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Sample records for striatal fdopa ki

  1. Automated striatal uptake analysis of 18F-FDOPA PET images applied to Parkinson's disease patients

    International Nuclear Information System (INIS)

    Chang Icheng; Lue Kunhan; Hsieh Hungjen; Liu Shuhsin; Kao, Chinhao K.

    2011-01-01

    6-[ 18 F]Fluoro-L-DOPA (FDOPA) is a radiopharmaceutical valuable for assessing the presynaptic dopaminergic function when used with positron emission tomography (PET). More specifically, the striatal-to-occipital ratio (SOR) of FDOPA uptake images has been extensively used as a quantitative parameter in these PET studies. Our aim was to develop an easy, automated method capable of performing objective analysis of SOR in FDOPA PET images of Parkinson's disease (PD) patients. Brain images from FDOPA PET studies of 21 patients with PD and 6 healthy subjects were included in our automated striatal analyses. Images of each individual were spatially normalized into an FDOPA template. Subsequently, the image slice with the highest level of basal ganglia activity was chosen among the series of normalized images. Also, the immediate preceding and following slices of the chosen image were then selected. Finally, the summation of these three images was used to quantify and calculate the SOR values. The results obtained by automated analysis were compared with manual analysis by a trained and experienced image processing technologist. The SOR values obtained from the automated analysis had a good agreement and high correlation with manual analysis. The differences in caudate, putamen, and striatum were -0.023, -0.029, and -0.025, respectively; correlation coefficients 0.961, 0.957, and 0.972, respectively. We have successfully developed a method for automated striatal uptake analysis of FDOPA PET images. There was no significant difference between the SOR values obtained from this method and using manual analysis. Yet it is an unbiased time-saving and cost-effective program and easy to implement on a personal computer. (author)

  2. Single cocaine exposure does not alter striatal pre-synaptic dopamine function in mice: an [18 F]-FDOPA PET study.

    Science.gov (United States)

    Bonsall, David R; Kokkinou, Michelle; Veronese, Mattia; Coello, Christopher; Wells, Lisa A; Howes, Oliver D

    2017-12-01

    Cocaine is a recreational drug of abuse that binds to the dopamine transporter, preventing reuptake of dopamine into pre-synaptic terminals. The increased presence of synaptic dopamine results in stimulation of both pre- and post-synaptic dopamine receptors, considered an important mechanism by which cocaine elicits its reinforcing properties. However, the effects of acute cocaine administration on pre-synaptic dopamine function remain unclear. Non-invasive imaging techniques such as positron emission tomography have revealed impaired pre-synaptic dopamine function in chronic cocaine users. Similar impairments have been seen in animal studies, with microdialysis experiments indicating decreased basal dopamine release. Here we use micro positron emission tomography imaging techniques in mice to measure dopamine synthesis capacity and determine the effect of acute cocaine administration of pre-synaptic dopamine function. We show that a dose of 20 mg/kg cocaine is sufficient to elicit hyperlocomotor activity, peaking 15-20 min post treatment (p cocaine treatment (KiCer: 0.0097 per min vs. 0.0112 per min in vehicle controls, p > 0.05). Furthermore, expression levels of two key enzymes related to dopamine synthesis, tyrosine hydroxylase and aromatic l-amino acid decarboxylase, within the striatum of scanned mice were not significantly affected by acute cocaine pre-treatment (p > 0.05). Our findings suggest that while the regulation of dopamine synthesis and release in the striatum have been shown to change with chronic cocaine use, leading to a reduced basal tone, these adaptations to pre-synaptic dopaminergic neurons are not initiated following a single exposure to the drug. © 2017 International Society for Neurochemistry.

  3. Reduced Uptake of FDOPA PET in End-Stage Liver Disease with Elevated Manganese Levels

    Science.gov (United States)

    Criswell, Susan R; Perlmutter, Joel S; Crippin, Jeffrey S; Videen, Tom O; Moerlein, Stephen M; Flores, Hubert P; Birke, Angela M; Racette, Brad A

    2013-01-01

    Objective To investigate whether manganese toxicity secondary to end state liver disease is associated with nigrastriatal dysfunction as measured by 6-[18F]fluoro-L-DOPA (FDOPA) PET imaging. Design Observational case report. Setting The Movement Disorder Center at Washington University in St. Louis. Patients An individual with manganese toxicity secondary to end stage liver disease. His FDOPA PET was compared with those of 10 idiopathic Parkinson disease patients and 10 age- and sex-matched healthy controls. Main Outcome Measure The average estimated net FDOPA uptake by Patlak graphical analysis for caudate, anterior putamen and posterior putamen. Results The FDOPA uptake for the patient with secondary manganese toxicity was reduced across all regions by more than 2 SDs compared with healthy controls: caudate (reduced 24.7%), anterior putamen (28.0%), and posterior putamen (29.3%). The ratio of uptake between the caudate/posterior putamen was 0.99 and was different from that of idiopathic Parkinson disease patients, in whom the greatest reduction of FDOPA was in the posterior putamen (mean [SD] ratio, 1.65 [0.41]). Conclusions Reduce striatal uptake of FDOPA uptake indicates dysfunction of the nigrostriatal pathways in manganese toxicity secondary to end stage liver disease. The pattern of striatal involvement with equal reduction of FDOPA uptake in the caudate compared with posterior putamen appears different from those previously reported in individuals with occupational manganese toxicity and idiopathic Parkinson disease and may be specific to manganese toxicity secondary to end stage liver disease. PMID:22410448

  4. Automated image registration for FDOPA PET studies

    International Nuclear Information System (INIS)

    Kang-Ping Lin; Sung-Cheng Huang, Dan-Chu Yu; Melega, W.; Barrio, J.R.; Phelps, M.E.

    1996-01-01

    In this study, various image registration methods are investigated for their suitability for registration of L-6-[18F]-fluoro-DOPA (FDOPA) PET images. Five different optimization criteria including sum of absolute difference (SAD), mean square difference (MSD), cross-correlation coefficient (CC), standard deviation of pixel ratio (SDPR), and stochastic sign change (SSC) were implemented and Powell's algorithm was used to optimize the criteria. The optimization criteria were calculated either unidirectionally (i.e. only evaluating the criteria for comparing the resliced image 1 with the original image 2) or bidirectionally (i.e. averaging the criteria for comparing the resliced image 1 with the original image 2 and those for the sliced image 2 with the original image 1). Monkey FDOPA images taken at various known orientations were used to evaluate the accuracy of different methods. A set of human FDOPA dynamic images was used to investigate the ability of the methods for correcting subject movement. It was found that a large improvement in performance resulted when bidirectional rather than unidirectional criteria were used. Overall, the SAD, MSD and SDPR methods were found to be comparable in performance and were suitable for registering FDOPA images. The MSD method gave more adequate results for frame-to-frame image registration for correcting subject movement during a dynamic FDOPA study. The utility of the registration method is further demonstrated by registering FDOPA images in monkeys before and after amphetamine injection to reveal more clearly the changes in spatial distribution of FDOPA due to the drug intervention. (author)

  5. Measurement of striatal dopamine metabolism with 6-[18F]-fluoro-L-dopa and PET

    International Nuclear Information System (INIS)

    Kuwabara, Y.; Otsuka, M.; Ichiya, Y.; Yoshikai, T.; Fukumura, T.; Masuda, K.; Kato, M.; Taniwaki, T.

    1992-01-01

    Striatal dopamine metabolism was studied with 6-[ 18 F]-fluoro-L-dopa ( 18 F-DOPA) and PET. The subjects were normal controls, and patients with Parkinson's disease (PD), parkinsonism, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Alzheimer's disease (AD), Huntington's disease (HD) and other cerebral disorders. Cerebral glucose metabolism (CMRGlc) was also measured in these patients. Striatal dopamine metabolism was evaluated by the relative striatal uptake of 18 F-DOPA referring cerebellum (S/C ratio). In normal controls, the S/C ratio was 2.82 ± 0.32 (n = 6, mean ± SD) at 120 min after injection of 18 F-DOPA. The S/C ratio was low in patients with PD, parkinsonism, MSA and PSP compared to the normal controls and thus coincident with the symptoms of parkinsonism due to decrease in striatal dopamine concentration. The decrease in the striatal CMRGlc was also observed in patients with parkinsonism and PSP, and it was preserved in patients with PD, thus representing that more neurons were damaged in patients with parkinsonism and PSP than in patients with PD. A patient with AD having symptoms of parkinsonism also showed a decrease in S/C ratio. In a patient with HD, the striatal CMRGlc sharply decreased, but the S/C ratio was normal. The measurements of striatal dopamine and glucose metabolism with PET may be useful for studying the pathophysiological mechanism in patients with cerebral disorders. (author)

  6. Acute and sustained effects of methylphenidate on cognition and presynaptic dopamine metabolism: an [18F]FDOPA PET study.

    Science.gov (United States)

    Schabram, Ina; Henkel, Karsten; Mohammadkhani Shali, Siamak; Dietrich, Claudia; Schmaljohann, Jörn; Winz, Oliver; Prinz, Susanne; Rademacher, Lena; Neumaier, Bernd; Felzen, Marc; Kumakura, Yoshitaka; Cumming, Paul; Mottaghy, Felix M; Gründer, Gerhard; Vernaleken, Ingo

    2014-10-29

    Methylphenidate (MPH) inhibits the reuptake of dopamine and noradrenaline. PET studies with MPH challenge show increased competition at postsynaptic D2/3-receptors, thus indirectly revealing presynaptic dopamine release. We used [(18)F]fluorodopamine ([(18)F]FDOPA)-PET in conjunction with the inlet-outlet model (IOM) of Kumakura et al. (2007) to investigate acute and long-term changes in dopamine synthesis capacity and turnover in nigrostriatal fibers of healthy subjects with MPH challenge. Twenty healthy human females underwent two dynamic [(18)F]FDOPA PET scans (124 min; slow bolus-injection; arterial blood sampling), with one scan in untreated baseline condition and the other after MPH administration (0.5 mg/kg, p.o.), in randomized order. Subjects underwent cognitive testing at each PET session. Time activity curves were obtained for ventral putamen and caudate and were analyzed according to the IOM to obtain the regional net-uptake of [(18)F]FDOPA (K; dopamine synthesis capacity) as well as the [(18)F]fluorodopamine washout rate (kloss, index of dopamine turnover). MPH substantially decreased kloss in putamen (-22%; p = 0.003). In the reversed treatment order group (MPH/no drug), K was increased by 18% at no drug follow-up. The magnitude of K at the no drug baseline correlated with cognitive parameters. Furthermore, individual kloss changes correlated with altered cognitive performance under MPH. [(18)F]FDOPA PET in combination with the IOM detects an MPH-evoked decrease in striatal dopamine turnover, in accordance with the known acute pharmacodynamics of MPH. Furthermore, the scan-ordering effect on K suggested that a single MPH challenge persistently increased striatal dopamine synthesis capacity. Attenuation of dopamine turnover by MPH is linked to enhanced cognitive performance in healthy females. Copyright © 2014 the authors 0270-6474/14/3414769-08$15.00/0.

  7. Common Variation in the DOPA Decarboxylase (DDC) Gene and Human Striatal DDC Activity In Vivo.

    Science.gov (United States)

    Eisenberg, Daniel P; Kohn, Philip D; Hegarty, Catherine E; Ianni, Angela M; Kolachana, Bhaskar; Gregory, Michael D; Masdeu, Joseph C; Berman, Karen F

    2016-08-01

    The synthesis of multiple amine neurotransmitters, such as dopamine, norepinephrine, serotonin, and trace amines, relies in part on DOPA decarboxylase (DDC, AADC), an enzyme that is required for normative neural operations. Because rare, loss-of-function mutations in the DDC gene result in severe enzymatic deficiency and devastating autonomic, motor, and cognitive impairment, DDC common genetic polymorphisms have been proposed as a source of more moderate, but clinically important, alterations in DDC function that may contribute to risk, course, or treatment response in complex, heritable neuropsychiatric illnesses. However, a direct link between common genetic variation in DDC and DDC activity in the living human brain has never been established. We therefore tested for this association by conducting extensive genotyping across the DDC gene in a large cohort of 120 healthy individuals, for whom DDC activity was then quantified with [(18)F]-FDOPA positron emission tomography (PET). The specific uptake constant, Ki, a measure of DDC activity, was estimated for striatal regions of interest and found to be predicted by one of five tested haplotypes, particularly in the ventral striatum. These data provide evidence for cis-acting, functional common polymorphisms in the DDC gene and support future work to determine whether such variation might meaningfully contribute to DDC-mediated neural processes relevant to neuropsychiatric illness and treatment.

  8. Synthetic improvement and animal experiment of 6-18F-DOPA

    International Nuclear Information System (INIS)

    Tang Ganghua; Tang Xiaolan; Wang Mingfang; Luo Lei; Li Zhi; Huang Zuhan; Zhang Lan; Wang Yongxian

    2002-01-01

    Objective: To study synthetic improvement and biodistribution of 6- 18 F-DOPA in normal rats and hemi-Parkinsonism rats. Methods: 6- 18 F-DOPA was synthesized from the starting material 6-nitropiperonal via multi-step reaction including the nucleophilic fluorination, reductive iodination with diiodosilane on Sep-Pak column, chiral catalytic phase-transfer alkylation, and hydrolysis reaction. Biodistribution of 6- 18 F-DOPA in normal rats and the brain of hemi-Parkinsonism rats was determined. Results: The total time of synthesis was less than 110 min, the total uncorrected radiochemical yield from potassium 6- 18 F-DOPA was 5%-18%, and the enantiomeric purity and radiochemical purity were above 97% and 98%, respectively. High uptake in the kidney, blood, striatum, and hippocampus, rapid blood clearance in the kidney and blood, long retaining time and high striatum/cerebellum and striatum/cortex 6- 18 F-DOPA uptake ratio were found in normal rats. Compared with the intact side of hemi-Parkinsonism rats and pseudo-operated group, 6- 18 F-DOPA uptake and striatum/cerebellum and striatum/cortex 6- 18 F-DOPA uptake ratio reduced significantly in the lesioned side of hemi-Parkinsonism rats (P 18 F-DOPA. The synthetic 6- 18 F-DOPA is allowed to be used to study the animal and Parkinson's disease with PET imaging

  9. FDOPA-PET as a paradigm of molecular imaging in oncology; FDOPA-PET als Paradigma molekularer Bildgebung in der Onkologie

    Energy Technology Data Exchange (ETDEWEB)

    Brink, I.; Hentschel, M.; Neumann, H.P.H.; Schaefer, O.; Moser, E. [Radiologische Universitaetsklinik, Abt. Nuklearmedizin, Universitaetsklinikum Freiburg (Germany); Medizinische Klinik, Abt. Nephrologie und Allgemeinmedizin, Universitaetsklinikum Freiburg (Germany); Abt. Diagnostische Radiologie, Universitaetsklinikum Freiburg (Germany)

    2007-03-15

    In recent years, positron emission tomography with 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) has become a wide-spread method in the diagnostics of Parkinson's disease. The amino acid is an important component in protein metabolism. As a precursor in the synthesis of catecholamines it is also of use in metabolic imaging of a variety, mostly neuroendocrine, tumors. The specific uptake mechanisms make FDOPA a paradigm of metabolic imaging. The current review assesses the value of the tracer in the diagnostics of different oncological diseases. It summarizes own experiences and the published results of oncological FDOPA PET-studies. Above all, there is a very high impact of FDOPA in the staging of pheochromocytomas and paragangliomas as well as serotonin-positive neuroendocrine tumors of the gastroentero-pancreatic system (NET-GEPs). Additionally, FDOPA extends the diagnostic possibilities in recurrent medullary thyroid cancer. In the imaging of tumors of the central nervous system, FDOPA represents an alternative to {sup 11}C-labelled PET-tracers. First reports show a high accuracy in the differentiation of radiation induced necrosis and recurrent disease in both high and low grade brain tumors. Furthermore, there is a correlation between the uptake of FDOPA and the expression of proliferation markers. Today, the noninvasive differentiation of focal and diffuse congenital hyperinsulinism has therapeutic consequences. In cases of focal disease, the extent of pancreas resection can be limited resulting in better prognosis without diabetes mellitus. (orig.)

  10. Fluorodopa is a Promising Fluorine-19 MRI Probe for Evaluating Striatal Dopaminergic Function in a Rat Model of Parkinson's Disease.

    Science.gov (United States)

    Yanagisawa, Daijiro; Oda, Keisuke; Inden, Masatoshi; Morikawa, Shigehiro; Inubushi, Toshiro; Taniguchi, Takashi; Hijioka, Masanori; Kitamura, Yoshihisa; Tooyama, Ikuo

    2017-07-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra projecting to the striatum. It has been estimated that approximately 80% of the striatal dopamine and 50% of nigral dopaminergic neurons are lost before the onset of typical motor symptoms, indicating that early diagnosis of PD using noninvasive imaging is feasible. Fluorine-19 ( 19 F) magnetic resonance imaging (MRI) represents a highly sensitive, easily available, low-background, and cost-effective approach to evaluate dopaminergic function using non-radioactive fluorine-containing dopaminergic agents. The aim of this study was to find a potent 19 F MRI probe to evaluate dopaminergic presynaptic function in the striatum. To select candidates for 19 F MRI probes, we investigated the following eight non-radioactive fluorine-containing dopaminergic agents: fluorodopa (F-DOPA), F-tyrosine, haloperidol, GBR13069 duhydrochloride, GBR12909 duhydrochloride, 3-bis-(4-fluorophenyl) methoxytropane hydrochloride, flupenthixol, and fenfluramine. In 19 F nuclear magnetic resonance measurements, F-tyrosine and F-DOPA displayed a relatively higher signal-to-noise ratio value in brain homogenates than in others. F-DOPA, but not F-tyrosine, induced the rotational behavior in a 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rat model. In addition, a significantly high amount of F-DOPA accumulated in the ipsilateral striatum of hemiparkinsonian rats after the injection. We performed 19 F MRI in PC12 cells and isolated rat brain using a 7T MR scanner. Our findings suggest that F-DOPA is a promising 19 F MRI probe for evaluating dopaminergic presynaptic function in the striatum of hemiparkinsonian rats. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. Net influx of plasma 6-[18F]fluoro-L-DOPA (FDOPA) to the ventral striatum correlates with prefrontal processing of affective stimuli.

    Science.gov (United States)

    Siessmeier, Thomas; Kienast, Thorsten; Wrase, Jana; Larsen, Jennifer Lynne; Braus, Dieter F; Smolka, Michael N; Buchholz, Hans Georg; Schreckenberger, Mathias; Rösch, Frank; Cumming, Paul; Mann, Karl; Bartenstein, Peter; Heinz, Andreas

    2006-07-01

    Dopaminergic neurotransmission in the ventral and dorsal striatum interact with central processing of rewarding and reward-indicating stimuli, and may affect frontocortical-striatal-thalamic circuits regulating goal-directed behaviour. Thirteen healthy male volunteers were investigated with multimodal imaging, using the radioligand 6-[(18)F]fluoro-l-DOPA (FDOPA) for positron emission tomography (PET) measurements of dopamine synthesis capacity, and also functional magnetic resonance imaging (fMRI) in a cognitive activation paradigm. We calculated the correlation between FDOPA net blood-brain influx (; ml/g/min) in the ventral and associative dorsal striatum and BOLD signal changes elicited by standardized affectively positive, negative and neutral visual stimuli. The magnitude of in the ventral striatum was positively correlated with BOLD signal increases in the left anterior cingulate cortex and right insular operculum elicited by positive vs. neutral stimuli, but not negative vs. neutral stimuli. In the dorsal striatum, the magnitude of was positively correlated with processing of positive and negative stimuli in the left dorsolateral prefrontal cortex. These findings suggest that dopamine synthesis capacity in the ventral striatum correlates with the attentional processing of rewarding positive stimuli in the anterior cingulate cortex of healthy subjects. Dopaminergic neurotransmission in the associative dorsal striatum has been associated previously with habit learning. The observed correlation between dopamine synthesis capacity in the dorsal striatum and BOLD signal changes in the dorsolateral prefrontal cortex suggests dopaminergic modulation of processing of emotional stimuli in brain areas associated with motor planning and executive behaviour control.

  12. FDOPA-PET as a paradigm of molecular imaging in oncology

    International Nuclear Information System (INIS)

    Brink, I.; Hentschel, M.; Neumann, H.P.H.; Schaefer, O.; Moser, E.

    2007-01-01

    In recent years, positron emission tomography with 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) has become a wide-spread method in the diagnostics of Parkinson's disease. The amino acid is an important component in protein metabolism. As a precursor in the synthesis of catecholamines it is also of use in metabolic imaging of a variety, mostly neuroendocrine, tumors. The specific uptake mechanisms make FDOPA a paradigm of metabolic imaging. The current review assesses the value of the tracer in the diagnostics of different oncological diseases. It summarizes own experiences and the published results of oncological FDOPA PET-studies. Above all, there is a very high impact of FDOPA in the staging of pheochromocytomas and paragangliomas as well as serotonin-positive neuroendocrine tumors of the gastroentero-pancreatic system (NET-GEPs). Additionally, FDOPA extends the diagnostic possibilities in recurrent medullary thyroid cancer. In the imaging of tumors of the central nervous system, FDOPA represents an alternative to 11 C-labelled PET-tracers. First reports show a high accuracy in the differentiation of radiation induced necrosis and recurrent disease in both high and low grade brain tumors. Furthermore, there is a correlation between the uptake of FDOPA and the expression of proliferation markers. Today, the noninvasive differentiation of focal and diffuse congenital hyperinsulinism has therapeutic consequences. In cases of focal disease, the extent of pancreas resection can be limited resulting in better prognosis without diabetes mellitus. (orig.)

  13. Loss of metabolites from monkey striatum during PET with FDOPA

    DEFF Research Database (Denmark)

    Cumming, P; Munk, O L; Doudet, D

    2001-01-01

    diffusion of [(18)F]fluorodopamine metabolites from brain. Consequently, time-radioactivity recordings of striatum are progressively influenced by metabolite loss. In linear analyses, the net blood-brain clearance of FDOPA (K(D)(i), ml g(-1) min(-1)) can be corrected for this loss by the elimination rate...... constant k(Lin)(cl) (min(-1)). Similarly, the DOPA decarboxylation rate constant (k(D)(3), min(-1)) calculated by compartmental analysis can also be corrected for metabolite loss by the elimination rate constant k(DA)(9) (min(-1)). To compare the two methods, we calculated the two elimination rate...

  14. {sup 18}F-FDOPA PET/MRI fusion in patients with primary/recurrent gliomas: Initial experience

    Energy Technology Data Exchange (ETDEWEB)

    Ledezma, Carlos J. [Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States)], E-mail: ledezmacjl@gmail.com; Chen, Wei [Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States)], E-mail: weichen@mednet.ucla.edu; Sai, Victor [School of Medicine, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States)], E-mail: vsai@ucla.edu; Freitas, Bonnie [Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States)], E-mail: bfreitas@mednet.ucla.edu; Cloughesy, Tim [Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States)], E-mail: tcloughe@ucla.edu; Czernin, Johannes [Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States)], E-mail: jczernin@mednet.ucla.edu; Pope, Whitney [Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States)], E-mail: wpope@mednet.ucla.edu

    2009-08-15

    Background and purpose: {sup 18}F-FDOPA PET demonstrates higher sensitivity and specificity for gliomas than traditional [{sup 18}F] FDG PET imaging. However, PET provides limited anatomic localization. The purpose of this study was to determine whether {sup 18}F-FDOPA PET/MRI fusion can provide precise anatomic localization of abnormal tracer uptake and how this activity corresponds to MR signal abnormality. Methods: Two groups of patients were analyzed. Group I consisted of 21 patients who underwent {sup 18}F-FDOPA PET and MRI followed by craniotomy for tumor resection. Group II consisted of 70 patients with a pathological diagnosis of glioma that had {sup 18}F-FDOPA PET and MRI but lacked additional pathologic follow-up. Fused {sup 18}F-FDOPA PET and MRI images were analyzed for concordance and correlated with histopathologic data. Results: Fusion technology facilitated precise anatomical localization of {sup 18}F-FDOPA activity. In group I, all 21 cases showed pathology-confirmed tumor. Of these, {sup 18}F-FDOPA scans were positive in 9/10 (90%) previously unresected tumors, and 11/11 (100%) of recurrent tumors. Of the 70 patients in group II, concordance between MRI and {sup 18}F-FDOPA was found in 49/54 (90.1%) of patients with sufficient follow-up; in the remaining 16 patients concordance could not be determined due to lack of follow-up. {sup 18}F-FDOPA labeling was comparable in both high- and low-grade gliomas and identified both enhancing and non-enhancing tumor equally well. In some cases, {sup 18}F-FDOPA activity preceded tumor detection on MRI. Conclusion: {sup 18}F-FDOPA PET/MRI fusion provides precise anatomic localization of tracer uptake and labels enhancing and non-enhancing tumor well. In a small minority of cases, {sup 18}F-FDOPA activity may identify tumor not visible on MRI.

  15. Loss of metabolites from monkey striatum during PET with FDOPA

    DEFF Research Database (Denmark)

    Cumming, P; Munk, O L; Doudet, D

    2001-01-01

    diffusion of [(18)F]fluorodopamine metabolites from brain. Consequently, time-radioactivity recordings of striatum are progressively influenced by metabolite loss. In linear analyses, the net blood-brain clearance of FDOPA (K(D)(i), ml g(-1) min(-1)) can be corrected for this loss by the elimination rate...... constant k(Lin)(cl) (min(-1)). Similarly, the DOPA decarboxylation rate constant (k(D)(3), min(-1)) calculated by compartmental analysis can also be corrected for metabolite loss by the elimination rate constant k(DA)(9) (min(-1)). To compare the two methods, we calculated the two elimination rate...... of the estimate was substantially improved upon correction for metabolite loss. The rate constants for metabolite loss were higher in MPTP-lesioned monkey striatum than in normal striatum. The high correlation between individual estimates of k(Lin)(cl) and k(DA)(9) suggests that both rate constants reveal loss...

  16. Evaluation of the ratio method compared with graphical analyses for estimating nigrostriatal function in human [sup 18]F-dopa PET studies with or without carbidopa

    Energy Technology Data Exchange (ETDEWEB)

    Otsuka, M.; Ichiya, Y.; Kuwabara, Y.; Fukumura, T.; Sasaki, M.; Masuda, K. (Kyushu Univ., Fukuoka (Japan). Dept. of Radiology)

    1993-10-01

    The striatal to cerebellar (S/C) activity ratio for estimating nigrostriatal function was compared with the Patlak analyses in [sup 18]F-dopa (FD) positron emission tomography (PET) with pretreatment with 100 mg carbidopa (CD). Two different time-activity curves of plasma FD or cerebellar [sup 18]F were used for the Patlak analyses. The S/C ratio increased linearly with time for 120 min and the ratio at 120 min correlated closely with the uptake constants by the two Patlak analyses in six normal volunteers and six Parkinsons disease patients. The S/C ratio and the uptake constant by the cerebellar Patlak analysis without CD also showed a fairly good correlation. Then, the S/C ratios with and without CD were compared. Since CD increased both the striatal and the cerebellar radioactivities proportionally within each subject, CD did not change the S/C ratios. The S/C ratios both with and without CD were simple and comparable to the uptake constants in the FD PET studies. (author).

  17. Brain 18F-DOPA PET and cognition in de novo Parkinson's disease

    International Nuclear Information System (INIS)

    Picco, Agnese; Arnaldi, Dario; Brugnolo, Andrea; Nobili, Flavio; Morbelli, Silvia; Bossert, Irene; Piccardo, Arnoldo; Girtler, Nicola; Marinelli, Lucio; Abbruzzese, Giovanni; Castaldi, Antonio; De Carli, Fabrizio; Campus, Claudio

    2015-01-01

    The role of mesocortical dopaminergic pathways in the cognitive function of patients with early Parkinson's disease (PD) needs to be further clarified. The study groups comprised 15 drug-naive patients with de novo PD and 10 patients with essential tremor (controls) who underwent 18 F-DOPA PET (static acquisition, normalization on mean cerebellar counts) and an extended neuropsychological test battery. Factor analysis with varimax rotation was applied to the neuropsychological test scores, to yield five factors from 16 original scores, which explained 82 % of the total variance. Correlations between cognitive factors and 18 F-DOPA uptake were assessed with SPM8, taking age and gender as nuisance variables. 18 F-DOPA uptake was significantly lower in PD patients than in controls in the bilateral striatum, mainly in the more affected (right) hemisphere, and in a small right temporal region. Significant positive correlations were found only in PD patients between the executive factor and 18 F-DOPA uptake in the bilateral anterior cingulate cortex (ACC) and the middle frontal gyrus, between the verbal fluency factor and 18 F-DOPA uptake in left BA 46 and the bilateral striatum, and between the visuospatial factor and 18 F-DOPA uptake in the left ACC and bilateral striatum. No correlations were found between 18 F-DOPA uptake and either the verbal memory factor or the abstraction-working memory factor. These data clarify the role of the mesocortical dopaminergic pathways in cognitive function in early PD, highlighting the medial frontal lobe, anterior cingulate, and left BA 46 as the main sites of cortical correlation with executive and language functions. (orig.)

  18. {sup 18}F-FDOPA PET/CT imaging of insulinoma revisited

    Energy Technology Data Exchange (ETDEWEB)

    Imperiale, Alessio; Namer, Izzie-Jacques [University Hospitals of Strasbourg, Department of Biophysics and Nuclear Medicine, Strasbourg (France); University of Strasbourg/CNRS and FMTS, Faculty of Medicine, ICube - UMR 7357, Strasbourg (France); Sebag, Frederic [Aix-Marseille University, Department of Endocrine Surgery, La Timone University Hospital, Marseille (France); Vix, Michel [University of Strasbourg, Department of General, Digestive, and Endocrine Surgery, IRCAD-IHU, Strasbourg (France); Castinetti, Frederic [Aix-Marseille University, Department of Endocrinology, Diabetes and Metabolic Disorders, La Timone University Hospital, Marseille (France); Kessler, Laurence; Moreau, Francois [University of Strasbourg, Department of Diabetology, University Hospital of Strasbourg, Strasbourg (France); Bachellier, Philippe [University Hospitals of Strasbourg, Department of Visceral Surgery and Transplantation, Strasbourg (France); Guillet, Benjamin; Mundler, Olivier [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Marseille (France); Taieb, David [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Marseille (France); Aix-Marseille University, Biophysics and Nuclear Medecine, La Timone University Hospital, European Center for Research in Medical Imaging, Marseille (France)

    2014-11-01

    {sup 18}F-FDOPA PET imaging is increasingly used in the work-up of patients with neuroendocrine tumours. It has been shown to be of limited value in localizing pancreatic insulin-secreting tumours in adults with hyperinsulinaemic hypoglycaemia (HH) mainly due to {sup 18}F-FDOPA uptake by the whole pancreatic gland. The objective of this study was to review our experience with {sup 18}F-FDOPA PET/CT imaging with carbidopa (CD) premedication in patients with HH in comparison with PET/CT studies performed without CD premedication in an independent population. A retrospective study including 16 HH patients who were investigated between January 2011 and December 2013 using {sup 18}F-FDOPA PET/CT (17 examinations) in two academic endocrine tumour centres was conducted. All PET/CT examinations were performed under CD premedication (200 mg orally, 1 - 2 h prior to tracer injection). The PET/CT acquisition protocol included an early acquisition (5 min after {sup 18}F-FDOPA injection) centred over the upper abdomen and a delayed whole-body acquisition starting 20 - 30 min later. An independent series of eight consecutive patients with HH and investigated before 2011 were considered for comparison. All patients had a reference whole-body PET/CT scan performed about 1 h after {sup 18}F-FDOPA injection. In all cases, PET/CT was performed without CD premedication. In the study group, {sup 18}F-FDOPA PET/CT with CD premedication was positive in 8 out of 11 patients with histologically proven insulinoma (73 %). All {sup 18}F-FDOPA PET/CT-avid insulinomas were detected on early images and 5 of 11 (45 %) on delayed ones. The tumour/normal pancreas uptake ratio was not significantly different between early and delayed acquisitions. Considering all patients with HH, including those without imaging evidence of disease, the detection rate of the primary lesions using CD-assisted {sup 18}F-FDOPA PET/CT was 53 %, showing 9 insulinomas in 17 studies performed. In the control group (without

  19. Images from18F-DOPA Scan in Congenital Hyperinsulinism: Not Always a Clue for Diagnosis.

    Science.gov (United States)

    Maines, Evelina; Giacomello, Luca; D'Onofrio, Mirko; Salgarello, Matteo; Gaudino, Rossella; Baggio, Laura; Bordugo, Andrea

    2017-12-01

    Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in childhood (Horm Res 70:65-72, 2008; J Clin Endocr Metab 93:869-875, 2008). 18- Fluoro-L-dihydroxy-phenylalanine ( 18 F-DOPA) positron emission tomography (PET) can detect areas of increased activity in the pancreas and may differentiate focal from diffuse CHI (J Clin Endocr Metab 93:869-875, 2008; Radiology 253:216-222, 2009). We here report the case of a girl who complained of recurrent episodes of severe hypoglycaemia despite previous partial pancreatectomy. To evaluate the need for additional surgical intervention, we performed 18 F-DOPA PET/computed tomography (CT), which showed a focal lesion corresponding to the anatomical region of the pancreatic tail. On the other hand, abdominal magnetic resonance imaging (MRI) clearly demonstrated that the 18 F-DOPA uptake was in a loop of bowel occupying the previous surgical bed. Our case highlights that bowel uptake can be a possible pitfall in the interpretation of 18 F-DOPA PET/CT in children affected by CHI, suggesting that when 18 F-DOPA PET/CT results do not fit the clinical picture, magnetic resonance imaging (MRI) may allow a more accurate correlation of the radiotracer activity with the underlying anatomical or pathological structure.

