objective: Evaluate the long-term safety and tolerability of 274 mg ADS-5102 for LID in PD. Methods: In an ongoing, open-label safety study (NCT02202551), PD patients with LID received 274 mg of ADS-5102 once daily at bedtime. Patients were recruited from previous ADS-5102 trials. In addition, patients were enrolled who were ineligible for previous ADS-5102 trials due to previous implantation of deep-brain stimulation (DBS) devices. The primary outcome measure was safety assessed through adverse events (AEs). Efficacy was assessed using the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Part IV and its subparts. Results: For this interim analysis, 223 patients received ADS-5102 for a mean duration of 348 (SD 182) days. The most common AEs included falls (25.1%), visual hallucinations (19.3%), peripheral edema (13.0%), and constipation (12.6%). Overall, 32 patients (14.3%) discontinued due to an AE. In patients receiving placebo in previous studies, the mean MDS-UPDRS, Part IV scores decreased by 3.4 points from baseline (n = 78) to week 8 and remained stable through week 64 (n = 21). In patients receiving ADS-5102 in previous studies, the mean baseline (n = 61) MDS-UPDRS, Part IV score was low due to the response to ADS-5102 in previous studies and remained stable through week 64 (total of 88 weeks; n = 21). The effect was primarily due to reduction in item 4.2 (functional impact of dyskinesia) and item 4.4 (functional impact of motor fluctuations). Conclusions: ADS-5102 was generally well tolerated in all groups, including DBS patients, and the safety profile was consistent with previous controlled studies. Long-term durability and tolerability were shown from the double-blind studies
Age constraints on Late Paleozoic evolution of continental crust from electron microprobe dating of monazite in the Peloritani Mountains (southern Italy): another example of resetting of monazite ages in high-grade rocks
Appel, Peter; Cirrincione, Rosolino; Fiannacca, Patrizia; Pezzino, Antonino
In situ monazite microprobe dating has been performed, for the first time, on trondhjemite and amphibolite facies metasediments from the Peloritani Mountains in order to obtain information about the age of metamorphism and intrusive magmatism within this still poorly known sector of the Hercynian Belt. All samples show single-stage monazite growth of Hercynian age. One migmatite and one biotitic paragneiss yielded monazite ages of 311 ± 4 and 298 ± 6 Ma, respectively. These ages fit with previous age determinations in similar rocks from southern Calabria, indicating a thermal metamorphic peak at about 300 Ma, at the same time as widespread granitoid magmatism. The older of the two ages might represent a slightly earlier event, possibly associated with the emplacement of an adjacent trondhjemite pluton, previously dated by SHRIMP at 314 Ma. No evidence for pre-Hercynian events and only a little indication for some monazite crystallization starting from ca. 360 Ma were obtained from monazite dating of the metasediments, suggesting either a single-stage metamorphic evolution or a significant resetting of the monazite isotope system during the main Hercynian event (ca. 300 Ma). Rare monazite from a trondhjemite sample yields evidence for a late-Hercynian age of about 275 Ma. This age is interpreted as representing a post-magmatic stage of metasomatic monazite crystallization, which significantly postdates the emplacement of the original magmatic body.
Rodriguez-Oroz, Maria C; López-Azcárate, Jon; Garcia-Garcia, David; Alegre, Manuel; Toledo, Jon; Valencia, Miguel; Guridi, Jorge; Artieda, Julio; Obeso, Jose A
frequencies and with different topography for the motor (dyskinesias) and behavioural (abnormal impulsivity) manifestations. These findings suggest that the activity recorded in parkinsonian patients with impulse control disorders stems from the associative-limbic area (ventral subthalamic area), which is coherent with premotor frontal cortical activity. Conversely, in patients with l-dopa-induced dyskinesias such activity is recorded in the motor area (dorsal subthalamic area) and it is coherent with cortical motor activity. Consequently, the subthalamic nucleus appears to be implicated in the motor and behavioural complications associated with dopaminergic drugs in Parkinson's disease, specifically engaging different anatomo-functional territories.
Egberto R. Barbosa
Full Text Available Ethylene oxide is a gas widely used in the production of industrial chemicals. It is also used to sterilize heat-sensitive medical supplies. Previous reports of acute and chronic exposure have described neurotoxic effects like peripheral neuropathy and cognitive impairment. We describe a pure parkinsonian syndrome following acute ethylene oxide intoxication. A 39-years-old male was referred to our Movement Disorders Clinic tor evaluation of a parkinsonian syndrome. He was acutely exposed to ethylene oxide four years before and remained comatose for three days, and gradually regained consciousness.. At that time he showed a global parkinsonian syndrome including bradykinesia, rigidity and rest tremor, with a severe motor disability; no other neurological disorders were found. The symptomatology was partially controlled with biperidene and levodopa plus carbidopa. Two years later he developed L-dopa induced dyskinesias. Four years after the intoxication he was evaluated at our clinic. General examination showed no abnormalities. Neurologic examination revealed a normal menta1 status. Motor evaluation disclosed moderate bradykinesia, rigidity and rest tremor, shuffling gait, poor facial mimic, stooped posture, and his speech was low and monotonous; deep tendon reflexes were brisk. The Hoehn-Yahr disability score was degree IV. Routine laboratory and radiological exams showed results within normal limits. The CSF examination was normal. Brain computed tomography and magnetic ressonance were normal. A trial with bromocriptine and levodopa plus carbidopa did not improve dyskinesia, and he was put on a schedule including amantadine and biperidene with improvement to grade III in Hoehn-Yahr scale. In the present case there was a clear relation between the acute exogenous intoxication and irreversible parkinsonism. No other causes for the condition were identified.
Full Text Available Antipsychotic-induced movement disorders are major side effects of antipsychotic drugs among schizophrenia patients, and include antipsychotic-induced parkinsonism (AIP and tardive dyskinesia (TD. Substantial pharmacogenetic work has been done in this field, and several susceptibility variants have been suggested. In this paper, the genetics of antipsychotic-induced movement disorders is considered in a broader context. We hypothesize that genetic variants that are risk factors for AIP and TD may provide insights into the pathophysiology of Parkinson's disease (PD. Since loss of dopaminergic stimulation (albeit pharmacological in AIP and degenerative in PD is shared by the two clinical entities, genes associated with susceptibility to AIP may be modifier genes that influence clinical expression of PD sub-phenotypes, such as age at onset, disease severity or rate of progression. This is due to their possible functional influence on compensatory mechanisms for striatal dopamine loss. Better compensatory potential might be beneficial at the early and later stages of the PD course. AIP vulnerability variants may also be related to latent impairment in the nigrostriatal pathway, affecting its functionality, and leading to subclinical dopaminergic deficits in the striatum. Susceptibility of PD patients to early development of L-dopa induced dyskinesia (LID, is an additional relevant sub-phenotype. LID may share a common genetic background with TD, with which it shares clinical features. Genetic risk variants may predispose to both phenotypes, exerting a pleiotropic effect. According to this hypothesis, elucidating the genetics of antipsychotic-induced movement disorders may advance our understanding of multiple aspects of PD and it clinical course, rendering this a potentially rewarding field of study.
Barbosa, E R; Comerlatti, L R; Haddad, M S; Scaff, M
Ethylene oxide is a gas widely used in the production of industrial chemicals. It is also used to sterilize heat-sensitive medical supplies. Previous reports of acute and chronic exposure have described neurotoxic effects like peripheral neuropathy and cognitive impairment. We describe a pure parkinsonian syndrome following acute ethylene oxide intoxication. A 39-years-old male was referred to our Movement Disorders Clinic for evaluation of a parkinsonian syndrome. He was acutely exposed to ethylene oxide four years before and remained comatose for three days, and gradually regained consciousness. At that time he showed a global parkinsonian syndrome including bradykinesia, rigidity and rest tremor, with a severe motor disability; no other neurological disorders were found. The symptomatology was partially controlled with biperidene and levodopa plus carbidopa. Two years later he developed L-dopa induced dyskinesias. Four years after the intoxication he was evaluated at our clinic. General examination showed no abnormalities. Neurologic examination revealed a normal mental status. Motor evaluation disclosed moderate bradykinesia, rigidity and rest tremor, shuffling gait, poor facial mimic, stooped posture, and his speech was low and monotonous; deep tendon reflexes were brisk. The Hoehn-Yahr disability score was degree IV. Routine laboratory and radiological exams showed results within normal limits. The CSF examination was normal. Brain computed tomography and magnetic ressonance were normal. A trial with bromocriptine and levodopa plus carbidopa did not improve dyskinesia, and he was put on a schedule including amantadine and biperidene with improvement to grade III in Hoehn-Yahr scale. In the present case there was a clear relation between the acute exogenous intoxication and irreversible parkinsonism.(ABSTRACT TRUNCATED AT 250 WORDS)
Deuterium-substituted L-DOPA displays increased behavioral potency and dopamine output in an animal model of Parkinson's disease: comparison with the effects produced by L-DOPA and an MAO-B inhibitor.
Malmlöf, Torun; Feltmann, Kristin; Konradsson-Geuken, Åsa; Schneider, Frank; Alken, Rudolf-Giesbert; Svensson, Torgny H; Schilström, Björn
The most effective treatment of Parkinson's disease (PD) L-DOPA is associated with major side effects, in particular L-DOPA-induced dyskinesia, which motivates development of new treatment strategies. We have previously shown that chronic treatment with a substantially lower dose of deuterium-substituted L-DOPA (D3-L-DOPA), compared with L-DOPA, produced equal anti-parkinsonian effect and reduced dyskinesia in 6-OHDA-lesioned rats. The advantageous effects of D3-L-DOPA are in all probability related to a reduced metabolism of deuterium dopamine by the enzyme monoamine oxidase (MAO). Therefore, a comparative neurochemical analysis was here performed studying the effects of D3-L-DOPA and L-DOPA on dopamine output and metabolism in 6-OHDA-lesioned animals using in vivo microdialysis. The effects produced by D3-L-DOPA and L-DOPA alone were additionally compared with those elicited when the drugs were combined with the MAO-B inhibitor selegiline, used in PD treatment. The different treatment combinations were first evaluated for motor activation; here the increased potency of D3-L-DOPA, as compared to that of L-DOPA, was confirmed and shown to be of equal magnitude as the effect produced by the combination of selegiline/L-DOPA. The extracellular levels of dopamine were also increased following both D3-L-DOPA and selegiline/L-DOPA administration compared with L-DOPA administration. The enhanced behavioral and neurochemical effects produced by D3-L-DOPA and the combination of selegiline/L-DOPA are attributed to decreased metabolism of released dopamine by MAO-B. The similar effect produced by D3-L-DOPA and selegiline/L-DOPA, respectively, is of considerable clinical interest since D3-L-DOPA, previously shown to exhibit a wider therapeutic window, in addition may reduce the need for adjuvant MAO-B inhibitor treatment.
Navarro, Gemma; Borroto-Escuela, Dasiel; Angelats, Edgar; Etayo, Íñigo; Reyes-Resina, Irene; Pulido-Salgado, Marta; Rodríguez-Pérez, Ana I; Canela, Enric I; Saura, Josep; Lanciego, José Luis; Labandeira-García, José Luis; Saura, Carlos A; Fuxe, Kjell; Franco, Rafael
Endocannabinoids are important regulators of neurotransmission and, acting on activated microglia, they are postulated as neuroprotective agents. Endocannabinoid action is mediated by CB1 and CB2 receptors, which may form heteromeric complexes (CB1-CB2Hets) with unknown function in microglia. We aimed at establishing the expression and signaling properties of cannabinoid receptors in resting and LPS/IFN-γ-activated microglia. In activated microglia mRNA transcripts increased (2 fold for CB1 and circa 20 fold for CB2), whereas receptor levels were similar for CB1 and markedly upregulated for CB2; CB1-CB2Hets were also upregulated. Unlike in resting cells, CB2 receptors became robustly coupled to Gi in activated cells, in which CB1-CB2Hets mediated a potentiation effect. Hence, resting cells were refractory while activated cells were highly responsive to cannabinoids. Interestingly, similar results were obtained in cultures treated with ß-amyloid (Aß1-42). Microglial activation markers were detected in the striatum of a Parkinson's disease (PD) model and, remarkably, in primary microglia cultures from the hippocampus of mutant β-amyloid precursor protein (APPSw,Ind) mice, a transgenic Alzheimer's disease (AD) model. Also of note was the similar cannabinoid receptor signaling found in primary cultures of microglia from APPSw,Ind and in cells from control animals activated using LPS plus IFN-γ. Expression of CB1-CB2Hets was increased in the striatum from rats rendered dyskinetic by chronic levodopa treatment. In summary, our results showed sensitivity of activated microglial cells to cannabinoids, increased CB1-CB2Het expression in activated microglia and in microglia from the hippocampus of an AD model, and a correlation between levodopa-induced dyskinesia and striatal microglial activation in a PD model. Cannabinoid receptors and the CB1-CB2 heteroreceptor complex in activated microglia have potential as targets in the treatment of neurodegenerative diseases
Krishnan, Giri P.; Bazhenov, Maxim; Pikovsky, Arkady
In this paper, we introduce and systematically study, in terms of phase response curves (PRC), the effect of a dual pulse excitation on the dynamics of an autonomous oscillator. Specifically, we test the deviations from a linear summation of phase advances from two small perturbations. We derive analytically a correction term, which generally appears for oscillators whose intrinsic dimensionality is greater than one. We demonstrate this effect in case of the Stuart-Landau model, and also in v...