  20. Parsing Heterogeneous Striatal Activity

    Directory of Open Access Journals (Sweden)

    Kae Nakamura

    2017-05-01

    Full Text Available The striatum is an input channel of the basal ganglia and is well known to be involved in reward-based decision making and learning. At the macroscopic level, the striatum has been postulated to contain parallel functional modules, each of which includes neurons that perform similar computations to support selection of appropriate actions for different task contexts. At the single-neuron level, however, recent studies in monkeys and rodents have revealed heterogeneity in neuronal activity even within restricted modules of the striatum. Looking for generality in the complex striatal activity patterns, here we briefly survey several types of striatal activity, focusing on their usefulness for mediating behaviors. In particular, we focus on two types of behavioral tasks: reward-based tasks that use salient sensory cues and manipulate outcomes associated with the cues; and perceptual decision tasks that manipulate the quality of noisy sensory cues and associate all correct decisions with the same outcome. Guided by previous insights on the modular organization and general selection-related functions of the basal ganglia, we relate striatal activity patterns on these tasks to two types of computations: implementation of selection and evaluation. We suggest that a parsing with the selection/evaluation categories encourages a focus on the functional commonalities revealed by studies with different animal models and behavioral tasks, instead of a focus on aspects of striatal activity that may be specific to a particular task setting. We then highlight several questions in the selection-evaluation framework for future explorations.

  1. Elevated [(18)F]FDOPA utilization in the periaqueductal gray and medial nucleus accumbens of patients with early Parkinson's disease

    DEFF Research Database (Denmark)

    Kumakura, Yoshitaka; Danielsen, Erik H; Gjedde, Albert

    2009-01-01

    of the impulse control disorders occurring in some PD patients under treatment with dopamine agonists. A focus of increased FDOPA influx and also V(d) was detected in the periaqueductal grey, consistent with some earlier reports based on reference tissue analysis. Increased FDOPA trapping in the periaqueductal......; ml g(-1) min(-1)) and steady-state trapping (V(d); ml g(-1)) in a group of well-characterized patients with early, asymmetric PD, who were contrasted with an age-matched control group. Subtraction of the population mean parametric maps revealed foci of increased FDOPA utilization K (+25...

  2. Presynaptic Dopamine Synthesis Capacity in Schizophrenia and Striatal Blood Flow Change During Antipsychotic Treatment and Medication-Free Conditions.

    Science.gov (United States)

    Eisenberg, Daniel Paul; Yankowitz, Lisa; Ianni, Angela M; Rubinstein, Dani Y; Kohn, Philip D; Hegarty, Catherine E; Gregory, Michael D; Apud, José A; Berman, Karen F

    2017-10-01

    Standard-of-care biological treatment of schizophrenia remains dependent upon antipsychotic medications, which demonstrate D 2 receptor affinity and elicit variable, partial clinical responses via neural mechanisms that are not entirely understood. In the striatum, where D 2 receptors are abundant, antipsychotic medications may affect neural function in studies of animals, healthy volunteers, and patients, yet the relevance of this to pharmacotherapeutic actions remains unresolved. In this same brain region, some individuals with schizophrenia may demonstrate phenotypes consistent with exaggerated dopaminergic signaling, including alterations in dopamine synthesis capacity; however, the hypothesis that dopamine system characteristics underlie variance in medication-induced regional blood flow changes has not been directly tested. We therefore studied a cohort of 30 individuals with schizophrenia using longitudinal, multi-session [ 15 O]-water and [ 18 F]-FDOPA positron emission tomography to determine striatal blood flow during active atypical antipsychotic medication treatment and after at least 3 weeks of placebo treatment, along with presynaptic dopamine synthesis capacity (ie, DOPA decarboxylase activity). Regional striatal blood flow was significantly higher during active treatment than during the placebo condition. Furthermore, medication-related increases in ventral striatal blood flow were associated with more robust amelioration of excited factor symptoms during active medication and with higher dopamine synthesis capacity. These data indicate that atypical medications enact measureable physiological alterations in limbic striatal circuitry that vary as a function of dopaminergic tone and may have relevance to aspects of therapeutic responses.

  3. Validation of18F-DOPA quality control using UPLC®-MS

    NARCIS (Netherlands)

    Schepers, Marianne; Maas, Bram; Bannink, Arjan; Boersma, Hendrikus H.; Zijlma, Rolf; De Vries, Erik F.J.; Elsinga, Philip H.; Luurtsema, Gert

    2013-01-01

    Objectives: 6-[18F]Fluoro-L-DOPA (FDOPA) is used to study the presynaptic dopamine synthesis in vivo using PET [1]. Major indications for this tracer are determination of the disease stage in Parkinson as well as detection of various neuroendocrine tumors and their metastases. Prior to set up a Good

  4. The applications of 18F-DOPA PET in Parkinson's disease

    International Nuclear Information System (INIS)

    Zuo Chuantao

    2000-01-01

    The injury of the presynaptic nigro-striae dopaminergic projection is the important mechanism of Parkinson's disease (PD). 18 F-DOPA PET provides a measure of the structure as well as the biochemical integrity of the dopaminergic neurons, which contribute to the early diagnosis, differentiation diagnosis, prognosis evaluation of PD

  5. KiWi Vision

    DEFF Research Database (Denmark)

    Schaffert, Sebastian; Bry, Francois; Dolog, Peter

    This deliverable describes the common vision of the KiWi project, ranging from motivation over use cases and usage scenarios to user interaction, system architecture and technologies, and the research that is performed as part of the project. The deliverable is intended for a wide audience to give...

  6. Total {sup 18}F-dopa PET tumour uptake reflects metabolic endocrine tumour activity in patients with a carcinoid tumour

    Energy Technology Data Exchange (ETDEWEB)

    Fiebrich, Helle-Brit; Walenkamp, Annemiek M.; Vries, Elisabeth G.E. de [University Medical Centre Groningen, Department of Medical Oncology, Groningen (Netherlands); Jong, Johan R. de; Koopmans, Klaas Pieter; Dierckx, Rudi A.J.O.; Brouwers, Adrienne H. [University Medical Centre Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); Kema, Ido P. [University Medical Centre Groningen, Department of Laboratory Medicine, Groningen (Netherlands); Sluiter, Wim; Links, Thera P. [University Medical Centre Groningen, Department of Endocrinology, Groningen (Netherlands)

    2011-10-15

    Positron emission tomography (PET) using 6-[{sup 18}F]fluoro-L-dihydroxyphenylalanine ({sup 18}F-dopa) has an excellent sensitivity to detect carcinoid tumour lesions. {sup 18}F-dopa tumour uptake and the levels of biochemical tumour markers are mediated by tumour endocrine metabolic activity. We evaluated whether total {sup 18}F-dopa tumour uptake on PET, defined as whole-body metabolic tumour burden (WBMTB), reflects tumour load per patient, as measured with tumour markers. Seventy-seven consecutive carcinoid patients who underwent an {sup 18}F-dopa PET scan in two previously published studies were analysed. For all tumour lesions mean standardised uptake values (SUVs) at 40% of the maximal SUV and tumour volume on {sup 18}F-dopa PET were determined and multiplied to calculate a metabolic burden per lesion. WBMTB was the sum of the metabolic burden of all individual lesions per patient. The 24-h urinary serotonin, urine and plasma 5-hydroxindoleacetic acid (5-HIAA), catecholamines (nor)epinephrine, dopamine and their metabolites, measured in urine and plasma, and serum chromogranin A served as tumour markers. All but 1 were evaluable for WBMTB; 74 patients had metastatic disease. {sup 18}F-dopa PET detected 979 lesions. SUV{sub max} on {sup 18}F-dopa PET varied up to 29-fold between individual lesions within the same patients. WBMTB correlated with urinary serotonin (r = 0.51) and urinary and plasma 5-HIAA (r = 0.78 and 0.66). WBMTB also correlated with urinary norepinephrine, epinephrine, dopamine and plasma dopamine, but not with serum chromogranin A. Tumour load per patient measured with {sup 18}F-dopa PET correlates with tumour markers of the serotonin and catecholamine pathway in urine and plasma in carcinoid patients, reflecting metabolic tumour activity. (orig.)

  7. Ventral striatal dopamine synthesis capacity predicts financial extravagance in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Andrew David Lawrence

    2013-02-01

    Full Text Available Impulse control disorders (ICDs, including disordered gambling, can occur in a significant number of patients with Parkinson’s disease (PD receiving dopaminergic therapy. The neurobiology underlying susceptibility to such problems is unclear, but risk likely results from an interaction between dopaminergic medication and a pre-existing trait vulnerability. Impulse control and addictive disorders form part of a broader psychopathological spectrum of disorders, which share a common underlying genetic vulnerability, referred to as externalizing. The broad externalizing risk factor is a continuously varying trait reflecting vulnerability to various impulse control problems, manifested at the overt level by disinhibitory symptoms and at the personality level by antecedent traits such as impulsivity and novelty/sensation seeking. Trait ‘disinhibition’ is thus a core endophenotype of ICDs, and a key target for neurobiological investigation. The ventral striatal dopamine system has been hypothesized to underlie individual variation in behavioural disinhibition. Here, we examined whether individual differences in ventral striatal dopamine synthesis capacity predicted individual variation in disinhibitory temperament traits in individuals with PD. Eighteen early-stage male PD patients underwent 6-[18F]Fluoro-L-DOPA (FDOPA positron emission tomography (PET scanning to measure striatal dopamine synthesis capacity, and completed a measure of disinhibited personality. Consistent with our predictions, we found that levels of ventral, but not dorsal, striatal dopamine synthesis capacity predicted disinhibited personality, particularly a propensity for financial extravagance. Our results are consistent with recent preclinical models of vulnerability to behavioural disinhibition and addiction proneness, and provide novel insights into the neurobiology of potential vulnerability to impulse control problems in PD and other disorders.

  8. {sup 18}F-FLT and {sup 18}F-FDOPA PET kinetics in recurrent brain tumors

    Energy Technology Data Exchange (ETDEWEB)

    Wardak, Mirwais; Schiepers, Christiaan; Dahlbom, Magnus; Phelps, Michael E.; Huang, Sung-Cheng [David Geffen School of Medicine at UCLA, Department of Molecular and Medical Pharmacology, Los Angeles, CA (United States); Cloughesy, Timothy F. [David Geffen School of Medicine at UCLA, Department of Neurology, Los Angeles, CA (United States)

    2014-06-15

    In this study, kinetic parameters of the cellular proliferation tracer {sup 18}F-3'-deoxy-3'-fluoro-l-thymidine (FLT) and the amino acid probe 3,4-dihydroxy-6-{sup 18}F-fluoro-l-phenylalanine (FDOPA) were measured before and early after the start of therapy, and were used to predict the overall survival (OS) of patients with recurrent malignant glioma using multiple linear regression (MLR) analysis. High-grade recurrent brain tumors in 21 patients (11 men and 10 women, age range 26 - 76 years) were investigated. Each patient had three dynamic PET studies with each probe: at baseline and after 2 and 6 weeks from the start of treatment. Treatment consisted of biweekly cycles of bevacizumab (an angiogenesis inhibitor) and irinotecan (a chemotherapeutic agent). For each study, about 3.5 mCi of FLT (or FDOPA) was administered intravenously and dynamic PET images were acquired for 1 h (or 35 min for FDOPA). A total of 126 PET scans were analyzed. A three-compartment, two-tissue model was applied to estimate tumor FLT and FDOPA kinetic rate constants using a metabolite- and partial volume-corrected input function. MLR analysis was used to model OS as a function of FLT and FDOPA kinetic parameters for each of the three studies as well as their relative changes between studies. An exhaustive search of MLR models using three or fewer predictor variables was performed to find the best models. Kinetic parameters from FLT were more predictive of OS than those from FDOPA. The three-predictor MLR model derived using information from both probes (adjusted R{sup 2} = 0.83) fitted the OS data better than that derived using information from FDOPA alone (adjusted R{sup 2} = 0.41), but was only marginally different from that derived using information from FLT alone (adjusted R{sup 2} = 0.82). Standardized uptake values (either from FLT alone, FDOPA alone, or both together) gave inferior predictive results (best adjusted R{sup 2} = 0.25). For recurrent malignant glioma treated

  9. Brain {sup 18}F-DOPA PET and cognition in de novo Parkinson's disease

    Energy Technology Data Exchange (ETDEWEB)

    Picco, Agnese; Arnaldi, Dario; Brugnolo, Andrea; Nobili, Flavio [University of Genoa and IRCCS AOU San Martino-IST, Clinical Neurology, Department of Neuroscience (DINOGMI), Genoa (Italy); Morbelli, Silvia; Bossert, Irene [University of Genoa and IRCCS AOU San Martino-IST, Nuclear Medicine, Department of Health Sciences (DISSAL), Genoa (Italy); Piccardo, Arnoldo [Ospedali Galliera, Nuclear Medicine, Department of Imaging Diagnostics, Genoa (Italy); Girtler, Nicola [University of Genoa and IRCCS AOU San Martino-IST, Clinical Neurology, Department of Neuroscience (DINOGMI), Genoa (Italy); IRCCS San Martino-IST, Clinical Psychology and Psychotherapy Unit, Genoa (Italy); Marinelli, Lucio; Abbruzzese, Giovanni [University of Genoa and IRCCS AOU San Martino-IST, Neurological Rehabilitation, Department of Neuroscience (DINOGMI), Genoa (Italy); Castaldi, Antonio [Ospedali Galliera, Radiology, Department of Imaging Diagnostics, Genoa (Italy); De Carli, Fabrizio [Consiglio Nazionale delle Ricerche (CNR), Institute of Bioimaging and Molecular Physiology, Genoa (Italy); Campus, Claudio [Istituto Italiano di Tecnologia, Genoa (Italy)

    2015-03-28

    The role of mesocortical dopaminergic pathways in the cognitive function of patients with early Parkinson's disease (PD) needs to be further clarified. The study groups comprised 15 drug-naive patients with de novo PD and 10 patients with essential tremor (controls) who underwent {sup 18}F-DOPA PET (static acquisition, normalization on mean cerebellar counts) and an extended neuropsychological test battery. Factor analysis with varimax rotation was applied to the neuropsychological test scores, to yield five factors from 16 original scores, which explained 82 % of the total variance. Correlations between cognitive factors and {sup 18}F-DOPA uptake were assessed with SPM8, taking age and gender as nuisance variables. {sup 18}F-DOPA uptake was significantly lower in PD patients than in controls in the bilateral striatum, mainly in the more affected (right) hemisphere, and in a small right temporal region. Significant positive correlations were found only in PD patients between the executive factor and {sup 18}F-DOPA uptake in the bilateral anterior cingulate cortex (ACC) and the middle frontal gyrus, between the verbal fluency factor and {sup 18}F-DOPA uptake in left BA 46 and the bilateral striatum, and between the visuospatial factor and {sup 18}F-DOPA uptake in the left ACC and bilateral striatum. No correlations were found between {sup 18}F-DOPA uptake and either the verbal memory factor or the abstraction-working memory factor. These data clarify the role of the mesocortical dopaminergic pathways in cognitive function in early PD, highlighting the medial frontal lobe, anterior cingulate, and left BA 46 as the main sites of cortical correlation with executive and language functions. (orig.)

  10. [18F]FDOPA PET as an Endophenotype for Parkinson’s Disease Linkage Studies

    Science.gov (United States)

    Racette, Brad A.; Good, Laura; Antenor, Jo Ann; McGee-Minnich, Lori; Moerlein, Stephen M.; Videen, Tom O.; Perlmutter, Joel S.

    2008-01-01

    Parkinson Disease (PD) is a late onset disorder with age-dependent penetrance that may confound genetic studies since affected individuals may not demonstrate clinical manifestations at the time of evaluation. The use of endophenotypes, biologic surrogates for clinical disease diagnoses, may permit more accurate classification of at-risk subjects. Positron emission tomography (PET) measurements of 6-[18F]fluorodopa ([18F]FDOPA) uptake indicate nigrostriatal neuronal integrity and may provide a useful endophenotype for PD linkage studies. We performed [18F]FDOPA PET in 11 members of a large, multi-incident Amish family with PD, 24 normals and 48 people with clinically definite idiopathic PD (PD controls). Clinical diagnoses in the Amish were clinically definite PD in four, clinically probable in one, clinically possible in five, and normal in one. Abnormal [18F]FDOPA posterior putamen uptake was defined as less than three standard deviations below the normal mean. The criteria were applied to the Amish sample to determine a PET endophenotype for each. We performed genetic simulations using SLINK to model the effect phenoconversion with the PET endophenotype had on logarithm of odds (LOD) scores. PET endophenotype confirmed the status of two clinically definite subjects. Two clinically definite Amish PD subjects had normal PETs. Two possible PD were converted to “PET definite PD”. The remainder had normal PETs. The average maximum LOD score with the pre-PET was 6.14±0.84. Simulating phenoconversion of subjects with unknown phenotypes increased the LOD score to 7.36±1.23. The [18F]FDOPA PET endophenotype permits phenoconversion in multi-incident PD families and may increase LOD score accuracy and power of an informative pedigree. PMID:16528749

  11. Orbitofrontal 18F-DOPA Uptake and Movement Preparation in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Lucio Marinelli

    2015-01-01

    Full Text Available In Parkinson’s disease (PD degeneration of mesocortical dopaminergic projections may determine cognitive and behavioral symptoms. Choice reaction time task is related to attention, working memory, and goal-directed behavior. Such paradigm involves frontal cortical circuits receiving mesocortical dopamine which are affected early in PD. The aim of this study is to characterize the role of dopamine on the cognitive processes that precede movement in a reaction time paradigm in PD. We enrolled 16 newly diagnosed and untreated patients with PD without cognitive impairment or depression and 10 control subjects with essential tremor. They performed multiple-choice reaction time task with the right upper limb and brain 18F-DOPA PET/CT scan. A significant inverse correlation was highlighted between average reaction time and 18F-DOPA uptake in the left lateral orbitofrontal cortex. No correlations were found between reaction time and PD disease severity or between reaction time and 18F-DOPA uptake in controls. Our study shows that in PD, but not in controls, reaction time is inversely related to the levels of dopamine in the left lateral orbitofrontal cortex. This novel finding underlines the role of dopamine in the lateral orbitofrontal cortex in the early stages of PD, supporting a relation between the compensatory cortical dopamine and movement preparation.

  12. Volumetric assessment of recurrent or progressive gliomas: comparison between F-DOPA PET and perfusion-weighted MRI

    Energy Technology Data Exchange (ETDEWEB)

    Cicone, Francesco [Sant' Andrea Hospital, Rome (Italy). Unit of Nuclear Medicine; Rome Sapienza Univ. (Italy). Dept. of Surgical and Medical Sciences and tranlational Medicine; Research Centre Juelich (Germany). Inst. of Neureoscience and Medicine; Filss, Christian P.; Langen, Karl-Josef [Research Centre Juelich (Germany). Inst. of Neureoscience and Medicine; RWTH Aachen Univ. Hospital (Germany). Dept. of Nuclear Medicine; Minniti, Giuseppe; Scaringi, Claudia [Rome Sapienza Univ. (Italy). Dept. of Surgical and Medical Sciences and tranlational Medicine; Sant' Andrea Hospital, Rome (Italy). Unit of Radiotherapy; Rossi-Espagnet, Camilla; Bozzao, Alessandro [Sant' Andrea Hospital, Rome (Italy). Unit of Neuroradiology; Rome Sapienza Univ. (Italy). Dept. of Neurosciences, Mental Health and Sensory Organs (Ne.S.M.O.S.); Papa, Annalisa; Scopinaro, Francesco [Sant' Andrea Hospital, Rome (Italy). Unit of Nuclear Medicine; Rome Sapienza Univ. (Italy). Dept. of Surgical and Medical Sciences and tranlational Medicine; Galldiks, Norbert [Research Centre Juelich (Germany). Inst. of Neureoscience and Medicine; Cologne Univ. (Germany). Dept. of Neurology; Shah, N. Jon [Research Centre Juelich (Germany). Inst. of Neureoscience and Medicine

    2015-05-01

    To compare the diagnostic information obtained with 6-[{sup 18}F]-fluoro-l-3,4-dihydroxyphenylalanine (F-DOPA) PET and relative cerebral blood volume (rCBV) maps in recurrent or progressive glioma. All patients with recurrent or progressive glioma referred for F-DOPA imaging at our institution between May 2010 and May 2014 were retrospectively included, provided that macroscopic disease was visible on conventional MRI images and that rCBV maps were available for comparison. The final analysis included 50 paired studies (44 patients). After image registration, automatic tumour segmentation of both sets of images was performed using the average signal in a large reference VOI including grey and white matter multiplied by 1.6. Tumour volumes identified by both modalities were compared and their spatial congruence calculated. The distances between F-DOPA uptake and rCBV hot spots, tumour-to-brain ratios (TBRs) and normalized histograms were also computed. On visual inspection, 49 of the 50 F-DOPA and 45 of the 50 rCBV studies were classified as positive. The tumour volume delineated using F-DOPA (F-DOPA{sub vol} {sub 1.6}) greatly exceeded that of rCBV maps (rCBV{sub vol} {sub 1.6}). The median F-DOPA{sub vol} {sub 1.6} and rCBV{sub vol} {sub 1.6} were 11.44 ml (range 0 - 220.95 ml) and 1.04 ml (range 0 - 26.30 ml), respectively (p < 0.00001). Overall, the median overlapping volume was 0.27 ml, resulting in a spatial congruence of 1.38 % (range 0 - 39.22 %). The mean hot spot distance was 27.17 mm (±16.92 mm). F-DOPA uptake TBR was significantly higher than rCBV TBR (1.76 ± 0.60 vs. 1.15 ± 0.52, respectively; p < 0.0001). The histogram analysis showed that F-DOPA provided better separation of tumour from background. In 6 of the 50 studies (12 %), however, physiological uptake in the striatum interfered with tumour delineation. The information provided by F-DOPA PET and rCBV maps are substantially different. Image interpretation is easier and a larger tumour extent

  13. Acute effects of three club drugs on the striatum of rats: Evaluation by quantitative autoradiography with [18F]FDOPA

    International Nuclear Information System (INIS)

    Fang, Chun-Kai; Chen, Hong-Wen; Wang, Wei-Hsun; Liu, Ren-Shen; Hwang, Jeng-Jong

    2013-01-01

    In this work, we used quantitative autoradiography to study the acute effect of cocaine, methamphetamine, and ketamine on the uptake of [ 18 F]FDOPA in the striatum of rats. Drugs were treated 0.5 h before (pre-treated), and 1.5 h after (post-treated) [ 18 F]FDOPA injections, rats were then sacrificed at 2 h post [ 18 F]FDOPA injections to determine the striatum/frontal cortex binding ratios in the striatum. The ratios were lower in the post-treated groups than those of the pre-treated groups, suggesting a net effect of inhibition of trapping of the tracer. The order of uptake inhibition is: ketamine>methamphetamine>cocaine

  14. {sup 18}F-DOPA PET/CT in the diagnosis and localization of persistent medullary thyroid carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Archier, Aurelien; Mundler, Olivier [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, Marseille (France); Aix-Marseille University, European Center for Research in Medical Imaging, Marseille (France); Heimburger, Celine [University Hospitals of Strasbourg, Department of Biophysics and Nuclear Medicine, Strasbourg (France); Guerin, Carole; Palazzo, Fausto F.; Henry, Jean-Francois; Sebag, Frederic [Aix-Marseille University, Department of Endocrine Surgery, Conception Hospital, Marseille (France); Morange, Isabelle [Aix-Marseille University, Department of Endocrinology, Conception Hospital, Marseille (France); Schneegans, Olivier [Paul Strauss Cancer Center, Department of Nuclear Medicine, Strasbourg (France); Abdullah, Ahmad Esmaeel [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, Marseille (France); Imperiale, Alessio [University Hospitals of Strasbourg, Department of Biophysics and Nuclear Medicine, Strasbourg (France); ICube, UMR 7357 University of Strasbourg/CNRS and FMTS, Faculty of Medicine, Strasbourg (France); Taieb, David [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, Marseille (France); Aix-Marseille University, European Center for Research in Medical Imaging, Marseille (France); Institut Paoli-Calmettes, Inserm UMR1068 Marseille Cancerology Research Center, Marseille (France)

    2016-06-15

    To evaluate the performance of {sup 18}F-l-dihydroxyphenylalanine ({sup 18}F-DOPA) PET/CT in the detection of locoregional and distant medullary thyroid carcinoma (MTC) metastases and to compare imaging findings with histological data. We retrospectively evaluated 86 MTC patients with persistently high serum calcitonin levels after initial surgery who had undergone {sup 18}F-DOPA PET/CT between January 2007 and December 2014 in two referral centres. They were followed up for at least 6 months after the PET/CT assessment. The results were compared with histological data or with the findings obtained during follow-up using a complementary imaging modality. {sup 18}F-DOPA PET/CT was positive in 65 of the 86 patients, corresponding to a patient-based sensitivity of 75.6 %. Distant metastatic disease (M1) was seen in 29 patients including 11 with previously unknown metastases revealed only by PET/CT. Among the 36 patients without distant metastatic spread, 25 had nodal involvement limited to the neck, and 10 of these 25 patients underwent reoperation. The lymph node compartment-based sensitivity of {sup 18}F-DOPA PET/CT was 100 % in the two institutions but lesion-based sensitivity was only 24 %. Preoperative and postoperative median calcitonin levels were 405 pg/mL (range 128 - 1,960 pg/mL) and 259 pg/mL (range 33 - 1,516 pg/mL), respectively. None of the patients achieved normalization of serum calcitonin after reoperation. {sup 18}F-DOPA PET/CT enables early diagnosis of a significant number of patients with distant metastasis. It has a limited sensitivity in the detection of residual disease but provides high performance for regional analysis. A surgical compartment-oriented approach could be the approach of choice whatever the number of nodes revealed by {sup 18}F-DOPA PET/CT. (orig.)

  15. Huntington's Disease and Striatal Signaling

    Directory of Open Access Journals (Sweden)

    Emmanuel eRoze

    2011-08-01

    Full Text Available Huntington’s Disease (HD is the most frequent neurodegenerative disease caused by an expansion of polyglutamines (CAG. The main clinical manifestations of HD are chorea, cognitive impairment and psychiatric disorders. The transmission of HD is autosomal dominant with a complete penetrance. HD has a single genetic cause, a well-defined neuropathology, and informative pre-manifest genetic testing of the disease is available. Striatal atrophy begins as early as 15 years before disease onset and continues throughout the period of manifest illness. Therefore, patients could theoretically benefit from therapy at early stages of the disease. One important characteristic of HD is the striatal vulnerability to neurodegeneration, despite similar expression of the protein in other brain areas. Aggregation of the mutated Huntingtin (HTT, impaired axonal transport, excitotoxicity, transcriptional dysregulation as well as mitochondrial dysfunction and energy deficits, are all part of the cellular events that underlie neuronal dysfunction and striatal death. Among these non-exclusive mechanisms, an alteration of striatal signaling is thought to orchestrate the downstream events involved in the cascade of striatal dysfunction.

  16. Estimation of patient dose in 18 F-FDG and 18 F-FDOPA PET/CT examinations

    Directory of Open Access Journals (Sweden)

    Aruna Kaushik

    2013-01-01

    Full Text Available Purpose: To estimate specific organ and effective doses to patients resulting from the 18 F-FDG ( 18 F-2-deoxy-D-glucose and 18 F-FDOPA (6-fluoro-( 18 F-L-3, 4-dihydroxyphenylalanine PET/CT examinations for whole body and brain. Materials and Methods: Three protocols for whole body and three for brain PET/CT were used. The CTDI values were measured using standard head and body CT phantoms and also computed using a software CT-Expo for dose evaluation from the CT component. OLINDA software based on MIRD method was used for estimating doses from the PET component of the PET/CT examination. Results: The organ doses from 18 F-FDG and 18 F-FDOPA whole body and brain PET/CT studies were estimated. The total effective dose from a typical protocol of whole body PET/CT examination was 14.4 mSv for females and 11.8 mSv for male patients from 18 F-FDG, whereas it was 11 mSv for female and 9.1 mSv for male patients from 18 F-FDOPA. The total effective doses from a typical protocol for PET/CT studies of brain was 6.5 mSv for females and 5.1 mSv for males from 18 F-FDG whereas it was 3.7 mSv for females and 2.8 mSv for males from 18 F-FDOPA. Conclusions: The effective radiation doses from whole body PET/CT examination was approximately 4-8 times higher than the background radiation dose from both 18 F-FDG and 18 F-FDOPA scans, while it was 1-3 times the background radiation dose from PET/CT scans of brain.

  17. Estimation of patient dose in (18)F-FDG and (18)F-FDOPA PET/CT examinations.

    Science.gov (United States)

    Kaushik, Aruna; Jaimini, Abhinav; Tripathi, Madhavi; D'Souza, Maria; Sharma, Rajnish; Mishra, Anil K; Mondal, Anupam; Dwarakanath, Bilikere S

    2013-01-01

    To estimate specific organ and effective doses to patients resulting from the (18)F-FDG ((18)F-2-deoxy-D-glucose) and (18)F-FDOPA (6-fluoro-((18)F)-L-3, 4-dihydroxyphenylalanine) PET/CT examinations for whole body and brain. Three protocols for whole body and three for brain PET/CT were used. The CTDI values were measured using standard head and body CT phantoms and also computed using a software CT-Expo for dose evaluation from the CT component. OLINDA software based on MIRD method was used for estimating doses from the PET component of the PET/CT examination. The organ doses from (18)F-FDG and (18)F-FDOPA whole body and brain PET/CT studies were estimated. The total effective dose from a typical protocol of whole body PET/CT examination was 14.4 mSv for females and 11.8 mSv for male patients from (18)F-FDG, whereas it was 11 mSv for female and 9.1 mSv for male patients from (18)F-FDOPA. The total effective doses from a typical protocol for PET/CT studies of brain was 6.5 mSv for females and 5.1 mSv for males from (18)F-FDG whereas it was 3.7 mSv for females and 2.8 mSv for males from (18)F-FDOPA. The effective radiation doses from whole body PET/CT examination was approximately 4-8 times higher than the background radiation dose from both (18)F-FDG and (18)F-FDOPA scans, while it was 1-3 times the background radiation dose from PET/CT scans of brain.

  18. Accuracy of F-DOPA PET and perfusion-MRI for differentiating radionecrotic from progressive brain metastases after radiosurgery

    Energy Technology Data Exchange (ETDEWEB)

    Cicone, Francesco; Papa, Annalisa; Scopinaro, Francesco [Sant' Andrea Hospital, Rome (Italy). Unit of Nuclear Medicine; ' ' Sapienza' ' Univ., Rome (Italy). Dept. of Surgical and Medicine Sciences and Translational Medicine; Minniti, Giuseppe; Scaringi, Claudia; Maurizi Enrici, Riccardo [' ' Sapienza' ' Univ., Rome (Italy). Dept. of Surgical and Medicine Sciences and Translational Medicine; Sant' Andrea Hospital, Rome (Italy). Unit of Radiotherapy; Romano, Andrea; Tavanti, Francesca; Bozzao, Alessandro [Sant' Andrea Hospital, Rome (Italy). Unit of Neuroradiology; Rome Univ. (Italy). Dept. of Neurosciences, Mental Health and Sensory Organs (Ne.S.M.O.S.)

    2015-01-15

    We assessed the performance of 6-[{sup 18}F]-fluoro-l-3,4-dihydroxyphenylalanine (F-DOPA) PET for differentiating radionecrosis (RN) from tumour progression (PD) in a population of patients with brain metastases, treated with stereotactic radiosurgery. The accuracy of F-DOPA PET was compared with that of perfusion-weighted magnetic resonance (perfusion-MR). In 42 patients with a total of 50 brain metastases from various primaries F-DOPA PET/CT was performed because of suspected radiological progression at the site of previously irradiated brain metastasis. Several semiquantitative PET parameters were recorded, and their diagnostic accuracy was compared by receiver operating characteristic curve analyses. The diagnosis was established by either surgery or follow-up. A comparison was made between F-DOPA PET and perfusion-MR sequences acquired no more than 3 weeks apart. Definitive outcome was available in 46 of the 50 lesions (20 PD, 26 RN). Of the 46 lesions, 11 were surgically excised while in the remaining 35 lesions the diagnosis was established by radiological and clinical criteria. The best diagnostic performance was obtained using the semiquantitative PET parameter maximum lesion to maximum background uptake ratio (SUVL{sub max}/Bkgr{sub max}). With a cut-off value of 1.59, a sensitivity of 90 % and a specificity of 92.3 % were achieved in differentiating RN from PD lesions (accuracy 91.3 %). Relative cerebral blood volume (rCBV) derived from perfusion-MR was available for comparison in 37 of the 46 metastases. Overall accuracy of rCBV was lower than that of all semiquantitative PET parameters under study. The best differentiating rCBV cut-off value was 2.14; this yielded a sensitivity of 86.7 % and a specificity of 68.2 % (accuracy 75.6 %). F-DOPA PET is a highly accurate tool for differentiating RN from PD brain metastases after stereotactic radiosurgery. In this specific setting, F-DOPA PET seems to perform better than perfusion-MR. (orig.)

  19. Carbidopa and physiological distribution of the 6-L-[{sup 18}F]-fluoro-dihydroxy-phenylalanine ({sup 18}F-DOPA); Carbidopa et biodistribution physiologique de la 6-L-[{sup 18}F]-fluorodihydroxyphenylalanine ({sup 18}F-DOPA)

    Energy Technology Data Exchange (ETDEWEB)

    Detour, J.; Hammer, C.; Lucas, A. [Hopitaux universitaires de Strasbourg, Service de radiopharmacie, 67 (France); Imperiale, A.; Constantinesco, A. [Hopitaux universitaires de Strasbourg, Service de biophysique et medecine nucleaire, 67 (France); Beretz, L. [Hopitaux universitaires de Strasbourg, pole de pharmacie-pharmacologie, 67 (France)

    2010-07-01

    Purpose: The administration of carbidopa, an peripheral inhibitor of decarboxylase DOPA, may be performed prior to a full body PET scan {sup 18}F-DOPA. There is currently no consensus regarding the routine use of this metabolic preparation (200 mg, 100 mg, 2 mg / kg, no pre-medication). Conclusions: The absence of pre-medication clearly increases pancreatic uptake of {sup 18}F-D.O.P.A.. These results suggest to reconsider the metabolic preparation based on carbidopa, particularly in cases of suspected clinico biological forms of diffuse hyper-insulinism (nesidioblastosis). Pre-medication in cases of digestive neuroendocrine tumors should be reconsidered. The dose-dependent effect of pre-medication on the tumor uptake remains to be explored. (N.C.)

  20. Comparison of {sup 18}F-dopa PET/CT and {sup 123}I-MIBG scintigraphy in stage 3 and 4 neuroblastoma: a pilot study

    Energy Technology Data Exchange (ETDEWEB)

    Piccardo, Arnoldo [Galliera Hospital, Nuclear Medicine Unit, Genoa (Italy); E.O. Ospedali Galliera, Department of Nuclear Medicine, Genoa (Italy); Lopci, Egesta; Nanni, Cristina; Fanti, Stefano [Sant' Orsola-Malpighi Hospital, Nuclear Medicine Unit, Bologna (Italy); Conte, Massimo; Garaventa, Alberto; Sorrentino, Stefania [G. Gaslini Hospital, Medical and Pediatric Oncology Division, Genoa (Italy); Foppiani, Luca [Endocrinology, Galliera Hospital, Genoa (Italy); Altrinetti, Vania; Bianchi, Pietro; Cabria, Manlio; Villavecchia, Giampiero [Galliera Hospital, Nuclear Medicine Unit, Genoa (Italy); Cistaro, Angela [PET Centre, IRMET, Turin (Italy); Pession, Andrea [S. Orsola-Malpighi Hospital, Department of Pediatric Oncohematology, Bologna (Italy); Puntoni, Matteo [Galliera Hospital, Scientific Directorate - Clinical Trial Research Unit, Genoa (Italy)

    2012-01-15

    {sup 18}F-Dopa positron emission tomography (PET)/CT has proved a valuable tool for the assessment of neuroendocrine tumours. So far no data are available on {sup 18}F-dopa utilization in neuroblastoma (NB). Our aim was to evaluate the role of {sup 18}F-dopa PET/CT in NB and compare its diagnostic value with that of {sup 123}I-metaiodobenzylguanidine (MIBG) scintigraphy in patients affected by stage 3-4 NB. We prospectively evaluated 28 paired {sup 123}I-MIBG and {sup 18}F-dopa PET/CT scans in 19 patients: 4 at the time of the NB diagnosis and 15 when NB relapse was suspected. For both imaging modalities we performed a scan-based and a lesion-based analysis and calculated sensitivity, specificity and accuracy. The standard of reference was based on clinical, imaging and histological data. NB localizations were confirmed in 17 of 19 patients. {sup 18}F-Dopa PET/CT and {sup 123}I-MIBG scintigraphy properly detected disease in 16 (94%) and 11 (65%), respectively. On scan-based analysis, {sup 18}F-dopa PET/CT showed a sensitivity and accuracy of 95 and 96%, respectively, while {sup 123}I-MIBG scanning showed a sensitivity and accuracy of 68 and 64%, respectively (p < 0.05). No significant difference in terms of specificity was found. In 9 of 28 paired scans (32%) PET/CT results influenced the patient management. We identified 156 NB localizations, 141 of which were correctly detected by {sup 18}F-dopa PET/CT and 88 by MIBG. On lesion-based analysis, {sup 18}F-dopa PET/CT showed a sensitivity and accuracy of 90% whereas {sup 123}I-MIBG scintigraphy showed a sensitivity and accuracy of 56 and 57%, respectively (p < 0.001). No significant difference in terms of specificity was found. In our NB population {sup 18}F-dopa PET/CT displayed higher overall accuracy than {sup 123}I-MIBG scintigraphy. Consequently, we suggest {sup 18}F-dopa PET/CT as a new opportunity for NB assessment. (orig.)

  1. Clinical value of {sup 18}F-fluorodihydroxyphenylalanine positron emission tomography/computed tomography ({sup 18}F-DOPA PET/CT) for detecting pheochromocytoma

    Energy Technology Data Exchange (ETDEWEB)

    Luster, Markus; Zeich, Katrin; Glatting, Gerhard; Buck, Andreas K.; Solbach, Christoph; Reske, Sven N. [University of Ulm, Department of Nuclear Medicine, Ulm (Germany); Karges, Wolfram [RWTH Aachen, Division of Endocrinology and Diabetes, Aachen (Germany); Pauls, Sandra [University of Ulm, Department of Radiology, Ulm (Germany); Verburg, Frederik A. [University of Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); Dralle, Henning [University Halle-Wittenberg, Department of General, Visceral and Vascular Surgery, Halle (Germany); Neumaier, Bernd [University of Ulm, Department of Nuclear Medicine, Ulm (Germany); Max-Planck-Institut fuer Neurologische Forschung, Section for Radiochemistry, Cologne (Germany); Mottaghy, Felix M. [University of Ulm, Department of Nuclear Medicine, Ulm (Germany); RWTH Aachen, Department of Nuclear Medicine, Aachen (Germany)

    2010-03-15

    In detecting pheochromocytoma (PHEO), positron emission tomography (PET) with the radiolabelled amine precursor {sup 18}F-fluorodihydroxyphenylalanine ({sup 18}F-DOPA) offers excellent specificity, while computed tomography (CT) provides high sensitivity and ability to localize lesions; therefore, the combination of these modalities could be advantageous in this setting. The aim of this study was to investigate whether combined {sup 18}F-DOPA PET/CT more accurately detects and localizes PHEO lesions than does each modality alone. {sup 18}F-DOPA PET, CT and {sup 18}F-DOPA PET/CT images of 25 consecutive patients undergoing diagnostic scanning of suspected sporadic or multiple endocrine neoplasia type 2 syndrome-associated PHEO were reviewed retrospectively in randomized sequence. Two blinded observers scored the images regarding the likelihood of PHEO being present and localizable. Results were correlated with subsequent clinical history and, when available, histology. Of the 19 lesions detected by all three modalities, PET identified each as positive for PHEO, but was unable to definitively localize 15 of 19 (79%). CT could definitively localize all 19 lesions, but could not definitively diagnose or exclude PHEO in 18 of 19 (95%) lesions. Furthermore, CT falsely identified as negative for PHEO one lesion which was judged to be positive for this tumor by both PET and PET/CT. Only in PET/CT scans were all 19 lesions accurately characterized and localized. On a per-patient basis, the sensitivity of {sup 18}F-DOPA PET/CT for PHEO was 100% and the specificity 88%, with a 100% positive predictive value and an 88% negative predictive value. {sup 18}F-DOPA PET/CT more accurately diagnoses and localizes adrenal and extra-adrenal masses suspicious for PHEO than do {sup 18}F-DOPA PET or CT alone. (orig.)

  2. Clinical value of 18F-fluorodihydroxyphenylalanine positron emission tomography/computed tomography (18F-DOPA PET/CT) for detecting pheochromocytoma

    International Nuclear Information System (INIS)

    Luster, Markus; Zeich, Katrin; Glatting, Gerhard; Buck, Andreas K.; Solbach, Christoph; Reske, Sven N.; Karges, Wolfram; Pauls, Sandra; Verburg, Frederik A.; Dralle, Henning; Neumaier, Bernd; Mottaghy, Felix M.

    2010-01-01

    In detecting pheochromocytoma (PHEO), positron emission tomography (PET) with the radiolabelled amine precursor 18 F-fluorodihydroxyphenylalanine ( 18 F-DOPA) offers excellent specificity, while computed tomography (CT) provides high sensitivity and ability to localize lesions; therefore, the combination of these modalities could be advantageous in this setting. The aim of this study was to investigate whether combined 18 F-DOPA PET/CT more accurately detects and localizes PHEO lesions than does each modality alone. 18 F-DOPA PET, CT and 18 F-DOPA PET/CT images of 25 consecutive patients undergoing diagnostic scanning of suspected sporadic or multiple endocrine neoplasia type 2 syndrome-associated PHEO were reviewed retrospectively in randomized sequence. Two blinded observers scored the images regarding the likelihood of PHEO being present and localizable. Results were correlated with subsequent clinical history and, when available, histology. Of the 19 lesions detected by all three modalities, PET identified each as positive for PHEO, but was unable to definitively localize 15 of 19 (79%). CT could definitively localize all 19 lesions, but could not definitively diagnose or exclude PHEO in 18 of 19 (95%) lesions. Furthermore, CT falsely identified as negative for PHEO one lesion which was judged to be positive for this tumor by both PET and PET/CT. Only in PET/CT scans were all 19 lesions accurately characterized and localized. On a per-patient basis, the sensitivity of 18 F-DOPA PET/CT for PHEO was 100% and the specificity 88%, with a 100% positive predictive value and an 88% negative predictive value. 18 F-DOPA PET/CT more accurately diagnoses and localizes adrenal and extra-adrenal masses suspicious for PHEO than do 18 F-DOPA PET or CT alone. (orig.)

  3. Radionecrosis versus disease progression in brain metastasis. Value of (18)F-DOPA PET/CT/MRI.

    Science.gov (United States)

    Hernández Pinzón, J; Mena, D; Aguilar, M; Biafore, F; Recondo, G; Bastianello, M

    2016-01-01

    The use of (18)F-DOPA PET/CT with magnetic resonance imaging fusion and the use of visual methods and quantitative analysis helps to differentiate between changes post-radiosurgery vs. suspicion of disease progression in a patient with brain metastases from melanoma, thus facilitating taking early surgical action. Copyright © 2016 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

  4. Novel use of F-DOPA PET/CT imaging in a child with paraganglioma/pheochromocytoma syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Levine, Daniel S.; Nadel, Helen R. [University of British Columbia, Department of Radiology and Nuclear Medicine, British Columbia Children' s Hospital, Vancouver (Canada); Metzger, Daniel L. [University of British Columbia, Department of Pediatrics, Division of Endocrinology, British Columbia Children' s Hospital, Vancouver (Canada); Oviedo, Angelica [University of British Columbia, Department of Pathology, British Columbia Children' s Hospital, Vancouver (Canada); Adam, Michael J. [University of British Columbia, Department of PET Chemistry, Tri-University Meson Facility (TRIUMF), Vancouver (Canada); Skarsgard, Erik [University of British Columbia, Department of Surgery, British Columbia Children' s Hospital, Vancouver (Canada)

    2011-10-15

    We report the use of F-DOPA PET/CT imaging in the evaluation of a teenager with marked hypertension and right pararenal, left adrenal and left para-aortic mass lesions. The use of the modality for this clinical application has not been described previously within the pediatric imaging literature. The value of this technique relative to conventional imaging modalities is discussed and warrants consideration of its use, if available, for evaluating children with suspected paragangliomas/pheochromocytomas. (orig.)

  5. Alterations in Striatal Synaptic Transmission are Consistent across Genetic Mouse Models of Huntington's Disease

    Directory of Open Access Journals (Sweden)

    Damian M Cummings

    2010-05-01

    Full Text Available Since the identification of the gene responsible for HD (Huntington's disease, many genetic mouse models have been generated. Each employs a unique approach for delivery of the mutated gene and has a different CAG repeat length and background strain. The resultant diversity in the genetic context and phenotypes of these models has led to extensive debate regarding the relevance of each model to the human disorder. Here, we compare and contrast the striatal synaptic phenotypes of two models of HD, namely the YAC128 mouse, which carries the full-length huntingtin gene on a yeast artificial chromosome, and the CAG140 KI*** (knock-in mouse, which carries a human/mouse chimaeric gene that is expressed in the context of the mouse genome, with our previously published data obtained from the R6/2 mouse, which is transgenic for exon 1 mutant huntingtin. We show that striatal MSNs (medium-sized spiny neurons in YAC128 and CAG140 KI mice have similar electrophysiological phenotypes to that of the R6/2 mouse. These include a progressive increase in membrane input resistance, a reduction in membrane capacitance, a lower frequency of spontaneous excitatory postsynaptic currents and a greater frequency of spontaneous inhibitory postsynaptic currents in a subpopulation of striatal neurons. Thus, despite differences in the context of the inserted gene between these three models of HD, the primary electrophysiological changes observed in striatal MSNs are consistent. The outcomes suggest that the changes are due to the expression of mutant huntingtin and such alterations can be extended to the human condition.

  6. Striatal mechanisms underlying movement, reinforcement, and punishment.

    Science.gov (United States)

    Kravitz, Alexxai V; Kreitzer, Anatol C

    2012-06-01

    Direct and indirect pathway striatal neurons are known to exert opposing control over motor output. In this review, we discuss a hypothetical extension of this framework, in which direct pathway striatal neurons also mediate reinforcement and reward, and indirect pathway neurons mediate punishment and aversion.

  7. Striatal Mechanisms Underlying Movement, Reinforcement, and Punishment

    OpenAIRE

    Kravitz, Alexxai V.; Kreitzer, Anatol C.

    2012-01-01

    Direct and indirect pathway striatal neurons are known to exert opposing control over motor output. In this review, we discuss a hypothetical extension of this framework, in which direct pathway striatal neurons also mediate reinforcement and reward, and indirect pathway neurons mediate punishment and aversion.

  8. Head-to-head comparison between 18F-FDOPA PET/CT and MR/CT angiography in clinically recurrent head and neck paragangliomas

    International Nuclear Information System (INIS)

    Heimburger, Celine; Hubele, Fabrice; Namer, Izzie Jacques; Veillon, Francis; Riehm, Sophie; Cavalcanti, Marcela; Taieb, David; Goichot, Bernard; Chabrier, Gerard; Petit-Thomas, Julie; Charpiot, Anne; Averous, Gerlinde; Imperiale, Alessio

    2017-01-01

    Head and neck paragangliomas (HNPGLs) can relapse after primary treatment. Optimal imaging protocols have not yet been established for posttreatment evaluation. The aim of the present study was to assess the diagnostic value of 18 F-FDOPA PET/CT and MR/CT angiography (MRA/CTA) in HNPGL patients with clinical relapse during their follow-up. Sixteen consecutive patients presenting with local pain, tinnitus, dysphagia, hoarse voice, cranial nerve involvement, deafness, or retrotympanic mass appearing during follow-up after the initial treatment of HNPGLs were retrospectively evaluated. Patients underwent both 18 F-FDOPA PET/CT and MRA (15 patents) or CTA (1 patent). Both methods were first assessed under blinded conditions and afterwards correlated. Head and neck imaging abnormalities without histological confirmation were considered true-positive results based on a consensus between radiologists and nuclear physicians and on further 18 F-FDOPA PET/CT and/or MRA. 18 F-FDOPA PET/CT and MRA/CTA were concordant in 14 patients and in disagreement in 2 patients. 18 F-FDOPA PET/CT and MRA/CTA identified, respectively, 12 and 10 presumed recurrent HNPGLs in 12 patients. The two lesions diagnosed by PET/CT only were confirmed during follow-up by otoscopic examination and MRA performed 29 and 17 months later. 18 F-FDOPA PET/CT images were only slightly influenced by the posttreatment sequelae, showing a better interobserver reproducibility than MRA/CTA. Finally, in 2 of the 16 studied patients, 18 F-FDOPA PET/CT detected two additional synchronous primary HNPGLs. 18 F-FDOPA PET/CT is highly sensitive in posttreatment evaluation of patients with HNPGLs, and also offers better interobserver reproducibility than MRA/CTA and whole-body examination. We therefore suggest that 18 F-FDOPA PET/CT is performed as the first diagnostic imaging modality in symptomatic patients with suspicion of HNPGL relapse after primary treatment when 68 Ga-labeled somatostatin analogues are not

  9. Head-to-head comparison between {sup 18}F-FDOPA PET/CT and MR/CT angiography in clinically recurrent head and neck paragangliomas

    Energy Technology Data Exchange (ETDEWEB)

    Heimburger, Celine; Hubele, Fabrice; Namer, Izzie Jacques [University Hospitals of Strasbourg, Department of Biophysics and Nuclear Medicine, Strasbourg (France); CNRS/University of Strasbourg, ICube, UMR 7357, Strasbourg (France); University of Strasbourg, FMTS, Faculty of Medicine, Strasbourg (France); Veillon, Francis; Riehm, Sophie; Cavalcanti, Marcela [University Hospitals of Strasbourg, Department of Radiology, Strasbourg (France); Taieb, David [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, Marseille (France); Aix-Marseille University, European Center for Research in Medical Imaging, Marseille (France); Institut Paoli-Calmettes, Inserm UMR1068 Marseille Cancerology Research Center, Marseille (France); Goichot, Bernard; Chabrier, Gerard [University Hospitals of Strasbourg, Department of Internal Medicine, Strasbourg (France); Petit-Thomas, Julie; Charpiot, Anne [University Hospitals of Strasbourg, Department of Otolaryngology and Maxillofacial Surgery, Strasbourg (France); Averous, Gerlinde [University Hospitals of Strasbourg, Department of Pathology, Strasbourg (France); Imperiale, Alessio [University Hospitals of Strasbourg, Department of Biophysics and Nuclear Medicine, Strasbourg (France); CNRS/University of Strasbourg, ICube, UMR 7357, Strasbourg (France); University of Strasbourg, FMTS, Faculty of Medicine, Strasbourg (France); Hautepierre University Hospital, Biophysics and Nuclear Medicine, Strasbourg Cedex (France)

    2017-06-15

    Head and neck paragangliomas (HNPGLs) can relapse after primary treatment. Optimal imaging protocols have not yet been established for posttreatment evaluation. The aim of the present study was to assess the diagnostic value of {sup 18}F-FDOPA PET/CT and MR/CT angiography (MRA/CTA) in HNPGL patients with clinical relapse during their follow-up. Sixteen consecutive patients presenting with local pain, tinnitus, dysphagia, hoarse voice, cranial nerve involvement, deafness, or retrotympanic mass appearing during follow-up after the initial treatment of HNPGLs were retrospectively evaluated. Patients underwent both {sup 18}F-FDOPA PET/CT and MRA (15 patents) or CTA (1 patent). Both methods were first assessed under blinded conditions and afterwards correlated. Head and neck imaging abnormalities without histological confirmation were considered true-positive results based on a consensus between radiologists and nuclear physicians and on further {sup 18}F-FDOPA PET/CT and/or MRA. {sup 18}F-FDOPA PET/CT and MRA/CTA were concordant in 14 patients and in disagreement in 2 patients. {sup 18}F-FDOPA PET/CT and MRA/CTA identified, respectively, 12 and 10 presumed recurrent HNPGLs in 12 patients. The two lesions diagnosed by PET/CT only were confirmed during follow-up by otoscopic examination and MRA performed 29 and 17 months later. {sup 18}F-FDOPA PET/CT images were only slightly influenced by the posttreatment sequelae, showing a better interobserver reproducibility than MRA/CTA. Finally, in 2 of the 16 studied patients, {sup 18}F-FDOPA PET/CT detected two additional synchronous primary HNPGLs. {sup 18}F-FDOPA PET/CT is highly sensitive in posttreatment evaluation of patients with HNPGLs, and also offers better interobserver reproducibility than MRA/CTA and whole-body examination. We therefore suggest that {sup 18}F-FDOPA PET/CT is performed as the first diagnostic imaging modality in symptomatic patients with suspicion of HNPGL relapse after primary treatment when {sup 68

  10. Ki67 expression in breast cancer

    Science.gov (United States)

    Elkablawy, Mohamed A.; Albasri, Abdulkader M.; Mohammed, Rabab A.; Hussainy, Akbar S.; Nouh, Magdy M.; Alhujaily, Ahmed S.

    2016-01-01

    Objectives: To evaluate Ki67 immunoexpression pattern in Saudi breast cancer (BC) patients and investigate any possible predictive or prognostic value for Ki67. Methods: This is a retrospective study designed to quantitatively assess the Ki67 proliferative index (PI) in retrieved paraffin blocks of 115 Saudi BC patients diagnosed between January 2005 and March 2015 at the Department of Pathology, King Fahd Hospital, Al Madinah Al Munawarah, Kingdom of Saudi Arabia. The Ki67 PI was correlated with individual and combined immunoprofile data of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) with their clinicopathological parameters. Results: Ki67 immunoreactivity was highly expressed (>25% of the tumor cells were positive) in 85 (73.9%) patients. The Ki67 PI was significantly associated with poor prognostic clinicopathological parameters including old age (pKi67 PI was significantly associated with BC molecular subtypes that were Her2/neu positive (luminal B and HER-2) subtypes compared with the Her2/neu negative (luminal A) subtype (pKi67 PI is significantly higher in Saudi BC patients comparing with the reported literature. Ki67 PI was highest in the HER-2 and luminal-B molecular subtypes. Along with other prognostic indicators, Ki67 PI may be useful in predicting prognosis and management of Saudi BC patients. PMID:26837394

  11. Philosophy, Psychology, Physics and Practice of Ki

    Directory of Open Access Journals (Sweden)

    S. Tsuyoshi Ohnishi

    2009-01-01

    Full Text Available Ki (in Japanese or Qi (in Chinese is the key concept in Eastern medicine, Eastern philosophy, as well as in martial arts. We explain the philosophical and psychological background of Ki. We emphasize that the unique aspects of Eastern philosophy are ‘non-linearity’ and ‘holistic’ approach. We then present physics aspect of Ki. Our experiments demonstrated that a ‘Ki-beam’ carries ‘entropy’ (or information, which is different from ‘energy’. We introduce our experience of having taught Ki to 37 beginners in the United States through the Nishino Breathing Method. If beginners had martial arts training or a strong background in music or dance, about half of them could sense Ki within 10 weeks (1 h class per week of practice.

  12. IDH mutation is paradoxically associated with higher {sup 18}F-FDOPA PET uptake in diffuse grade II and grade III gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Verger, A. [APHM, La Timone Hospital, Department of Nuclear Medicine, Marseille (France); Lorraine University, Department of Nuclear Medicine and Nancyclotep Imaging Platform, CHRU Nancy, Nancy (France); Lorraine University, IADI, INSERM, UMR 947, Nancy (France); Metellus, P. [Centre Hospitalier Prive Clairval, Department of Neurosurgery, Marseille (France); Aix-Marseille University, INSERM, UMR 911, Marseille (France); Sala, Q. [APHM, La Timone Hospital, Department of Nuclear Medicine, Marseille (France); Colin, C. [Aix-Marseille University, INSERM, UMR 911, Marseille (France); Bialecki, E. [Centre Hospitalier Prive Clairval, Department of Neurosurgery, Marseille (France); Taieb, D. [APHM, La Timone Hospital, Department of Nuclear Medicine, Marseille (France); Aix-Marseille University, CERIMED, Marseille (France); Chinot, O. [Aix-Marseille University, INSERM, UMR 911, Marseille (France); APHM, La Timone Hospital, Department of Neuro-Oncology, Marseille (France); Figarella-Branger, D. [Aix-Marseille University, INSERM, UMR 911, Marseille (France); APHM, La Timone Hospital, Department of Anatomopathology, Marseille (France); Guedj, E. [APHM, La Timone Hospital, Department of Nuclear Medicine, Marseille (France); Aix-Marseille University, CERIMED, Marseille (France); Aix-Marseille University, Institut de Neurosciences de la Timone, CNRS, UMR 7289, Marseille (France); Hopital de la Timone, Service Central de Biophysique et Medecine Nucleaire, Marseille (France)

    2017-08-15

    The World Health Organization Classification of Tumors of the Central Nervous System has recently been updated by the integration of diagnostic and prognostic molecular parameters, giving pivotal attention to IDH mutation as a favourable factor. Amino acid PET is increasingly used in the management of gliomas, but its prognostic value is a matter of debate. The aim of this study was to assess the relationship between IDH mutation and {sup 18}F-FDOPA uptake on PET in newly diagnosed gliomas. A total of 43 patients, presenting with diffuse astrocytic and oligodendroglial grade II and III gliomas, reclassified according to the 2016 WHO classification of tumours of the CNS, were retrospectively included. They had all undergone {sup 18}F-FDOPA PET at an initial stage before surgery and histological diagnosis. {sup 18}F-FDOPA uptake values were compared between patients with and without IDH mutation in terms of maximum standardized uptake value (SUVmax) ratios between tumour and normal contralateral brain (T/N), and between tumour and striatum (T/S). Patients with IDH mutation showed higher {sup 18}F-FDOPA T/N SUVmax ratios (1.6 vs. 1.2) and T/S SUVmax ratios (0.9 vs. 0.6) than patients without IDH mutation (p < 0.05). This study showed paradoxically higher {sup 18}F-FDOPA uptake in diffuse grade II and III gliomas with IDH mutation. Despite evident interest in the management of gliomas, and especially in relation to posttherapy evaluation, our findings raise the question of the prognostic value of {sup 18}F-FDOPA uptake on PET uptake in this group of patients. This may be related to differences in amino acid integration, metabolism, or cell differentiation. (orig.)

  13. Prognostic value of {sup 18}F-DOPA PET/CT at the time of recurrence in patients affected by neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Piccardo, Arnoldo [Galliera Hospital, Nuclear Medicine Unit, Genoa (Italy); E.O. Ospedali Galliera, Department of Nuclear Medicine, Genoa (Italy); Puntoni, Matteo [Galliera Hospital, Clinical Trial Research Unit, Genoa (Italy); Lopci, Egesta; Fanti, Stefano [Sant' Orsola-Malpighi Hospital, Nuclear Medicine Unit, Bologna (Italy); Conte, Massimo; Sorrentino, Stefania; Garaventa, Alberto [G. Gaslini Children' s Hospital, Department of Hematology-Oncology, Genoa (Italy); Foppiani, Luca [Galliera Hospital, Internal Medicine, Genoa (Italy); Morana, Giovanni [G. Gaslini Children' s Hospital, Department of Pathology and Radiology, Genoa (Italy); Naseri, Mehrdad; Villavecchia, Giampiero [Galliera Hospital, Nuclear Medicine Unit, Genoa (Italy); Cistaro, Angelina [IRMET, PET Centre, Turin (Italy)

    2014-06-15

    The aim of this study was to investigate the relationship between {sup 123}I-metaiodobenzylguanidine (MIBG) scan semi-quantification and a new {sup 18}F-DOPA positron emission tomography (PET)/CT score in patients with suspected or documented neuroblastoma (NB) relapse and to assess the association between these two parameters and progression-free survival (PFS)/overall survival (OS). We analysed 24 NB patients who had undergone {sup 123}I-MIBG and {sup 18}F-DOPA PET/CT scans at the time of suspected relapse, after applying a proper scoring system for each scan. In time-to-event analyses, the score distributions were regarded as continuous and were categorized in tertiles and medians. We used Kaplan-Meier curves and Cox proportional hazard models for PFS and OS in order to estimate the independent prognostic impact of {sup 123}I-MIBG and {sup 18}F-DOPA PET/CT scans. The {sup 123}I-MIBG and {sup 18}F-DOPA scores were highly and positively correlated (Spearman's rho = 0.8, p < 0.001). Over a median follow-up of 14 months (range 6-82), 12 cases of disease progression and 6 deaths occurred. Multivariate Cox models showed a higher risk of disease progression [hazard ratio (HR) 17.0, 95 % confidence interval (CI) 2.7-109] in NB patients with {sup 123}I-MIBG score > 3 (3rd tertile) and an even higher risk (HR:37.2, 95 % CI 2.4-574) in those with {sup 18}F-DOPA whole-body metabolic burden (WBMB) >7.5 (median), after adjustment for all main clinical/pathological factors considered. Kaplan-Meier analyses showed a significant association with OS (log-rank p = 0.01 and p = 0.03 for {sup 123}I-MIBG and {sup 18}F-DOPA WBMB, respectively). Our results confirm the good agreement between {sup 18}F-DOPA PET/CT and {sup 123}I-MIBG scan in patients affected by NB relapse. In time-to-event analyses, {sup 123}I-MIBG scan and {sup 18}F-DOPA PET/CT scores were independently and significantly associated with disease progression. (orig.)

  14. A retrospective comparison between 68Ga-DOTA-TOC PET/CT and 18F-DOPA PET/CT in patients with extra-adrenal paraganglioma.

    Science.gov (United States)

    Kroiss, Alexander; Putzer, Daniel; Frech, Andreas; Decristoforo, Clemens; Uprimny, Christian; Gasser, Rudolf Wolfgang; Shulkin, Barry Lynn; Url, Christoph; Widmann, Gerlig; Prommegger, Rupert; Sprinzl, Georg Mathias; Fraedrich, Gustav; Virgolini, Irene Johanna

    2013-12-01

    (18)F-Fluoro-L-dihydroxyphenylalanine ((18)F-DOPA) PET offers high sensitivity and specificity in the imaging of nonmetastatic extra-adrenal paragangliomas (PGL) but lower sensitivity in metastatic or multifocal disease. These tumours are of neuroendocrine origin and can be detected by (68)Ga-DOTA-Tyr(3)-octreotide ((68)Ga-DOTA-TOC) PET. Therefore, we compared (68)Ga-DOTA-TOC and (18)F-DOPA as radiolabels for PET/CT imaging for the diagnosis and staging of extra-adrenal PGL. Combined cross-sectional imaging was the reference standard. A total of 5 men and 15 women (age range 22 to 73 years) with anatomical and/or histologically proven extra-adrenal PGL were included in this study. Of these patients, 5 had metastatic or multifocal lesions and 15 had single sites of disease. Comparative evaluation included morphological imaging with CT and functional imaging with (68)Ga-DOTA-TOC PET and (18)F-DOPA PET. The imaging results were analysed on a per-patient and a per-lesion basis. The maximum standardized uptake value (SUVmax) of each functional imaging modality in concordant tumour lesions was measured. Compared with anatomical imaging, (68)Ga-DOTA-TOC PET and (18)F-DOPA PET each had a per-patient and per-lesion detection rate of 100% in nonmetastatic extra-adrenal PGL. However, in metastatic or multifocal disease, the per-lesion detection rate of (68)Ga-DOTA-TOC was 100% and that of (18)F-DOPA PET was 56.0%. Overall, (68)Ga-DOTA-TOC PET identified 45 lesions; anatomical imaging identified 43 lesions, and (18)F-DOPA PET identified 32 lesions. The overall per-lesion detection rate of (68)Ga-DOTA-TOC PET was 100% (McNemar, P TOC PET and 11.8 ± 7.9 for (18)F-DOPA PET (Mann-Whitney U test, P TOC PET may be superior to (18)F-DOPA PET and diagnostic CT in providing valuable information for pretherapeutic staging of extra-adrenal PGL, particularly in surgically inoperable tumours and metastatic or multifocal disease.