Stuebe, Alison M.; Rich-Edwards, Janet W.
For maternal metabolism, pregnancy ends not with delivery, but with weaning. In several recent epidemiological studies, authors have reported an association between duration of breast-feeding and reduced maternal risk of metabolic disease. These findings parallel data from animal models showing favorable changes in metabolism associated with lactation. During gestation, visceral fat accumulates, and insulin resistance and lipid and triglyceride levels increase. These changes appear to reverse more quickly, and more completely, with lactation. In this article, we review animal and human studies regarding the effects of lactation on adiposity, lipid, and glucose homeostasis. We hypothesize that lactation plays an important role in “resetting” maternal metabolism after pregnancy. PMID:19031350
Hugo Alejandro Vega Ortega
Full Text Available A discinesia ciliar primária (DCP, anteriormente conhecida como síndrome dos cílios imóveis, é uma doença hereditária autossômica recessiva que inclui vários padrões de defeitos em sua ultra-estrutura ciliar. Sua forma clínica mais grave é a síndrome de Kartagener (SK, a qual é encontrada em 50% dos casos de DCP. A DCP causa deficiência ou mesmo estase no transporte de secreções em todo o trato respiratório, favorecendo a proliferação de vírus e bactérias. Sua incidência varia de 1:20.000 a 1:60.000. Como conseqüência, os pacientes apresentam infecções crônicas e repetidas desde a infância e geralmente são portadores de bronquite, pneumonia, hemoptise, sinusite e infertilidade. As bronquiectasias e outras infecções crônicas podem ser o resultado final das alterações irreversíveis dos brônquios, podendo progredir para cor pulmonale crônico e suas conseqüências. Somente a metade dos pacientes afetados pela DCP apresenta todos os sintomas, condição denominada SK completa; no restante, não ocorre situs inversus, condição denominada SK incompleta. O diagnóstico é feito com base no quadro clínico e confirmado por meio da microscopia eletrônica de transmissão. Como não há tratamento especifico para a DCP, recomenda-se que, tão logo seja feito o diagnóstico, as infecções secundárias sejam tratadas com antibióticos potentes e medidas profiláticas sejam adotadas. Neste trabalho, relatamos seis casos de DCP (cinco casos de SK completa e um caso de SK incompleta e revisamos a literatura sobre o assunto, tendo como foco os aspectos diagnósticos, terapêuticos e clínicos desta doença.Primary ciliary dyskinesia (PCD, previously known as immotile cilia syndrome, is an autosomal recessive hereditary disease that includes various patterns of ciliary ultrastructural defects. The most serious form is Kartagener syndrome (KS, which accounts for 50% of all cases of PCD. The incidence of PCD ranges from 1
Calabresi, Paolo; Ghiglieri, Veronica; Mazzocchetti, Petra; Corbelli, Ilenia; Picconi, Barbara
The long-term replacement therapy with the dopamine (DA) precursor 3,4-dihydroxy-l-phenylalanine (L-DOPA) is a milestone in the treatment of Parkinson's disease (PD). Although this drug precursor can be metabolized into the active neurotransmitter DA throughout the brain, its therapeutic benefit is due to restoring extracellular DA levels within the dorsal striatum, which lacks endogenous DA as a consequence of the neurodegenerative process induced by the disease. In the early phases of PD, L-DOPA treatment is able to restore both long-term depression (LTD) and long-term potentiation (LTP), two major forms of corticostriatal synaptic plasticity that are altered by dopaminergic denervation. However, unlike physiological DA transmission, this therapeutic approach in the advanced phase of the disease leads to abnormal peaks of DA, non-synaptically released, which are supposed to trigger behavioural sensitization, namely L-DOPA-induced dyskinesia. This condition is characterized by a loss of synaptic depotentiation, an inability to reverse previously induced LTP. In the advanced stages of PD, L-DOPA can also induce non-motor fluctuations with cognitive dysfunction and neuropsychiatric symptoms such as compulsive behaviours and impulse control disorders. Although the mechanisms underlying the role of L-DOPA in both motor and behavioural symptoms are still incompletely understood, recent data from electrophysiological and imaging studies have increased our understanding of the function of the brain areas involved and of the mechanisms implicated in both therapeutic and adverse actions of L-DOPA in PD patients. © 2015 The Author(s) Published by the Royal Society. All rights reserved.
Shahani, Neelam; Swarnkar, Supriya; Giovinazzo, Vincenzo; Morgenweck, Jenny; Bohn, Laura M; Scharager-Tapia, Catherina; Pascal, Bruce; Martinez-Acedo, Pablo; Khare, Kshitij; Subramaniam, Srinivasa
The striatum of the brain coordinates motor function. Dopamine-related drugs may be therapeutic to patients with striatal neurodegeneration, such as Huntington's disease (HD) and Parkinson's disease (PD), but these drugs have unwanted side effects. In addition to stimulating the release of norepinephrine, amphetamines, which are used for narcolepsy and attention-deficit/hyperactivity disorder (ADHD), trigger dopamine release in the striatum. The guanosine triphosphatase Ras homolog enriched in the striatum (Rhes) inhibits dopaminergic signaling in the striatum, is implicated in HD and L-dopa-induced dyskinesia, and has a role in striatal motor control. We found that the guanine nucleotide exchange factor RasGRP1 inhibited Rhes-mediated control of striatal motor activity in mice. RasGRP1 stabilized Rhes, increasing its synaptic accumulation in the striatum. Whereas partially Rhes-deficient (Rhes+/-) mice had an enhanced locomotor response to amphetamine, this phenotype was attenuated by coincident depletion of RasGRP1. By proteomic analysis of striatal lysates from Rhes-heterozygous mice with wild-type or partial or complete knockout of Rasgrp1, we identified a diverse set of Rhes-interacting proteins, the "Rhesactome," and determined that RasGRP1 affected the composition of the amphetamine-induced Rhesactome, which included PDE2A (phosphodiesterase 2A; a protein associated with major depressive disorder), LRRC7 (leucine-rich repeat-containing 7; a protein associated with bipolar disorder and ADHD), and DLG2 (discs large homolog 2; a protein associated with chronic pain). Thus, this Rhes network provides insight into striatal effects of amphetamine and may aid the development of strategies to treat various neurological and psychological disorders associated with the striatal dysfunction. Copyright © 2016, American Association for the Advancement of Science.
Lazzara, Carol A.; Riley, Rebeccah R.; Rane, Anand; Andersen, Julie K.; Kim, Yong-Hwan
Lithium has recently been suggested to have neuroprotective effects in several models of neurodegenerative disease including Parkinson’s disease (PD). Levodopa (L-Dopa) replacement therapy remains the most common and effective treatment for PD, although it induces the complication of L-Dopa induced dyskinesia after years of use. Here we examined the potential use of lithium in combination with L-Dopa/Carbidopa for both reducing MPTP-induced abnormal involuntary movements (AIMs) as well as protecting against cell death in MPTP-lesioned mice. Chronic lithium administration (0.127% LiCl in the feed) in the presence of daily L-Dopa/Carbidopa injection for a period of 2 months was sufficient to effectively reduce MPTP-induced AIMs in mice. Mechanistically, lithium was found to suppress MPTP-induced calpain activities in vivo coinciding with down-regulation of calpain-1 but not calpain-2 expression in both the striatum (ST) and the brain stem (BS). Calpain inhibition has previously been associated with increased levels of the rate-limiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), which is probably mediated by the up-regulation of the transcription factors MEF-2A and 2D. Lithium was found to induce up-regulation of TH expression in the ST and the BS, as well as in N27 rat dopaminergic cells. Further, histone acetyltransferase (HAT) expression was substantially up-regulated by lithium treatment in vitro. These results suggest the potential use of lithium in combination with L-Dopa/Carbidopa not only as a neuroprotectant, but also for reducing AIMs and possibly alleviating potential side-effects associated with the current treatment for PD. PMID:26119916
Full Text Available In Parkinson’s disease (PD, there are alterations of the basal ganglia (BG thalamo-cortical networks, primarily due to degeneration of nigrostrial dopaminergic neurons. These changes in subcortical networks lead to plastic changes in primary motor cortex (M1, which mediates cortical motor output and is a potential target for treatment of PD. Studies investigating the motor cortical plasticity using non-invasive transcranial magnetic stimulation (TMS have found altered plasticity in PD, but there are inconsistencies among these studies. This is likely because plasticity depends on many factors such as the extent of dopaminergic loss and disease severity, response to dopaminergic replacement therapies, development of L-dopa-induced dyskinesias (LID, the plasticity protocol used, medication and stimulation status in patients treated with deep brain stimulation (DBS. The influences of LID and DBS on BG and M1 plasticity have been explored in animal models and in PD patients. In addition, many other factors such age, genetic factors (e.g. brain derived neurotropic factor and other neurotransmitters or receptors polymorphism, emotional state, time of the day, physical fitness have been documented to play role in the extent of plasticity induced by TMS in human studies. In this review, we summarize the studies that investigated M1 plasticity in PD and demonstrate how these afore-mentioned factors affect motor cortical plasticity in PD. We conclude that it is important to consider the clinical, demographic and technical factors that influence various plasticity protocols while developing these protocols as diagnostic or prognostic tools in PD. We also discuss how the modulation of cortical excitability and the plasticity with these non-invasive brain stimulation techniques facilitate the understanding of the pathophysiology of PD and help design potential therapeutic possibilities in this disorder.
Paquette, Melanie A; Martinez, Alex A; Macheda, Teresa; Meshul, Charles K; Johnson, Steven W; Berger, S Paul; Giuffrida, Andrea
Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson's disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT(1A) receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT(1A) agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT(1A) antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT(1A) agonism. Combined with previous work from our group, our results support the investigation of 5-HT(1A) agonists as pharmacotherapies for LID in PD patients. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.
Udupa, Kaviraja; Chen, Robert
In Parkinson’s disease (PD), there are alterations of the basal ganglia (BG) thalamocortical networks, primarily due to degeneration of nigrostriatal dopaminergic neurons. These changes in subcortical networks lead to plastic changes in primary motor cortex (M1), which mediates cortical motor output and is a potential target for treatment of PD. Studies investigating the motor cortical plasticity using non-invasive transcranial magnetic stimulation (TMS) have found altered plasticity in PD, but there are inconsistencies among these studies. This is likely because plasticity depends on many factors such as the extent of dopaminergic loss and disease severity, response to dopaminergic replacement therapies, development of l-DOPA-induced dyskinesias (LID), the plasticity protocol used, medication, and stimulation status in patients treated with deep brain stimulation (DBS). The influences of LID and DBS on BG and M1 plasticity have been explored in animal models and in PD patients. In addition, many other factors such age, genetic factors (e.g., brain derived neurotropic factor and other neurotransmitters or receptors polymorphism), emotional state, time of the day, physical fitness have been documented to play role in the extent of plasticity induced by TMS in human studies. In this review, we summarize the studies that investigated M1 plasticity in PD and demonstrate how these afore-mentioned factors affect motor cortical plasticity in PD. We conclude that it is important to consider the clinical, demographic, and technical factors that influence various plasticity protocols while developing these protocols as diagnostic or prognostic tools in PD. We also discuss how the modulation of cortical excitability and the plasticity with these non-invasive brain stimulation techniques facilitate the understanding of the pathophysiology of PD and help design potential therapeutic possibilities in this disorder. PMID:24027555
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Asanuma, Masato; Miyazaki, Ikuko; Kikkawa, Yuri; Kimoto, Naotaka; Takeshima, Mika; Murakami, Shinki; Miyoshi, Ko
Prostaglandin H synthase exerts not only cyclooxygenase activity but also peroxidase activity. The latter activity of the enzyme is thought to couple with oxidation of dopamine to dopamine quinone. Therefore, it has been proposed that cyclooxygenase inhibitors could suppress dopamine quinone formation. In the present study, we examined effects of various cyclooxygenase inhibitors against excess methyl L-3,4-dihydroxyphenylalanine (L-DOPA)-induced quinoprotein (protein-bound quinone) formation and neurotoxicity using dopaminergic CATH.a cells. The treatment with aspirin inhibited excess methyl L-DOPA-induced quinoprotein formation and cell death. However, acetaminophen did not show protective effects, and indomethacin and meloxicam rather aggravated these methyl L-DOPA-induced changes. Aspirin and indomethacin did not affect the level of glutathione that exerts quenching dopamine quinone in dopaminergic cells. In contrast with inhibiting effects of higher dose in the previous reports, relatively lower dose of aspirin that affected methyl L-DOPA-induced quinoprotein formation and cell death failed to prevent cyclooxygenase-induced dopamine chrome generation in cell-free system. Furthermore, aspirin but not acetaminophen or meloxicam showed direct dopamine quinone-scavenging effects in dopamine-semiquinone generating systems. The present results suggest that cyclooxygenase shows little contribution to dopamine oxidation in dopaminergic cells and that protective effects of aspirin against methyl L-DOPA-induced dopamine quinone neurotoxicity are based on its cyclooxygenase-independent property.