  15. Grading and outcome prediction of pediatric diffuse astrocytic tumors with diffusion and arterial spin labeling perfusion MRI in comparison with 18F-DOPA PET

    Energy Technology Data Exchange (ETDEWEB)

    Morana, Giovanni; Tortora, Domenico; Severino, Mariasavina; Rossi, Andrea [Istituto Giannina Gaslini, Neuroradiology Unit, Genoa (Italy); Piccardo, Arnoldo; Cabria, Manlio [Ente Ospedaliero Ospedali Galliera, Nuclear Medicine Unit, Genoa (Italy); Puntoni, Matteo [Ente Ospedaliero Ospedali Galliera, Clinical Trial Unit, Scientific Directorate, Genoa (Italy); Nozza, Paolo [Istituto Giannina Gaslini, Pathology Unit, Genoa (Italy); Ravegnani, Marcello; Consales, Alessandro; Mascelli, Samantha; Raso, Alessandro [Istituto Giannina Gaslini, Neurosurgery Unit, Genoa (Italy); Verrico, Antonio; Milanaccio, Claudia [Istituto Giannina Gaslini, Neuro-oncology Unit, Genoa (Italy)

    2017-11-15

    The aim of this study was to investigate MRI-derived diffusion weighted imaging (DWI) and arterial spin labeling (ASL) perfusion imaging in comparison with {sup 18}F-dihydroxyphenylalanine (DOPA) PET with respect to diagnostic performance in tumor grading and outcome prediction in pediatric patients with diffuse astrocytic tumors (DAT). We retrospectively analyzed 26 children with histologically proven treatment naive low and high grade DAT who underwent ASL and DWI performed within 2 weeks of {sup 18}F-DOPA PET. Relative ASL-derived cerebral blood flow max (rCBF max) and DWI-derived minimum apparent diffusion coefficient (rADC min) were compared with {sup 18}F-DOPA uptake tumor/normal tissue (T/N) and tumor/striatum (T/S) ratios, and correlated with World Health Organization (WHO) tumor grade and progression-free survival (PFS). Statistics included Pearson's chi-square and Mann-Whitney U tests, Spearman's rank correlation, receiver operating characteristic (ROC) analysis, discriminant function analysis (DFA), Kaplan-Meier survival curve, and Cox analysis. A significant correlation was demonstrated between rCBF max, rADC min, and {sup 18}F-DOPA PET data (p < 0.001). Significant differences in terms of rCBF max, rADC min, and {sup 18}F-DOPA uptake were found between low- and high-grade DAT (p ≤ 0.001). ROC analysis and DFA demonstrated that T/S and T/N values were the best parameters for predicting tumor progression (AUC 0.93, p < 0.001). On univariate analysis, all diagnostic tools correlated with PFS (p ≤ 0.001); however, on multivariate analysis, only {sup 18}F-DOPA uptake remained significantly associated with outcome (p ≤ 0.03), while a trend emerged for rCBF max (p = 0.09) and rADC min (p = 0.08). The combination of MRI and PET data increased the predictive power for prognosticating tumor progression (AUC 0.97, p < 0.001). DWI, ASL and {sup 18}F-DOPA PET provide useful complementary information for pediatric DAT grading. {sup 18}F-DOPA uptake

  16. Comparison between 68Ga-DOTA-NOC and 18F-DOPA PET for the detection of gastro-entero-pancreatic and lung neuro-endocrine tumours.

    Science.gov (United States)

    Ambrosini, Valentina; Tomassetti, Paola; Castellucci, Paolo; Campana, Davide; Montini, Giancarlo; Rubello, Domenico; Nanni, Cristina; Rizzello, Anna; Franchi, Roberto; Fanti, Stefano

    2008-08-01

    (18)F-FDG positron emission tomography (PET) value for the assessment of neuro-endocrine tumours (NET) is limited. Preliminary studies indicate that (18)F-DOPA and (68)Ga-DOTA-NOC are more accurate for disease assessment and (68)Ga-DOTA peptides provide additional data on receptor status that are crucial for targeted radionuclide therapy. At present, there are no comparative studies investigating their role in NET. The aim of this study was to compare (68)Ga-DOTA-NOC and (18)F-DOPA for the evaluation of gastro-entero-pancreatic and lung neuro-endocrine tumours. Thirteen patients with biopsy-proven NET (gastro-entero-pancreatic or pulmonary) were prospectively enrolled and scheduled for (18)F-DOPA and (68)Ga-DOTA-NOC PET. PET results obtained with both tracers were compared with each other, with other conventional diagnostic procedures (CT, ultrasound) and with follow-up (clinical, imaging). The most common primary tumour site was the pancreas (8/13) followed by the ileum (2/13), the lung (2/13) and the duodenum (1/13). The carcinoma was well differentiated in 10/13 and poorly differentiated in 3/13 cases. (68)Ga-DOTA-NOC PET was positive, showing at least one lesion, in 13/13 cases while (18)F-DOPA PET was positive in 9/13. On a lesions basis, (68)Ga-DOTA-NOC identified more lesions than (18)F-DOPA (71 vs 45), especially at liver, lung and lymph node level. (68)Ga-DOTA-NOC correctly identified the primary site in six of eight non-operated cases (in five cases, the primary was surgically removed before PET), while (18)F-DOPA identified the primary only in two of eight cases. Although the patients studied are few and heterogeneous, our data show that (68)Ga-DOTA-NOC is accurate for the detection of gastro-entero-pancreatic and lung neuro-endocrine tumours in either the primary or metastatic site and that it offers several advantages over (18)F-DOPA.

  17. Comparison between 68Ga-DOTA-NOC and 18F-DOPA PET for the detection of gastro-entero-pancreatic and lung neuro-endocrine tumours

    International Nuclear Information System (INIS)

    Ambrosini, Valentina; Tomassetti, Paola; Castellucci, Paolo; Campana, Davide; Montini, Giancarlo; Rubello, Domenico; Nanni, Cristina; Rizzello, Anna; Franchi, Roberto; Fanti, Stefano

    2008-01-01

    18 F-FDG positron emission tomography (PET) value for the assessment of neuro-endocrine tumours (NET) is limited. Preliminary studies indicate that 18 F-DOPA and 68 Ga-DOTA-NOC are more accurate for disease assessment and 68 Ga-DOTA peptides provide additional data on receptor status that are crucial for targeted radionuclide therapy. At present, there are no comparative studies investigating their role in NET. The aim of this study was to compare 68 Ga-DOTA-NOC and 18 F-DOPA for the evaluation of gastro-entero-pancreatic and lung neuro-endocrine tumours. Thirteen patients with biopsy-proven NET (gastro-entero-pancreatic or pulmonary) were prospectively enrolled and scheduled for 18 F-DOPA and 68 Ga-DOTA-NOC PET. PET results obtained with both tracers were compared with each other, with other conventional diagnostic procedures (CT, ultrasound) and with follow-up (clinical, imaging). The most common primary tumour site was the pancreas (8/13) followed by the ileum (2/13), the lung (2/13) and the duodenum (1/13). The carcinoma was well differentiated in 10/13 and poorly differentiated in 3/13 cases. 68 Ga-DOTA-NOC PET was positive, showing at least one lesion, in 13/13 cases while 18 F-DOPA PET was positive in 9/13. On a lesions basis, 68 Ga-DOTA-NOC identified more lesions than 18 F-DOPA (71 vs 45), especially at liver, lung and lymph node level. 68 Ga-DOTA-NOC correctly identified the primary site in six of eight non-operated cases (in five cases, the primary was surgically removed before PET), while 18 F-DOPA identified the primary only in two of eight cases. Although the patients studied are few and heterogeneous, our data show that 68 Ga-DOTA-NOC is accurate for the detection of gastro-entero-pancreatic and lung neuro-endocrine tumours in either the primary or metastatic site and that it offers several advantages over 18 F-DOPA. (orig.)

  18. Rat striatal muscarinic receptors coupled to the inhibition of adenylyl cyclase activity: potent block by the selective m4 ligand muscarinic toxin 3 (MT3).

    Science.gov (United States)

    Olianas, M C; Adem, A; Karlsson, E; Onali, P

    1996-05-01

    1. In rat striatal membranes, muscarinic toxin 3 (MT3), a selective ligand of the cloned m4 receptor subtype, antagonized the acetylcholine (ACh) inhibition of forskolin- and dopamine D1 receptor-stimulated adenylyl cyclase activities with pA2 values of 8.09 and 8.15, respectively. 2. In radioligand binding experiments, MT3 increased the Kd but did not change the Bmax value of [3H]-N-methylscopolamine (3H]-NMS) binding to rat striatal muscarinic receptors. The toxin displaced the major portion of the [3H]-NMS binding sites with a Ki of 8.0 nM. 3. In rat myocardium, MT3 antagonized the ACh inhibition of adenylyl cyclase with a Ki value of 860 nM. 4. In rat cerebral cortical membranes prelabelled with [3H]-myo-inositol, MT3 counteracted the methacholine stimulation of [3H]-inositol phosphates formation with a Ki value of 113 nM. 5. The present study shows that MT3 is a potent antagonist of the striatal muscarinic receptors coupled to inhibition of adenylyl cyclase activity. This finding provides strong evidence for the classification of these receptors as pharmacologically equivalent to the m4 gene product (M4). On the other hand, the weaker potencies of MT3 in antagonizing the muscarinic responses in cerebral cortex and in the heart are consistent with the reported lower affinities of the toxin for the cloned m1 and m2 receptor subtypes, respectively.

  19. Striatal cholinergic interneuron regulation and circuit effects

    Directory of Open Access Journals (Sweden)

    Sean Austin Lim

    2014-10-01

    Full Text Available The striatum plays a central role in motor control and motor learning. Appropriate responses to environmental stimuli, including pursuit of reward or avoidance of aversive experience all require functional striatal circuits. These pathways integrate synaptic inputs from limbic and cortical regions including sensory, motor and motivational information to ultimately connect intention to action. Although many neurotransmitters participate in striatal circuitry, one critically important player is acetylcholine (ACh. Relative to other brain areas, the striatum contains exceptionally high levels of ACh, the enzymes that catalyze its synthesis and breakdown, as well as both nicotinic and muscarinic receptor types that mediate its postsynaptic effects. The principal source of striatal ACh is the cholinergic interneuron (ChI, which comprises only about 1-2% of all striatal cells yet sends dense arbors of projections throughout the striatum. This review summarizes recent advances in our understanding of the factors affecting the excitability of these neurons through acute effects and long term changes in their synaptic inputs. In addition, we discuss the physiological effects of ACh in the striatum, and how changes in ACh levels may contribute to disease states during striatal dysfunction.

  20. Huntington’s Disease and Striatal Signaling

    Science.gov (United States)

    Roze, Emmanuel; Cahill, Emma; Martin, Elodie; Bonnet, Cecilia; Vanhoutte, Peter; Betuing, Sandrine; Caboche, Jocelyne

    2011-01-01

    Huntington’s Disease (HD) is the most frequent neurodegenerative disease caused by an expansion of polyglutamines (CAG). The main clinical manifestations of HD are chorea, cognitive impairment, and psychiatric disorders. The transmission of HD is autosomal dominant with a complete penetrance. HD has a single genetic cause, a well-defined neuropathology, and informative pre-manifest genetic testing of the disease is available. Striatal atrophy begins as early as 15 years before disease onset and continues throughout the period of manifest illness. Therefore, patients could theoretically benefit from therapy at early stages of the disease. One important characteristic of HD is the striatal vulnerability to neurodegeneration, despite similar expression of the protein in other brain areas. Aggregation of the mutated Huntingtin (HTT), impaired axonal transport, excitotoxicity, transcriptional dysregulation as well as mitochondrial dysfunction, and energy deficits, are all part of the cellular events that underlie neuronal dysfunction and striatal death. Among these non-exclusive mechanisms, an alteration of striatal signaling is thought to orchestrate the downstream events involved in the cascade of striatal dysfunction. PMID:22007160

  1. IDH mutation is paradoxically associated with higher18F-FDOPA PET uptake in diffuse grade II and grade III gliomas.

    Science.gov (United States)

    Verger, A; Metellus, Ph; Sala, Q; Colin, C; Bialecki, E; Taieb, D; Chinot, O; Figarella-Branger, D; Guedj, E

    2017-08-01

    The World Health Organization Classification of Tumors of the Central Nervous System has recently been updated by the integration of diagnostic and prognostic molecular parameters, giving pivotal attention to IDH mutation as a favourable factor. Amino acid PET is increasingly used in the management of gliomas, but its prognostic value is a matter of debate. The aim of this study was to assess the relationship between IDH mutation and 18 F-FDOPA uptake on PET in newly diagnosed gliomas. A total of 43 patients, presenting with diffuse astrocytic and oligodendroglial grade II and III gliomas, reclassified according to the 2016 WHO classification of tumours of the CNS, were retrospectively included. They had all undergone 18 F-FDOPA PET at an initial stage before surgery and histological diagnosis. 18 F-FDOPA uptake values were compared between patients with and without IDH mutation in terms of maximum standardized uptake value (SUVmax) ratios between tumour and normal contralateral brain (T/N), and between tumour and striatum (T/S). Patients with IDH mutation showed higher 18 F-FDOPA T/N SUVmax ratios (1.6 vs. 1.2) and T/S SUVmax ratios (0.9 vs. 0.6) than patients without IDH mutation (p IDH mutation. Despite evident interest in the management of gliomas, and especially in relation to posttherapy evaluation, our findings raise the question of the prognostic value of 18 F-FDOPA uptake on PET uptake in this group of patients. This may be related to differences in amino acid integration, metabolism, or cell differentiation.

  2. An International Ki67 Reproducibility Study

    Science.gov (United States)

    2013-01-01

    Background In breast cancer, immunohistochemical assessment of proliferation using the marker Ki67 has potential use in both research and clinical management. However, lack of consistency across laboratories has limited Ki67’s value. A working group was assembled to devise a strategy to harmonize Ki67 analysis and increase scoring concordance. Toward that goal, we conducted a Ki67 reproducibility study. Methods Eight laboratories received 100 breast cancer cases arranged into 1-mm core tissue microarrays—one set stained by the participating laboratory and one set stained by the central laboratory, both using antibody MIB-1. Each laboratory scored Ki67 as percentage of positively stained invasive tumor cells using its own method. Six laboratories repeated scoring of 50 locally stained cases on 3 different days. Sources of variation were analyzed using random effects models with log2-transformed measurements. Reproducibility was quantified by intraclass correlation coefficient (ICC), and the approximate two-sided 95% confidence intervals (CIs) for the true intraclass correlation coefficients in these experiments were provided. Results Intralaboratory reproducibility was high (ICC = 0.94; 95% CI = 0.93 to 0.97). Interlaboratory reproducibility was only moderate (central staining: ICC = 0.71, 95% CI = 0.47 to 0.78; local staining: ICC = 0.59, 95% CI = 0.37 to 0.68). Geometric mean of Ki67 values for each laboratory across the 100 cases ranged 7.1% to 23.9% with central staining and 6.1% to 30.1% with local staining. Factors contributing to interlaboratory discordance included tumor region selection, counting method, and subjective assessment of staining positivity. Formal counting methods gave more consistent results than visual estimation. Conclusions Substantial variability in Ki67 scoring was observed among some of the world’s most experienced laboratories. Ki67 values and cutoffs for clinical decision-making cannot be transferred between laboratories without

  3. LibKiSAO: a Java library for Querying KiSAO

    Directory of Open Access Journals (Sweden)

    Zhukova Anna

    2012-09-01

    Full Text Available Abstract Background The Kinetic Simulation Algorithm Ontology (KiSAO supplies information about existing algorithms available for the simulation of Systems Biology models, their characteristics, parameters and inter-relationships. KiSAO enables the unambiguous identification of algorithms from simulation descriptions. Information about analogous methods having similar characteristics and about algorithm parameters incorporated into KiSAO is desirable for simulation tools. To retrieve this information programmatically an application programming interface (API for KiSAO is needed. Findings We developed libKiSAO, a Java library to enable querying of the KiSA Ontology. It implements methods to retrieve information about simulation algorithms stored in KiSAO, their characteristics and parameters, and methods to query the algorithm hierarchy and search for similar algorithms providing comparable results for the same simulation set-up. Using libKiSAO, simulation tools can make logical inferences based on this knowledge and choose the most appropriate algorithm to perform a simulation. LibKiSAO also enables simulation tools to handle a wider range of simulation descriptions by determining which of the available methods are similar and can be used instead of the one indicated in the simulation description if that one is not implemented. Conclusions LibKiSAO enables Java applications to easily access information about simulation algorithms, their characteristics and parameters stored in the OWL-encoded Kinetic Simulation Algorithm Ontology. LibKiSAO can be used by simulation description editors and simulation tools to improve reproducibility of computational simulation tasks and facilitate model re-use.

  4. Personalization Component for KiWi Framework

    DEFF Research Database (Denmark)

    Durao, Frederico; Xu, Guandong; Kotowski, Jakub

    2010-01-01

    . The personalization component is responsible for addressing and delivering information to individuals regarding their roles and preferences, explicitly or implicitly inferred from their activities in the system. Personalization is a essential for KiWi since this in a multi-user environment and individuals has......In this report we present the personalization component implemented for KiWi addressing diverse aspects such as motivation scenarios, configuration management, formal models, implementations and some real case scenarios on how personalization can be applied to support software project management...... different interests and needs when using the system....

  5. PET with {sup 18}F-DOPA in the imaging of parathyroid adenoma in patients with primary hyperparathyroidism. A pilot study

    Energy Technology Data Exchange (ETDEWEB)

    Lange-Nolde, A.; Zajic, T.; Brink, I.; Moser, E.; Hoegerle, S. [Univ. Hospital Freiburg (Germany). Div. of Nuclear Medicine; Slawik, M. [Univ. Cambridge, Addenbrooke (United Kingdom). Dept. of Clinical Biochemistry and Medicine; Reincke, M. [Univ. Hospital Munich (Germany). Dept. of Internal Medicine, Div. Endocrinology and Diabetes

    2006-07-01

    Preoperative localization of parathyroid adenomas (PA) can shorten operation time and improve curative rate; it becomes especially important in minimally invasive surgical techniques: Aim of this study was to investigate whether positron emission tomography (PET) with 3-,4-dihydroxy-6{sup 18}F-fluorophenylalanine ({sup 18}F-DOPA), which showed very promising results in other neuroendocrine tumours, also helps to localize PA. Patients, methods: Eight patients with proven primary hyperparathyroidism were studied preoperatively with PET. Seven also underwent sctintigraphy with {sup 99m}Tc-MIBI and ultrasonography of the neck. All patients were operated and the histological finding was used as a gold standard. Results: All eight patients had a histologically proven PA. None of the PA showed any detectable uptake of {sup 18}F-DOPA. However, ultrasonography detected 5/7 PA, scintigraphy detected 3/7 PA. Conclusion: These results suggest that PET with {sup 18}F-DOPA is not useful in the detection of Pa in patients with primary hyperparathyroidism. (orig.)

  6. 18F-FDOPA and 18F-FLT positron emission tomography parametric response maps predict response in recurrent malignant gliomas treated with bevacizumab.

    Science.gov (United States)

    Harris, Robert J; Cloughesy, Timothy F; Pope, Whitney B; Nghiemphu, Phioanh L; Lai, Albert; Zaw, Taryar; Czernin, Johannes; Phelps, Michael E; Chen, Wei; Ellingson, Benjamin M

    2012-08-01

    The current study examined the use of voxel-wise changes in (18)F-FDOPA and (18)F-FLT PET uptake, referred to as parametric response maps (PRMs), to determine whether they were predictive of response to bevacizumab in patients with recurrent malignant gliomas. Twenty-four patients with recurrent malignant gliomas who underwent bevacizumab treatment were analyzed. Patients had MR and PET images acquired before and at 2 time points after bevacizumab treatment. PRMs were created by examining the percentage change in tracer uptake between time points in each image voxel. Voxel-wise increase in PET uptake in areas of pretreatment contrast enhancement defined by MRI stratified 3-month progression-free survival (PFS) and 6-month overall survival (OS) according to receiver-operating characteristic curve analysis. A decrease in PET tracer uptake was associated with longer PFS and OS, whereas an increase in PET uptake was associated with short PFS and OS. The volume fraction of increased (18)F-FDOPA PET uptake between the 2 posttreatment time points also stratified long- and short-term PFS and OS (log-rank, P PRMs after bevacizumab treatment may be a useful biomarker for predicting PFS and that FDOPA PET PRMs are also predictive of OS in recurrent gliomas treated with bevacizumab.

  7. Molecular Regulation of Striatal Development: A Review

    Directory of Open Access Journals (Sweden)

    A. E. Evans

    2012-01-01

    Full Text Available The central nervous system is composed of the brain and the spinal cord. The brain is a complex organ that processes and coordinates activities of the body in bilaterian, higher-order animals. The development of the brain mirrors its complex function as it requires intricate genetic signalling at specific times, and deviations from this can lead to brain malformations such as anencephaly. Research into how the CNS is specified and patterned has been studied extensively in chick, fish, frog, and mice, but findings from the latter will be emphasised here as higher-order mammals show most similarity to the human brain. Specifically, we will focus on the embryonic development of an important forebrain structure, the striatum (also known as the dorsal striatum or neostriatum. Over the past decade, research on striatal development in mice has led to an influx of new information about the genes involved, but the precise orchestration between the genes, signalling molecules, and transcription factors remains unanswered. We aim to summarise what is known to date about the tightly controlled network of interacting genes that control striatal development. This paper will discuss early telencephalon patterning and dorsal ventral patterning with specific reference to the genes involved in striatal development.

  8. Kaurismäki Soome parim

    Index Scriptorium Estoniae

    2007-01-01

    Soome filmiauhinna Jussi võitis A. Kaurismäki "Äärelinna tuled" ("Laitakaupungin valot"), viis Jussit sai Aku Louhimiehe film "Jäine linn" ("Valkoinen kaupunki") ja kaks Jussit Eesti osalusega "Igavese armastuse sõdalane - Jade Warrior"

  9. Diagnostic utility of PET/CT with {sup 18}F-DOPA and {sup 18}F-FDG in persistent or recurrent medullary thyroid carcinoma: the importance of calcitonin and carcinoembryonic antigen cutoff

    Energy Technology Data Exchange (ETDEWEB)

    Romero-Lluch, Ana Reyes; Guerrero-Vazquez, Raquel; Martinez-Ortega, Antonio Jesus; Navarro-Gonzalez, Elena [Hospital Universitario Virgen del Rocio, Unidad de Gestion Clinica de Endocrinologia y Nutricion, Seville (Spain); Cuenca-Cuenca, Juan Ignacio; Tirado-Hospital, Juan Luis; Borrego-Dorado, Isabel [Hospital Universitario Virgen del Rocio, Unidad de Medicina Nuclear, Seville (Spain)

    2017-11-15

    This study sought to evaluate and compare the utility of 18-F-fluorodihydroxyphenylalanine ({sup 18}F-DOPA) and 18-F-fluorodeoxyglucose ({sup 18}F-FDG) positron emission tomography/computed tomography (PET/CT) for identification of lesions in patients with recurrent medullary thyroid carcinoma (MTC). In addition, we analyzed the correlation between the calcitonin (Ct), carcinoembryonic antigen (CEA) levels, each doubling time (DT), and PET positivity. We evaluated the reliability of the 150 pg/mL Ct cutoff set by the American Thyroid Association guidelines for further imaging (including {sup 18}F-DOPA PET/CT). We prospectively recruited 18 patients with recurrent MTC, identified by elevation of Ct or CEA. Each patient underwent a {sup 18}F-FDG PET/CT and a {sup 18}F-DOPA PET/CT. Abnormal uptakes were detected with {sup 18}F-DOPA (n=12) and {sup 18}F-FDG (n=9), (sensitivity of 66.7% vs. 50%; p<0.01). Twenty-eight lesions were detected with {sup 18}F-DOPA vs. 16 lesions with {sup 18}F-FDG (1.56±1.5 vs. 0.89±1.18 lesions per patient; p=0.01). None of our patients showed additional lesions with {sup 18}F-FDG in comparison to {sup 18}F-DOPA. Patient-based detection rate increased significantly with Ct levels ≥150 pg/mL vs. Ct<150 pg/mL for both {sup 18}F-DOPA (sensitivity 90.9% vs. 28.6%; p=0.013) and {sup 18}F-FDG PET/CT (sensitivity 72.7% vs. 14.3%; p=0.025). Using a CEA cutoff of ≥5 ng/mL, detection rates of {sup 18}F-DOPA and {sup 18}F-FDG PET/CT were 81.1% and 72.7%, respectively. No correlation between Ct-DT or CEA-DT and PET positivity was found. Histological confirmation was obtained in eight patients. {sup 18}F-DOPA PET/CT appears to be superior to {sup 18}F-FDG PET/CT in detecting and locating lesions in patients with recurrent MTC. This technique tends to be especially useful in patients with negative results in other imaging modalities and Ct≥150 pg/mL or CEA≥5 ng/mL. (orig.)

  10. Comparison of {sup 18}F-DOPA, {sup 18}F-FDG and {sup 68}Ga-somatostatin analogue PET/CT in patients with recurrent medullary thyroid carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Treglia, Giorgio; Castaldi, Paola; Villani, Maria Felicia; Perotti, Germano; Giordano, Alessandro; Rufini, Vittoria [Catholic University of the Sacred Heart, Institute of Nuclear Medicine, Policlinico A. Gemelli, Rome (Italy); Waure, Chiara de [Catholic University of the Sacred Heart, Institute of Hygiene, Policlinico A. Gemelli, Rome (Italy); Filice, Angelina; Versari, Annibale [Santa Maria Nuova Hospital, Nuclear Medicine Unit, Reggio Emilia (Italy); Ambrosini, Valentina; Fanti, Stefano [University of Bologna, Nuclear Medicine Unit, Sant' Orsola-Malpighi Hospital, Bologna (Italy); Cremonini, Nadia [Ospedale Maggiore, Unit of Endocrinology, Bologna (Italy); Santimaria, Monica [Catholic University of the Sacred Heart, PET Radiopharmacy Unit, Policlinico A. Gemelli, Rome (Italy)

    2012-04-15

    To retrospectively evaluate and compare {sup 18}F-FDG, {sup 18}F-DOPA and {sup 68}Ga-somatostatin analogues for PET/CT in patients with residual/recurrent medullary thyroid carcinoma (MTC) suspected on the basis of elevated serum calcitonin levels. Included in the study were 18 patients with recurrent MTC in whom functional imaging with the three tracers was performed. The PET/CT results were compared on a per-patient basis and on a per-lesion-basis. At least one focus of abnormal uptake was observed on PET/CT in 13 patients with {sup 18}F-DOPA (72.2% sensitivity), in 6 patients with {sup 68}Ga-somatostatin analogues (33.3%) and in 3 patients with {sup 18}F-FDG (16.7%) (p < 0.01). There was a statistically significant difference in sensitivity between {sup 18}F-DOPA and {sup 18}F-FDG PET/CT (p < 0.01) and between {sup 18}F-DOPA and {sup 68}Ga-somatostatin analogue PET/CT (p = 0.04). Overall, 72 lesions were identified on PET/CT with the three tracers. {sup 18}F-DOPA PET/CT detected 85% of lesions (61 of 72), {sup 68}Ga-somatostatin analogue PET/CT 20% (14 of 72) and {sup 18}F-FDG PET/CT 28% (20 of 72). There was a statistically significant difference in the number of lymph node, liver and bone lesions detected with the three tracers (p < 0.01). In particular, post-hoc tests showed a significant difference in the number of lymph node, liver and bone lesions detected by {sup 18}F-DOPA PET/CT and {sup 18}F-FDG PET/CT (p < 0.01 for all the analyses) and by {sup 18}F-DOPA PET/CT and {sup 68}Ga-somatostatin analogue PET/CT (p < 0.01 for all the analyses). The PET/CT results led to a change in management of eight patients (44%). {sup 18}F-DOPA PET/CT seems to be the most useful imaging method for detecting recurrent MTC lesions in patients with elevated serum calcitonin levels, performing better than {sup 18}F-FDG and {sup 68}Ga-somatostatin analogue PET/CT. {sup 18}F-FDG may complement {sup 18}F-DOPA in patients with an aggressive tumour. (orig.)

  11. Striatal dopamine transporter binding correlates with serum BDNF levels in patients with striatal dopaminergic neurodegeneration

    DEFF Research Database (Denmark)

    Ziebell, Morten; Khalid, Usman; Klein, Anders B

    2012-01-01

    BDNF levels in patients with parkinsonism. Twenty-one patients with abnormal in vivo striatal dopamine transporter (DAT) binding as evidenced with [(123)I]PE2I SPECT brain scanning were included. Samples for serum BDNF levels were collected at the time of the SPECT scanning, and BDNF was measured...

  12. KiCad challenges the big ones

    CERN Multimedia

    Antonella Del Rosso

    2015-01-01

    Printed Circuit Boards (PCB) are the heart of any electronic device, including your toaster and your smartphone. Designing PCBs is the job of electronic engineers who, so far, have often had no option but to use proprietary tools to design complex circuits. Thanks to the efforts that CERN experts have put in to improve the free KiCad software, that situation is about to change.   KiCad's development started in 1992 as a way to design PCBs, the units that control how an electronic device works. Since 2013, experts in the Beams department have made important contributions to KiCad as part of the Open Hardware Initiative (OHI), which provides a framework to facilitate knowledge exchange across the electronic design community. “Our vision is to allow the hardware developers to share as easily as their software colleagues,” says Javier Serrano, head of the BE-CO-HT section and OHI initiator. “Software sources are easily shared online because they are text ...

  13. In vivo biodistribution of no-carrier-added 6-18F-fluoro-3,4-dihydroxy-L-phenylalanine (18F-DOPA), produced by a new nucleophilic substitution approach, compared with carrier-added 18F-DOPA, prepared by conventional electrophilic substitution.

    Science.gov (United States)

    Kuik, Willem-Jan; Kema, Ido P; Brouwers, Adrienne H; Zijlma, Rolf; Neumann, Kiel D; Dierckx, Rudi A J O; DiMagno, Stephen G; Elsinga, Philip H

    2015-01-01

    A novel synthetic approach to 6-(18)F-fluoro-3,4-dihydroxy-L-phenylalanine ((18)F-DOPA), involving the nucleophilic substitution of a diaryliodonium salt precursor with non-carrier-added (18)F-fluoride, yielded a product with a specific activity that was 3 orders of magnitude higher than the product of the conventional synthesis method, involving an electrophilic substitution of a trialkylstannane precursor with (18)F2. We performed a direct comparison of high- and low-specific-activity (18)F-DOPA in a neuroendocrine tumor model to determine whether this difference in specific activity has implications for the biologic behavior and imaging properties of (18)F-DOPA. (18)F-DOPA was produced via the novel synthesis method, yielding (18)F-DOPA-H with a high specific activity (35,050 ± 4,000 GBq/mmol). This product was compared in several experiments with conventional (18)F-DOPA-L with a low specific activity (11 ± 2 GBq/mmol). In vitro accumulation experiments with the human pancreatic neuroendocrine tumor cell line BON-1 were performed at both 0 °C and 37 °C and at 37 °C in the presence of pharmacologic inhibitors of proteins involved in the uptake mechanism of (18)F-DOPA. Small-animal PET experiments were performed in athymic nude mice bearing a BON-1 tumor xenograft. At 37 °C, the uptake of both (18)F-DOPA-H and (18)F-DOPA-L did not differ significantly during a 60-min accumulation experiment in BON-1 cells. At 0 °C, the uptake of (18)F-DOPA-L was significantly decreased, whereas the lower temperature did not alter the uptake of (18)F-DOPA-H. The pharmacologic inhibitors carbidopa and tetrabenazine also revealed differential effects between the 2 types of (18)F-DOPA in the 60-min accumulation experiment. The small-animal PET experiments did not show any significant differences in distribution and metabolism of (18)F-DOPA-H and (18)F-DOPA-L in carbidopa-pretreated mice. The advantages of the novel synthesis of (18)F-DOPA, which relies on nucleophilic

  14. Interlaboratory variability of Ki67 staining in breast cancer.

    Science.gov (United States)

    Focke, Cornelia M; Bürger, Horst; van Diest, Paul J; Finsterbusch, Kai; Gläser, Doreen; Korsching, Eberhard; Decker, Thomas

    2017-10-01

    Postanalytic issues of Ki67 assessment in breast cancers like counting method standardisation and interrater bias have been subject of various studies, but little is known about analytic variability of Ki67 staining between pathology labs. Our aim was to study interlaboratory variability of Ki67 staining in breast cancer using tissue microarrays (TMAs) and central assessment to minimise preanalytic and postanalytic influences. Thirty European pathology labs stained serial slides of a TMA set of breast cancer tissues with Ki67 according to their routine in-house protocol. The Ki67-labelling index (Ki67-LI) of 70 matched samples was centrally assessed by one observer who counted all cancer cells per sample. We then tested for differences between the labs in Ki67-LI medians by analysing variance on ranks and in proportions of tumours classified as luminal A after dichotomising oestrogen receptor-positive cancers into cancers showing low (Ki67-LI using Cochran's Q. Substantial differences between the 30 labs were indicated for median Ki67-LI (0.65%-33.0%, p cancers classified as luminal A (17%-57%, p Ki67 staining of breast cancer tissue was found between 30 routine pathology labs. Clinical use of the Ki67-LI for therapeutic decisions should be considered only fully aware of lab-specific reference values. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. A novel model for Ki67 assessment in breast cancer.

    Science.gov (United States)

    Romero, Quinci; Bendahl, Pär-Ola; Fernö, Mårten; Grabau, Dorthe; Borgquist, Signe

    2014-06-16

    Ki67 is currently the proliferation biomarker of choice, with both prognostic and predictive value in breast cancer. A lack of consensus regarding Ki67 use in pre-analytical, analytical and post-analytical practice may hinder its formal acceptance in the clinical setting. One hundred breast cancer samples were stained for Ki67. A standard estimation of Ki67 using fixed denominators of 200, 400 and 1 000 counted tumor cells was performed, and a cut-off at 20% was applied, Ki67static. A novel stepwise counting strategy for Ki67 estimation, Ki67scs, was developed based on rejection regions derived from exact two-sided binomial confidence intervals for proportions. Ki67scs was defined by the following parameters: the cut-off (20%), minimum (50) and maximum (400) number of tumor cells to count, increment (10) and overall significance level of the test procedure (0.05). Results from Ki67scs were compared to results from the Ki67static estimation with fixed denominators. For Ki67scs, the median number of tumor cells needed to determine Ki67 status was 100; the average, 175. Among 38 highly proliferative samples, the average Ki67scs fraction was 45%. For these samples, the fraction decreased from 39% to 37% to 35% with static counting of 200, 400 and 1 000 cells, respectively. The largest absolute difference between the estimation methods was 23% (42% (Ki67scs) vs. 19% (Ki67static)) and resulted in an altered sample classification. Among the 82 unequivocal samples, 74 samples received the same classification using both Ki67scs and Ki67static. Of the eight disparate samples, seven were classified highly proliferative by Ki67static when 200 cells were counted; whereas all eight cases were classified as low proliferative when 1 000 cells were counted. Ki67 estimation using fixed denominators may be inadequate, particularly for tumors demonstrating extensive heterogeneity. We propose a time saving stepwise counting strategy, which acknowledges small highly proliferative hot

  16. {sup 18}F-FDG PET/CT-Negative Recurrent High-Grade Anaplastic Astrocytoma Detected by {sup 18}F-FDOPA PET-CT

    Energy Technology Data Exchange (ETDEWEB)

    Karunanithi, Sellam; Singh, Harmandeep; Sharma, Punit; Gupta, Deepak Kumar; Bal, Chandrasekhar [All India Institute of Medical Sciences, New Delhi (India)

    2013-12-15

    A 37-year-old woman with grade 3 anaplastic astrocytoma (AA) of the left frontal lobe, underwent surgical excision, chemotherapy and external beam radiation therapy in 2004. After being in remission for 5 years, recurrence was suspected clinically when she presented with seizures. The result of contrast-enhanced magnetic resonance imaging (MRI) was equivocal for recurrence and radiation necrosis (not available ). The patient was then referred for {sup 18}F-fluorodeoxyglucose ({sup 18}F-FDG) positron emission tomography-computed tomography (PET-CT), as the initial primary tumour was high grade in nature. {sup 18}F-FDG PET-CT was negative for recurrence and demonstrated only post-operative changes in the left frontal region (Fig. 1a, b, arrow). Due to strong clinical suspicion, 3,4-dihydroxy-6-{sup 18}F-fluoro-L-phenylalanine ({sup 18}F-FDOPA) PET-CT was done, 5 days after {sup 18}F-FDG PET-CT. The study revealed an {sup 18}F-FDOPA-avid mass lesion in the left frontal region (Fig. 1c, d, arrow), thereby confirming the presence of recurrent disease. The patient underwent surgical resection of the mass, and it was confirmed by histopathology as grade 3 AA. However, after a short asymptomatic period of 4 months the patient became symptomatic again. Follow-up MRI after 6 months of surgery revealed presence of ipsilateral and contralateral multifocal contrast enhancing recurrent mass lesions (Fig. 1e, f, arrow), suggesting the progression of disease. The patient was started on temozolamide but she died after 8 months' follow-up. Though MRI is routinely used in assessment of brain tumours, its ability to differentiate between treatment-induced changes and residual or recurrent tumour is limited. {sup 18}F-FDG PET was the first tracer used for assessment of brain tumours; however, it has a low tumour-to-background ratio in brain, limiting its utility. {sup 18}F-FDG uptake correlates with tumour grade, with high-grade gliomas (grades III and IV) showing higher uptake

  17. Politički marketing i politički sustav

    OpenAIRE

    Šiber, Ivan

    2000-01-01

    U ovom radu autor daje određenje političkog marketinga i naglašava njegovu povezanost s demokratskim poretkom, prikazuje razvoj političkog marketinga od stranačkog k marketinškom konceptu, razmatra politički marketing kao svojevrsnu konstrukciju političke zbilje i analizira politički marketing u Hrvatskoj. U radu se naglašava još uvijek svojevrstan otpor političkom marketingu kod onih koji bi ga trebali koristiti, ali i neke objektivne okolnosti koje otežavaju njegovu primjenu poput nedostatk...

  18. 18F-FDOPA PET/CT-Guided Radiofrequency Ablation of Liver Metastases from Neuroendocrine Tumours: Technical Note on a Preliminary Experience

    Energy Technology Data Exchange (ETDEWEB)

    Cazzato, Roberto Luigi, E-mail: gigicazzato@hotmail.it; Garnon, Julien, E-mail: juleiengarnon@gmail.com [Nouvel Hôpital Civil (Hôpitaux Universitaires de Strasbourg, HUS), Department of Interventional Radiology (France); Ramamurthy, Nitin, E-mail: nitin-ramamurthy@hotmail.com [Norfolk and Norwich University Hospital, Department of Radiology (United Kingdom); Tsoumakidou, Georgia, E-mail: georgia.tsoumakidou@chru-strasbourg.fr [Nouvel Hôpital Civil (Hôpitaux Universitaires de Strasbourg, HUS), Department of Interventional Radiology (France); Imperiale, Alessio, E-mail: alessio.imperiale@chru-strasbourg.fr; Namer, Izzie Jacques, E-mail: izzie.jacques.namer@chru-strasbourg.fr [Hôpital de Hautepierre (Hôpitaux Universitaires de Strasbourg, HUS), Department of Biophysics and Nuclear Medicine (France); Bachellier, Philippe, E-mail: philippe.bachellier@chru-strasbourg.fr [Hôpital de Hautepierre (Hôpitaux Universitaires de Strasbourg, HUS), Hepato-Pancreato-Biliary Surgery and Liver Transplantation (France); Caudrelier, Jean, E-mail: jean.caudrelier@chru-strasbourg.fr; Rao, Pramod, E-mail: pramodrao@me.com; Koch, Guillaume, E-mail: guillaume.koch@chru-strasbourg.fr; Gangi, Afshin, E-mail: gangi@unistra.fr [Nouvel Hôpital Civil (Hôpitaux Universitaires de Strasbourg, HUS), Department of Interventional Radiology (France)

    2016-09-15

    AimTo review our preliminary experience with 6-l-18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT-guided radiofrequency ablation (RFA) of liver metastases from neuroendocrine tumours (NETs).Materials and MethodsThree patients (mean age 51.3 years; range 43–56) with gastro-entero pancreatic NET (GEP-NET) liver metastases underwent 18F-FDOPA PET/CT-guided RFA. Patients were referred with oligometastatic hepatic-confined disease (1–6 metastases; <3 cm) on 18F-FDOPA PET/CT; poor lesion visualisation on US, CT, and MR; and ongoing symptoms. Procedures were performed in an interventional PET/CT scanner under general anaesthesia using a split-dose protocol. Lesion characteristics, procedural duration and technical success (accurate probe placement and post-procedural ablation-zone photopaenia), complications, patient and operator dose, and clinical outcomes were evaluated.ResultsThirteen liver metastases (mean size 11.4 mm, range 8–16) were treated in three patients (two presented with “carcinoid syndrome”). Technical success was 100 % with a mean procedural duration of 173.3 min (range 90–210) and no immediate complications. Mean patient dose was 2844 mGy·cm (range 2104–3686). Operator and radiographer doses were acceptable other than the operator’s right hand in the first case (149 µSv); this normalised in the second case. There was no local tumour or extra-hepatic disease progression at mid-term follow-up (mean 12.6 months; range 6–20); however, two cases progressed with new liver metastases at different sites. There was 100 % clinical success (n = 2) in resolving carcinoid syndrome symptoms.Conclusion18F-FDOPA PET/CT-guided RFA appears technically feasible, safe, and effective in patients with GEP-NETs and low-burden hepatic metastases. Further prospective studies are required to elucidate its precise role in tailored multimodality management of GEP-NET liver metastases.

  19. Kulturološki razvoj masovne komunikacije

    OpenAIRE

    Balvan, Luka

    2017-01-01

    članku su prikazani rani početci masovne komunikacije u kontekstu vremena i društvene važnosti te kako je kulturološki gledano razvoj masovne komunikacije duboko povezan s rađanjem kulture i svega onoga što ona nosi. Slijedi prikaz što masovna komunikacija razumijeva/razumije, kada do nje dolazi i koji se točno mediji smatraju masovnim. Razmatra se i odnos masovnih medija i kulturnog diskursa, jer je teško zamisliti kulturni identitet u društvu koje je posredovano masovno...

  20. Ki67 measured after neoadjuvant chemotherapy for primary breast cancer.

    Science.gov (United States)

    von Minckwitz, Gunter; Schmitt, Wolfgang D; Loibl, Sibylle; Müller, Berit M; Blohmer, Jens U; Sinn, Bruno V; Eidtmann, Holger; Eiermann, Wolfgang; Gerber, Bernd; Tesch, Hans; Hilfrich, Jörn; Huober, Jens; Fehm, Tanja; Barinoff, Jana; Rüdiger, Thomas; Erbstoesser, Erhard; Fasching, Peter A; Karn, Thomas; Müller, Volkmar; Jackisch, Christian; Denkert, Carsten

    2013-08-15

    The value of Ki67 measured on residual disease after neoadjuvant chemotherapy is not sufficiently described. Participants of the GeparTrio study with primary breast cancer randomly received neoadjuvant response-guided [8 cycles TAC (docetaxel/doxorubicin/cyclophosphamide) in responding and TAC-NX (vinorelbine/capecitabine) in nonresponding patients] or conventional (6 cycles TAC) chemotherapy according to interim response assessment. Ki-67 levels were centrally measured immunohistochemically after neoadjuvant treatment if tumor tissue was available. Here, we analyze 1,151 patients having a pathologic complete response (pCR; n, 484), or residual disease with low (0-15%), intermediate (15.1-35%), or high (35.1-100%) posttreatment Ki67 levels in 488, 77, and 102 patients, respectively. Patients with high posttreatment Ki67 levels showed higher risk for disease relapse (P Ki67 levels. Patients with low Ki67 levels showed a comparable outcome to patients with a pCR (P = 0.211 for disease-free and P = 0.779 for overall survival). Posttreatment Ki67 levels provided more prognostic information than pretreatment Ki67 levels or changes of Ki67 from pre- to posttreatment. Information on pCR plus posttreatment Ki67 levels surmount the prognostic information of pCR alone in hormone-receptor-positive disease [hazard ratios (HR), 1.82-5.88] but not in hormone-receptor-negative disease (HR: 0.61-1.73). Patients with conventional and response-guided treatment did not show a different distribution of posttreatment Ki67 (P = 0.965). Posttreatment Ki67 levels provide prognostic information for patients with hormone-receptor-positive breast cancer and residual disease after neoadjuvant chemotherapy. Levels were not prognostic for outcome after response-guided chemotherapy. High posttreatment Ki67 indicates the need for innovative postneoadjuvant treatments. ©2013 AACR.

  1. 18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT scans as diagnostic tools in focal congenital hyperinsulinism

    DEFF Research Database (Denmark)

    Christiansen, Charlotte Dahl; Petersen, Henrik; Nielsen, Anne Lerberg

    2018-01-01

    (68Ga-DOTANOC) PET/CT as diagnostic tools in focal CHI. Methods: PET/CT scans of children with CHI admitted to Odense University Hospital between August 2005 and June 2016 were retrospectively evaluated visually and by their maximal standardized uptake values (SUVmax) by two independent examiners...... in 34 patients, no surgery in 21 patients. Fifty-one patients had a classifiable outcome, either by histology (n = 33, 22 focal lesions, 11 non-focal) or by genetics (n = 18, all non-focal). The predictive performance of 18F-DOPA PET/CT to identify focal CHI was identical by visual- and cut......Purpose: Focal congenital hyperinsulinism (CHI) is curable by surgery, which is why identification of the focal lesion is crucial. We aimed to determine the use of 18F–fluoro-dihydroxyphenylalanine (18F-DOPA) PET/CT vs. 68Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic-acid-1-Nal3-octreotide...

  2. Assessment of striatal & postural deformities in patients with Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Sanjay Pandey

    2016-01-01

    Interpretation & conclusions: Our results showed that striatal and postural deformities were common and present in about half of the patients with PD. These deformities we more common in patients with advanced stage of PD.

  3. Prefrontal cortex and striatal activation by feedback in Parkinson's disease

    NARCIS (Netherlands)

    Keitz, Martijn; Koerts, Janneke; Kortekaas, Rudie; Renken, Remco; de Jong, Bauke M.; Leenders, Klaus L.

    2008-01-01

    Positive feedbacks reinforce goal-directed behavior and evoke pleasure. in Parkinson's disease (PD) the striatal dysfunction impairs motor performance, but also may lead to decreased positive feedback (reward) processing. This study investigates two types of positive feedback processing (monetary

  4. Striatal dysfunction in attention deficit and hyperkinetic disorder

    Energy Technology Data Exchange (ETDEWEB)

    Lou, H.C.; Henriksen, L.; Bruhn, P.; Borner, H.; Nielsen, J.B.

    1989-01-01

    We have previously reported that periventricular structures are hypoperfused in attention deficit and hyperactivity disorder (ADHD). This study has expanded the number of patients, who were divided into two groups: six patients with pure ADHD, and 13 patients with ADHD in combination with other neurologic symptoms. By using xenon 133 inhalation and emission tomography, the regional cerebral blood flow distribution was determined and compared with a control group. Striatal regions were found to be hypoperfused and, by inference, hypofunctional in both groups. This hypoperfusion was statistically significant in the right striatum in ADHD, and in both striatal regions in ADHD with other neuropsychologic and neurologic symptoms. The primary sensory and sensorimotor cortical regions were highly perfused. Methylphenidate increased flow to striatal and posterior periventricular regions, and tended to decrease flow to primary sensory regions. Low striatal activity, partially reversible with methylphenidate, appears to be a cardinal feature in ADHD.

  5. Striatal dysfunction in attention deficit and hyperkinetic disorder

    International Nuclear Information System (INIS)

    Lou, H.C.; Henriksen, L.; Bruhn, P.; Borner, H.; Nielsen, J.B.

    1989-01-01

    We have previously reported that periventricular structures are hypoperfused in attention deficit and hyperactivity disorder (ADHD). This study has expanded the number of patients, who were divided into two groups: six patients with pure ADHD, and 13 patients with ADHD in combination with other neurologic symptoms. By using xenon 133 inhalation and emission tomography, the regional cerebral blood flow distribution was determined and compared with a control group. Striatal regions were found to be hypoperfused and, by inference, hypofunctional in both groups. This hypoperfusion was statistically significant in the right striatum in ADHD, and in both striatal regions in ADHD with other neuropsychologic and neurologic symptoms. The primary sensory and sensorimotor cortical regions were highly perfused. Methylphenidate increased flow to striatal and posterior periventricular regions, and tended to decrease flow to primary sensory regions. Low striatal activity, partially reversible with methylphenidate, appears to be a cardinal feature in ADHD

  6. Striatal grafts in a rat model of Huntington's disease

    DEFF Research Database (Denmark)

    Guzman, R; Meyer, M; Lövblad, K O

    1999-01-01

    Survival and integration into the host brain of grafted tissue are crucial factors in neurotransplantation approaches. The present study explored the feasibility of using a clinical MR scanner to study striatal graft development in a rat model of Huntington's disease. Rat fetal lateral ganglionic...... eminences grown as free-floating roller-tube cultures can be successfully grafted in a rat Huntington model and that a clinical MR scanner offers a useful noninvasive tool for studying striatal graft development....

  7. Striatal direct and indirect pathways control decision-making behavior

    OpenAIRE

    Macpherson, Tom; Morita, Makiko; Hikida, Takatoshi

    2014-01-01

    Despite our ever-changing environment, animals are remarkably adept at selecting courses of action that are predictive of optimal outcomes. While requiring the contribution of a number of brain regions, a vast body of evidence implicates striatal mechanisms of associative learning and action selection to be critical to this ability. While numerous models of striatal-based decision-making have been developed, it is only recently that we have begun to understand the precise contributions of spe...

  8. [Expression of Ki67 and clinicopathological features in breast cancer].

    Science.gov (United States)

    Wang, Baona; Wang, Xiang; Wang, Jing; Xuan, Lixue; Wang, Zhongzhao; Wang, Xin; Gao, Jidong; Zhang, Haizeng

    2014-04-01

    To analyze the relationship between the expression level of Ki67 and clinicopathological features in breast cancer. Data of 918 female patients with invasive ductal breast carcinoma treated in the Cancer Hospital, Chinese Academy of Medical Sciences from Jan. to Dec. 2010 were analyzed retrospectively. The correlation of Ki67 expression and other clinicopathological features in the breast cancer was analyzed. Among the 918 cases, the Ki67 index was 0.9% to 95% (mean value 27.8%). Taking the Ki67 index 14% as the boundary to divide the patients into two subgroups, 263 cases (28.6%) were ≤ 14%, and 655 cases (71.4%) were >14%. There were significant differences between the Ki67 expression and age, tumor size, axillary lymph nodes status, histological grade and the expressions of C-erbB-2, estrogen receptor (ER) and progesterone receptor (PR) (P Ki67 indexes of Ki67 expression in luminal B (30.44%), HER-2 overexpression (36.77%) and triple negative (47.40%) subtypes were significantly higher than that in the luminal A subtype (21.36%)(P Ki67 in triple-negative subtype (47.40%) was significantly higher than that in the non-triple-negative subtype (24.79%)(P Ki67 index is significantly correlated with the age, tumor TNM stage, axillary lymph node status, histological grading, ER status, PR status and HER-2 status. A high expression level of Ki67 is a poor prognostic factor for breast cancer. The expression level of Ki67 should be detected routinely and it may become a useful prognostic marker in the treatment of breast cancer.

  9. Preparation and characterization of PAN–KI complexed gel polymer

    Indian Academy of Sciences (India)

    The structural, miscibility and the chemical rapport between PAN and KI are investigated using X-ray diffraction, Fourier transform infrared spectroscopy and differential scanning calorimetry methods. The conductivity is enhanced with the increase in KI concentration and temperature. The maximum conductivity at 30 ∘ C is ...

  10. Preparation and characterization of PAN–KI complexed gel polymer ...

    Indian Academy of Sciences (India)

    The structural, miscibility and the chemical rapport between PAN and KI are investigated using X-ray diffraction, Fourier transform infrared spectroscopy and differential scanning calorimetry methods. The conductivity is enhanced with the increase in KI concentration and temperature. The maximum conductivity at 30 ∘ C is ...

  11. Interlaboratory variability of Ki67 staining in breast cancer

    NARCIS (Netherlands)

    Focke, Cornelia M.; Bürger, Horst; van Diest, Paul J.; Finsterbusch, Kai; Gläser, Doreen; Korsching, Eberhard; Decker, Thomas; Anders, M.; Bollmann, R.; Eiting, Fr; Friedrich, K.; Habeck, J. O.; Haroske, G.; Hinrichs, B.; Behrens, A.; Krause, Lars Udo; Braun-Lang, U.; Lorenzen, J.; Minew, N.; Mlynek-Kersjes, M.; Nenning, H.; Packeisen, J.; Poche-de Vos, F.; Reyher-Klein, S.; Rothacker, D.; Schultz, M.; Sturm, U.; Tawfik, M.; Berghäuser, K. H.; Böcker, W; Cserni, G.; Habedank, S.; Lax, S.; Moinfar, F.; Regitnig, P.; Reiner-Concin, A.; Rüschoff, J.; Varga, Z.; Woziwodski, J.

    2017-01-01

    Background Postanalytic issues of Ki67 assessment in breast cancers like counting method standardisation and interrater bias have been subject of various studies, but little is known about analytic variability of Ki67 staining between pathology labs. Our aim was to study interlaboratory variability

  12. Ki-67 protein: a proliferation index in breast cancer

    Directory of Open Access Journals (Sweden)

    Shervin Kheirandish

    2015-09-01

    Full Text Available Various clinicopathological factors are evaluated in different studies on carcinomas to demonstrate their prognostic and predictive significance during the diagnosis and therapeutic procedures of the malignancy. Ki-67 is a biomarker that was proposed as a cell proliferation related nuclear antigen, and it only expresses in growing and proliferating cells. This unique feature of Ki-67 makes it a subject of interest in different investigations. Evaluating the Ki-67 expression has been demonstrated to be beneficial in determining the tumor behavior including tumor size, stage, grading and patient survival. Moreover, it might be helpful in selecting the preferred subsequent treatment strategy. Due to the importance of Ki-67 index, we aim to briefly review its properties and the importance of its expression during various types of malignancies. At last, the prognostic and predictive value of Ki-67 would be overviewed regarding the efficacy of neoadjuvant and adjuvant therapies in breast cancer patients.

  13. Does human presynaptic striatal dopamine function predict social conformity?

    Science.gov (United States)

    Stokes, Paul R A; Benecke, Aaf; Puraite, Julita; Bloomfield, Michael A P; Shotbolt, Paul; Reeves, Suzanne J; Lingford-Hughes, Anne R; Howes, Oliver; Egerton, Alice

    2014-03-01

    Socially desirable responding (SDR) is a personality trait which reflects either a tendency to present oneself in an overly positive manner to others, consistent with social conformity (impression management (IM)), or the tendency to view one's own behaviour in an overly positive light (self-deceptive enhancement (SDE)). Neurochemical imaging studies report an inverse relationship between SDR and dorsal striatal dopamine D₂/₃ receptor availability. This may reflect an association between SDR and D₂/₃ receptor expression, synaptic dopamine levels or a combination of the two. In this study, we used a [¹⁸F]-DOPA positron emission tomography (PET) image database to investigate whether SDR is associated with presynaptic dopamine function. Striatal [¹⁸F]-DOPA uptake, (k(i)(cer), min⁻¹), was determined in two independent healthy participant cohorts (n=27 and 19), by Patlak analysis using a cerebellar reference region. SDR was assessed using the revised Eysenck Personality Questionnaire (EPQ-R) Lie scale, and IM and SDE were measured using the Paulhus Deception Scales. No significant associations were detected between Lie, SDE or IM scores and striatal [¹⁸F]-DOPA k(i)(cer). These results indicate that presynaptic striatal dopamine function is not associated with social conformity and suggests that social conformity may be associated with striatal D₂/₃ receptor expression rather than with synaptic dopamine levels.

  14. Interobserver Variability of Ki-67 Measurement in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Yul Ri Chung

    2016-03-01

    Full Text Available Background: As measurement of Ki-67 proliferation index is an important part of breast cancer diagnostics, we conducted a multicenter study to examine the degree of concordance in Ki-67 counting and to find factors that lead to its variability. Methods: Thirty observers from thirty different institutions reviewed Ki-67–stained slides of 20 different breast cancers on whole sections and tissue microarray (TMA by online system. Ten of the 20 breast cancers had hot spots of Ki-67 expression. Each observer scored Ki-67 in two different ways: direct counting (average vs. hot spot method and categorical estimation. Intraclass correlation coefficient (ICC of Ki-67 index was calculated for comparative analysis. Results: For direct counting, ICC of TMA was slightly higher than that of whole sections using average method (0.895 vs 0.858. The ICC of tumors with hot spots was lower than that of tumors without (0.736 vs 0.874. In tumors with hot spots, observers took an additional counting from the hot spot; the ICC of whole sections using hot spot method was still lower than that of TMA (0.737 vs 0.895. In categorical estimation, Ki-67 index showed a wide distribution in some cases. Nevertheless, in tumors with hot spots, the range of distribution in Ki-67 categories was decreased with hot spot method and in TMA platform. Conclusions: Interobserver variability of Ki-67 index for direct counting and categorical estimation was relatively high. Tumors with hot spots showed greater interobserver variability as opposed to those without, and restricting the measurement area yielded lower interobserver variability.

  15. Vrstniški pritisk in uporaba drog pri mladostnikih

    OpenAIRE

    Tomažič, Katra

    2017-01-01

    Tema magistrskega dela je vrstniški pritisk in uporaba drog med mladostniki. Sestavljeno je iz teoretičnega in empiričnega dela. V teoretičnem smo se seznanili z obdobjem odraščanja oziroma adolescence, ki velja za nekakšno prelomnico med otroštvom in odraslostjo. Nekaj besed smo namenili razlogom, zaradi katerih naj bi mladi začeli uporabljati droge, vendar smo se nekoliko bolj osredotočili na vrstniški pritisk in vrstniške skupine, saj je le-ta zavzemal bistvo našega magistrskega dela. Med ...

  16. Alternativni pedgoški koncepti v Veliki Britaniji

    OpenAIRE

    Kralj, Mateja

    2017-01-01

    Alternativni pedagoški koncepti postajajo vedno bolj razširjena oblika izobraževanja, zato se posledično pojavlja zmeraj več šol, ki sledijo miselnosti že uveljavljenih konceptov ali pa šole same najdejo svoj koncept, ki sledi miselnosti ustanoviteljev in aktualnim razmeram. Kljub vedno večji razširjenosti alternativnih konceptov, to področje še zmeraj ni dovolj raziskano, saj hitro ugotovimo, da je na voljo veliko informacij le o že uveljavljenih konceptih (Montessori, Waldorf, Summerhill, ...

  17. Guideline for PET/CT imaging of neuroendocrine neoplasms with {sup 68}Ga-DOTA-conjugated somatostatin receptor targeting peptides and {sup 18}F-DOPA

    Energy Technology Data Exchange (ETDEWEB)

    Bozkurt, Murat Fani [Hacettepe University Faculty of Medicine Department of Nuclear Medicine, Ankara (Turkey); Virgolini, Irene; Decristoforo, Clemens [Medical University Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Balogova, Sona [Comenius University and St. Elisabeth Oncology Institute, Department of Nuclear Medicine, Bratislava (Slovakia); Tenon Hospital AP-HP and Universite Pierre et Marie Curie, Department of Nuclear Medicine, Paris (France); Beheshti, Mohsen [St. Vincent' s Hospital, PET-CT Center, Department of Nuclear Medicine and Endocrinology, Linz (Austria); Paracelsus Medical University, Department of Nuclear Medicine, Salzburg (Austria); Rubello, Domenico [Santa Maria della Misericordia Hospital, Department of Nuclear Medicine, PET Center and Medical Physics and Radiology, Rovigo (Italy); Ambrosini, Valentina; Fanti, Stefano [University of Bologna, Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Bologna (Italy); Kjaer, Andreas [National University Hospital and University of Copenhagen, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen (Denmark); Delgado-Bolton, Roberto [San Pedro Hospital and Centre for Biomedical Research of La Rioja (CIBIR), Department of Diagnostic Imaging (Radiology) and Nuclear Medicine, Logrono (Spain); Kunikowska, Jolanta [Medical University of Warsaw, Nuclear Medicine, Warsaw (Poland); Oyen, Wim J.G. [Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London (United Kingdom); Chiti, Arturo [Humanitas University, Nuclear Medicine Department, Rozzano, MI (Italy); Giammarile, Francesco [University of Lyon, Nuclear Medicine, Lyon (France)

    2017-08-15

    Neuroendocrine neoplasms are a heterogenous group of tumours, for which nuclear medicine plays an important role in the diagnostic work-up as well as in the targeted therapeutic options. This guideline is aimed to assist nuclear medicine physicians in recommending, performing, reporting and interpreting the results of somatostatin receptor (SSTR) PET/CT imaging using {sup 68}Ga-DOTA-conjugated peptides, as well as {sup 18}F-DOPA imaging for various neuroendocrine neoplasms. The previous procedural guideline by EANM regarding the use PET/CT tumour imaging with {sup 68}Ga-conjugated peptides has been revised and updated with the relevant and recent literature in the field with contribution of distinguished experts. (orig.)

  18. Current status of PET imaging of neuroendocrine tumours ([18F]FDOPA, [68Ga]tracers, [11C]/[18F]-HTP).

    Science.gov (United States)

    Ambrosini, V; Morigi, J J; Nanni, C; Castellucci, P; Fanti, S

    2015-03-01

    Neuroendocrine neoplasms (NEN) functional imaging is an evolving field that witnessed major advances in the past two decades. The routine use of PET/CT with an array of new radiotracers to specifically study NEN resulted in an increase in lesions detection. Currently, PET radiopharmaceuticals for NEN imaging include both metabolic ([18F]DOPA, [18F]FDG, [11C]/[18F]-HTP) and receptor-mediated compounds ([68Ga]DOTA-peptides). Discussion is still on-going regarding the clinical setting that may benefit the most from the use of one tracer over the other. [68Ga]DOTA-peptides are accurate for the detection of well differentiated NEN and are increasingly employed. Moreover, providing data on somatostatin receptors expression on NEN cells, they represent a fundamental procedure to be performed before starting therapy, as well as to guide treatment, with either hot or cold somatostatin analogues. The easy and economic synthesis process also favours their clinical employment even in centres without an on-site cyclotron. [18F]DOPA is accurate for studying well differentiated tumours however the difficult and expensive synthesis have limited its clinical employment. It currently can be successfully used for imaging tumours with variable to low expression of SSR (medullary thyroid carcinoma, neuroblastoma, pheocromocytoma), that cannot be accurately studied with [68Ga]DOTA-peptides. [11C]/[18F]-HTP has also been proposed to image well differentiated NEN, on the basis of serotonin pathway activity, for which [11C]/[18F]-HTP can be used as precursor. However, although preliminary data are encouraging, the feasibility of its widespread clinical use is still under discussion, mainly limited by a complex synthesis process and more proven advantages over other currently employed compounds. This review aims to provide an overview of the current status and clinical application of PET tracers to image well differentiated NEN and to focus on the still open-issues of debate.

  19. Current status of PET imaging of neuroendocrine tumours ([18F]FDOPA, [68Ga]traces, [11C/[18F]-HTP)

    International Nuclear Information System (INIS)

    Ambrosini, A.; Morgini, J.J.; Nanni, C.; Castellucci, P.; Fanti, S.

    2015-01-01

    Neuroendocrine neoplasms (NEN) functional imaging is an evolving field that witnessed major advances in the past two decades. The routine use of PET/CT with an array of new radiotracers to specifically study NEN resulted in an increase in lesions detection. Currently, PET radiopharmaceuticals for NEN imaging include both metabolic ([18F]DOPA, [18F]FDG, [11C]/[18F]-HTP) and receptor-mediated compounds ([68Ga]DOTA-peptides). Discussion is still on-going regarding the clinical setting that may benefit the most from the use of one tracer over the other. [68Ga]DOTA-peptides are accurate for the detection of well differentiated NEN and are increasingly employed. Moreover, providing data on somatostatin receptors expression on NEN cells, they represent a fundamental procedure to be performed before starting therapy, as well as to guide treatment, with either hot or cold somatostatin analogues. The easy and economic synthesis process also favours their clinical employment even in centres without an on-site cyclotron. [18F]DOPA is accurate for studying well differentiated tumours however the difficult and expensive synthesis have limited its clinical employment. It currently can be successfully used for imaging tumours with variable to low expression of SSR (medullary thyroid carcinoma, neuroblastoma, pheocromocytoma), that cannot be accurately studied with [68Ga]DOTA-peptides. [11C]/[18F]-HTP has also been proposed to image well differentiated NEN, on the basis of serotonin pathway activity, for which [11C]/[18F]-HTP can be used as precursor. However, although preliminary data are encouraging, the feasibility of its widespread clinical use is still under discussion, mainly limited by a complex synthesis process and more proven advantages over other currently employed compounds. This review aims to provide an overview of the current status and clinical application of PET tracers to image well differentiated NEN and to focus on the still open-issues of debate

  20. Striatal dopamine release codes uncertainty in pathological gambling

    DEFF Research Database (Denmark)

    Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka

    2012-01-01

    Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain—striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear...... dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand......, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis...

  1. Re-emergence of striatal cholinergic interneurons in movement disorders.

    Science.gov (United States)

    Pisani, Antonio; Bernardi, Giorgio; Ding, Jun; Surmeier, D James

    2007-10-01

    Twenty years ago, striatal cholinergic neurons were central figures in models of basal ganglia function. But since then, they have receded in importance. Recent studies are likely to lead to their re-emergence in our thinking. Cholinergic interneurons have been implicated as key players in the induction of synaptic plasticity and motor learning, as well as in motor dysfunction. In Parkinson's disease and dystonia, diminished striatal dopaminergic signalling leads to increased release of acetylcholine by interneurons, distorting network function and inducing structural changes that undoubtedly contribute to the symptoms. By contrast, in Huntington's disease and progressive supranuclear palsy, there is a fall in striatal cholinergic markers. This review gives an overview of these recent experimental and clinical studies, placing them within the context of the pathogenesis of movement disorders.

  2. Reduced striatal D2 receptor binding in myoclonus-dystonia

    International Nuclear Information System (INIS)

    Beukers, R.J.; Weisscher, N.; Tijssen, M.A.J.; Booij, J.; Zijlstra, F.; Amelsvoort, T.A.M.J. van

    2009-01-01

    To study striatal dopamine D 2 receptor availability in DYT11 mutation carriers of the autosomal dominantly inherited disorder myoclonus-dystonia (M-D). Fifteen DYT11 mutation carriers (11 clinically affected) and 15 age- and sex-matched controls were studied using 123 I-IBZM SPECT. Specific striatal binding ratios were calculated using standard templates for striatum and occipital areas. Multivariate analysis with corrections for ageing and smoking showed significantly lower specific striatal to occipital IBZM uptake ratios (SORs) both in the left and right striatum in clinically affected patients and also in all DYT11 mutation carriers compared to control subjects. Our findings are consistent with the theory of reduced dopamine D 2 receptor (D2R) availability in dystonia, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out. (orig.)