Full Text Available A readership study, employing an online survey (n = 275, was conducted to determine the reading preferences of students, faculty, staff, and alumni for the student magazine and web site of a technological university. The print version (53% was preferred over the online version (22%, with 25% having no preference. Internet and social media were the preferred news media with Facebook dominating all other sites. Few had downloaded the app (7%, despite the fact that 92% owned smartphones. Attitudes toward news were positive and predictive of reading specific sections. Reading the technology section was significantly related to being “part of my daily habit,” “part of my civic duty,” “helpful in making choices,” and negatively related to “inconvenient.” Additional qualitative responses are discussed.
switching phenomena like redox effects in the resistance changes, filament formation and the percolation of the defects in the oxide (Choi et al 2005; Waser 2009). Researchers have used several techniques to investigate the mechanism such as conductive atomic force micro- scopy (C-AFM), high resolution transmission ...
Kingdom (87%). United States United Kingdom France Germany Japan Feature phone/Smartphone 78% 87% 74% 76% 96% Media player with web access 24...extracting and analyzing data from Android smartphones. It is distributed as a standalone virtual appliance that runs on a VMware 12 workstation. The pre...of Amazon Cloud Player USERDATA/Root/media/0/Android/data/com.andrew.apollo/cac he/ImageCache/3910b1e0ccab19bc46fd9db27cca49c9.0 Image cache data
McKemmish, S.; Iacovino, L.; Ketelaar, E.; Castan, M.; Russell, L.
This paper provides an analysis of the Indigenous human rights agenda and identifies its relevance to Australian archivists.1 Based on this analysis and exploration of how far existing archival programs address archives-related Indigenous human rights issues, it presents a road map and action agenda
...: test the hypothesis that multiple nightly bouts of exercise will induce significant delays in the endogenous circadian rhythms of core body temperature, plasma melatonin, reaction time, alertness...
Sou Nobukawa; Haruhiko Nishimura; Teruya Yamanishi; Jian-Qin Liu
... potential between spike and hyperpolarization. As one of the hybrid spiking neuron models, Izhikevich neuron model can reproduce major spike patterns observed in the cerebral cortex only by tuning a few parameters and also exhibit chaotic states...
Paul E Dux
Full Text Available Key to successfully negotiating our environment is our ability to adapt to current settings based on recent experiences and behaviour. Response conflict paradigms (e.g., the Stroop task have provided evidence for increases in executive control after errors, leading to slowed responses that are more likely to be correct, and less susceptible to response congruency effects. Here we investigate whether failures of perceptual awareness, rather than failures at decisional or response stages of information processing, lead to similar adjustments in visual attention. We employed an attentional blink task in which subjects often fail to consciously register the second of two targets embedded in a rapid serial visual presentation stream of distractors, and examined how target errors influence performance on subsequent trials. Performance was inferior after Target 2 errors and these inter-trial effects were independent of the temporal lag between the targets and were not due to more global changes in attention across runs of trials. These results shed light on the nature of attentional calibration in response to failures of perceptual consciousness.
Generalized linear models (GLMs) are generalizations of linear regression models, which allow fitting regression models to response data that follow a general exponential family. GLMs are used widely in social sciences for fitting regression models to count data, qualitative response data and duration data. While a variety of specification tests have been developed for the linear regression model and are routinely applied for testing for misspecification of functional form, omitted variables,...
Yadlapalli, Swathi; Wani, Khursheed A; Xu, X Z Shawn
How past experiences reshape behavior is not well understood. In this issue, two studies (Schild et al., 2014; Yu et al., 2014) dissected the molecular mechanisms underlying experience-dependent plasticity in thermosensory behavior. They show that Ca(2+)/calmodulin-dependent kinase I (CaMKI) regulates thermal preferences according to past experience. Copyright © 2014 Elsevier Inc. All rights reserved.
Oklejewicz, Malgorzata; Destici, Eugin; Tamanini, Filippo; Hut, Roelof A.; Janssens, Roel; van der Horst, Gijsbertus T. J.
To anticipate the momentum of the day, most organisms have developed an internal clock that drives circadian rhythms in metabolism, physiology, and behavior . Recent studies indicate that cell-cycle progression and DNA-damage-response pathways are under circadian control [2-4]. Because circadian
Full Text Available Epigenetic regulation can be altered by environmental cues including abiotic and biotic stresses. In most cases, environmentally-induced epigenetic changes are transient, but in some cases they are maintained for extensive periods of time and may even be transmitted to the next generation. However, the underlying mechanisms of transgenerational transmission of environmentally-induced epigenetic states remain largely unknown. Such traits can be adaptive, but also can have negative consequences if the parentally inherited epigenetic memory interferes with canonical environmental responses of the progeny. This review highlights recent insights into the mechanisms preventing transgenerational transmission of environmentally-induced epigenetic states in plants, which resemble those of germline reprogramming in mammals.
Moreover, the Cu/ZrO2/ATO device which the ZrO2 thin film annealed at 300 °C can be measured as resistive switching sweeps at 200, 100 and 50 K. It was found that the ratio of off/on reduced when the measured temperature decreased. When the - measurement temperature decreases, on decreases obviously ...
strove to limit the reach of Soviet and Japanese revisionism in China.242 Franklin Delano Roosevelt’s recognition of the Union of Soviet Socialist...Ibid. 85. Mark A Smith , A Russian Chronology, JulySeptember 2008, London, UK: Conflict Studies Research Centre Advanced Research Assessments Group
Correction for ‘‘HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment...0188 Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing ...instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send
Koulani, Chrysanthi Sofia; Prunescu, Remus Mihail; Hviid, Christian Anker
of the art is represented by the method of trim and respond based on pressure alarms. This study investigates the operation of the SPR control method of trim and respond based on pressure alarms in a CO2 demand application where large air volumes are provided to three classrooms. The investigation was based...... on simulations performed with a fully dynamic model of a VAV ventilation system that was developed in the Simulink programming tool which is add-on software to MATLAB mathematical programming language. The Simulink model was developed in previous research work and was built based on the International Building...... Physics Toolbox (IBPT), which is a library of blocks constructed for the thermal analysis in building physics. For the purpose of the current investigation the IBPT toolbox was remodelled to integrate the calculation of the airflow demand based on the CO2 concentration occurring in the zone...
Hart, E. C.; Rasmussen, P.; Secher, N. H.
Alterations in the carotid baroreflex (CBR) control of arterial pressure may explain the reduction in arterial pressure and left ventricular (LV) function after prolonged exercise. We examined the CBR control of heart rate (HR) and mean arterial pressure (MAP), in addition to changes in LV functi...
Full Text Available Almost two decades after the Barcelona Declaration, the European Union (EU is still struggling to engage positively with its southern neighbours. Security has been the key concern in this relationship, with the EU putting forward a short-term agenda, often inconsistent with the policies, institutions and long-term goals of the Euro-Mediterranean Partnership. This article argues that the so-called Arab Spring has induced a soul-searching process within the European institutions that has opened the possibility for Brussels to reinvent its relations with the Middle East and North Africa countries, particularly in the field of security.
The EU presents itself as a 'privileged partner' of Africa and characterises the latter as a 'natural partner' in the search for a new world order, an order based on norms, rules and greater equity for developing states. Africa's geo-strategic importance due to its proximity to Europe, its growing value as a trading and investment ...
Bonuccelli, Ubaldo; Del Dotto, Paolo; Rascol, Olivier
In the last two decades, the usefulness of dopamine receptor agonists in the symptomatic treatment of Parkinson' disease (PD) has been demonstrated in many randomized controlled clinical trials. The initial role of such compounds as an adjunctive therapy to L-dopa to improve motor fluctuations has now expanded to the treatment of early PD as initial monotherapy. The rationale for the use of dopamine receptor agonists in early disease is to delay or reduce the incidence of motor complications resulting from long-term L-dopa therapy, probably by virtue of less pulsatile stimulation of postsynaptic dopamine receptors. Indeed, controlled trials with both ergot and non-ergot dopamine receptor agonists, such as cabergoline, pergolide, pramipexole and ropinirole, have shown lower risk of motor fluctuations and dyskinesias than with L-dopa, when used as monotherapy in early PD patients. The benefit of agonists in preventing motor complications is, however, balanced by a smaller effect on motor symptoms compared with L-dopa. Moreover, a greater incidence of side-effects, particularly somnolence, hallucinations and leg oedema, occurs with dopamine receptor agonists. Because of the risk of fibrotic reactions, ergot derivatives (bromocriptine, cabergoline, and pergolide) are not recommended as first-line antiparkinsonian medication. In younger patients, who are usually more prone to developing L-dopa-induced motor complications, the initial treatment with dopamine receptor agonists can be recommended. Further pharmacological refinement of PD management with these drugs may result from new formulations of old drugs, such as once-daily prolonged-release ropinirole, or new agonists, such as the rotigotine patch, that can allow more continuous dopaminergic stimulation and improve patient compliance with the drug treatment. Theoretically, another advantage of dopamine receptor agonists is the potential for a neuroprotective effect, through many different mechanisms of actions
Full Text Available Background and the purpose of the study: In Parkinsons disease (PD prolong use of L-DOPA causes some motor disorders such as wearing-off and L-DOPA induced dyskinesia (LID. In this investigation the effect of 8-OHDAPT, as a 5-HT1A agonist on anti-cataleptic effect of L-DOPA in 6-hydroxydopamine (6-OHDA lesioned male Wistar rats was investigated. Methods: Catalepsy was induced by unilateral injection of 6-OHDA (8 μg/2μl/rat into the central region of the SNc. After 3 weeks as a recovery period, animals received intraperitoneally (i.p. L-DOPA (15 mg/kg twice daily for 20 days, and anti-cataleptic effect of L-DOPA was assessed by bar-test at days of 5, 10, 15 and 20. Results and major conclusion: The results showed that L-DOPA had anti-cataleptic effect only until the day of 15, and its effect was decreased on the day of 20. On the day of 21, rats were co-injected with three different doses of 8-OHDAPT (0.1, 0.5 and 2.5 mg/kg, i.p. and L-DOPA (15 mg/kg, ip. 8-Hydroxy-2-(di-n-propylamino tetralin (8-OHDAPT improved anti-cataleptic effect of L-DOPA at the dose of 0.5 mg/kg. Moreover the effect of 8-OHDAPT on anti-cataleptic effect of L-DOPA (15 mg/kg, ip was abolished by 1-(2-methyoxyphenyl-4-[4-(2-phthalamido butyl] piperazine hydrobromide (NAN-190; 0.5 mg/kg, i.p. as a 5-HT1A receptor antagonist. According to the obtained results, it may be concluded that activation of 5-HT1A receptors by 8-OHDAPT may improve anti-cataleptic effect of L-DOPA in a 6-OHDA- induced rat model of PD. Further studies are required to clarify the exact mechanism of interaction between 5-HT1A and dopaminergic neurons.
Andringa, G; Lubbers, L; Drukarch, B; Stoof, J C; Cools, A R
The aim of this study was twofold: (1) to study the predictive validity of the drug-naive, bilaterally MPTP-treated monkey as an animal model of Parkinson's disease (PD), and (2) to investigate the therapeutic and undesired effects of the D1 agonist SKF 82958 as compared to L-DOPA treatment, in drug-naive and L-DOPA pretreated monkeys. A detailed ethogram was used, allowing the separation of therapeutic and undesired effects. Eight weeks after bilateral intracarotid MPTP administration, SKF 82958 (1 mg/kg, n = 4, SKF 82958, naive group) or methyl-L-DOPA + carbi-dopa (10 + 2.5 mg/kg, n = 4, L-DOPA group) was administered intramuscularly for 22 days. After a drug-free period of eight weeks, the L-DOPA group was treated with SKF 82958 for 22 days (SKF 82959, 1 mg/kg, n=4, pretreated). All drug treatments increased the parameters used classically to evaluate dopaminergic drugs, namely body displacement, dyskinesia and dystonia. However, the new detailed analysis revealed that L-DOPA, but not SKF 82958, had therapeutic effects, reflected by an increase in goal-directed fore-limb use. SKF 82958, but not L-DOPA, induced additional undesired effects; including epileptoid behaviours in both drug-naive and drug-pretreated monkeys. In one L-DOPA-unresponsive monkey, SKF 82958 did induce minor therapeutic effects, as well as undesired effects. Although the effects of SKF 82958 on fore-limb movements, rotational behaviours and body displacement were comparable in the naive and pretreated group, SKF 82958 re-initiated undesired effects in the L-DOPA pretreated group from day one. It is concluded that the bilaterally MPTP-treated monkey is an animal model with predictive validity for PD: it adequately predicts the therapeutic effects and undesired effects of L-DOPA. Furthermore, it is concluded that SKF 82958 is less effective than L-DOPA in the treatment of PD, because it did not induce therapeutic effects, but instead elicited several undesired effects.
Makia J. Marafie
Dec 22, 2014 ... Case report: Here we are presenting Kartagener syndrome in a consanguineous Kuwaiti family with a novel ... The first child was a boy, diagnosed antenatally with situs inversus totalis. He was born at full term, after an uncomplicated pregnancy, with complex cyanotic congenital heart disease. His medical ...
Lucas, Jane S; Alanin, Mikkel Christian; Collins, Samuel
is inappropriate since differences in pathophysiology, morbidity and prognosis risk treatment failure and lack of adherence. Areas covered: Review authors searched PubMed and Cochrane databases for publications relating to management of children with PCD. Because of the paucity of data, we emphasise the need...
13. c: Dermal denticles (diamond-shaped scales) of great white shark ; depending on species, there may be three to six riblets per scale (five to...the results of the modeling of chaos control by sharks . Skins of great white ,33 Atlantic sharpnose,36 and tiger shark37 dermal denticles (dd), with...Denticles of Great White Shark ," Electron Microscope Unit, University of Cape Town, Smithsonian Museum of Natural History, http://ocean.si.edu/ocean
for Afghanistan, proclaiming that the United States was responsible for his deportation . It is believed that he was introduced to Omar by ISI agents...Dmitry Rogozin, has noted that the United States has been successful in eradicating drugs in Colombia , in part because the ratio of soldiers to
Fuentes Enriquez de Salamanca, S.; Nood, van E.; Tims, S.; Heikamp-de Jong, I.; Braak, ter C.J.F.; Keller, J.J.; Zoetendal, E.G.; Vos, de W.M.
Recurrent Clostridium difficile infection (CDI) can be effectively treated by infusion of a healthy donor faeces suspension. However, it is unclear what factors determine treatment efficacy. By using a phylogenetic microarray platform, we assessed composition, diversity and dynamics of faecal
Madsen, P L; Linde, R; Hasselbalch, S G
In the clinical setting it has been shown that activation will increase cerebral glucose uptake in excess of cerebral oxygen uptake. To study this phenomenon further, this study presents an experimental setup that enables precise determination of the ratio between cerebral uptake of glucose...... and oxygen in the awake rat. Global CBF was measured by the Kety-Schmidt technique, and the ratio between cerebral uptake rates for oxygen, glucose, and lactate was calculated from cerebral arterial-venous differences. During baseline conditions, rats were kept in a closed box designed to minimize...... interference. During baseline conditions CBF was 1.08 +/- 0.25 mL x g(-1) x minute(-1), and the cerebral oxygen to glucose uptake ratio was 5.5. Activation was induced by opening the sheltering box for 6 minutes. Activation increased CBF to 1.81 mL x g(-1) x minute(-1). During activation cerebral glucose...
Manoogian, Emily N C; Leise, Tanya L; Bittman, Eric L
The duper mutation in Syrian hamsters shortens the free-running period of locomotor activity (τDD) to about 23 h and results in a type 0 phase-response curve (PRC) to 15-min light pulses. To determine whether exaggerated phase shifts are specific to photic cues and/or restricted to subjective night, we subjected hamsters to novel wheel confinements and dark pulses during subjective day. Small phase shifts elicited by the nonphotic cue were comparable in mutant and wild-type (WT) hamsters, but dark pulses triggered larger shifts in dupers. To assess further the effects of the duper mutation on light-dark transitions, we transferred hamsters between constant light (LL) and constant dark (DD) or between DD and LL at various circadian phases. Duper hamsters displayed significantly larger phase shifts than WT hamsters when transferred from LL to DD during subjective day and from DD to LL during subjective night. The variability of phase shifts in response to all light/dark transitions was significantly greater in duper hamsters at all time points. In addition, most duper hamsters, but none of the WTs, displayed transient ultradian wheel-running patterns for 5 to 12 days when transferred from light to dark at CT 18. The χ(2) periodogram and autocorrelation analyses indicate that these ultradian patterns differ from the disruption of rhythmicity by SCN lesions or exposure to constant bright light. We conclude that the duper mutation specifically amplifies phase shifts to photic cues and may destabilize coupling of circadian organization upon photic challenge due to weakened coupling among components of the circadian pacemaker. Mathematical modeling of the circadian pacemaker supports this hypothesis. © 2015 The Author(s).
Mistlberger, Ralph E; Belcourt, Jodi; Antle, Michael C
Circadian rhythms in Syrian hamsters can be phase shifted by procedures that stimulate wheel running ("exercise") in the mid-subjective day (the hamster's usual sleep period). The authors recently demonstrated that keeping hamsters awake by gentle handling, without continuous running, is sufficient to mimic this effect. Here, the authors assessed whether wakefulness, independent of wheel running, also mediates phase shifts to dark pulses during the midsubjective day in hamsters free-running in constant light (LL). With running wheels locked during a 3 h dark pulse on day 3 of LL, hamsters (N = 16) averaged only 43+/-15 min of spontaneous wake time and phase shifted only 24+/-43 min. When wheels were open during a dark pulse, two hamsters remained awake, ran continuously, and showed phase advance shifts of 7.3 h and 8.7 h, respectively, whereas the other hamsters were awake awake for 3 h without running. Additional time in LL (10 and 20 days) did not potentiate the waking or phase shift response to dark pulses. When all hamsters were sleep deprived with wheels locked during a dark pulse, phase advance shifts averaged 261+/-110 min and ranged up to 7.3 h. These shifts are large compared to those previously observed in response to the 3 h sleep deprivation procedure. Additional tests revealed that this potentiated shift response is dependent on LL prior to sleep deprivation but not LL after sleep deprivation. A final sleep deprivation test showed that a small part of the potentiation may be due to suppression of spontaneous wheel running by LL. These results indicate that some correlate of waking, other than continuous running, mediates the phase-shifting effect of dark pulses in the mid-subjective day. The mechanism by which LL potentiates shifting remains to be determined. The lack of effect of subsequent LL on the magnitude of shifts to sleep deprivation in the dark suggests that LL reduces responsivity to light by processes that take >3 h of dark to reverse.
Muraro, Paolo A; Abrahamsson, Sofia V
According to current concepts for multiple sclerosis (MS), a fundamental pathogenic role is played by T- and B-cells that inappropriately recognize self antigens and initiate a cell-mediated or humoral inflammatory reaction that injures myelin and axons, and results in neural dysfunction and loss. Transplantation of bone marrow-derived hematopoietic stem cells following high-dose immunosuppression is being evaluated as an experimental treatment for severe forms of immune-mediated disorders, including MS. The primary goal of this therapeutic approach is to induce medication-free remission from new disease activity by correcting the immune aberrations that promote the attack against self tissue; this approach is termed 'immune repair'. In this review, the clinical experience gained from the use of autologous hematopoietic stem cell transplantation in treating severe forms of MS are presented, and the current understanding of the mechanisms underlying the mode of action of this treatment, including depletion of disease-mediating immune cells, rejuvenation of the immune repertoire and improvement of regulatory cell function, is discussed.
...: test the hypothesis that multiple nightly bouts of exercise will induce significant delays in the endogenous circadian rhythms of core body temperature, plasma - melatonin, reaction time, alertness...
Iulia Monica Oehler-Șincai
Full Text Available In the present paper, our main objective is to bring to the forefront two notable processes, as a result of the world financial and economic crisis. On the one side, we underline the increasing role of the emerging countries (especially that of China, Brazil, Russia and India in the world economy and, on the other side, we underscore the remodelling of the patterns of economic growth and development in the case of the BRICS countries. The Russian Federation, Brazil and South Africa rapidly eased out of the recession in 2009, while China and India continued to record robust growth rates. Nevertheless, in 2012, one can remark the precipitate slowdown of the GDP growth in all the five analysed economies. This demonstrates that the emerging economies were not able to “decouple” from the world economy and, on the contrary, they were deeply affected by the adverse economic situation in the USA and the EU (especially the Euro Zone. At the same time, China’s economic slowdown negatively influences Brazil, Russia, India and South Africa, as China represents the largest trading partner for them, after the EU. At the same time, one should not ignore the actual weaknesses of these economies. For instance, inflation represents a “common vulnerability” of the BRICS. In this situation, the selection of the most viable instrument of monetary policy represents a veritable challenge for the authorities in these countries, as the economic growth should be stimulated but, at the same time, inflation has to be tempered. Besides, unemployment rate in South Africa is already at high levels. The fiscal deficit, as a percentage of GDP is excessive in India and South Africa and the public debt to GDP ratio is extremely high in India and Brazil. During the world financial and economic crisis, the authorities and companies, both public and private, concentrated their attention more and more on the internal markets, with a high absorption capacity. Without giving up exports and FDI as engines of economic growth, the administrative bodies at macro and microeconomic levels understood that the internal demand represents a complementary source of growth. In contrast with the most developed countries, which intensely resorted to austerity measures, the BRICS were able to adopt stimulus measures. Such Keynesian moves were possible, as the emerging countries entered the global crisis with strong macroeconomic and financial positions. As a matter of fact, the world financial and economic crisis erupted in a moment considered by the international experts as the “most prosperous” for these countries. The general measures adopted in order to stimulate the economy in the field of fiscal policy and monetary policy were combined with specific, sectoral ones. Such measures managed even to attenuate the negative effects of the global crisis at social level. Infrastructure development though public investment projects is used by the BRICS governments as one of the principal means to stimulate economic growth and jobs creation. Our paper concludes that, for the BRICS countries, the classical engines for economic growth like exports and inward FDI are complemented by additional growth engines: internal demand (spurred by the high level of remittances from abroad, the outward FDI, innovation and infrastructure development.
to reduced physical working capacity and or- thostatic tolerance, restoration of blood volume has clinical implications for the recovery of normal...PC. Cardiovascular deconditioning during spaceflight and the use of saline as a countermeasure to orthostatic intolerance. Aviat Space Environ Med 56
Lam, T.J.G.M.; Jansen, J.; Wessels, R. J.
Background Prudent use of antibiotics is important to prevent antibiotic resistance in humans and in animals. For this reason politicians demanded a decrease of total antibiotic use and of use of critically important antibiotics in animal husbandry in the Netherlands. In the dairy sector the use of antibiotics almost halved in the years 2009?2015, with a decrease of the use of critically important antibiotics to very low levels. Theory of behaviour change To realize a sustainable decrease in ...
effectiveness; (2) outline a comprehensive, multidisciplinary approach that focuses on all aspects of behavioral healthcare; (3) reinforce commanders...confidential communication made between the patient and a psychotherapist . However, the privilege does not apply in the case of administrative...develop a CTP through the collaboration of a multidisciplinary team of physicians, case managers, specialty care providers, occupational therapists
Fago, Angela; Mathews, A.J.; Brittain, T.
We propose a new hypothesis for the molecular mechanism by which neuroglobin exerts its protective effect in hypoxia-induced cell death. Our recent observation of a very rapid electron-transfer reaction between ferrous neuroglobin and ferric cytochrome c is central to this hypothesis. In contrast...... apoptotic pathway. Our hypothesis also fits well with a number of previously uncorrelated findings, including the localization of neuroglobin in close proximity to mitochondria, the high concentration of neuroglobin in cells whose basal rates of aerobic metabolism are extremely high, and the cell types...... to previously suggested roles for neuroglobin, related to its putative but unlikely oxygen storage/transport properties or its ability to react with nitrogen oxides, we suggest that ferrous neuroglobin exerts its protective effect via modulation of the early events in the intrinsic apoptotic pathway. We suggest...
Lam, T. J. G. M.; Wessels, R. J.; Jansen, Jolanda
BACKGROUND: Prudent use of antibiotics is important to prevent antibiotic resistance in humans and in animals. For this reason politicians demanded a decrease of total antibiotic use and of use of critically important antibiotics in animal husbandry in the Netherlands. In the dairy sector the use of
Grözinger, Michael; Beersma, Domien G.M.; Fell, Jürgen; Röschke, Joachim
In selective REM sleep deprivation (SRSD), the occurrence of stage REM is repeatedly interrupted by short awakenings. Typically, the interventions aggregate in clusters resembling the REM episodes in undisturbed sleep. This salient phenomenon can easily be explained if the nonREM–REM sleep process
Grozinger, M; Beersma, DGM; Fell, J; Roschke, J
In selective REM sleep deprivation (SRSD), the occurrence of stage REM is repeatedly interrupted by short awakenings. Typically, the interventions aggregate in clusters resembling the REM episodes in undisturbed sleep. This salient phenomenon can easily be explained if the nonREM-REM sleep process
Scott, W.E.; Nye, C.J.; Waythomas, C.F.; Neal, C.A.