  3. Impairment of striatal mitochondrial function by acute paraquat poisoning.

    Science.gov (United States)

    Czerniczyniec, Analía; Lanza, E M; Karadayian, A G; Bustamante, J; Lores-Arnaiz, S

    2015-10-01

    Mitochondria are essential for survival. Their primary function is to support aerobic respiration and to provide energy for intracellular metabolic pathways. Paraquat is a redox cycling agent capable of generating reactive oxygen species. The aim of the present study was to evaluate changes in cortical and striatal mitochondrial function in an experimental model of acute paraquat toxicity and to compare if the brain areas and the molecular mechanisms involved were similar to those observed after chronic exposure. Sprague-Dawley rats received paraquat (25 mg/Kg i.p.) or saline and were sacrificed after 24 h. Paraquat treatment decreased complex I and IV activity by 37 and 21 % respectively in striatal mitochondria. Paraquat inhibited striatal state 4 and state 3 KCN-sensitive respiration by 80 % and 62 % respectively, indicating a direct effect on respiratory chain. An increase of 2.2 fold in state 4 and 2.3 fold in state 3 in KCN-insensitive respiration was observed in striatal mitochondria from paraquat animals, suggesting that paraquat redox cycling also consumed oxygen. Paraquat treatment increased hydrogen peroxide production (150 %), TBARS production (42 %) and cardiolipin oxidation/depletion (12 %) in striatal mitochondria. Also, changes in mitochondrial polarization was induced after paraquat treatment. However, no changes were observed in any of these parameters in cortical mitochondria from paraquat treated-animals. These results suggest that paraquat treatment induced a clear striatal mitochondrial dysfunction due to both paraquat redox cycling reactions and impairment of the mitochondrial electron transport, causing oxidative damage. As a consequence, mitochondrial dysfunction could probably lead to alterations in cellular bioenergetics.

  4. Proteostasis in striatal cells and selective neurodegeneration in Huntington's disease.

    Science.gov (United States)

    Margulis, Julia; Finkbeiner, Steven

    2014-01-01

    Selective neuronal loss is a hallmark of neurodegenerative diseases, including Huntington's disease (HD). Although mutant huntingtin, the protein responsible for HD, is expressed ubiquitously, a subpopulation of neurons in the striatum is the first to succumb. In this review, we examine evidence that protein quality control pathways, including the ubiquitin proteasome system, autophagy, and chaperones, are significantly altered in striatal neurons. These alterations may increase the susceptibility of striatal neurons to mutant huntingtin-mediated toxicity. This novel view of HD pathogenesis has profound therapeutic implications: protein homeostasis pathways in the striatum may be valuable targets for treating HD and other misfolded protein disorders.

  5. Zaslužki trgovine z ljudmi v Sloveniji

    OpenAIRE

    Kosem, Špela

    2016-01-01

    V diplomskem delu predstavljamo problematiko trgovine z ljudmi v Sloveniji. Uradne statistike velikega dela trgovine z ljudmi ne zajamejo, saj je velik del ostaja neodkrite ali nedokazane. Podatke in ocene zato v diplomskem delu pridobivamo s poglobljenimi intervjuju z zaposlenimi, ki se pri svojem delu neposredno srečujejo s primeri in posledicami trgovine z ljudmi. Z analizo rezultatov ugotavljamo, da so dobički v trgovini z ljudmi zlasti v razmerju s tveganji za trgovce izjemno visoki, vel...

  6. Ki67 assessment in breast cancer: an update.

    Science.gov (United States)

    Penault-Llorca, Frederique; Radosevic-Robin, Nina

    2017-02-01

    Although immunohistochemical detection of the Ki67 antigen has been used for many years to assess cancer proliferation, this marker is still not recommended for routine use in clinical management of breast cancer. The major reason for this situation is a lack of a standardised procedure for Ki67 assessment as well as persistence of several issues of debate with regards to the Ki67 assay interpretation and the marker's clinical utility. Nowadays Ki67 assessment is principally used for estimation of prognosis and guiding the decision on adjuvant treatment choice, as well as for prediction of response to neoadjuvant treatment in ER+/HER2- breast cancer. In ER-/HER2+ and ER-/HER2- tumours, high post-neoadjuvant Ki67 index is associated with unfavourable prognosis. We review here the elements impacting analytical validity of the Ki67 immunohistochemical assay, the evidence of its clinical utility and the current recommendations for its use in breast cancer management. Copyright © 2016 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

  7. Dysregulation of striatal projection neurons in Parkinson's disease.

    Science.gov (United States)

    Beck, Goichi; Singh, Arun; Papa, Stella M

    2018-03-01

    The loss of nigrostriatal dopamine (DA) is the primary cause of motor dysfunction in Parkinson's disease (PD), but the underlying striatal mechanisms remain unclear. In spite of abundant literature portraying structural, biochemical and plasticity changes of striatal projection neurons (SPNs), in the past there has been a data vacuum from the natural human disease and its close model in non-human primates. Recently, single-cell recordings in advanced parkinsonian primates have generated new insights into the altered function of SPNs. Currently, there are also human data that provide direct evidence of profoundly dysregulated SPN activity in PD. Here, we review primate recordings that are impacting our understanding of the striatal dysfunction after DA loss, particularly through the analysis of physiologic correlates of parkinsonian motor behaviors. In contrast to recordings in rodents, data obtained in primates and patients demonstrate similar major abnormalities of the spontaneous SPN firing in the alert parkinsonian state. Furthermore, these studies also show altered SPN responses to DA replacement in the advanced parkinsonian state. Clearly, there is yet much to learn about the striatal discharges in PD, but studies using primate models are contributing unique information to advance our understanding of pathophysiologic mechanisms.

  8. Striatal volume predicts level of video game skill acquisition.

    Science.gov (United States)

    Erickson, Kirk I; Boot, Walter R; Basak, Chandramallika; Neider, Mark B; Prakash, Ruchika S; Voss, Michelle W; Graybiel, Ann M; Simons, Daniel J; Fabiani, Monica; Gratton, Gabriele; Kramer, Arthur F

    2010-11-01

    Video game skills transfer to other tasks, but individual differences in performance and in learning and transfer rates make it difficult to identify the source of transfer benefits. We asked whether variability in initial acquisition and of improvement in performance on a demanding video game, the Space Fortress game, could be predicted by variations in the pretraining volume of either of 2 key brain regions implicated in learning and memory: the striatum, implicated in procedural learning and cognitive flexibility, and the hippocampus, implicated in declarative memory. We found that hippocampal volumes did not predict learning improvement but that striatal volumes did. Moreover, for the striatum, the volumes of the dorsal striatum predicted improvement in performance but the volumes of the ventral striatum did not. Both ventral and dorsal striatal volumes predicted early acquisition rates. Furthermore, this early-stage correlation between striatal volumes and learning held regardless of the cognitive flexibility demands of the game versions, whereas the predictive power of the dorsal striatal volumes held selectively for performance improvements in a game version emphasizing cognitive flexibility. These findings suggest a neuroanatomical basis for the superiority of training strategies that promote cognitive flexibility and transfer to untrained tasks.

  9. Dorsal striatal dopamine, food preference and health perception in humans

    NARCIS (Netherlands)

    Wallace, D.L.; Aarts, E.; Dang, L.C.; Greer, S.M.; Jagust, W.J.; D'Esposito, M.

    2014-01-01

    To date, few studies have explored the neurochemical mechanisms supporting individual differences in food preference in humans. Here we investigate how dorsal striatal dopamine, as measured by the positron emission tomography (PET) tracer [(18)F]fluorometatyrosine (FMT), correlates with food-related

  10. Prothymosin-alpha and Ki-67 expression in pituitary adenomas

    Directory of Open Access Journals (Sweden)

    Iga Wierzbicka-Tutka

    2016-11-01

    Full Text Available Introduction: Prothymosin alpha (PTMA, a nuclear oncoprotein involved in cell cycle regulation, is used as a prognostic marker in many cancers. The histopathology of pituitary carcinomas and locally invasive adenomas is indistinguishable from that of benign tumors. A new marker is needed to differentiate these lesions. We evaluated PTMA in pituitary adenomas to determine its usefulness as a prognostic factor of tumor proliferation.Material/Methods: We conducted a retrospective analysis of a group of 27 patients, including 15 females (56% and 12 males (44% with a mean age of 58.6±12 years, who underwent pituitary tumor surgery between 2003 and 2012. The Ki-67 and PTMA-nuclear (PTMA-n and PTMA-cytoplasmic (PTMA-c indices were determined by immunohistochemical staining. We studied histopathological features, clinical symptoms, and magnetic resonance imaging or computed tomography performed before surgery and one year following surgery to evaluate tumor size and progression.Results: The expression of Ki-67 was revealed in 77.8% of adenomas, PTMA-n in 81.5% and PTMA-c in 92.6%. The mean value of the Ki-67 index was 1.8%, PTMA-n was 1.84%, and PTMA-c was 35.6%. There was a significant positive correlation between Ki-67 and PTMA-n (p=0.009. We did not find any correlation between Ki-67, PTMA-c, and tumor progression. PTMA-n was found to be correlated with tumor size (p=0.045 and was higher in the case of gonadotropinomas (p=0.026.Conclusions: The positive nuclear expression of Ki-67 and PTMA was observed in the majority of pituitary adenomas. Neither the expression of Ki-67 nor that of PTMA-c was related to tumor recurrence or local invasion.

  11. Interobserver concordance of Ki67 labeling index in breast cancer: Japan Breast Cancer Research Group Ki67 ring study.

    Science.gov (United States)

    Mikami, Yoshiki; Ueno, Takayuki; Yoshimura, Kenichi; Tsuda, Hitoshi; Kurosumi, Masafumi; Masuda, Shinobu; Horii, Rie; Toi, Masakazu; Sasano, Hironobu

    2013-11-01

    The standardized assessment of Ki67 labeling index (LI) is of clinical importance to identify patients with primary breast cancer who could benefit from chemotherapy. In this study, we evaluated the interobserver concordance of Ki67 LI assessment. Six surgical pathologists participated and all the slides were prepared from archival breast cancer tissues fixed in 10% buffered formalin for 24 h and stained with MIB-1. Three independent studies were conducted. In the first study, 30 stained slides were assessed using two different methods: the scoring system, with a positive rate scored from 1 (0-9%) to 10 (90-100%) by visual estimate; and the counting method, with approximately 1000 cells counted in hot spots. In the second study, 20 tumors with Ki67 LI 5-25% were assessed, and in the third study, 15 printed photographs of stained slides were assessed to avoid variations by selecting different fields. In study 1, the counting system (intraclass correlation coefficient [ICC], 0.66 [95% confidence interval 0.52-0.78]) demonstrated a better correlation than the scoring system (ICC, 0.57 [0.42-0.72]). In study 2, the assessment for Ki67 LI of 5-25% demonstrated a correlation (ICC, 0.68 [0.50-0.81]) similar to that of study 1 (unrestricted range of Ki67 LI). In study 3, the assessment of Ki67 LI by counting yielded a good concordance (ICC, 0.94 [0.88-0.97]). In conclusion, there was better concordance with the counting system, and concordance was high when the assessed field was predetermined, indicating that the selection of the evaluation area is critical for obtaining reproducible Ki67 LI in breast cancer. © 2013 Japanese Cancer Association.

  12. Prospective comparison of {sup 68}Ga-DOTATATE and {sup 18}F-FDOPA PET/CT in patients with various pheochromocytomas and paragangliomas with emphasis on sporadic cases

    Energy Technology Data Exchange (ETDEWEB)

    Archier, Aurelien; Taieb, David [Aix-Marseille University, Department of Nuclear Medicine, La Timone and North University Hospital, Marseille (France); Aix-Marseille University, European Center for Research in Medical Imaging, Marseille (France); Inserm UMR1068 Marseille Cancerology Research Center, Institut Paoli-Calmettes, Marseille (France); Varoquaux, Arthur; Beschmout, Eva [Aix-Marseille University, Department of Medical Imaging, Conception Hospital, Marseille (France); Garrigue, Philippe; Guillet, Benjamin [Aix-Marseille University, Department of Nuclear Medicine, La Timone and North University Hospital, Marseille (France); Aix-Marseille University, Department of Radiopharmacy, La Timone and North University Hospital, Marseille (France); Montava, Marion; Fakhry, Nicolas [Aix-Marseille University, Department of Otorhinolaryngology-Head and Neck Surgery, Conception Hospital, Marseille (France); Guerin, Carole; Sebag, Frederic [Aix-Marseille University, Department of Endocrine Surgery, Conception Hospital, Marseille (France); Gabriel, Sophie [Aix-Marseille University, Department of Nuclear Medicine, La Timone and North University Hospital, Marseille (France); Aix-Marseille University, European Center for Research in Medical Imaging, Marseille (France); Morange, Isabelle; Castinetti, Frederic [Aix-Marseille University, Department of Endocrinology, Conception Hospital, Marseille (France); Barlier, Anne [Aix-Marseille, University, Laboratory of Biochemistry and Molecular Biology, Conception Hospital, Marseille (France); Loundou, Anderson [Aix-Marseille University, Department of Public Health, Marseille (France); Pacak, Karel [National Institutes of Health, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD (United States)

    2016-07-15

    Pheochromocytomas/paragangliomas (PHEOs/PGLs) overexpress somatostatin receptors and recent studies have already shown excellent results in the localization of these tumors using {sup 68}Ga-labeled somatostatin analogs ({sup 68}Ga-DOTA-SSA), especially in patients with germline succinate dehydrogenase subunit B gene (SDHB) mutations and head and neck PGLs (HNPGLs). The value of {sup 68}Ga-DOTA-SSA has to be established in sporadic cases, including PHEOs. Thus, the aim of this study was to compare {sup 68}Ga-DOTATATE PET/CT, {sup 18}F-FDOPA PET/CT, and conventional imaging in patients with various PHEOs/PGLs with a special emphasis on sporadic cases, including those located in the adrenal gland. {sup 68}Ga-DOTATATE, {sup 18}F-FDOPA PET/CT, and conventional imaging (contrast-enhanced CT and MRI with MR angiography sequences) were prospectively performed in 30 patients (8 with SDHD mutations, 1 with a MAX mutation and 21 sporadic cases) with PHEO/PGL at initial diagnosis or relapse. The patient-based sensitivities were 93 % (28/30), 97 % (29/30), and 93 % (28/30) for {sup 68}Ga-DOTATATE PET/CT, {sup 18}F-FDOPA PET/CT, and conventional imaging, respectively. The lesion-based sensitivities were 93 % (43/46), 89 % (41/46), and 76 % (35/46) for {sup 68}Ga-DOTATATE PET/CT, {sup 18}F-FDOPA PET/CT, and conventional imaging respectively (p = 0.042). {sup 68}Ga-DOTATATE PET/CT detected a higher number of HNPGLs (30/30) than {sup 18}F-FDOPA PET/CT (26/30; p = 0.112) and conventional imaging (24/30; p = 0.024). {sup 68}Ga-DOTATATE PET/CT missed two PHEOs of a few millimeters in size and a large recurrent PHEO. One lesion was considered false-positive on {sup 68}Ga-DOTATATE PET/CT and corresponded to a typical focal lesion of fibrous dysplasia on MRI. Among the 11 lesions missed by conventional imaging, 7 were detected by conventional imaging with knowledge of the PET results (4 HNPGLs, 2 LNs, and 1 recurrent PHEO). {sup 68}Ga-DOTATATE PET/CT is the most sensitive tool in the

  13. Assessment of Ki67 in Breast Cancer: Recommendations from the International Ki67 in Breast Cancer Working Group

    Science.gov (United States)

    Nielsen, Torsten O.; A’Hern, Roger; Bartlett, John; Coombes, R. Charles; Cuzick, Jack; Ellis, Matthew; Henry, N. Lynn; Hugh, Judith C.; Lively, Tracy; McShane, Lisa; Paik, Soon; Penault-Llorca, Frederique; Prudkin, Ljudmila; Regan, Meredith; Salter, Janine; Sotiriou, Christos; Smith, Ian E.; Viale, Giuseppe; Zujewski, Jo Anne; Hayes, Daniel F.

    2011-01-01

    Uncontrolled proliferation is a hallmark of cancer. In breast cancer, immunohistochemical assessment of the proportion of cells staining for the nuclear antigen Ki67 has become the most widely used method for comparing proliferation between tumor samples. Potential uses include prognosis, prediction of relative responsiveness or resistance to chemotherapy or endocrine therapy, estimation of residual risk in patients on standard therapy and as a dynamic biomarker of treatment efficacy in samples taken before, during, and after neoadjuvant therapy, particularly neoadjuvant endocrine therapy. Increasingly, Ki67 is measured in these scenarios for clinical research, including as a primary efficacy endpoint for clinical trials, and sometimes for clinical management. At present, the enormous variation in analytical practice markedly limits the value of Ki67 in each of these contexts. On March 12, 2010, an international panel of investigators with substantial expertise in the assessment of Ki67 and in the development of biomarker guidelines was convened in London by the cochairs of the Breast International Group and North American Breast Cancer Group Biomarker Working Party to consider evidence for potential applications. Comprehensive recommendations on preanalytical and analytical assessment, and interpretation and scoring of Ki67 were formulated based on current evidence. These recommendations are geared toward achieving a harmonized methodology, create greater between-laboratory and between-study comparability, and allow earlier valid applications of this marker in clinical practice. PMID:21960707

  14. Quality assurance trials for Ki67 assessment in pathology.

    Science.gov (United States)

    Raap, M; Ließem, S; Rüschoff, J; Fisseler-Eckhoff, A; Reiner, A; Dirnhofer, S; von Wasielewski, R; Kreipe, H

    2017-10-01

    Ki67 is a broadly used proliferation marker in surgical pathology with an obvious need for standardization to improve reproducibility of assessment. Here, we present results of the so far only existing round robin tests on Ki67, organized annually in Germany, Austria, and Switzerland from 2010 to 2015 with up to 160 participating laboratories (QuIP). In each quality assessment trial, eight probes from each breast cancer, neuroendocrine tumor, and malignant lymphoma were compiled on a tissue microarray (TMA). TMAs were stained in the participants' laboratories with antibodies and procedures also applied in their daily routine. Participating pathologists were expected to assign Ki67 values to one of four different categories for each tumor type. All local stainings and evaluations were reassessed by the organizing panel and compared to a preset standard. On average, 95% of participants reached the benchmark of over 80% concordance rates with the Ki67 category pre-established by the panel. Automatization and type of antibody did not affect the success rate. Concordance rates differed between tumor entities being highest in each tumor type with either very high or very low labeling indices. Lower rates were seen for intermediate Ki67 levels. Staining quality improved during the observation period as did inter-observer concordance with 85% of participants achieving excellent agreement (kappa > 0.8) in the first year and over 95% in 2015. In conclusion, regular external quality assurance trials have been established as a tool to improve the reproducibility and reliability of the prognostic and predictive proliferation marker Ki67.

  15. Quantum dots-based quantitative and in situ multiple imaging on ki67 and cytokeratin to improve ki67 assessment in breast cancer.

    Science.gov (United States)

    Yuan, Jing Ping; Wang, Lin Wei; Qu, Ai Ping; Chen, Jia Mei; Xiang, Qing Ming; Chen, Chuang; Sun, Sheng-Rong; Pang, Dai-Wen; Liu, Juan; Li, Yan

    2015-01-01

    As a marker for tumor cell proliferation, Ki67 has important impacts on breast cancer (BC) prognosis. Although immunohistochemical staining is the current standard method, variations in analytical practice make it difficult for pathologists to manually measure Ki67 index. This study was to develop a fluorescent spectrum-based quantitative analysis of Ki67 expression by quantum-dots (QDs) multiple imaging technique. A QDs-based in situ multiple fluorescent imaging method was developed, which stained nuclear Ki67 as red signal and cytoplasmic cytokeratin (CK) as green signal. Both Ki67 and CK signals were automatically separated and quantified by professional spectrum analysis software. This technique was applied to tissue microarrays from 240 BC patients. Both Ki67 and CK values, and Ki67/CK ratio were obtained for each patient, and their prognostic value on 5-year disease free survival was assessed. This method simultaneously stains nuclear Ki67 and cytoplasmic CK with clear signal contrast, making it easy for signal separation and quantification. The total fluorescent signal intensities of both Ki67 sum and CK sum were obtained, and Ki67/CK ratio calculated. Ki67 sum and Ki67/CK ratio were each attributed into two grades by X-tile software based on the best P value principle. Multivariate analysis showed Ki67 grade (P = 0.047) and Ki67/CK grade (P = 0.004) were independent prognostic factors. Furthermore, area under curve (AUC) of ROC analysis for Ki67/CK grade (AUC: 0.683, 95%CI: 0.613-0.752) was higher than Ki67 grade (AUC: 0.665, 95%CI: 0.596-0.734) and HER-2 gene (AUC: 0.586, 95%CI: 0.510-0.661), but lower than N stage (AUC: 0.760, 95%CI: 0.696-0.823) and histological grade (AUC: 0.756, 95%CI: 0.692-0.820) on predicting the risk for recurrence. A QDs-based quantitative and in situ multiple imaging on Ki67 and CK was developed to improve Ki67 assessment in BC, and Ki67/CK grade had better performance than Ki67 grade in predicting prognosis.

  16. Quantum dots-based quantitative and in situ multiple imaging on ki67 and cytokeratin to improve ki67 assessment in breast cancer.

    Directory of Open Access Journals (Sweden)

    Jing Ping Yuan

    Full Text Available As a marker for tumor cell proliferation, Ki67 has important impacts on breast cancer (BC prognosis. Although immunohistochemical staining is the current standard method, variations in analytical practice make it difficult for pathologists to manually measure Ki67 index. This study was to develop a fluorescent spectrum-based quantitative analysis of Ki67 expression by quantum-dots (QDs multiple imaging technique.A QDs-based in situ multiple fluorescent imaging method was developed, which stained nuclear Ki67 as red signal and cytoplasmic cytokeratin (CK as green signal. Both Ki67 and CK signals were automatically separated and quantified by professional spectrum analysis software. This technique was applied to tissue microarrays from 240 BC patients. Both Ki67 and CK values, and Ki67/CK ratio were obtained for each patient, and their prognostic value on 5-year disease free survival was assessed.This method simultaneously stains nuclear Ki67 and cytoplasmic CK with clear signal contrast, making it easy for signal separation and quantification. The total fluorescent signal intensities of both Ki67 sum and CK sum were obtained, and Ki67/CK ratio calculated. Ki67 sum and Ki67/CK ratio were each attributed into two grades by X-tile software based on the best P value principle. Multivariate analysis showed Ki67 grade (P = 0.047 and Ki67/CK grade (P = 0.004 were independent prognostic factors. Furthermore, area under curve (AUC of ROC analysis for Ki67/CK grade (AUC: 0.683, 95%CI: 0.613-0.752 was higher than Ki67 grade (AUC: 0.665, 95%CI: 0.596-0.734 and HER-2 gene (AUC: 0.586, 95%CI: 0.510-0.661, but lower than N stage (AUC: 0.760, 95%CI: 0.696-0.823 and histological grade (AUC: 0.756, 95%CI: 0.692-0.820 on predicting the risk for recurrence.A QDs-based quantitative and in situ multiple imaging on Ki67 and CK was developed to improve Ki67 assessment in BC, and Ki67/CK grade had better performance than Ki67 grade in predicting prognosis.

  17. Striatal Vulnerability in Huntington’s Disease: Neuroprotection Versus Neurotoxicity

    Directory of Open Access Journals (Sweden)

    Ryoma Morigaki

    2017-06-01

    Full Text Available Huntington’s disease (HD is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat encoding an abnormally long polyglutamine tract (PolyQ in the huntingtin (Htt protein. In HD, striking neuropathological changes occur in the striatum, including loss of medium spiny neurons and parvalbumin-expressing interneurons accompanied by neurodegeneration of the striosome and matrix compartments, leading to progressive impairment of reasoning, walking and speaking abilities. The precise cause of striatal pathology in HD is still unknown; however, accumulating clinical and experimental evidence suggests multiple plausible pathophysiological mechanisms underlying striatal neurodegeneration in HD. Here, we review and discuss the characteristic neurodegenerative patterns observed in the striatum of HD patients and consider the role of various huntingtin-related and striatum-enriched proteins in neurotoxicity and neuroprotection.

  18. Striatal dopamine release codes uncertainty in pathological gambling

    DEFF Research Database (Denmark)

    Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka

    2012-01-01

    Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain—striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear...... function of expected reward and an inverse U-shaped function of uncertainty. In this study, we investigated the dopaminergic coding of reward and uncertainty in 18 pathological gambling sufferers and 16 healthy controls. We used positron emission tomography (PET) with the tracer [11C]raclopride to measure...... dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand...

  19. Endocannabinoid-dopamine interactions in striatal synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Brian Neil Mathur

    2012-04-01

    Full Text Available The nigrostriatal dopaminergic system is implicated in action control and learning. A large body of work has focused on the contribution of this system to modulation of the corticostriatal synapse, the predominant synapse type in the striatum. Signaling through the D2 dopamine receptor is necessary for endocannabinoid-mediated depression of corticostriatal glutamate release. Here we review the known details of this mechanism and discuss newly discovered signaling pathways interacting with this system that ultimately exert dynamic control of cortical input to the striatum and striatal output. This topic is timely with respect to Parkinson’s disease given recent data indicating changes in the striatal endocannabinoid system in patients with this disorder.

  20. The Cognitive Architecture of Spatial Navigation: Hippocampal and Striatal Contributions.

    Science.gov (United States)

    Chersi, Fabian; Burgess, Neil

    2015-10-07

    Spatial navigation can serve as a model system in cognitive neuroscience, in which specific neural representations, learning rules, and control strategies can be inferred from the vast experimental literature that exists across many species, including humans. Here, we review this literature, focusing on the contributions of hippocampal and striatal systems, and attempt to outline a minimal cognitive architecture that is consistent with the experimental literature and that synthesizes previous related computational modeling. The resulting architecture includes striatal reinforcement learning based on egocentric representations of sensory states and actions, incidental Hebbian association of sensory information with allocentric state representations in the hippocampus, and arbitration of the outputs of both systems based on confidence/uncertainty in medial prefrontal cortex. We discuss the relationship between this architecture and learning in model-free and model-based systems, episodic memory, imagery, and planning, including some open questions and directions for further experiments. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Centrality of striatal cholinergic transmission in basal ganglia function

    Directory of Open Access Journals (Sweden)

    Paola eBonsi

    2011-02-01

    Full Text Available Work over the past two decades revealed a previously unexpected role for striatal cholinergic interneurons in the context of basal ganglia function. The recognition that these interneurons are essential in synaptic plasticity and motor learning represents a significant step ahead in deciphering how the striatum processes cortical inputs, and why pathological circumstances cause motor dysfunction.Loss of the reciprocal modulation between dopaminergic inputs and the intrinsic cholinergic innervation within the striatum appears to be the trigger for pathophysiological changes occurring in basal ganglia disorders. Accordingly, there is now compelling evidence showing profound changes in cholinergic markers in these disorders, in particular Parkinson’s disease and dystonia.Based on converging experimental and clinical evidence, we provide an overview of the role of striatal cholinergic transmission in physiological and pathological conditions, in the context of the pathogenesis of movement disorders.

  2. Motor tics evoked by striatal disinhibition in the rat

    Science.gov (United States)

    Bronfeld, Maya; Yael, Dorin; Belelovsky, Katya; Bar-Gad, Izhar

    2013-01-01

    Motor tics are sudden, brief, repetitive movements that constitute the main symptom of Tourette syndrome (TS). Multiple lines of evidence suggest the involvement of the cortico-basal ganglia system, and in particular the basal ganglia input structure—the striatum in tic formation. The striatum receives somatotopically organized cortical projections and contains an internal GABAergic network of interneurons and projection neurons' collaterals. Disruption of local striatal GABAergic connectivity has been associated with TS and was found to induce abnormal movements in model animals. We have previously described the behavioral and neurophysiological characteristics of motor tics induced in monkeys by local striatal microinjections of the GABAA antagonist bicuculline. In the current study we explored the abnormal movements induced by a similar manipulation in freely moving rats. We targeted microinjections to different parts of the dorsal striatum, and examined the effects of this manipulation on the induced tic properties, such as latency, duration, and somatic localization. Tics induced by striatal disinhibition in monkeys and rats shared multiple properties: tics began within several minutes after microinjection, were expressed solely in the contralateral side, and waxed and waned around a mean inter-tic interval of 1–4 s. A clear somatotopic organization was observed only in rats, where injections to the anterior or posterior striatum led to tics in the forelimb or hindlimb areas, respectively. These results suggest that striatal disinhibition in the rat may be used to model motor tics such as observed in TS. Establishing this reliable and accessible animal model could facilitate the study of the neural mechanisms underlying motor tics, and the testing of potential therapies for tic disorders. PMID:24065893

  3. Neuroglial plasticity at striatal glutamatergic synapses in Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Rosa M Villalba

    2011-08-01

    Full Text Available Striatal dopamine denervation is the pathological hallmark of Parkinson’s disease (PD. Another major pathological change described in animal models and PD patients is a significant reduction in the density of dendritic spines on medium spiny striatal projection neurons. Simultaneously, the ultrastructural features of the neuronal synaptic elements at the remaining corticostriatal and thalamostriatal glutamatergic axo-spinous synapses undergo complex ultrastructural remodeling consistent with increased synaptic activity (Villalba et al., 2011. The concept of tripartite synapses (TS was introduced a decade ago, according to which astrocytes process and exchange information with neuronal synaptic elements at glutamatergic synapses (Araque et al., 1999a. Although there has been compelling evidence that astrocytes are integral functional elements of tripartite glutamatergic synaptic complexes in the cerebral cortex and hippocampus, their exact functional role, degree of plasticity and preponderance in other CNS regions remain poorly understood. In this review, we discuss our recent findings showing that neuronal elements at cortical and thalamic glutamatergic synapses undergo significant plastic changes in the striatum of MPTP-treated parkinsonian monkeys. We also present new ultrastructural data that demonstrate a significant expansion of the astrocytic coverage of striatal TS synapses in the parkinsonian state, providing further evidence for ultrastructural compensatory changes that affect both neuronal and glial elements at TS. Together with our limited understanding of the mechanisms by which astrocytes respond to changes in neuronal activity and extracellular transmitter homeostasis, the role of both neuronal and glial components of excitatory synapses must be considered, if one hopes to take advantage of glia-neuronal communication knowledge to better understand the pathophysiology of striatal processing in parkinsonism, and develop new PD

  4. Motor tics evoked by striatal disinhibition in the rat

    Directory of Open Access Journals (Sweden)

    Maya eBronfeld

    2013-09-01

    Full Text Available Motor tics are sudden, brief, repetitive movements that constitute the main symptom of Tourette syndrome (TS. Multiple lines of evidence suggest the involvement of the cortico-basal ganglia system, and in particular the basal ganglia input structure – the striatum in tic formation. The striatum receives somatotopically organized cortical projections and contains an internal GABAergic network of interneurons and projection neurons collaterals. Disruption of local striatal GABAergic connectivity has been associated with TS and was found to induce abnormal movements in model animals. We have previously described the behavioral and neurophysiological characteristics of motor tics induced in monkeys by local striatal microinjections of the GABAA antagonist bicuculline. In the current study we explored the abnormal movements induced by a similar manipulation in freely moving rats. We targeted microinjections to different parts of the dorsal striatum, and examined the effects of this manipulation on the induced tic properties, such as latency, duration and somatic localization. Tics induced by striatal disinhibition in monkeys and rats shared multiple properties: tics began within several minutes after microinjection, were expressed solely in the contralateral side, and waxed and waned around a mean inter-tic interval of 1-4 s. A clear somatotopic organization was observed only in rats, where injections to the anterior or posterior striatum led to tics in the forelimb or hindlimb areas, respectively. These results suggest that striatal disinhibition in the rat may be used to model motor tics such as observed in TS. Establishing this reliable and accessible animal model could facilitate the study of the neural mechanisms underlying motor tics, and the testing of potential therapies for tic disorders.

  5. Ki-67 immunoreactivity in meningiomas--determination of the proliferative potential of meningiomas using the monoclonal antibody Ki-67

    DEFF Research Database (Denmark)

    Madsen, C; Schrøder, H D

    1997-01-01

    The proliferative potential of 66 human intracranial meningiomas (15 benign, 15 atypical, 15 recurrent, 13 bone-invasive, and 8 brain-invasive) was investigated by means of immunohisto-chemistry using the monoclonal antibody Ki-67. This antibody recognizes a nuclear antigen present in human cells...... during all active phases of the cell cycle, but absent in the resting phase. The purpose of this retrospective study was to estimate the Ki-67-labelling index (L.I.) and see if this index could help discriminate between the different groups of meningiomas. Our results demonstrated that L.I. could...

  6. In vivo neurochemical characterization of clothianidin induced striatal dopamine release.

    Science.gov (United States)

    Faro, L R F; Oliveira, I M; Durán, R; Alfonso, M

    2012-12-16

    Clothianidin (CLO) is a neonicotinoid insecticide with selective action on nicotinic acetylcholine receptors. The aim of this study was to determine the neurochemical basis for CLO-induced striatal dopamine release using the microdialysis technique in freely moving and conscious rats. Intrastriatal administration of CLO (3.5mM), produced an increase in both spontaneous (2462 ± 627% with respect to basal values) and KCl-evoked (4672 ± 706% with respect to basal values) dopamine release. This effect was attenuated in Ca(2+)-free medium, and was prevented in reserpine pre-treated animals or in presence of tetrodotoxin (TTX). To investigate the involvement of dopamine transporter (DAT), the effect of CLO was observed in presence of nomifensine. The coadministration of CLO and nomifensine produced an additive effect on striatal dopamine release. The results suggest that the effect of CLO on striatal dopamine release is predominantly mediated by an exocytotic mechanism, Ca(2+), vesicular and TTX-dependent and not by a mechanism mediated by dopamine transporter. Published by Elsevier Ireland Ltd.

  7. Neuroinflammation alters voltage-dependent conductance in striatal astrocytes

    Science.gov (United States)

    Karpuk, Nikolay; Burkovetskaya, Maria

    2012-01-01

    Neuroinflammation has the capacity to alter normal central nervous system (CNS) homeostasis and function. The objective of the present study was to examine the effects of an inflammatory milieu on the electrophysiological properties of striatal astrocyte subpopulations with a mouse bacterial brain abscess model. Whole cell patch-clamp recordings were performed in striatal glial fibrillary acidic protein (GFAP)-green fluorescent protein (GFP)+ astrocytes neighboring abscesses at postinfection days 3 or 7 in adult mice. Cell input conductance (Gi) measurements spanning a membrane potential (Vm) surrounding resting membrane potential (RMP) revealed two prevalent astrocyte subsets. A1 and A2 astrocytes were identified by negative and positive Gi increments vs. Vm, respectively. A1 and A2 astrocytes displayed significantly different RMP, Gi, and cell membrane capacitance that were influenced by both time after bacterial exposure and astrocyte proximity to the inflammatory site. Specifically, the percentage of A1 astrocytes was decreased immediately surrounding the inflammatory lesion, whereas A2 cells were increased. These changes were particularly evident at postinfection day 7, revealing increased cell numbers with an outward current component. Furthermore, RMP was inversely modified in A1 and A2 astrocytes during neuroinflammation, and resting Gi was increased from 21 to 30 nS in the latter. In contrast, gap junction communication was significantly decreased in all astrocyte populations associated with inflamed tissues. Collectively, these findings demonstrate the heterogeneity of striatal astrocyte populations, which experience distinct electrophysiological modifications in response to CNS inflammation. PMID:22457466

  8. Transient and steady-state selection in the striatal microcircuit

    Directory of Open Access Journals (Sweden)

    Adam eTomkins

    2014-01-01

    Full Text Available Although the basal ganglia have been widely studied and implicated in signal processing and action selection, little information is known about the active role the striatal microcircuit plays in action selection in the basal ganglia-thalamo-cortical loops. To address this knowledge gap we use a large scale three dimensional spiking model of the striatum, combined with a rate coded model of the basal ganglia-thalamo-cortical loop, to asses the computational role the striatum plays in action selection. We identify a robust transient phenomena generated by the striatal microcircuit, which temporarily enhances the difference between two competing cortical inputs. We show that this transient is sufficient to modulate decision making in the basal ganglia-thalamo-cortical circuit. We also find that the transient selection originates from a novel adaptation effect in single striatal projection neurons, which is amenable to experimental testing. Finally, we compared transient selection with models implementing classical steady-state selection. We challenged both forms of model to account for recent reports of paradoxically enhanced response selection in Huntington's Disease patients. We found that steady-state selection was uniformly impaired under all simulated Huntington's conditions, but transient selection was enhanced given a sufficient Huntington's-like increase in NMDA receptor sensitivity. Thus our models provide an intriguing hypothesis for the mechanisms underlying the paradoxical cognitive improvements in manifest Huntington's patients.

  9. Fractal analysis of striatal dopamine re-uptake sites

    International Nuclear Information System (INIS)

    Kuikka, J.T.; Bergstroem, K.A.; Tiihonen, J.; Raesaenen, P.; Karhu, J.

    1997-01-01

    Spatial variation in regional blood flow, metabolism and receptor density within the brain and in other organs is measurable even with a low spatial resolution technique such as emission tomography. It has been previously shown that the observed variance increases with increasing number of subregions in the organ/tissue studied. This resolution-dependent variance can be described by fractal analysis. We studied striatal dopamine re-uptake sites in 39 healthy volunteers with high-resolution single-photon emission tomography using iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane ([ 123 I]β-CIT). The mean fractal dimension was 1.15±0.07. The results indicate that regional striatal dopamine re-uptake sites involve considerable spatial heterogeneity which is higher than the uniform density (dimension=1.00) but much lower than complete randomness (dimension=1.50). There was a gender difference, with females having a higher heterogeneity in both the left and the right striatum. In addition, we found striatal asymmetry (left-to-right heterogeneity ratio of 1.19±0.15; P<0.001), suggesting functional hemispheric lateralization consistent with the control of motor behaviour and integrative functions. (orig.). With 5 figs., 1 tab

  10. Coenite seiklused ja Kim Ki-duki huumor / Merit Kask

    Index Scriptorium Estoniae

    Kask, Merit

    2007-01-01

    60-nda Cannes'i filmifestivali filme : Ethan ja Joel Coen'i "Pole maad vanadele meestele" ("No Country for Old Men" ; Ameerika Ühendriigid), Kim Ki-duki "Hingetõmme" ("Soom"/"Breath" ; Lõuna-Korea) ja Raphael Nadjari "Tehilim" (Prantsusmaa - Iisrael - Ameerika Ühendriigid)

  11. Prikljutshenija Koenov i jumor Kim Ki-duka / Merit Kask

    Index Scriptorium Estoniae

    Kask, Merit

    2007-01-01

    60-nda Cannes'i filmifestivali filme : Ethan ja Joel Coen'i "Pole maad vanadele meestele" ("No Country for Old Men" ; Ameerika Ühendriigid), Kim Ki-duki "Hingetõmme" ("Soom"/"Breath" ; Lõuna-Korea) ja Raphael Nadjari "Tehilim" (Prantsusmaa - Iisrael - Ameerika Ühendriigid)

  12. MEASUREMENT OF REACTION TIME IN QWAN KI DO

    Directory of Open Access Journals (Sweden)

    A Cojocariu

    2011-06-01

    Full Text Available The aim of this study is to identify the simple and choice reaction time to visual stimuli, for the upper limbs, in beginner and advanced practitioners of the Qwan Ki Do martial art, and also to identify differences between the various populations of the study. We used a total of 73 male subjects, aged between 18 and 33, taken from three groups. The first group (control was composed of 47 students in physical education and sport (group 1, the second group was composed of 18 beginner (less than 1 year athletes practising Qwan Ki Do (group 2, and the third group was composed of 8 athletes practising Qwan Ki Do with great experience (group 3. As a result of the measurements, we concluded that the simple reaction time has, in general, similar values in all the research groups (239.6±7.4 in group 1, 221.9±5.5 in group 2 and 207±6.6 in group 3 – data are expressed as mean ± standard error mean. Also, the choice reaction time in group 3 (376±4.7 ms for the dominant hand and 376±5.4 ms for the non-dominant hand is significantly lower (p 0.05, are probably due to the specific training in Qwan Ki Do, based on equal involvement in effort of both body halves.

  13. see Solanki GK 813 Ahn Choon Ki Robust chaos synchronization ...

    Indian Academy of Sciences (India)

    Adegoke Kunle. Continuous quantum phase transitions in the one-dimensional spin-1/2 axial next- nearest-neighbour Ising model in two or- thogonal magnetic fields. 293. Agarwal M K see Solanki G K. 813. Ahn Choon Ki. Robust chaos synchronization using input-to-state stable control. 705. Ahuja B L see Dashora Alpa.

  14. An international study to increase concordance in Ki67 scoring

    DEFF Research Database (Denmark)

    Polley, Mei-Yin C; Leung, Samuel C Y; Gao, Dongxia

    2015-01-01

    Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from...

  15. KiT: a MATLAB package for kinetochore tracking.

    Science.gov (United States)

    Armond, Jonathan W; Vladimirou, Elina; McAinsh, Andrew D; Burroughs, Nigel J

    2016-06-15

    During mitosis, chromosomes are attached to the mitotic spindle via large protein complexes called kinetochores. The motion of kinetochores throughout mitosis is intricate and automated quantitative tracking of their motion has already revealed many surprising facets of their behaviour. Here, we present 'KiT' (Kinetochore Tracking)-an easy-to-use, open-source software package for tracking kinetochores from live-cell fluorescent movies. KiT supports 2D, 3D and multi-colour movies, quantification of fluorescence, integrated deconvolution, parallel execution and multiple algorithms for particle localization. KiT is free, open-source software implemented in MATLAB and runs on all MATLAB supported platforms. KiT can be downloaded as a package from http://www.mechanochemistry.org/mcainsh/software.php The source repository is available at https://bitbucket.org/jarmond/kit and under continuing development. Supplementary data are available at Bioinformatics online. jonathan.armond@warwick.ac.uk. © The Author 2016. Published by Oxford University Press.

  16. Statistical inconsistencies in the KiDS-450 data set

    Science.gov (United States)

    Efstathiou, George; Lemos, Pablo

    2018-05-01

    The Kilo-Degree Survey (KiDS) has been used in several recent papers to infer constraints on the amplitude of the matter power spectrum and matter density at low redshift. Some of these analyses have claimed tension with the Planck Λ cold dark matter cosmology at the ˜2σ-3σ level, perhaps indicative of new physics. However, Planck is consistent with other low-redshift probes of the matter power spectrum such as redshift-space distortions and the combined galaxy-mass and galaxy-galaxy power spectra. Here, we perform consistency tests of the KiDS data, finding internal tensions for various cuts of the data at ˜2.2σ-3.5σ significance. Until these internal tensions are understood, we argue that it is premature to claim evidence for new physics from KiDS. We review the consistency between KiDS and other weak lensing measurements of S8, highlighting the importance of intrinsic alignments for precision cosmology.

  17. [3H]Dopamine accumulation and release from striatal slices in young, mature and senescent rats

    International Nuclear Information System (INIS)

    Thompson, J.M.

    1981-01-01

    Examinations of [ 3 H]dopamine ([ 3 H]DA) release following KCl or amphetamine administration in striatal slices from young (7 month), mature (12 month) and senescent (24 month) Wistar rats showed no age-related changes. Further, the amount of [ 3 H]DA accumulated in the striatal slices showed no changes with age. Thus, previously reported age-related deficits in motor behavior (i.e. rotational) are not produced by changes in striatal DA accumulation or release. (Auth.)

  18. Ki-67 as a prognostic marker according to breast cancer molecular subtype

    OpenAIRE

    Soliman, Nahed A.; Yussif, Shaimaa M.

    2016-01-01

    Objective: Ki-67 plays an important function in cell division, but its exact role is still unknown. Moreover, few works regarding its overall function were published. The present study evaluated the clinical significance of Ki-67 index as a prognostic marker and predictor of recurrence in different molecular subtypes of breast cancer. The relationship of Ki-67 index with different clinicopathological factors was also analyzed. Methods: Ki-67 index was measured in 107 cases of primary breast c...

  19. Body and Ki in Gicheon : practices of self-cultivation in contemporary Korea

    NARCIS (Netherlands)

    Jeon, Y.

    2017-01-01

    In this dissertation I study the social phenomenon of ki suryŏn (ki-training) as an invented tradition and examine how it functions within Korean society. Mind-body practices referred to as qigong in China and ki suryŏn in Korea are re-constructed in modernity on the basis of ancient East-Asian

  20. DNA synapsis through transient tetramerization triggers cleavage by Ecl18kI restriction enzyme

    NARCIS (Netherlands)

    Zaremba, M.; Lyubchenko, Y.L.; Laurens, N.; van den Broek, B.; Wuite, G.J.L.; Siksnys, V.

    2010-01-01

    To cut DNA at their target sites, restriction enzymes assemble into different oligomeric structures. The Ecl18kI endonuclease in the crystal is arranged as a tetramer made of two dimers each bound to a DNA copy. However, free in solution Ecl18kI is a dimer. To find out whether the Ecl18kI dimer or

  1. Differences in Expression of EGFR, Ki67 and p-EPK in Oral Cavity ...

    African Journals Online (AJOL)

    Overexpression of EGFR and Ki67 and loss of p-EPK were observed more frequently in HPV negative tumors. Multivariate Cox regression analysis showed that Ki67 expression had a significantly unfavorable impact on relapse free survival in oropharyngeal cancer. Conclusion: The expression levels of EGFR, Ki67, and ...

  2. Clinical impact of ki-67 labeling index in non-small cell lung cancer

    DEFF Research Database (Denmark)

    Jakobsen, Jan Nyrop; Sørensen, Jens Benn

    2013-01-01

    The ki-67 index is a marker of proliferation in malignant tumors. Studies from the period 2000 to 2012 on the prognostic and predictive value of ki-67 labeling index (LI) in non-small cell cancer (NSCLC) are reviewed. Twenty-eight studies reported on the prognostic value of ki-67 index with various...

  3. Astro-WISE for KiDS survey production and quality control

    NARCIS (Netherlands)

    Kleijn, G.V.; de Jong, Jelte; Valentijn, E.; Kuijken, K.; Consortiums, KiDS; Consortium, Astro-WISE; Ballester, P.; Egret, D.; Lorente, N.P.F.

    The Kilo Degree Survey (KiDS) is a 1500 square degree optical imaging survey with the recently commissioned OmegaCAM wide-field imager on the VLT Survey Telescope (VST). A suite of data products will be delivered to ESO and the community by the KiDS survey team. Spread over Europe, the KiDS team

  4. 3-Nitropropionic acid neurotoxicity in organotypic striatal and corticostriatal slice cultures is dependent on glucose and glutamate

    DEFF Research Database (Denmark)

    Storgaard, J; Kornblit, B T; Zimmer, J

    2000-01-01

    Mitochondrial inhibition by 3-nitropropionic acid (3-NPA) causes striatal degeneration reminiscent of Huntington's disease. We studied 3-NPA neurotoxicity and possible indirect excitotoxicity in organotypic striatal and corticostriatal slice cultures. Neurotoxicity was quantified by assay...

  5. Adenosine–cannabinoid receptor interactions. Implications for striatal function

    Science.gov (United States)

    Ferré, Sergi; Lluís, Carme; Justinova, Zuzana; Quiroz, César; Orru, Marco; Navarro, Gemma; Canela, Enric I; Franco, Rafael; Goldberg, Steven R

    2010-01-01

    Adenosine and endocannabinoids are very ubiquitous non-classical neurotransmitters that exert a modulatory role on the transmission of other more ‘classical’ neurotransmitters. In this review we will focus on their common role as modulators of dopamine and glutamate neurotransmission in the striatum, the main input structure of the basal ganglia. We will pay particular attention to the role of adenosine A2A receptors and cannabinoid CB1 receptors. Experimental results suggest that presynaptic CB1 receptors interacting with A2A receptors in cortico-striatal glutamatergic terminals that make synaptic contact with dynorphinergic medium-sized spiny neurons (MSNs) are involved in the motor-depressant and addictive effects of cannabinoids. On the other hand, postsynaptic CB1 receptors interacting with A2A and D2 receptors in the dendritic spines of enkephalinergic MSNs and postsynaptic CB1 receptors in the dendritic spines of dynorphinergic MSN are probably involved in the cataleptogenic effects of cannabinoids. These receptor interactions most probably depend on the existence of a variety of heteromers of A2A, CB1 and D2 receptors in different elements of striatal spine modules. Drugs selective for the different striatal A2A and CB1 receptor heteromers could be used for the treatment of neuropsychiatric disorders and drug addiction and they could provide effective drugs with fewer side effects than currently used drugs. This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x PMID:20590556

  6. Striatal degeneration impairs language learning: evidence from Huntington's disease.

    Science.gov (United States)

    De Diego-Balaguer, R; Couette, M; Dolbeau, G; Dürr, A; Youssov, K; Bachoud-Lévi, A-C

    2008-11-01

    Although the role of the striatum in language processing is still largely unclear, a number of recent proposals have outlined its specific contribution. Different studies report evidence converging to a picture where the striatum may be involved in those aspects of rule-application requiring non-automatized behaviour. This is the main characteristic of the earliest phases of language acquisition that require the online detection of distant dependencies and the creation of syntactic categories by means of rule learning. Learning of sequences and categorization processes in non-language domains has been known to require striatal recruitment. Thus, we hypothesized that the striatum should play a prominent role in the extraction of rules in learning a language. We studied 13 pre-symptomatic gene-carriers and 22 early stage patients of Huntington's disease (pre-HD), both characterized by a progressive degeneration of the striatum and 21 late stage patients Huntington's disease (18 stage II, two stage III and one stage IV) where cortical degeneration accompanies striatal degeneration. When presented with a simplified artificial language where words and rules could be extracted, early stage Huntington's disease patients (stage I) were impaired in the learning test, demonstrating a greater impairment in rule than word learning compared to the 20 age- and education-matched controls. Huntington's disease patients at later stages were impaired both on word and rule learning. While spared in their overall performance, gene-carriers having learned a set of abstract artificial language rules were then impaired in the transfer of those rules to similar artificial language structures. The correlation analyses among several neuropsychological tests assessing executive function showed that rule learning correlated with tests requiring working memory and attentional control, while word learning correlated with a test involving episodic memory. These learning impairments significantly

  7. Mechanisms mediating parallel action monitoring in fronto-striatal circuits.

    Science.gov (United States)

    Beste, Christian; Ness, Vanessa; Lukas, Carsten; Hoffmann, Rainer; Stüwe, Sven; Falkenstein, Michael; Saft, Carsten

    2012-08-01

    Flexible response adaptation and the control of conflicting information play a pivotal role in daily life. Yet, little is known about the neuronal mechanisms mediating parallel control of these processes. We examined these mechanisms using a multi-methodological approach that integrated data from event-related potentials (ERPs) with structural MRI data and source localisation using sLORETA. Moreover, we calculated evoked wavelet oscillations. We applied this multi-methodological approach in healthy subjects and patients in a prodromal phase of a major basal ganglia disorder (i.e., Huntington's disease), to directly focus on fronto-striatal networks. Behavioural data indicated, especially the parallel execution of conflict monitoring and flexible response adaptation was modulated across the examined cohorts. When both processes do not co-incide a high integrity of fronto-striatal loops seems to be dispensable. The neurophysiological data suggests that conflict monitoring (reflected by the N2 ERP) and working memory processes (reflected by the P3 ERP) differentially contribute to this pattern of results. Flexible response adaptation under the constraint of high conflict processing affected the N2 and P3 ERP, as well as their delta frequency band oscillations. Yet, modulatory effects were strongest for the N2 ERP and evoked wavelet oscillations in this time range. The N2 ERPs were localized in the anterior cingulate cortex (BA32, BA24). Modulations of the P3 ERP were localized in parietal areas (BA7). In addition, MRI-determined caudate head volume predicted modulations in conflict monitoring, but not working memory processes. The results show how parallel conflict monitoring and flexible adaptation of action is mediated via fronto-striatal networks. While both, response monitoring and working memory processes seem to play a role, especially response selection processes and ACC-basal ganglia networks seem to be the driving force in mediating parallel conflict

  8. Dysregulation of Striatal Dopamine Receptor Binding in Suicide.

    Science.gov (United States)

    Fitzgerald, Megan L; Kassir, Suham A; Underwood, Mark D; Bakalian, Mihran J; Mann, J John; Arango, Victoria

    2017-03-01

    Inconsistent evidence implicates disruptions of striatal dopaminergic indices in suicide and major depression. To determine whether there are alterations in the striatal dopamine system in suicide, we conducted a quantitative autoradiographic survey of dopamine transporter (DAT; [ 3 H]mazindol), D1 receptor ([ 3 H]SCH23390), and D2 receptor ([ 3 H]sulpiride) binding in the dorsal striatum postmortem from matched suicides and controls. Axis I and axis II psychiatric diagnosis, recent treatment history, and early life adversity (ELA) were determined by psychological autopsy. Mean DAT, D2, and D1 receptor binding did not differ in suicide. However, there was a positive correlation between D1 and D2 receptor binding in the dorsal striatum of control subjects (R 2 =0.31, p<0.05) that was not present in suicides (R 2 =0.00, p=0.97). In suicides and controls with reported ELA, there was no correlation between striatal DAT and D1 receptor binding (R 2 =0.07, p=0.33), although DAT and D1 receptor binding was positively correlated in subjects with no report of ELA (R 2 =0.32, p<0.05). After controlling for age, there were no significant ELA-related mean differences. Binding of D1 receptors and DAT throughout the striatum correlated negatively with age (D1 receptor: R 2 =0.12, p<0.05; DAT: R 2 =0.36, p<0.001). There appears to be an imbalance in dopaminergic receptor and transporter expression related to suicide that differs from that associated with ELA or age.

  9. Neuroinflammation alters voltage-dependent conductance in striatal astrocytes.

    Science.gov (United States)

    Karpuk, Nikolay; Burkovetskaya, Maria; Kielian, Tammy

    2012-07-01

    Neuroinflammation has the capacity to alter normal central nervous system (CNS) homeostasis and function. The objective of the present study was to examine the effects of an inflammatory milieu on the electrophysiological properties of striatal astrocyte subpopulations with a mouse bacterial brain abscess model. Whole cell patch-clamp recordings were performed in striatal glial fibrillary acidic protein (GFAP)-green fluorescent protein (GFP)(+) astrocytes neighboring abscesses at postinfection days 3 or 7 in adult mice. Cell input conductance (G(i)) measurements spanning a membrane potential (V(m)) surrounding resting membrane potential (RMP) revealed two prevalent astrocyte subsets. A1 and A2 astrocytes were identified by negative and positive G(i) increments vs. V(m), respectively. A1 and A2 astrocytes displayed significantly different RMP, G(i), and cell membrane capacitance that were influenced by both time after bacterial exposure and astrocyte proximity to the inflammatory site. Specifically, the percentage of A1 astrocytes was decreased immediately surrounding the inflammatory lesion, whereas A2 cells were increased. These changes were particularly evident at postinfection day 7, revealing increased cell numbers with an outward current component. Furthermore, RMP was inversely modified in A1 and A2 astrocytes during neuroinflammation, and resting G(i) was increased from 21 to 30 nS in the latter. In contrast, gap junction communication was significantly decreased in all astrocyte populations associated with inflamed tissues. Collectively, these findings demonstrate the heterogeneity of striatal astrocyte populations, which experience distinct electrophysiological modifications in response to CNS inflammation.

  10. Impaired striatal Akt signaling disrupts dopamine homeostasis and increases feeding.

    Directory of Open Access Journals (Sweden)

    Nicole Speed

    Full Text Available The prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address "food-abuse" disorders. We demonstrate a molecular link between impairment of a central kinase (Akt involved in insulin signaling induced by exposure to a high-fat (HF diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT. Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.We show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.Acquired disruption of brain insulin action may confer risk for and/or underlie "food-abuse" disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to "the fast food

  11. PSIHOLOŠKI VIDIKI BARV PRI IZDELAVI LOGOTIPA

    OpenAIRE

    Bauman, Anja

    2015-01-01

    Osrednja tema diplomske naloge so psihološki vidiki barv pri izdelavi logotipa. Diplomska naloga zajema tako teoretični kot tudi empirični del. V teoretičnem delu je predstavljen logotip in njegovi kriteriji uspešnosti. Prav tako pa so predstavljene tudi barve, njeni učinki ter značilnosti. Empirični del diplomske naloge pa se ukvarja z analizo obstoječih in izdelanih logotipov.

  12. The prognostic value of Ki67 in systemically untreated patients with node-negative breast cancer.

    Science.gov (United States)

    Pathmanathan, Nirmala; Balleine, Rosemary L; Jayasinghe, Upali W; Bilinski, Kellie L; Provan, Pamela J; Byth, Karen; Bilous, A Michael; Salisbury, Elizabeth L; Boyages, John

    2014-03-01

    To evaluate the utility of Ki67 as a prognostic marker in a series of patients with node-negative breast cancer untreated with adjuvant systemic therapy. The cohort consisted of 203 cases treated with breast conserving surgery and radiation only; median follow-up was 183 months (range 156-277 months). An immunohistochemical panel of oestrogen receptor (ER), progesterone receptor (PR), cytokeratin (CK)5/6 and Ki67 and human epidermal growth factor 2 in situ hybridization (HER2-ISH) was performed on the tumour samples. Ki67 scores were evaluable in 193/203 patients (95.1%). The primary outcome was breast cancer specific survival (BCSS). Of the cohort, 29 (14.2%) died of breast cancer. A cut off of 10% separated tumours into a 'Ki67-low' (n=70) or 'Ki67-high' group (n=123). The breast cancer specific survival was 97.1% and 77.6% for Ki67-low and Ki67-high groups, respectively. Univariate analysis showed that in this lymph node-negative cohort, the predictors for BCSS were tumour size, Ki67, LVI, age and histological grade 3. Multivariable analysis showed that Ki67 index and lymphovascular space invasion were independent predictors of breast cancer death. To examine the utility of Ki67 in assignment of immunohistochemically molecular subtypes, cases were assigned into Luminal A (ER-positive, HER2-negative, Ki67 ≤14%), Luminal B (ER-positive, HER2-negative, Ki67 >14%) and triple negative (ER/PR-negative and HER2-negative, any Ki67). The 15-year breast cancer specific survival was 91.7%, 79.4% and 75.8%, respectively. A statistically significant difference in breast cancer specific survival is seen in groups defined using Ki67 and receptor status, whereas histological grading was not a significant predictor of survival. Ki67 immunostaining provides prognostic information beyond traditionally assessed clinicopathological variables.

  13. Cognitive emotion regulation modulates the balance of competing influences on ventral striatal aversive prediction error signals.

    Science.gov (United States)

    Mulej Bratec, Satja; Xie, Xiyao; Wang, Yijun; Schilbach, Leonhard; Zimmer, Claus; Wohlschläger, Afra M; Riedl, Valentin; Sorg, Christian

    2017-02-15

    Cognitive emotion regulation (CER) is a critical human ability to face aversive emotional stimuli in a flexible way, via recruitment of specific prefrontal brain circuits. Animal research reveals a central role of ventral striatum in emotional behavior, for both aversive conditioning, with striatum signaling aversive prediction errors (aPE), and for integrating competing influences of distinct striatal inputs from regions such as the prefrontal cortex (PFC), amygdala, hippocampus and ventral tegmental area (VTA). Translating these ventral striatal findings from animal research to human CER, we hypothesized that successful CER would affect the balance of competing influences of striatal afferents on striatal aPE signals, in a way favoring PFC as opposed to 'subcortical' (i.e., non-isocortical) striatal inputs. Using aversive Pavlovian conditioning with and without CER during fMRI, we found that during CER, superior regulators indeed reduced the modulatory impact of 'subcortical' striatal afferents (hippocampus, amygdala and VTA) on ventral striatal aPE signals, while keeping the PFC impact intact. In contrast, inferior regulators showed an opposite pattern. Our results demonstrate that ventral striatal aPE signals and associated competing modulatory inputs are critical mechanisms underlying successful cognitive regulation of aversive emotions in humans. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Fronto-striatal atrophy correlates of neuropsychiatric dysfunction in frontotemporal dementia (FTD and Alzheimer's disease (AD

    Directory of Open Access Journals (Sweden)

    Dong Seok Yi

    Full Text Available ABSTRACT Behavioural disturbances in frontotemporal dementia (FTD are thought to reflect mainly atrophy of cortical regions. Recent studies suggest that subcortical brain regions, in particular the striatum, are also significantly affected and this pathology might play a role in the generation of behavioural symptoms. Objective: To investigate prefrontal cortical and striatal atrophy contributions to behavioural symptoms in FTD. Methods: One hundred and eighty-two participants (87 FTD patients, 39 AD patients and 56 controls were included. Behavioural profiles were established using the Cambridge Behavioural Inventory Revised (CBI-R and Frontal System Behaviour Scale (FrSBe. Atrophy in prefrontal (VMPFC, DLPFC and striatal (caudate, putamen regions was established via a 5-point visual rating scale of the MRI scans. Behavioural scores were correlated with atrophy rating scores. Results: Behavioural and atrophy ratings demonstrated that patients were significantly impaired compared to controls, with bvFTD being most severely affected. Behavioural-anatomical correlations revealed that VMPFC atrophy was closely related to abnormal behaviour and motivation disturbances. Stereotypical behaviours were associated with both VMPFC and striatal atrophy. By contrast, disturbance of eating was found to be related to striatal atrophy only. Conclusion: Frontal and striatal atrophy contributed to the behavioural disturbances seen in FTD, with some behaviours related to frontal, striatal or combined fronto-striatal pathology. Consideration of striatal contributions to the generation of behavioural disturbances should be taken into account when assessing patients with potential FTD.

  15. Reciprocal influences of nigral cells and striatal patch neurons in dissociated co-cultures

    NARCIS (Netherlands)

    Aronica, E.; Costantini, L. C.; Snyder-Keller, A.

    1996-01-01

    Our previous work has shown that the functional efficacy of nigral tissue transplants into dopamine (DA)-depleted rats is increased when embryonic striatal tissue is included (Costantini et al.: Exp Neurol 127:219-231, 1994). To examine further the influence of striatal patch neurons in this regard,

  16. GABAERGIC MODULATION OF STRIATAL CHOLINERGIC INTERNEURONS - AN IN-VIVO MICRODIALYSIS STUDY

    NARCIS (Netherlands)

    DEBOER, P; WESTERINK, BHC

    Striatal cholinergic interneurons have been shown to receive input from striatal gamma-aminobutyric acid (GABA)-containing cell elements. GABA is known to act on two different types of receptors, the GABA(A) and the GABA(B) receptor. Using in vivo microdialysis, we have studied the effect of

  17. No association between striatal dopamine transporter binding and body mass index

    DEFF Research Database (Denmark)

    van de Giessen, Elsmarieke; Hesse, Swen; Caan, Matthan W A

    2013-01-01

    Dopamine is one among several neurotransmitters that regulate food intake and overeating. Thus, it has been linked to the pathophysiology of obesity and high body mass index (BMI). Striatal dopamine D(2) receptor availability is lower in obesity and there are indications that striatal dopamine tr...

  18. Adenosine Receptor Heteromers and their Integrative Role in Striatal Function

    Directory of Open Access Journals (Sweden)

    Sergi Ferré

    2007-01-01

    Full Text Available By analyzing the functional role of adenosine receptor heteromers, we review a series of new concepts that should modify our classical views of neurotransmission in the central nervous system (CNS. Neurotransmitter receptors cannot be considered as single functional units anymore. Heteromerization of neurotransmitter receptors confers functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Some of these characteristics can be used as a “biochemical fingerprint” to identify neurotransmitter receptor heteromers in the CNS. This is exemplified by changes in binding characteristics that are dependent on coactivation of the receptor units of different adenosine receptor heteromers. Neurotransmitter receptor heteromers can act as “processors” of computations that modulate cell signaling, sometimes critically involved in the control of pre- and postsynaptic neurotransmission. For instance, the adenosine A1-A2A receptor heteromer acts as a concentration-dependent switch that controls striatal glutamatergic neurotransmission. Neurotransmitter receptor heteromers play a particularly important integrative role in the “local module” (the minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit, where they act as processors mediating computations that convey information from diverse volume-transmitted signals. For instance, the adenosine A2A-dopamine D2 receptor heteromers work as integrators of two different neurotransmitters in the striatal spine module.

  19. St Gallen 2015 subtyping of luminal breast cancers : impact of different Ki67-based proliferation assessment methods

    NARCIS (Netherlands)

    Focke, Cornelia M.|info:eu-repo/dai/nl/413647927; van Diest, Paul J.|info:eu-repo/dai/nl/075281775; Decker, Thomas

    2016-01-01

    Ki67 has been proposed as prognostic proliferation marker in luminal breast cancer (BC), but little is known on the influence of Ki67 assessment methods on subtyping into luminal A- and B-like tumors. Our aim was to study the influence of different Ki67-labeling index (Ki67-LI) assessment methods on

  20. Can Ki-67 Play a Role in Prediction of Breast Cancer Patients' Response to Neoadjuvant Chemotherapy?

    Directory of Open Access Journals (Sweden)

    Juhasz-Böss Ingolf

    2014-01-01

    Full Text Available Background. Currently the choice of breast cancer therapy is based on prognostic factors. The proliferation marker Ki-67 is used increasingly to determine the method of therapy. The current study analyses the predictive value of Ki-67 in foreseeing breast cancer patients’ responses to neoadjuvant chemotherapy. Methods. This study includes patients with invasive breast cancer treated between 2008 and 2013. The clinical response was assessed by correlating Ki-67 to histological examination, mammography, and ultrasonography findings. Results. The average Ki-67 value in our patients collectively (n=77 is 34.9 ± 24.6%. The average Ki-67 value is the highest with 37.4 ± 24.0% in patients with a pCR. The Ki-67 values do not differ significantly among the 3 groups: pCR versus partial pathological response versus stable disease/progress (P=0.896. However, Ki-67 values of patients with luminal, Her2 enriched, and basal-like cancers differed significantly from each other. Furthermore, within the group of luminal tumors Ki-67 values of patients with versus without pCR also differed significantly. Conclusion. Our data shows that the Ki-67 value predicts the response to neoadjuvant chemotherapy as a function of the molecular subtype, reflecting the daily routine concerning Ki-67 and its impressing potential and limitation as a predictive marker for neoadjuvant chemotherapy response.