Kasatochi Island, the subaerial portion of a small volcano in the western Aleutian volcanic arc, erupted on 7-8 August 2008. Pyroclastic flows and surges swept the island repeatedly and buried most of it and the near-shore zone in decimeters to tens of meters of deposits. Several key seabird rookeries in taluses were rendered useless. The eruption lasted for about 24 hours and included two initial explosive pulses and pauses over a 6-hr period that produced ash-poor eruption clouds, a 10-hr period of continuous ash-rich emissions initiated by an explosive pulse and punctuated by two others, and a final 8-hr period of waning ash emissions. The deposits of the eruption include a basal muddy tephra that probably reflects initial eruptions through the shallow crater lake, a sequence of pumiceous and lithic-rich pyroclastic deposits produced by flow, surge, and fall processes during a period of energetic explosive eruption, and a fine-grained upper mantle of pyroclastic-fall and -surge deposits that probably reflects the waning eruptive stage as lake and ground water again gained access to the erupting magma. An eruption with similar impact on the island's environment had not occurred for at least several centuries. Since the 2008 eruption, the volcano has remained quiet other than emission of volcanic gases. Erosion and deposition are rapidly altering slopes and beaches. ?? 2010 Regents of the University of Colorado.
CD 15 – L – Battelle Memorial Institute Oklahoma CD 4 – FSDB – Tec-Masters Inc.; S – Telos OK, LLC Oregon CD 1 – L – Heifetz , Halle Consulting Group...the Industrial Base 15 of 15 On Point for America Ground Systems Industrial Enterprise Points of Contract: Ronald J. Coppinger 309-782-4065
Ellaway, Rachel; Dubé, Tim; Cooper, Gerry; Graves, Lisa
Although students' transition into medical school is a critical step in their professional journey, orientation has been relatively under-researched, particularly with regard to its intersections with schools' social missions. This paper reports on a study looking at the implicit messages of orientation to the Northern Ontario School of Medicine's undergraduate program. An extended mixed methods study was conducted to look at different aspects of the School's Orientation Week. The term "hidden curriculum" was used to shape inquiry, both in its broad sense of implicit educational experiences and messages and in its more specific sense of the educational messages sent by a medical school's culture and activities. Data were collected using participant surveys, focus groups, and interviews. Transcripts and free-text survey responses were analyzed to identify underlying themes. Orientation Week was generally well received and was generally perceived by different stakeholders (such as students, school leaders, and community members) as a positive and necessary undertaking. However, there were points of contention and confusion that created a hidden curriculum with respect to participants' identities, both as students and as future health professionals. Orientation to undergraduate medical training can be successfully linked to a school's social mission, but in doing so it can send complex and unintended messages to the participants that may be perceived quite differently based on their circumstances and expectations.
"On 7 July 2009, NATO officially opened the debate over the alliance's new Strategic Concept. Over the course of its history, the military alliance has evolved from a coalition of states, aligned together against the threat posed by the Soviet Union, into a truly global entity, affiliated with other organisations and international actors and faced with new threats in the areas of security and defence. Seeking a new raison d’être, NATO is going back to its roots; working more closely with Russ...
Harris, Carol E.; Barter, Barbara G.
As health threats appear with increasing regularity in our food systems and other food crises loom worldwide, we look to rural areas to provide local and nutritious foods. Educationally, we seek approaches to food studies that engage students and their communities and, ultimately, lead to positive action. Yet food studies receive only generic…
Full Text Available Temporal coding of spike-times using oscillatory mechanisms allied to spike-time dependent plasticity could represent a powerful mechanism for neuronal communication. However, it is unclear how temporal coding is constructed at the single neuronal level. Here we investigate a novel class of highly regular, metronome-like neurones in the rat brainstem which form a major source of cerebellar afferents. Stimulation of sensory inputs evoked brief periods of inhibition that interrupted the regular firing of these cells leading to phase-shifted spike-time advancements and delays. Alongside phase-shifting, metronome cells also behaved as band-pass filters during rhythmic sensory stimulation, with maximal spike-stimulus synchronisation at frequencies close to the idiosyncratic firing frequency of each neurone. Phase-shifting and band-pass filtering serve to temporally align ensembles of metronome cells, leading to sustained volleys of near-coincident spike-times, thereby transmitting synchronised sensory information to downstream targets in the cerebellar cortex.
debris. The main module gearbox housing is inspected for damage to the paint system. The swashplate grease shield is inspected for debonding. The... swashplate uniball is inspected for sand entrapment. All wire bundles and cannon plugs are inspected for sand entrapment and corrosion. The lower
Ellaway, Rachel; Dubé, Tim; Cooper, Gerry; Graves, Lisa
Background Although students’ transition into medical school is a critical step in their professional journey, orientation has been relatively under-researched, particularly with regard to its intersections with schools’ social missions. This paper reports on a study looking at the implicit messages of orientation to the Northern Ontario School of Medicine’s undergraduate program. Methods An extended mixed methods study was conducted to look at different aspects of the School’s Orientation Week. The term “hidden curriculum” was used to shape inquiry, both in its broad sense of implicit educational experiences and messages and in its more specific sense of the educational messages sent by a medical school’s culture and activities. Data were collected using participant surveys, focus groups, and interviews. Transcripts and free-text survey responses were analyzed to identify underlying themes. Results Orientation Week was generally well received and was generally perceived by different stakeholders (such as students, school leaders, and community members) as a positive and necessary undertaking. However, there were points of contention and confusion that created a hidden curriculum with respect to participants’ identities, both as students and as future health professionals. Conclusion Orientation to undergraduate medical training can be successfully linked to a school’s social mission, but in doing so it can send complex and unintended messages to the participants that may be perceived quite differently based on their circumstances and expectations. PMID:28344720
Kawashima, T.; Zhou, Y.; Yew, K. S.; Ang, D. S.
We show that the negative photoconductivity property of the nanoscale filamentary breakdown path in the SiO2 electrolyte of the SiO2/Cu conductive bridge resistive random access memory (CBRAM) stack is affected by the number of positive-voltage sweeps applied to the Cu electrode (with respect to a non-metal counter electrode). The path's photo-response to white light, of a given intensity, is suppressed with an increasing number of applied positive-voltage sweeps. When this occurs, the path may only be disrupted by the light of a higher intensity. It is further shown that the loss of the path's photosensitivity to the light of a given intensity can be recovered using a negative-voltage sweep (which eliminates the path), followed by the reformation of the path by a positive-voltage sweep. The above behavior is, however, not seen in the SiO2/Si stack (which involves a non-metal Si electrode), suggesting that the photo-response modulation effect is related to the Cu electrode. The demonstrated reversible electrical modulation of the path's photo-response may afford greater flexibility in the electro-optical control of the CBRAM device.
Mohamed Y Attia
Full Text Available Background Bronchial asthma is an allergic disorder characterized by excessive hyperactive nature of the airways, which depends on many cytokines such as interleukin-4 (IL-4 and IL-5 that are responsible for the allergic inflammatory response. One of the strategies in the management of bronchial asthma is the induction of synthesis of IL-10; it has an inhibitory effect on the synthesis of the T-helper-2 (Th2 cytokines. Th2 cells play a triggering role in the activation/recruitment of immunoglobulin E antibody-producing B cells, mast cells, and eosinophil cells. To assess regulatory changes in the immune system, in patients with allergy and asthma, we studied the cytokine profile in serum in comparison with normal healthy controls. The study was carried out in Allergy and Immunology Unit, Ain Shams University Hospitals. A total of 170 patients with various allergies and asthmatic conditions were studied, for cytokines in the serum by enzyme-linked immunosorbent assay using kits from Immune Technology, and analyzed to identify the triggering factors or main contributors toward allergy and asthma. Our study showed increase in the levels of IL-4, IL-5, and IL-6 in all groups, which was nonsignificant. However, the levels of IL-10, IL-13, and tumor necrosis factor-α were highly significantly increased. Besides, we found correlation of granulocyte macrophage colony-stimulating factor with IL-10. Significant positive correlation with different cytokines was observed. Most of these patients showed increase in immunoglobulin E levels. This study gives a better understanding of how cytokines are the mediators of balance of Th1 and Th2 immune responses and how immunoglobulin E synthesis is controlled by cytokines. Further studies will eventually lead to improved treatment strategies in the clinical management of immunoglobulin E-mediated allergy.
Full Text Available Database merupakan sebuah hal yang penting untuk menyimpan data, dengan database organisasi akan mendapatkan keuntungan dalam beberapa hal, seperti kecepatan akases dan mengurangi penggunaan kertas, namun dengan implementasi database tidak jarang administrator database lupa akan password yang digunakan, hal ini akan mempersulit dalam proses penangganan database. Penelitian ini bertujuan untuk menggali cara mereset password level root pada relational database management system MySQL.
Full Text Available The ripening physiology of detached fruit is altered by low oxygen conditions with profound effects on quality parameters. To study hypoxia-related processes and regulatory mechanisms, apple (Malus domestica, cv Granny Smith fruit, harvested at commercial ripening, were kept at 1°C under normoxic (control and hypoxic (0.4 and 0.8 kPa oxygen conditions for up to 60 days. NMR analyses of cortex tissue identified eight metabolites showing significantly different accumulations between samples, with ethanol and alanine displaying the most pronounced difference between hypoxic and normoxic treatments A rapid up-regulation of alcohol dehydrogenase and pyruvate-related metabolism (lactate dehydrogenase, pyruvate decarboxylase, alanine aminotransferase gene expression was detected under both hypoxic conditions with a more pronounced effect induced by the lowest (0.4 kPa oxygen concentration. Both hypoxic conditions negatively affected ACC synthase and ACC oxidase transcript accumulation. Analysis of RNA-seq data of samples collected after 24 days of hypoxic treatment identified more than 1,000 genes differentially expressed when comparing 0.4 vs 0.8 kPa oxygen concentration samples. Genes involved in cell-wall, minor and major CHO, amino acid and secondary metabolisms, fermentation and glycolysis as well as genes involved in transport, defense responses and oxidation-reduction appeared to be selectively affected by treatments. The lowest oxygen concentration induced a higher expression of transcription factors belonging to AUX/IAA, WRKY, HB, Zinc-finger families, while MADS box family genes were more expressed when apples were kept under 0.8 kPa oxygen. Out of the eight group VII ERF members present in apple genome, two genes showed a rapid up-regulation under hypoxia, and western blot analysis showed that apple MdRAP2.12 proteins were differentially accumulated in normoxic and hypoxic samples, with the highest level reached under 0.4 kPa oxygen. These data suggest that ripe apple tissues finely and specifically modulate sensing and regulatory mechanisms in response to different hypoxic stress conditions.
Full Text Available After nearly nine decades of benign neglect, Turkey has set about reestablishing its influence in the Middle East. Although most observers agree that the United States and Turkey share a number of overlapping goals in the Middle East, Turkey's recent rapprochement with Iran has drawn the ire of the United States. In tandem, Turkey's relations with Israel, Washington's closest ally in the region, have deteriorated rapidly following Israel's war in Gaza and the events aboard the Mavi Marmara. These coinciding events have further complicated U.S.-Turkish relations and have led a number of pundits in Washington to openly question Turkey's ideological orientation. If Ankara and Washington want to mend relations they should acknowledge that their disagreements are not about their overall vision or intention for the region, but over how to implement and carry out foreign policy. Both Ankara and Washington should do a better job of enumerating their long-term regional policy goals and engage in a broader dialogue to clearly transmit these ideas to each other, while working together to achieve them.
Over the past fifteen years, the professional context of arts and design, in terms of production, distribution and consumption, has largely changed as a result of technological developments. However, art and design education programmes in the Netherlands have mostly failed to constructively
Norman, M. D.; Borg, L. E.; Nyquist, L. E.; Bogard, D. D.
Lunar ferroan anorthosites (FANs) are relics of an ancient, primary feldspathic crust that is widely believed to have crystallized from a global magma ocean. Compositions and ages of FANs provide fundamental information about the origin and magmatic evolution of the Moon, while the petrology and thermal history of lunar FANs illustrate the structure and impact history of the lunar crust. Here we report petrologic, geochemical, and isotopic (Nd-Sr-Ar) studies of a ferroan noritic anorthosite clast from lunar breccia 67215 to improve our understanding of the composition, age, and thermal history of the Moon.
Biau, Emmanuel; Torralba, Mireia; Fuentemilla, Lluis; de Diego Balaguer, Ruth; Soto-Faraco, Salvador
Speakers often accompany speech with spontaneous beat gestures in natural spoken communication. These gestures are usually aligned with lexical stress and can modulate the saliency of their affiliate words. Here we addressed the consequences of beat gestures on the neural correlates of speech perception. Previous studies have highlighted the role played by theta oscillations in temporal prediction of speech. We hypothesized that the sight of beat gestures may influence ongoing low-frequency neural oscillations around the onset of the corresponding words. Electroencephalographic (EEG) recordings were acquired while participants watched a continuous, naturally recorded discourse. The phase-locking value (PLV) at word onset was calculated from the EEG from pairs of identical words that had been pronounced with and without a concurrent beat gesture in the discourse. We observed an increase in PLV in the 5-6 Hz theta range as well as a desynchronization in the 8-10 Hz alpha band around the onset of words preceded by a beat gesture. These findings suggest that beats help tune low-frequency oscillatory activity at relevant moments during natural speech perception, providing a new insight of how speech and paralinguistic information are integrated. Copyright © 2015 Elsevier Ltd. All rights reserved.
Madsen, Astrid Hellerup; Green, Kent; Buchvald, Frederik
-score TLC, and indices of N2 MBW were significantly abnormal, but VO2peak only correlated with FEV1 and DLCO/VA. VO2peak correlated with complaints of moderate or significant limitations in vigorous activities (P = 0.0001), exhibited by 39% of PCD...
Marthin, J K; Nielsen, K G
. 282 subjects, 117 consecutive referrals, 59 PCDs, 49 CF patients and 57 healthy subjects, were included. All methods separated significantly between PCD and non-PCD, including CF with reliability, in ranking order BH-nNO>OE-R-nNO>TB-nNO. Acceptability in children ranked in reverse order. A problematic...... high fraction (39%) of false positive TB-nNO was found in young children. An unexpected large fraction (6.8%) of PCDs had nNO values above cut-off. nNO is a helpful first-line tool in real-life PCD work-up in all age groups if the sampling method is chosen according to age. nNO can be misleading...
Full Text Available Several case reports have described stories of schizophrenia patients reporting no discomfort in response to several medical conditions which normally elicit pain. Comparatively, experimental studies performed on pain perception in schizophrenia have not documented hypoalgesic responses that are as frank as those reported in these clinical cases. Here, we report the case of a female patient with schizoaffective disorder, who displayed markedly reduced pain perception during an experimental heat pain paradigm. Compared to a large group of healthy volunteers that we tested in 3 previous studies using the same psychophysical procedure, the experimental temperature required to induce moderate pain was radically increased in this patient (z-score = 3.6. The patient had mild psychiatric symptoms and had insight into her symptoms. She had drug-induced dyskinetic symptoms. This case report illustrates that it is possible to observe marked reductions in pain perception in schizophrenia patients tested in experimental settings but that the phenomenon is relatively rare. Regardless of the exact nature of pain indifference in schizophrenia, it can delay diagnosis and treatment of medical problems in these patients. Future studies in the field will need to pay attention to drug-induced extrapyramidal symptoms.
Provencher, Matthew T; Kirby, Hannah; McDonald, Lucas S; Golijanin, Petar; Gross, Daniel; Campbell, Kevin J; LeClere, Lance; Sanchez, George; Anthony, Shawn; Romeo, Anthony A
Pectoralis minor (PM) tightness has been linked to pain and dysfunction of the shoulder joint secondary to anterior tilt and internal rotation of the scapula, thus causing secondary impingement of the subacromial space. To describe outcomes pertaining to nonoperative and operative treatment via surgical release of the PM tendon for pathologic PM tightness in an active population. Case series; Level of evidence, 4. Over a 3-year period, a total of 46 patients were enrolled (mean age, 25.5 years; range, 18-33 years). Inclusion criteria consisted of symptomatic shoulder pain, limited range of overhead motion, inability to participate in overhead lifting activities, and examination findings consistent with scapular dysfunction secondary to a tight PM with tenderness to palpation of the PM tendon. All patients underwent a lengthy physical therapy and stretching program (mean, 11.4 months; range, 3-23 months), which was followed by serial examinations for resolution of symptoms and scapular tilt. Of the 46 patients, 6 (13%) were unable to adequately stretch the PM and underwent isolated mini-open PM release. Outcomes were assessed with scapula protraction measurements and pain scales as well as American Shoulder and Elbow Surgeons (ASES), Single Assessment Numeric Evaluation (SANE), and visual analog scale (VAS) scores. Forty of the 46 patients (87%) resolved the tight PM and scapular-mediated symptoms with a dedicated therapy program (pre- and posttreatment mean outcome scores: 58 and 91 [ASES], 50 and 90 [SANE], 4.9 and 0.8 [VAS]; P shoulder symptoms after surgical release of the PM. Additional research is necessary to evaluate the long-term efficacy of isolated PM treatment.
Jia Hou, MD, PhD
Conclusions: Pneumothorax might be one of the complications of the PCD. Combination therapy including ICS+ LA beta2 agonist and carbocistein could be a potential therapy to reduce the frequency of acute exacerbations and delay progression of PCD.
C. Alanin, M.; G. Nielsen, K.; von Buchwald, C.
from 107 patients with PCD (median age 17 years, range 0–74 years) (median age at diagnosis 7.8 years, range 0–63 years). Haemophilus influenzae was the most frequent microorganism. Other common pathogens were P. aeruginosa, Streptococcus pneumoniae, Moraxella catarrhalis and Staphylococcus aureus...
Møller, Maria E.; Alanin, Mikkel C.; Grønhøj, Christian
, and microbiology analyses from the nose or paranasal sinuses. Results: We included 46 studies (1823 patients) from 16 countries. Staphylococcus aureus was found in 30% of the noses and sinuses of patients with CF. Other common bacteria found included Pseudomonas aeruginosa, coagulase negative staphylococci......, and Haemophilus influenzae. In PCD, H. influenzae was the most common bacteria (28%), followed by Streptococcus pneumoniae and P. aeruginosa. If studies that included nonsurgical swab and blowing samples were excluded, then P. aeruginosa was the most common bacterium in patients with CF (34%) and in patients...... with PCD (50%), followed by S. aureus and H. influenza. Conclusion: S. aureus, P. aeruginosa, coagulase negative staphylococci, and H. influenzae dominated in the upper airways of patients with CF. In patients with PCD, H. influenzae, S. pneumoniae, and P. aeruginosa dominated. When studies that included...
Full Text Available Background: Glucose transporter type 1 deficiency syndrome is due to de novo mutations in the SLC2A1 gene encoding the glucose transporter type 1. Phenomenology Shown: Paroxysmal motor manifestations induced by exercise or fasting may be the main manifestations of glucose transporter type 1 deficiency syndrome. Educational Value: Proper identification of the paroxysmal events and early diagnosis is important since the disease is potentially treatable.
Alanin, Mikkel Christian; Johansen, Helle Krogh; Aanaes, Kasper
effect of combined endoscopic sinus surgery (ESS) and concomitant medical treatment. Objectives: The purpose of this research, which is the first study addressing bacteriology in the sinuses of patients with PCD, was to examine the association between sinus and lung infections. Methods: We reviewed...... patients (88%) exhibited intermittent or chronic pulmonary infection with P. aeruginosa. Sinus cultures were obtained during ESS in seven patients. The sinuses were colonized with P. aeruginosa in four of seven patients (57%). Bacterial sinusitis was found in five of seven patients (71%) and the same...... findings of bacterial pathogens from the sinuses obtained during ESS and the lung infection status in eight PCD patients over a 6 year period. Precipitins against P. aeruginosa were used as a marker of severity of chronic infection and effect of treatment. Results: Preoperatively, seven of the eight...
Full Text Available Background. Breast carcinoma is the most common malignancy in women worldwide. It is most commonly associated with metastases to the liver, lung, bone, and the brain. Invasive lobular carcinoma is a less common pathology with slightly higher metastases to the upper gastrointestinal tract. Invasive lobular carcinoma metastasis to the gallbladder is extremely rare. Method. In this paper we are presenting a case of a 67-year-old female with metastases of invasive lobular breast cancer to the gallbladder six years after her therapy. Conclusion. This case clearly signifies the nature of the micrometastatic foci of the invasive lobular carcinoma even many years after a successful treatment.
Eggink, H.; Kremer, D.; Brouwer, O. F.; Contarino, M. F.; van Egmond, M. E.; Elema, A.; Folmer, K.; van Hoorn, J. F.; van de Pol, L. A.; Roelfsema, Vincent; Tijssen, M. A. J.
Objective: Cerebral palsy (CP) can be classified as spastic, dyskinetic, ataxic or combined. Correct classification is essential for symptom-targeted treatment. This study aimed to investigate agreement among professionals on the phenotype of children with CP based on standardized videos. Methods:
Conclusions: Depression, anxiety, and low levels of quality of life were prevalent in patients with PKD. Co-occurrence of depression and anxiety was common among these patients. Regular mental health interventions could set depression and anxiety as intervention targets. Considering that the motor episodes could be elicited by voluntary movements and sometimes also by emotional stress, and that symptoms may get worsened with longer duration and higher frequency when patients are stressed out, intervention or treatment of depression and anxiety might improve the motor symptoms and overall quality of life in PKD patients.
Kumar Jha, Pawan; Bouâouda, Hanan; Gourmelen, Sylviane; Dumont, Stephanie; Fuchs, Fanny; Goumon, Yannick; Bourgin, Patrice; Kalsbeek, A.; Challet, Etienne
Circadian rhythms in nocturnal and diurnal mammals are primarily synchronized to local time by the light-dark cycle. However, non-photic factors, such as behavioural arousal and metabolic cues, can also phase-shift the master clock in the suprachiasmatic nuclei (SCN) and/or reduce the synchronizing
Full Text Available In the initial alignment process of strapdown inertial navigation system (SINS, large initial misalignment angles always bring nonlinear problem, which causes alignment failure when the classical linear error model and standard Kalman filter are used. In this paper, the problem of large misalignment angles in SINS initial alignment is investigated, and the key reason for alignment failure is given as the state covariance from Kalman filter cannot represent the true one during the steady filtering process. According to the analysis, an alignment method for SINS based on multiresetting the state covariance matrix of Kalman filter is designed to deal with large initial misalignment angles, in which classical linear error model and standard Kalman filter are used, but the state covariance matrix should be multireset before the steady process until large misalignment angles are decreased to small ones. The performance of the proposed method is evaluated by simulation and car test, and the results indicate that the proposed method can fulfill initial alignment with large misalignment angles effectively and the alignment accuracy of the proposed method is as precise as that of alignment with small misalignment angles.
Long, Shibing; Perniola, Luca; Cagli, Carlo; Buckley, Julien; Lian, Xiaojuan; Miranda, Enrique; Pan, Feng; Liu, Ming; Suñé, Jordi
...) is promising in novel memory and logic device applications. Understanding the physics of RS and the nature of CF is of utmost importance to control the performance, variability and reliability of resistive switching memory (RRAM...
Habraken, Milou Maria Petronella; Bondarouk, Tatiana; Bondarouk, Tanya; Ruel, Huub; Parry, Emma
Purpose – This chapter aims to encourage and guide Smart Industry HRM-related research by addressing upcoming challenges developed using a Job Design lens. Methodology/approach – The challenges are constructed based on a developed overview of the existing body of work related to Job Design and a
Full Text Available BACKGROUND: Signals generated by the inflammed intestine are thought to contribute to metabolic derangement. The intestinal microbiota contributes to instructing the immune system beyond the intestinal wall and its modulation is a potential target for treating systemic disorders. AIMS: To investigate the pathogenetic role of low grade intestinal inflammation in the development of steatohepatitis and atherosclerosis in a model of genetic dyslipidemia and to test the therapeutic potential of a probiotics intervention in protecting against development of these disorders. RESULTS: ApoE(-/- mice were randomized to receive vehicle or VSL#3, a mixture of eight probiotics, at the dose of 20×10(9 colony-forming units/kg/day for three months alone or in combination with 0.2% of dextran sulfate sodium (DSS in drinking water. Administering DSS to ApoE(-/- mice failed to induce signs and symptoms of colitis but increased intestinal permeability to dextran FITC and, while had no effect on serum lipids, increased the blood levels of markers of liver injury and insulin resistance. DSS administration associated with low level inflammation of intestinal and mesenteric adipose tissues, caused liver histopathology features of steatohepatitis and severe atherosclerotic lesions in the aorta. These changes were prevented by VSL#3 intervention. Specifically, VSL#3 reversed insulin resistance, prevented development of histologic features of mesenteric adipose tissue inflammation, steatohepatitis and reduced the extent of aortic plaques. Conditioned media obtained from cultured probiotics caused the direct transactivation of peroxisome proliferator-activated receptor-γ, Farnesoid-X-receptors and vitamin D receptor. CONCLUSIONS: Low grade intestinal inflammation drives a transition from steatosis to steatohepatitis and worsens the severity of atherosclerosis in a genetic model of dyslipidemia. VSL#3 intervention modulates the expression of nuclear receptors, corrects for insulin resistance in liver and adipose tissues and protects against development of steatohepatitis and atherosclerosis.
METASYS (extended architecture ) platform. The three-month demonstration showed approximately 37% of fan energy savings for the TTR method and...Local utilities may have different rate structures for the demonstration sites, and often energy use charge is only a (sometimes small) portion of the...number is based on the “Base Structure Report – Fiscal Year 2015 Baseline” [DoD, 2016]. Projected annual energy cost savings are estimated based on
Acoustic CR neuromodulation caused the longest significant reduction of delta and gamma and increase of alpha power in the auditory cortex region. Noisy CR-like stimulation had weaker and LFR stimulation hardly any electrophysiological after-effects. This qualitative difference further supports the assertion that long-term effects of acoustic CR neuromodulation on tinnitus are mediated by a specific disruption of synchronous neural activity. Furthermore, our results indicate that acute electrophysiological after-effects might serve as a marker to further improve desynchronizing sound stimulation.
Galíndez, G; Seal, C E; Daws, M I; Lindow, L; Ortega-Baes, P; Pritchard, H W
Thermal time models for seed germination assume a continuum of rate responses in the sub-optimal temperature range. Generally, the models describe germination performance in non-dormant seeds at constant temperatures, yet alternating temperature (AT) is a feature of many natural environments. We studied the possible interacting effects of AT on germination progress in photoblastic seeds of three aromatic-medicinal Verbenaceae species in the genera Lippia and Aloysia. For Lippia turbinata f. turbinata and L. turbinata f. magnifolia seed, germination only occurred in light conditions, while for L. integrifolia and Aloysia citriodora it was significantly higher in the light than in darkness. Although relative light germination (RLG) was not different between constant and AT in the sub-optimal range, AT raised the base temperature for germination progress (Tb ) from ca. 3-6 °C in constant temperature to 7-12 °C in AT. Among the species, thermal time for 50% seed germination [θT(50) ] was 55-100 °Cd at constant temperature. Although AT resulted in slight modifications to θT(50) , the germination rate at comparable average temperatures in the sub-optimal range was slower than under constant temperatures. For all species, the proportion of germinated seeds was similar for constant and AT. Our results suggest that an interaction between cool temperature and darkness during AT treatment limits the temperature range permissive for germination in these positively photoblastic seed, reflecting both close adaptation to the natural ecology and niche requirements of the species. © 2016 German Botanical Society and The Royal Botanical Society of the Netherlands.
Zou, L; Jankovic, J; Rowe, D B; Xie, W; Appel, S H; Le, W
Pramipexole, a novel non-ergoline dopamine (DA) agonist, has been applied successfully for treatment of Parkinson's disease (PD). We report here that pramipexole can protect dopaminergic cell line Mes23.5 against dopamine- and levodopa-induced cytotoxicity possibly through a mechanism related to antioxidant activity. In the MES 23.5 cultures, DA and L-DOPA induce a dose- and time-dependent cytotoxicity, as determined by tetrazolium salt and trypan blue assays. Furthermore, an in situ terminal deoxynucleotidyl transferase assay demonstrates that DA-induced cell death is apoptotic. Pretreatment with pramipexole in a concentration range (4-100 microM) significantly attenuates DA- or L-DOPA-induced cytotoxicity and apoptosis, an action which is not blocked by D3 antagonist U-99194 A or D2 antagonist raclopride. Pramipexole also protects MES 23.5 cells from hydrogen peroxide-induced cytotoxicity in a dose-dependent manner. In cell-free system, pramipexole can effectively inhibit the formation of melanin, an end product resulting from DA or L-DOPA oxidation. These results indicate that pramipexole exerts its neuroprotective effect possibly through a mechanism, which is independent of DA receptors but related to antioxidation or scavenging of free radicals (e.g. hydrogen peroxide). As a direct DA agonist and potentially neuroprotective agent, pramipexole remains attractive in the treatment of PD.
Alanin, Mikkel Christian; Aanaes, Kasper; Hoiby, Niels
patients (62%). Four patients with preoperative P. aeruginosa lung colonization (25%) had no regrowth during follow-up; 2 of these had P. aeruginosa sinusitis. Sinonasal symptoms were improved 12 months after ESS and we observed a trend toward better lung function after ESS. Conclusion We demonstrated...... an improvement in CRS-related symptoms after ESS and adjuvant therapy. In selected PCD patients, the suggested regimen may postpone chronic lung infection with P. aeruginosa and stabilize lung function....
Dodel, Richard C; Karin Berger; Oertel, Wolfgang H.
Idiopathic Parkinson's disease (PD) is a common chronic progressive neurodegenerative disorder associated with the progressive loss of dopaminergic neurons in the substantia nigra. The natural course of the disease may lead to severe disability despite a variety of pharmacological and surgical treatment options. Levodopa is still the most effective symptomatic treatment for PD; however, long term use can cause a number of adverse effects including motor complications, nausea and vomiting, pos...
Deepmala Thakur; Basavraj Motimath; Raghavendra M
Background: Forward head posture (FHP), the most common deviation from the normal curvature in cervical spine. Craniocervical flexor muscle strengthening is frequently used treatment for FHP. Scapular dykinesia (SD) is the alteration in the normal static or dynamic motion of the scapula during coupled scapulohumeral movements. Shoulder stabilization exercises are an effective treatment for SD. As both FHP and SD are related to each other, the objective of the study was to find and compare the...
Portman, AT; van Laar, T; Staal, MJ; Rutgers, AWF; Journee, HL; Leenders, KL
We assessed the efficacy of chronic stimulation of the subthalamic nucleus (STN-DBS) in 20 patients with Parkinson's disease (PD) by means of clinical assessments and patient diaries 12 months after surgery. STN-DBS reduced the UPDRS part III off-medication score by 33%, and successively improved
Fuchs, Oliver; Pfarr, Nicole; Pohlenz, Joachim; Schmidt, Heinrich
"Monocarboxylate transporter 8" ("MCT8" or SLC16A2) is important for the neuronal uptake of triiodothyronine (T3) in its function as a specific and active transporter of thyroid hormones across the cell membrane, thus being essential for human brain development. We report on a German male with Allan-Herndon-Dudley syndrome…
Munkholm, Mathias; Nielsen, Kim Gjerum; Mortensen, Jann
primarily to results from nasal ciliary function testing, to electron microscopic (EM) examination of the ultrastructure of the cilia, and to the final clinical diagnosis. RESULTS: Of the 239 patients, 27 ended up with a final clinical diagnosis of definitive PCD. No patients with a PRMC test...... a high rate of conclusive results (90 %). Children test providing evaluation of the mucociliary clearance...... of the entire lung. Its greatest strength is its ability to reject a suspected PCD diagnosis with great certainty. In our material, this accounted for 2/3 of referred patients. In addition, the test has a high rate of conclusive results. According to our analyses, reference equations on children would benefit...
Baumann, Michèle; Amara, Marie-Emmanuelle; Haas, Claude
Faire de la prison un temps utile (formation, éducation, santé) pour favoriser la réinsertion et limiter la récidive résume les règles pénitentiaires européennes et les recommandations du Conseil de l’Europe. Aujourd'hui, la prison a pour mission l’exécution des peines, mais aussi celle de préparer les individus à chercher, trouver et conserver un emploi. Formation, éducation, travail en ateliers, régime de la semi-liberté sont des activités proposées aux détenus du Centre Pénitentiaire de Gi...
Reilly, Timothy J.; Focazio, Michael J.; Simmons, Dale L.
In the immediate aftermath of natural disasters, public health officials and other first responders engage in many activities to protect the public and ecosystems in the affected area. These activities include critical tasks designed to minimize adverse consequences resulting from chemical and microbial contaminant exposures, such as acute disease incidence and transmission. However, once these urgent priorities have been met and situations requiring immediate attention have been stabilized, questions regarding the potential longer term threats to humans and ecosystems associated with persistent contaminant exposures remain. Research conducted to address these questions is frequently challenged by the lack of available baseline contaminant information collected before the event for comparison and perspective. In addition, deployments of field crews and collection of environmental samples typically occur days, weeks, or months after the event. Consequently, during and in the aftermath of disasters, public health agencies commonly advise the public to disinfect water, avoid contact with disturbed infrastructure (such as sewer lines), and (or) refrain from use of recreational waters, with the general focus on acute health threats; however, the persisting effects of such releases on local recreational waters, fisheries, and other estuarine habitats are often undetermined.
Full Text Available Somatic cells reprogrammed into induced pluripotent stem cells (iPSCs acquire features of human embryonic stem cells (hESCs and thus represent a promising source for cellular therapy of debilitating diseases, such as age-related disorders. However, reprogrammed cell lines have been found to harbor various genomic alterations. In addition, we recently discovered that the mitochondrial DNA of human fibroblasts also undergoes random mutational events upon reprogramming. Aged somatic cells might possess high susceptibility to nuclear and mitochondrial genome instability. Hence, concerns over the oncogenic potential of reprogrammed cells due to the lack of genomic integrity may hinder the applicability of iPSC-based therapies for age-associated conditions. Here, we investigated whether aged reprogrammed cells harboring chromosomal abnormalities show resistance to apoptotic cell death or mitochondrial-associated oxidative stress, both hallmarks of cancer transformation. Four iPSC lines were generated from dermal fibroblasts derived from an 84-year-old woman, representing the oldest human donor so far reprogrammed to pluripotency. Despite the presence of karyotype aberrations, all aged-iPSCs were able to differentiate into neurons, re-establish telomerase activity, and reconfigure mitochondrial ultra-structure and functionality to a hESC-like state. Importantly, aged-iPSCs exhibited high sensitivity to drug-induced apoptosis and low levels of oxidative stress and DNA damage, in a similar fashion as iPSCs derived from young donors and hESCs. Thus, the occurrence of chromosomal abnormalities within aged reprogrammed cells might not be sufficient to over-ride the cellular surveillance machinery and induce malignant transformation through the alteration of mitochondrial-associated cell death. Taken together, we unveiled that cellular reprogramming is capable of reversing aging-related features in somatic cells from a very old subject, despite the presence of genomic alterations. Nevertheless, we believe it will be essential to develop reprogramming protocols capable of safeguarding the integrity of the genome of aged somatic cells, before employing iPSC-based therapy for age-associated disorders.
Atkins, Norman, Jr.
Intercellular signaling is vital to communication within neuronal circuits. The suprachiasmatic nucleus (SCN), the master circadian clock of mammals, contains a dense collection of neurons that align their intrinsic rhythmicity with environmental stimulus and physiological state. While peptide physiology has been demonstrated as a contributor to…
Distrutti, Eleonora; O'Reilly, Julie-Ann; McDonald, Claire; Cipriani, Sabrina; Renga, Barbara; Lynch, Marina A; Fiorucci, Stefano
The intestinal microbiota is increasingly recognized as a complex signaling network that impacts on many systems beyond the enteric system modulating, among others, cognitive functions including learning, memory and decision-making processes. This has led to the concept of a microbiota-driven gut-brain axis, reflecting a bidirectional interaction between the central nervous system and the intestine. A deficit in synaptic plasticity is one of the many changes that occurs with age. Specifically, the archetypal model of plasticity, long-term potentiation (LTP), is reduced in hippocampus of middle-aged and aged rats. Because the intestinal microbiota might change with age, we have investigated whether the age-related deficit in LTP might be attenuated by changing the composition of intestinal microbiota with VSL#3, a probiotic mixture comprising 8 Gram-positive bacterial strains. Here, we report that treatment of aged rats with VSL#3 induced a robust change in the composition of intestinal microbiota with an increase in the abundance of Actinobacteria and Bacterioidetes, which was reduced in control-treated aged rats. VSL#3 administration modulated the expression of a large group of genes in brain tissue as assessed by whole gene expression, with evidence of a change in genes that impact on inflammatory and neuronal plasticity processes. The age-related deficit in LTP was attenuated in VSL#3-treated aged rats and this was accompanied by a modest decrease in markers of microglial activation and an increase in expression of BDNF and synapsin. The data support the notion that intestinal microbiota can be manipulated to positively impact on neuronal function.
Oh, Myongkeun; Matveev, Victor
Phase response is a powerful concept in the analysis of both weakly and non-weakly perturbed oscillators such as regularly spiking neurons, and is applicable if the oscillator returns to its limit cycle trajectory between successive perturbations. When the latter condition is violated, a formal application of the phase return map may yield phase values outside of its definition domain; in particular, strong synaptic inhibition may result in negative values of phase. The effect of a second perturbation arriving close to the first one is undetermined in this case. However, here we show that for a Morris-Lecar model of a spiking cell with strong time scale separation, extending the phase response function definition domain to an additional negative value branch allows to retain the accuracy of the phase response approach in the face of such strong inhibitory coupling. We use the resulting extended phase response function to accurately describe the response of a Morris-Lecar oscillator to consecutive non-weak synaptic inputs. This method is particularly useful when analyzing the dynamics of three or more non-weakly coupled cells, whereby more than one synaptic perturbation arrives per oscillation cycle into each cell. The method of perturbation prediction based on the negative-phase extension of the phase response function may be applicable to other excitable cell models characterized by slow voltage dynamics at hyperpolarized potentials.
Juel, Jacob; Olesen, Søren Schou; Olesen, Anne Estrup
INTRODUCTION: Chronic pancreatitis (CP) is an inflammatory disease that causes irreversible damage to pancreatic tissue. Pain is its most prominent symptom. In the absence of pathology suitable for endoscopic or surgical interventions, pain treatment usually includes opioids. However, opioids oft...
Dulfano, Isabel; Rubio, Fernando
The objective of this paper is to trace the actual demand on enrolments over time, as much as the history of wavering public and academic sentiment towards teaching and speaking Spanish in this country during the last century. Secondarily, we examine the question of the value of mother tongue fluency or the acquisition, mastery and usage of the…
Sebert, S P; Dellschaft, N S; Chan, L L Y; Street, H; Henry, M; Francois, C; Sharma, V; Fainberg, H P; Patel, N; Roda, J; Keisler, D; Budge, H; Symonds, M E
Fetal growth restriction followed by accelerated postnatal growth contributes to impaired metabolic function in adulthood. The extent to which these outcomes may be mediated centrally within the hypothalamus, as opposed to in the periphery within the digestive tract, remains unknown. In a sheep model, we achieved intrauterine growth restriction experimentally by maternal nutrient restriction (R) that involved a 40% reduction in food intake through late gestation. R offspring were then either reared singly to accelerate postnatal growth (RA) or as twins and compared with controls also reared singly. From weaning, all offspring were maintained indoors until adulthood. A reduced litter size accelerated postnatal growth for only the first month of lactation. Independently from postnatal weight gain and later fat mass, R animals developed insulin resistance as adults. However, restricted accelerated offspring compared with both the control accelerated and restricted restricted offspring ate less and had higher fasting plasma leptin as adults, an adaptation which was accompanied by changes in energy sensing and cell proliferation within the abomasum. Additionally, although fetal restriction down-regulated gene expression of mammalian target of rapamycin and carnitine palmitoyltransferase 1-dependent pathways in the abomasum, RA offspring compensated for this by exhibiting greater activity of AMP-activated kinase-dependent pathways. This study demonstrates a role for perinatal nutrition in the peripheral control of food intake and in energy sensing in the gastric mucosal and emphasizes the importance of diet in early life in regulating energy metabolism during adulthood.
Escobar, Mª Ángeles
A positive approach to Second Language (L2) acquisition is to follow Chomsky's (1981) Principles and Parameters theory. Following the latest approach of the Minimalist Program (Chomsky 1995), the question of whether language acquisition involves the acquisition of morphological features that define a particular language is discussed. We would also like to examine age-related effects (Birdsong 2000) and L2 development in the acquisition of one particular linguistic phenomenon, relative clauses...
Rubattu, Speranza; Triposkiadis, Filippos
The natriuretic peptide (NP) system, which includes atrial natriuretic peptide, B-type natriuretic peptide, and C-type natriuretic peptide, has an important role in cardiovascular homeostasis, promoting a number of physiological effects including diuresis, vasodilation, and inhibition of the renin-angiotensin-aldosterone system. Heart failure (HF) is associated with defects in NP processing and synthesis, and there is a strong relationship between NP levels and disease state. NPs are useful biomarkers in HF, and their use in diagnosis and evaluation of prognosis is well established, particularly in patients with HF with reduced ejection fraction (HFrEF). There has also been interest in their use to guide disease management and therapeutic decision making. An understanding of NPs in HF has also resulted in interest in synthetic NPs for the treatment of HF and in treatments that target neprilysin, a protease that degrades NPs. A novel drug, the angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696), which simultaneously inhibits neprilysin and blocks the angiotensin II type I receptor, was shown to have a favorable efficacy and safety profile in patients with HFrEF and has been approved for use in such patients in Europe and the USA. In light of the development of treatments that target neprilysin and of recent data in relation to synthetic NPs, it is timely to review the current understanding of the role of NPs in HF and their use in diagnosis, evaluating prognosis and guiding treatment, as well as their place in HF therapy.
Sharyl N. Cross Dr.
Full Text Available Russia has been targeted with a series of terrorist attacks over the past several years, and there are a growing number of extremist groups operating throughout Russia’s society utilizing the Internet/social media to promote their narratives and objectives. Russia’s policy community has created institutional mechanisms and laws to address the challenge of violent extremism in the Internet/social media, and recognizes the importance of international cooperation toward these ends. This study, based on primary research conducted in Moscow in 2012, defines Russia’s assessment of domestic and international sources violent extremist threats; explains Moscow’s perspective on balancing democratic principles with the challenge of countering violent extremism in the Internet/social media; assesses existing capacities and impediments to further international collaboration with Russia in countering violent extremism in the Internet/social media spheres; defines specific initiatives that Russia, the United States, and other nations of the world community could advance to enhance international cooperation in countering violent extremism throughout the world cyber community.
Kattenstroth, Jan C; Kalisch, Tobias; Sczesny-Kaiser, Matthias; Greulich, Wolfgang; Tegenthoff, Martin; Dinse, Hubert R
Repetitive sensory stimulation (RSS) adapts the timing of stimulation protocols used in cellular studies to induce synaptic plasticity. In healthy subjects, RSS leads to widespread sensorimotor cortical reorganization paralleled by improved sensorimotor behavior. Here, we investigated whether RSS reduces sensorimotor upper limb impairment in patients with subacute stroke more effectively than conventional therapy. A single-blinded sham-controlled clinical trial assessed the effectiveness of RSS in treating sensorimotor deficits of the upper limbs. Patients with subacute unilateral ischemic stroke were randomly assigned to receive standard therapy in combination with RSS or with sham RSS. Patients were masked to treatment allocation. RSS consisted of intermittent 20 Hz electrical stimulation applied on the affected hand for 45 min/day, 5 days per week, for 2 weeks, and was transmitted using custom-made stimulation-gloves with built-in electrodes contacting each fingertip separately. Before and after the intervention, we assessed light-touch and tactile discrimination, proprioception, dexterity, grip force, and subtasks of the Jebsen Taylor hand-function test for the non-affected and the affected hand. Data from these quantitative tests were combined into a total performance index serving as primary outcome measure. In addition, tolerability and side effects of RSS intervention were recorded. Seventy one eligible patients were enrolled and randomly assigned to receive RSS treatment (n = 35) or sham RSS (n = 36). Data of 25 patients were not completed because they were transferred to another hospital, resulting in n = 23 for each group. Before treatment, sensorimotor performance between groups was balanced (p = 0.237). After 2 weeks of the intervention, patients in the group receiving standard therapy with RSS showed significantly better restored sensorimotor function than the control group (standardized mean difference 0.57; 95% CI -0.013-1.16; p = 0.027) RSS treatment was superior in all domains tested. Repetitive sensory stimulation was well tolerated and accepted, and no adverse events were observed. Rehabilitation including RSS enhanced sensorimotor recovery more effectively than standard therapy alone. Rehabilitation outcome between the effects of RSS and standard therapy was largest for sensory and motor improvement; however, the results for proprioception and everyday tasks were encouraging warranting further studies in more severe patients. The trial was retrospectively registered January 31, 2012 under DRKS00003515 ( https://www.drks.de/drks_web/navigate.do;jsessionid=AEE2585CCB82A22A2B285470B37C47C8?navigationId=results ).
Lowe, J. J.; Ramsey, C. B.; Housley, R. A.; Lane, C. S.; Tomlinson, E. L.; Stringer, C.; Davies, W.; Barton, N.; Pollard, M.; Gamble, C.; Menzies, M.; Rohling, E.; Roberts, A.; Blockley, S.; Cullen, V.; Grant, K.; Lewis, M.; MacLeod, A.; White, D.; Albert, P.; Hardiman, M.; Lee, S.; Oh, A.; Satow, C.; Cross, J. K.; Bramham Law, C.; Todman, A.; Bourne, A.; Matthews, I.; Müller, W.; Smith, V.; Wulf, S.; Anghelinu, M.; Antl-Weiser, W.; Bar-Yosef, O.; Borić, D.; Boscato, P.; Ronchitelli, A.; Chabai, V.; Veselsky, A.; Uthmeier, T.; Farrand, W.; Gjipali, I.; Ruka, R.; Güleç, E.; Karavanić, I.; Karkanas, P.; King, T.; Komšo, D.; Koumouzelis, M.; Kyparissi, N.; Lengyel, G.; Mester, Z.; Neruda, P.; Nigst, P.; Haesaerts, P.; Panagopoulou, E.; Shalamanov-Korobar, L.; Tolevski, I.; Sinitsyn, A.; Sirakov, N.; Guadelli, A.; Guadelli, J.-L.; Ferrier, C.; Škrdla, Petr; Slimak, L.; Soler, N.; Soller, J.; Soressi, M.; Tushabramishvilii, N.; Zilhão, J.; Angelucci, D.; Cullen, V. L.; Lincoln, P.; Staff, R.; Flower, K.; Aouadi-Abdeljaouad, N.; Belhouchet, L.; Barker, G.; Bouzouggar, A.; Van Peer, P.; Kindermann, K.; Gerken, K.; Niemann, H.; Tipping, R.; Saville, A.; Ward, T.; Clausen, I.; Weber, M.-J.; Kaiser, K.; Torksdorf, J. F.; Turner, F.; Veil, S.; Nygaard, N.; Pyne-O'Donnel, S. D. F.; Masojć, M.; Nalepka, D.; Jurochnik, A.; Kabaciński, J.; Antoine, P.; Olive, M.; Christensen, M.; Bodu, P.; Debout, G.; Orliac, M.; De Bie, M.; Van Gils, M.; Paulissen, E.; Brou, L.; Leesch, D.; Hadorn, P.; Thew, N.; Riede, F.; Heinen, M.; Joris, O.; Richter, J.; Knipping, M.; Stika, H.-P.; Friedrich, M.; Conard, N. J.; Malina, M.; Kind, C.-J.; Beutelspacher, T.; Mortensen, M. F.; Burdukiewicz, J. M.; Szynkiewicz, A.; Połtowicz-Bobak, M.; Bobak, D.; Wiśniewski, A.; Przeździecki, M.; Valde-Nowak, P.; Muzyczuk, A.; Davies, L.; Morgan, P.; Aydar, E.; Çubukçu, E.; Brown, R.; Coltelli, M.; Lo Castro, D.; Cioni, R.; DeRosa, R.; Donato, P.; Di Roberto, A.; Gertisser, R.; Giordano, G.; Branney, M.; Jordan, N.; Keller, J.; Kinvig, H.; Gottsman, J.; Blundy, J.; Marani, M.; Orsi, G.; Civetta, L.; Arienzo, I.; Carandente, A.; Rosi, M.; Zanchetta, G.; Seghedi, I.; Szakacs, A.; Sulpizio, R.; Thordarson, T.; Trincardi, F.; Vigliotti, L.; Asioli, A.; Piva, A.; Andrič, M.; Brauer, A.; de Klerk, P.; Filippi, M.-L.; Finsinger, W.; Galović, L.; Jones, T.; Lotter, A.; Müller, U.; Pross, J.; Mangerud, J.; Lohne, Ø.; Pyne-O'Donnell, S.; Markovic, S.; Pini, R.; Ravazzi, C.; Theuerkauf, M.; Tzedakis, C.; Margari, V.; Veres, D.; Wastegård, S.; Ortiz, J. E.; Torres, T.; Díaz-Bautista, A.; Moreno, A.; Valero-Garcés, B.; Lowick, S.; Ottolini, L.
Roč. 118, 15 June 2015 (2015), s. 1-17 ISSN 0277-3791 Institutional support: RVO:68081758 Keywords : Last Glacial stage * Dansgaard-Oeschger and Heinrich events * Abrupt environmental transitions (AETs) * Middle to Upper Palaeolithic * Volcanic ash isochrons * Tephra geochemistry * Tephra database Subject RIV: AC - Archeology, Anthropology, Ethnology Impact factor: 4.521, year: 2015
Full Text Available The intestinal microbiota is increasingly recognized as a complex signaling network that impacts on many systems beyond the enteric system modulating, among others, cognitive functions including learning, memory and decision-making processes. This has led to the concept of a microbiota-driven gut-brain axis, reflecting a bidirectional interaction between the central nervous system and the intestine. A deficit in synaptic plasticity is one of the many changes that occurs with age. Specifically, the archetypal model of plasticity, long-term potentiation (LTP, is reduced in hippocampus of middle-aged and aged rats. Because the intestinal microbiota might change with age, we have investigated whether the age-related deficit in LTP might be attenuated by changing the composition of intestinal microbiota with VSL#3, a probiotic mixture comprising 8 Gram-positive bacterial strains. Here, we report that treatment of aged rats with VSL#3 induced a robust change in the composition of intestinal microbiota with an increase in the abundance of Actinobacteria and Bacterioidetes, which was reduced in control-treated aged rats. VSL#3 administration modulated the expression of a large group of genes in brain tissue as assessed by whole gene expression, with evidence of a change in genes that impact on inflammatory and neuronal plasticity processes. The age-related deficit in LTP was attenuated in VSL#3-treated aged rats and this was accompanied by a modest decrease in markers of microglial activation and an increase in expression of BDNF and synapsin. The data support the notion that intestinal microbiota can be manipulated to positively impact on neuronal function.
Mormann, F.; Fell, J.; Axmacher, N.; Weber, B.; Lehnertz, K.; Elger, C.E.; Fernandez, G.S.E.
We analyzed intracranial electroencephalographic (EEG) recordings from the medial temporal lobes of 12 epilepsy patients during a continuous word recognition paradigm, contrasting trials of correctly recognized repeated words (hits) and correctly identified new words (correct rejections). Using a
Mouza, Chrystalla; Yang, Hui; Pan, Yi-Cheng; Ozden, Sule Yilmaz; Pollock, Lori
This study presents the design of an educational technology course for pre-service teachers specific to incorporating computational thinking in K-8 classroom settings. Subsequently, it examines how participation in the course influences pre-service teachers' dispositions and knowledge of computational thinking concepts and the ways in which such…