  1. Ki67 and p53 in gastrointestinal stromal tumors - GIST Ki67 and p53 em tumores estromais gastrointestinais - GIST

    Directory of Open Access Journals (Sweden)

    Lúcio Roberto de Oliveira das Neves

    2009-06-01

    Full Text Available CONTEXT: Gastrointestinal stromal tumor (GIST is the most common mesenchymal tumor. Cellular proliferation and apoptosis is gaining importance for predicting prognosis in several cancers. OBJECTIVE: To investigate the Ki67 and p53 immunostaining in GISTs. METHODS: Specimens from 40 patients with GIST were assessed for immunohistochemical expression of Ki67 and p53. The tumors were divided according the risk of recurrence in two groups: I with high or intermediate risk and; II with low or very low risk. RESULTS: Among the 40 patients, 21 were men, the mean age was 56 years, 16 occurred in the small intestine and 13 in the stomach, 5 in the retroperitonium, 4 in the colon or rectum and 2 in the mesenterium. Thirty two tumors were from group I and 8 from group II. Half of the patients developed recurrence, being 90% of the group I (P = 0.114. The tumor Ki67 labelling index ranged from 0.02 to 0.35 (mean level 0.12. This index was marginally higher in the group I patients with recurrence (P = 0.09 compared to the patients of the same group without recurrence. p53 staining was expressed in 65% of the GISTs. A higher frequency of p53 and Ki67 had been found in the group I tumors when compared to the other group (P = 0.022; OR = 8.00 - IC 95%: 1.32-48.65. CONCLUSION: The most common site was the small intestine and 80% had a malignant potential justifying the high recurrence observed. No significant correlation was found between p53 and overall outcome of the patients. In group I patients, the evaluation Ki67LI may be a marker of prognosis. The positivity of both markers is higher among the patients with worst prognosis than in the others.CONTEXTO: Os tumores estromais gastrointestinais (GIST são os tumores mesenquimais mais frequentes. A proliferação intestinal e a apoptose são cada vez mais importantes na avaliação do prognóstico de diversos cânceres. OBJETIVO: Avaliar a imunoexpressão de Ki67 e p53 em GIST. MÉTODOS: Foram estudados a

  2. Menstrual cycle could affect Ki67 expression in estrogen receptor-positive breast cancer patients.

    Science.gov (United States)

    Horimoto, Yoshiya; Arakawa, Atsushi; Tanabe, Masahiko; Kuroda, Keiji; Matsuoka, Joe; Igari, Fumie; Himuro, Takanori; Yoshida, Yuko; Tokuda, Emi; Shimizu, Hideo; Hino, Okio; Saito, Mitsue

    2015-10-01

    Ki67 is a potent prognostic marker for determining systemic treatment of patients with hormone receptor-positive breast cancer. However, evaluation of Ki67 expression can be difficult, due mostly to its heterogeneity. The Ki67 expression level, which indicates that a cell is undergoing division (cell cycle), rises when proliferation activity increases. Thus, Ki67 expression might be affected by hormonal stimuli. We hypothesised that Ki67 expression level might change during the menstrual cycle. We examined pairs of biopsy and surgical specimens from individual patients to evaluate this hypothesis. First, the effects of estradiol on Ki67 expression in breast cancer cell lines were examined employing immunocytochemistry and Western blotting. Next, differences in Ki67 expression between biopsy and surgical specimens from 131 patients with estrogen receptor-positive tumours were retrospectively examined. In vitro experiments showed Ki67 expression in estrogen receptor-positive cancer cells to be dependent on estradiol stimulation. Ki67 expression was higher in biopsy samples collected in the luteal phase than in those from other phases. When biopsy and surgical samples were obtained at different times during the menstrual cycle in the same individual, there were differences in Ki67 expression between these samples. Those collected in the luteal phase showed higher Ki67 expression than samples obtained during other phases (pKi67 expression varied in the same patients according to menstrual cycle phase. Our results suggest that Ki67 expression in estrogen receptor-positive breast cancer should be carefully assessed bearing in mind the patient's menstrual cycle, since the interpretation of expression could affect treatment decisions. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  3. Striatal dopamine release induced by repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex: effect of aging

    Energy Technology Data Exchange (ETDEWEB)

    Bang, Seong Ae; Cho, Sang Soo; Yoon, Eun Jin; Kim, Ji Sun; Lee, Byung Chul; Kim, Yu Kyeong; Kim, Sang Eun [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of)

    2007-07-01

    We previously demonstrated dopamine (DA) release in the bilateral striatal regions following prefrontal repetitive transcranial magnetic stimulation (rTMS) in young subjects. Several lines of evidence support substantial age-related changes in human dopaminergic neurotransmission. One possible explanation is alteration of cortico striatal neural connection with aging. Therefore, we investigated how frontal activation by rTMS influences striatal DA release in the elderly with SPECT measurements of striatal binding of [123I]iodobenzamide (lBZM), a DA D2 receptor radioligand that is sensitive to endogenous DA. Five healthy elderly male subjects (age, 64 3 y) were studied with brain [123I]IBZM SPECT under three conditions (resting, sham stimulation, and active rTMS over left dorsolateral prefrontal cortex (DLPFC)), while receiving a bolus plus constant infusion of [123I]IBZM. rTMS session consisted of three blocks. In each block, 15 trains of 2 sec duration were delivered with 10 Hz stimulation frequency and 100% motor threshold. Striatal V3', calculated as (striatal - occipital)/occipital radioactivity, was measured under equilibrium condition at baseline and after sham and active rTMS. Sham stimulation did not affect striatal V3'. rTMS over left DLPFC induced no significant change in V3' in the right striatum compared with baseline condition (0.91 0.25 vs. 0.96 0.25, P = NS). Interestingly, left striatal V3' showed a significant increase after rTMS over left DLPFC compared with sham condition (1.09 0.33 vs. 0.93 0.27, P < 0.05; 17.0 11.1% increase). These results are discrepant from previous ones from young subjects, who showed frontal rTMS-induced reduction of striatal V3', indicating rTMS-induced striatal DA release. We found no significant striatal DA release induced by rTMS over DLPFC in healthy elderly subjects using in vivo binding competition techniques. These results may support an altered cortico striatal circuit in normal aging.

  4. Regulation of drugs affecting striatal cholinergic activity by corticostriatal projections

    International Nuclear Information System (INIS)

    Ladinsky, H.

    1986-01-01

    Research demonstrates that the chronic degeneration of the corticostriatal excitatory pathway makes the cholinergic neurons of the striatum insensitive to the neuropharmacological action of a number of different drugs. Female rats were used; they were killed and after the i.v. infusion of tritium-choline precursor, choline acetyltransferase activity was measured. Striatal noradrenaline, dopamine and serotonin content was measured by electrochemical detection coupled with high pressure liquid chromatography. Uptake of tritium-glutamic acid was estimated. The data were analyzed statistically. It is shown that there is evidence that the effects of a number of drugs capable of depressing cholinergic activity through receptor-mediated responses are operative only if the corticostriatal pathway is integral. Neuropharmacological responses in the brain appear to be the result of an interaction between several major neurotransmitter systems

  5. Striatal grafts in a rat model of Huntington's disease

    DEFF Research Database (Denmark)

    Guzman, R; Meyer, M; Lövblad, K O

    1999-01-01

    , which was found unaltered for the first 21 days posttransplantation, whereas a hypointense graft signal was detected at 99 days posttransplantation. At 2 days posttransplantation, T2-weighted images showed the graft region as a hyperintense area surrounded by a rim of low signal intensity but at later...... time-points graft location could not be further verified. Measures for graft size and ventricle size obtained from MR images highly correlated with measures obtained from histologically processed sections (R = 0.8, P ...Survival and integration into the host brain of grafted tissue are crucial factors in neurotransplantation approaches. The present study explored the feasibility of using a clinical MR scanner to study striatal graft development in a rat model of Huntington's disease. Rat fetal lateral ganglionic...

  6. Astrocytosis in parkinsonism: considering tripartite striatal synapses in physiopathology?

    Science.gov (United States)

    Charron, Giselle; Doudnikoff, Evelyne; Canron, Marie-Helene; Li, Qin; Véga, Céline; Marais, Sebastien; Baufreton, Jérôme; Vital, Anne; Oliet, Stéphane H R; Bezard, Erwan

    2014-01-01

    The current concept of basal ganglia organization and function in physiological and pathophysiological conditions excludes the most numerous cells in the brain, i.e., the astrocytes, present with a ratio of 10:1 neuron. Their role in neurodegenerative condition such as Parkinson's disease (PD) remains to be elucidated. Before embarking into physiological investigations of the yet-to-be-identified "tripartite" synapses in the basal ganglia in general and the striatum in particular, we therefore characterized anatomically the PD-related modifications in astrocytic morphology, the changes in astrocytic network connections and the consequences on the spatial relationship between astrocytic processes and asymmetric synapses in normal and PD-like conditions in experimental and human PD. Our results unravel a dramatic regulation of striatal astrocytosis supporting the hypothesis of a key role in (dys) regulating corticostriatal transmission. Astrocytes and their various properties might thus represent a therapeutic target in PD.

  7. Astrocytosis in parkinsonism: considering tripartite striatal synapses in physiopathology?

    Directory of Open Access Journals (Sweden)

    Giselle eCharron

    2014-09-01

    Full Text Available The current concept of basal ganglia organization and function in physiological and pathophysiological conditions excludes the most numerous cells in the brain, i.e. the astrocytes, present with a ratio of 10:1 neuron. Their role in neurodegenerative condition such as Parkinson’s disease (PD remains to be elucidated. Before embarking into physiological investigations of the yet-to-be-identified tripartite synapses in the basal ganglia in general and the striatum in particular, we therefore characterized anatomically the PD-related modifications in astrocytic morphology, the changes in astrocytic network connections and the consequences on the spatial relationship between astrocytic processes and asymmetric synapses in normal and PD-like conditions in experimental and human PD. Our results unravel a dramatic regulation of striatal astrocytosis supporting the hypothesis of a key role in (dysregulating corticostriatal transmission. Astrocytes and their various properties might thus represent a therapeutic target in PD.

  8. Regulation of bat echolocation pulse acoustics by striatal dopamine.

    Science.gov (United States)

    Tressler, Jedediah; Schwartz, Christine; Wellman, Paul; Hughes, Samuel; Smotherman, Michael

    2011-10-01

    The ability to control the bandwidth, amplitude and duration of echolocation pulses is a crucial aspect of echolocation performance but few details are known about the neural mechanisms underlying the control of these voice parameters in any mammal. The basal ganglia (BG) are a suite of forebrain nuclei centrally involved in sensory-motor control and are characterized by their dependence on dopamine. We hypothesized that pharmacological manipulation of brain dopamine levels could reveal how BG circuits might influence the acoustic structure of bat echolocation pulses. A single intraperitoneal injection of a low dose (5 mg kg(-1)) of the neurotoxin 1-methyl-4-phenylpyridine (MPTP), which selectively targets dopamine-producing cells of the substantia nigra, produced a rapid degradation in pulse acoustic structure and eliminated the bat's ability to make compensatory changes in pulse amplitude in response to background noise, i.e. the Lombard response. However, high-performance liquid chromatography (HPLC) measurements of striatal dopamine concentrations revealed that the main effect of MPTP was a fourfold increase rather than the predicted decrease in striatal dopamine levels. After first using autoradiographic methods to confirm the presence and location of D(1)- and D(2)-type dopamine receptors in the bat striatum, systemic injections of receptor subtype-specific agonists showed that MPTP's effects on pulse acoustics were mimicked by a D(2)-type dopamine receptor agonist (Quinpirole) but not by a D(1)-type dopamine receptor agonist (SKF82958). The results suggest that BG circuits have the capacity to influence echolocation pulse acoustics, particularly via D(2)-type dopamine receptor-mediated pathways, and may therefore represent an important mechanism for vocal control in bats.

  9. Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development.

    Science.gov (United States)

    Forcelli, Patrick A; Janssen, Megan J; Vicini, Stefano; Gale, Karen

    2012-09-01

    Drug exposure during critical periods of brain development may adversely affect nervous system function, posing a challenge for treating infants. This is of particular concern for treating neonatal seizures, as early life exposure to drugs such as phenobarbital is associated with adverse neurological outcomes in patients and induction of neuronal apoptosis in animal models. The functional significance of the preclinical neurotoxicity has been questioned due to the absence of evidence for functional impairment associated with drug-induced developmental apoptosis. We used patch-clamp recordings to examine functional synaptic maturation in striatal medium spiny neurons from neonatal rats exposed to antiepileptic drugs with proapoptotic action (phenobarbital, phenytoin, lamotrigine) and without proapoptotic action (levetiracetam). Phenobarbital-exposed rats were also assessed for reversal learning at weaning. Recordings from control animals revealed increased inhibitory and excitatory synaptic connectivity between postnatal day (P)10 and P18. This maturation was absent in rats exposed at P7 to a single dose of phenobarbital, phenytoin, or lamotrigine. Additionally, phenobarbital exposure impaired striatal-mediated behavior on P25. Neuroprotective pretreatment with melatonin, which prevents drug-induced neurodevelopmental apoptosis, prevented the drug-induced disruption in maturation. Levetiracetam was found not to disrupt synaptic development. Our results provide the first evidence that exposure to antiepileptic drugs during a sensitive postnatal period impairs physiological maturation of synapses in neurons that survive the initial drug insult. These findings suggest a mechanism by which early life exposure to antiepileptic drugs can impact cognitive and behavioral outcomes, underscoring the need to identify therapies that control seizures without compromising synaptic maturation. Copyright © 2012 American Neurological Association.

  10. Speech-induced striatal dopamine release is left lateralized and coupled to functional striatal circuits in healthy humans: A combined PET, fMRI and DTI study

    Science.gov (United States)

    Simonyan, Kristina; Herscovitch, Peter; Horwitz, Barry

    2013-01-01

    Considerable progress has been recently made in understanding the brain mechanisms underlying speech and language control. However, the neurochemical underpinnings of normal speech production remain largely unknown. We investigated the extent of striatal endogenous dopamine release and its influences on the organization of functional striatal speech networks during production of meaningful English sentences using a combination of positron emission tomography (PET) with the dopamine D2/D3 receptor radioligand [11C]raclopride and functional MRI (fMRI). In addition, we used diffusion tensor tractography (DTI) to examine the extent of dopaminergic modulatory influences on striatal structural network organization. We found that, during sentence production, endogenous dopamine was released in the ventromedial portion of the dorsal striatum, in its both associative and sensorimotor functional divisions. In the associative striatum, speech-induced dopamine release established a significant relationship with neural activity and influenced the left-hemispheric lateralization of striatal functional networks. In contrast, there were no significant effects of endogenous dopamine release on the lateralization of striatal structural networks. Our data provide the first evidence for endogenous dopamine release in the dorsal striatum during normal speaking and point to the possible mechanisms behind the modulatory influences of dopamine on the organization of functional brain circuits controlling normal human speech. PMID:23277111

  11. Digital image analysis of Ki67 in hot spots is superior to both manual Ki67 and mitotic counts in breast cancer.

    Science.gov (United States)

    Stålhammar, Gustav; Robertson, Stephanie; Wedlund, Lena; Lippert, Michael; Rantalainen, Mattias; Bergh, Jonas; Hartman, Johan

    2017-12-08

    During pathological examination of breast tumours, proliferative activity is routinely evaluated by a count of mitoses. Adding immunohistochemical stains of Ki67 provides extra prognostic and predictive information. However, the currently used methods for these evaluations suffer from imperfect reproducibility. It is still unclear whether analysis of Ki67 should be performed in hot spots, in the tumour periphery, or as an average of the whole tumour section. The aim of this study was to compare the clinical relevance of mitoses, Ki67 and phosphohistone H3 in two cohorts of primary breast cancer specimens (total n = 294). Both manual and digital image analysis scores were evaluated for sensitivity and specificity for luminal B versus A subtype as defined by PAM50 gene expression assays, for high versus low transcriptomic grade, for axillary lymph node status, and for prognostic value in terms of prediction of overall and relapse-free survival. Digital image analysis of Ki67 outperformed the other markers, especially in hot spots. Tumours with high Ki67 expression and high numbers of phosphohistone H3-positive cells had significantly increased hazard ratios for all-cause mortality within 10 years from diagnosis. Replacing manual mitotic counts with digital image analysis of Ki67 in hot spots increased the differences in overall survival between the highest and lowest histological grades, and added significant prognostic information. Digital image analysis of Ki67 in hot spots is the marker of choice for routine analysis of proliferation in breast cancer. © 2017 John Wiley & Sons Ltd.

  12. Can Histological Grade and Mitotic Index Replace Ki67 to Determine Luminal Breast Cancer Subtypes?

    Science.gov (United States)

    Oddó, David; Pulgar, Dahiana; Elgueta, Nicole; Acevedo, Francisco; Razmiliz, Dravna; Navarro, María Elena; Camus, Mauricio; Merino, Tomás; Retamal, Ignacio; Pérez-Sepúlveda, Alejandra; Villarroel, Alejandra; Galindo, Héctor; Peña, José; Sánchez, César

    2018-01-27

    Introduction: Breast cancer can be classified into subtypes based on immunohistochemical markers, with Ki67 expression levels being used to divide luminal BC tumors in luminal A and B subtypes; however, Ki67 is not routinely determined due to a lack of standardization. Objective: To evaluate histological grade and Eliminate: the mitotic index to determine if they can be used as an alternative method to Ki67 staining for luminal subtype definition. Methods: We evaluated estrogen receptor positive breast cancer tissue samples. Pathological analysis included determination of Ki67. A low level of Ki67 was defined as breast cancer samples; 24 (15,9%) were classified as I; 74 as HG II (49%), and 53 (35,1%) as HG III. The median value for Ki67 was 13% (range: Ki67 values significantly lower than HG II and III tumors (Anova, Tamhane test p=0,001). A higher Ki67 value was related to a higher MI (Rho Sperman p=0,336; R2= 0,0273). ROC curve analysis determined that a MI ≥ 3 had a sensibility of 61.9% and specificity of 66.7% in predicting a high Ki67 value (≥14%) (area under the curve: 0,691; p =0,0001). A HG I tumor or HG II-III with MI ≤2, had a high probability of corresponding to a LA tumor (76,3%), as defined using Ki67 expression, while the probability of a LB subtype was higher with HG II-III and a MI ≥3 (57.4%). Global discrimination was 68.1%. Conclusions: For the LA subtype, our predictive model showed a good correlation of HG and MI with the classification based on Ki67Ki67 determination seems to be needed for this group of patients. Creative Commons Attribution License

  13. New insight into Ki67 expression at the invasive front in breast cancer.

    Directory of Open Access Journals (Sweden)

    Peng Gong

    Full Text Available PURPOSE: To investigate the distribution of Ki67+ cells in breast cancer in relation to clinical-pathological parameters and prognosis. MATERIALS AND METHODS: Ki67 expression status was detected in 1,086 breast cancer specimens using immunohistochemistry staining and examining the relationship between the Ki67+ cells' location. Subsequently, clinical-pathological parameters and prognosis were determined. RESULTS: In total, Ki67 protein expression was found in 781 (71.92% of the 1,086 breast cancer specimens. Among the 781 Ki67+ cases, 461 were defined as diffuse type and 320 were defined as borderline type. After universal correlation analysis, significant differences were observed in age, histological grade, metastatic nodes, postoperative distant metastasis, and molecular subtype between Ki67+ and Ki67- cases (P = 0.01, 0.001, 0.001, 0.001, and 0.001, respectively. After subgroup analysis, the borderline cases were found to be characterized by a high distant metastasis rate compared to the diffuse cases as well as the Ki67- cases (P = 0.001. No differences were observed between diffuse type or Ki67- cases (P = 0.105. Multivariate analysis showed that age, tumor size, histological grade, lymph node metastasis, molecular subtype, and the Ki67 distribution pattern were observed to be related to postoperative distant metastasis (all P<0.05. Furthermore, borderline type was shown to attain a significantly more distant bone and liver metastasis and worse disease-specific survival than the other types (P = 0.001. In the Cox regression test, the Ki67 distribution pattern was detected as an independent prognostic factor (P = 0.001. CONCLUSION: The distribution pattern of Ki67 may be a new independent prognostic factor for breast cancer.

  14. Striatal and extra-striatal dopamine transporter in cannabis and tobacco addiction: a high resolution PET study

    International Nuclear Information System (INIS)

    Leroy, C.; Martinot, J.L.; Duchesnay, E.; Artiges, E.; Ribeiro, M.J.; Trichard, Ch.; Karila, L.; Lukasiewicz, M.; Benyamina, A.; Reynaud, M.; Martinot, J.L.; Duchesnay, E.; Artiges, E.; Comtat, C.; Artiges, E.; Trichard, Ch.

    2011-01-01

    The dopamine (DA) system is known to be involved in the reward and dependence mechanisms of addiction. However, modifications in dopaminergic neurotransmission associated with long-term tobacco and cannabis use have been poorly documented in vivo. In order to assess striatal and extra-striatal dopamine transporter (DAT) availability in tobacco and cannabis addiction, three groups of male age-matched subjects were compared: 11 healthy non-smoker subjects, 14 tobacco-dependent smokers (17.6 ± 5.3 cigarettes/day for 12.1 ± 8.5 years) and 13 cannabis and tobacco smokers (CTS) (4.8 ± 5.3 cannabis joints/day for 8.7 ± 3.9 years). DAT availability was examined in positron emission tomography (HRRT) with a high resolution research tomograph after injection of [ 11 C]PE2I, a selective DAT radioligand. Region of interest and voxel-by-voxel approaches using a simplified reference tissue model were performed for the between-group comparison of DAT availability. Measurements in the dorsal striatum from both analyses were concordant and showed a mean 20% lower DAT availability in drug users compared with controls. Whole-brain analysis also revealed lower DAT availability in the ventral striatum, the midbrain, the middle cingulate and the thalamus (ranging from -15 to -30%). The DAT availability was slightly lower in all regions in CTS than in subjects who smoke tobacco only, but the difference does not reach a significant level. These results support the existence of a decrease in DAT availability associated with tobacco and cannabis addictions involving all dopaminergic brain circuits. These findings are consistent with the idea of a global decrease in cerebral DA activity in dependent subjects. (authors)

  15. Intratumoral heterogeneity of Ki67 expression in early breast cancers exceeds variability between individual tumours.

    Science.gov (United States)

    Focke, Cornelia M; Decker, Thomas; van Diest, Paul J

    2016-11-01

    Regional differences in proliferative activity are commonly seen within breast cancers, but little is known on the extent of intratumoral heterogeneity of Ki67 expression. Our aim was to study the intratumoral heterogeneity of Ki67 expression in early breast cancers and its association with clinicopathological features, such as oestrogen receptor (ER) status, grade and histological subtype. The Ki67-labelling index (Ki67-LI) was assessed in hot, cold and intermediate spots of 233 invasive breast cancers by counting a total of 1020 cells, according to a protocol of the International Ki67 in Breast Cancer Working Group. Differences between the spots per tumour were analysed further for clinicopathological subgroups defined by ER status, grade and histological subtype. All clinicopathological subgroups showed significant differences in Ki67-LI between hot, intermediate and cold spots (P cancers (72.6 versus 49.2%, P cancers. Nested analysis of variance indicated that in both ER-positive and ER-negative cancers, variance in Ki67-LI within tumours contributed more to the total variance (56% for ER-positive, 60% for ER-negative cancers) than the variance between tumours. Intratumoral heterogeneity in Ki67-LI is a ubiquitous phenomenon across various pathological subgroups of breast cancer that may impact assessment of Ki67 levels for clinical decision-making, and sheds new light on recommended cut-offs. © 2016 John Wiley & Sons Ltd.

  16. An interobserver reproducibility analysis of Ki67 visual assessment in breast cancer.

    Science.gov (United States)

    Shui, Ruohong; Yu, Baohua; Bi, Rui; Yang, Fei; Yang, Wentao

    2015-01-01

    Ki67 labeling index (LI) is used as a predictive marker and is associated with prognosis in breast cancer. However, standardised methodologies for measurement are lacking which has limited its application in clinical practice. In this study, we evaluated the interobserver concordance of visual assessment of Ki67 LI in breast cancer. Ki67-immunostained slides of 160 cases of primary invasive breast cancer were visual assessed by five breast pathologists with two different methods to choose the scoring fields: (1) hot-spot score, (2) average score. Proportions of positive invasive tumor cells at 10 % intervals were scored. The intra-class correlation coefficient (ICC) was used to assess the interobserver reproducibility. (1) A perfect concordance of Ki67 LI was demonstrated according to both score methods (P30% Ki-67 LI). The concordance was relatively low in intermediate Ki67 LI group compared with low and high Ki67 LI groups. (3) All cases were classified into three groups by paired-difference (d) between means of hot-spot score and average score (dKi67 LI at 10 % intervals is a candidate for a standard method in breast cancer clinical practice. Average score and hot-spot score of visual assessment both demonstrated a perfect concordance, and an overall average assessment across the whole section including hot spots may be a better method. Interobserver concordance of intermediate Ki67 LI in which most cutoffs are located for making clinical decisions was relatively low.

  17. Cortico-Striatal Spike-Timing Dependent Plasticity After Activation of Subcortical Pathways

    OpenAIRE

    Schulz, Jan M.; Redgrave, Peter; Reynolds, John N. J.

    2010-01-01

    Cortico-striatal spike-timing dependent plasticity (STDP) is modulated by dopamine in vitro. The present study investigated STDP in vivo using alternative procedures for modulating dopaminergic inputs. Postsynaptic potentials (PSP) were evoked in intracellularly recorded spiny neurons by electrical stimulation of the contralateral motor cortex. PSPs often consisted of up to three distinct components, likely representing distinct cortico-striatal pathways. After baseline recording, bicucullin...

  18. A negative relationship between ventral striatal loss anticipation response and impulsivity in borderline personality disorder

    OpenAIRE

    Herbort, Maike C.; Soch, Joram; W?stenberg, Torsten; Krauel, Kerstin; Pujara, Maia; Koenigs, Michael; Gallinat, J?rgen; Walter, Henrik; Roepke, Stefan; Schott, Bj?rn H.

    2016-01-01

    Patients with borderline personality disorder (BPD) frequently exhibit impulsive behavior, and self-reported impulsivity is typically higher in BPD patients when compared to healthy controls. Previous functional neuroimaging studies have suggested a link between impulsivity, the ventral striatal response to reward anticipation, and prediction errors. Here we investigated the striatal neural response to monetary gain and loss anticipation and their relationship with impulsivity in 21 female BP...

  19. Opposite Effects of Stimulant and Antipsychotic Drugs on Striatal Fast-Spiking Interneurons

    OpenAIRE

    Wiltschko, Alexander B; Pettibone, Jeffrey R; Berke, Joshua D

    2010-01-01

    Psychomotor stimulants and typical antipsychotic drugs have powerful but opposite effects on mood and behavior, largely through alterations in striatal dopamine signaling. Exactly how these drug actions lead to behavioral change is not well understood, as previous electrophysiological studies have found highly heterogeneous changes in striatal neuron firing. In this study, we examined whether part of this heterogeneity reflects the mixture of distinct cell types present in the striatum, by di...

  20. Corticostriatal interactions in the generation of tic-like behaviors after local striatal disinhibition

    Science.gov (United States)

    Pogorelov, Vladimir; Xu, Meiyu; Smith, Haleigh R.; Buchanan, Gordon F.; Pittenger, Christopher

    2015-01-01

    The pathophysiology of the tics that define Gilles de la Tourette syndrome (TS) is not well understood. Local disinhibition within the striatum has been hypothesized to play a pathogenic role. In support of this, experimental disinhibition by local antagonism of GABA-A receptors within the striatum produces tic-like phenomenology in monkey and rat. We replicated this effect in mice via local picrotoxin infusion into the dorsal striatum. Infusion of picrotoxin into sensorimotor cortex produced similar movements, accompanied by signs of behavioral activation; higher-dose picrotoxin in the cortex produced seizures. Striatal inhibition with local muscimol completely abolished tic-like movements after either striatal or cortical picrotoxin, confirming their dependence on the striatal circuitry; in contrast, cortical muscimol attenuated but did not abolish movements produced by striatal picrotoxin. Striatal glutamate blockade eliminated tic-like movements after striatal picrotoxin, indicating that glutamatergic afferents are critical for their generation. These studies replicate and extend previous work in monkey and rat, providing additional validation for the local disinhibition model of tic generation. Our results reveal a key role for corticostriatal glutamatergic afferents in the generation of tic-like movements in this model. PMID:25597650

  1. Serial imaging of bilateral striatal necrosis associated with acidaemia in adults

    International Nuclear Information System (INIS)

    Kamei, S.; Takasu, T.; Mori, N.; Yoshihashi, K.; Shikata, E.

    1996-01-01

    Bilateral striatal necrosis in acute encephalopathy has been reported in a small number of adults with methanol or cyanide intoxication, hypoxic encephalopathy or haemolytic-uraemic syndrome. Acute encephalopathy with bilateral striatal necrosis has been reported in infants and children. However, the pathogenesis of the necrosis remains unclear. This is the first report of serial imaging from the very early yo chronic stage in two acute encephalopathic adults with bilateral striatal necrosis. A clinicoradiological study is presented for clarification of the pathological process and pathogenesis. Striatal lesions were not detected in the very early stages, but only thereafter. Serial studies suggested that the lesions were caused by delayed neuronal death. These patients had severe lactic acidosis, near the limit for survival. There hav ebeen few reports of adults with acute encephalopathy and bilateral striatal necrosis in whom arterial pH was described; all these exhibited marked acidosis. The common pathophysiological condition among these encephalopathies with bilateral striatal necrosis could be lactic acidosis elicited by impairnment of ATP generation through the Krebs cycle. The striatum might represent one of the target areas of Krebs-cycle blockade. (orig.)

  2. Conjugate Shear Fractures at 'Ki Corona,' Southeast Parga Chasma, Venus

    Science.gov (United States)

    Willis, J. J.; Hansen, V. L.

    1996-03-01

    Brittle tensile failure of Venus' surface is evident in many tectonic regimes, including as extension fractures associated with caldera collapse, radial and concentric fractures of coronae, fractures normal to folds, and fracture belts. However, evidence of brittle shear failure has been described at only two localities_intersecting fractures oblique to wrinkle ridges in Lavinia Planitia were interpreted as conjugate shear fractures by Watters, and en echelon fractures in Guinevere Planitia record dominant extension. but with a component of shear. We confirm these earlier interpretations, and recognize the widespread nature of conjugate shear fractures across the Venus surface, identifying examples at over 100 locations in varied tectonic regimes, including coronae, wrinkle-ridged plains, and fracture belts. However, we focus here on fracture and fold relations at "Ki Corona" (46.8 degrees S, 302.5 degrees E), and their implications toward corona evolution.

  3. Sexualidad violenta en el cine de Kim Ki-duk

    Directory of Open Access Journals (Sweden)

    Daniel Muñoz Ruiz

    2011-07-01

    Full Text Available En sus más de 110 años de vida el cine ha representado la sexualidad humana en todas sus modalidades y desde los más variados puntos de vista. El cine de Kim Ki-duk ha sorprendido y escandalizado al público por su crudeza y, a veces, excesiva violencia. El director surcoreano ha explorado a lo largo de su filmografía el tema del sexo siempre desde puntos de vista dramáticos y hasta truculentos. En sus películas la mayoría de las relaciones sexuales carecen de amor y afecto. Nunca son placenteras. La violación, la prostitución, la violencia de género y las frustraciones sexuales son temas recurrentes en su cine.

  4. Thyroid cancers after Chernobyl: importance of prophylaxis by KI

    International Nuclear Information System (INIS)

    Schlumberger, M.

    1994-01-01

    Since 1990, more than 400 thyroid cancers have been observed in children in southern Belarus and northern Ukraine. Screening is of minor significance on account of the highly increased incidence of these cancers, their agressivity and frequent diagnosis at a metastatic stage. Several arguments speak for the responsibility of the Chernobyl accident: (1) importance of the initial contamination; (2) geographical distribution, the incidence being higher in the more severely contaminated areas; (3) time distribution, the incidence increasing steadily since 1990. Iodine 131 is very likely the agent responsible for this increase. These data underline the significance of KI prophylaxis of thyroid irradiation in case of nuclear power plant accident, especially for children on whom it is practically without any danger. (author). 23 refs., 1 tab

  5. Prognostic significance of the Ki67 scoring categories in breast cancer subgroups.

    Science.gov (United States)

    Niikura, Naoki; Masuda, Shinobu; Kumaki, Nobue; Xiaoyan, Tang; Terada, Mizuho; Terao, Mayako; Iwamoto, Takayuki; Oshitanai, Risa; Morioka, Toru; Tuda, Banri; Okamura, Takuho; Saito, Yuki; Suzuki, Yasuhiro; Tokuda, Yutaka

    2014-10-01

    Immunohistochemical (IHC) expression of Ki67 has a prognostic and predictive value for breast cancer, and the IHC Ki67 labeling index is estimated by counting the number of positive and negative cells. It has not been clarified whether IHC Ki67 estimated using a semiquantitative scoring system has a prognostic value. We aimed to estimate the usefulness of scoring categories of IHC Ki67 as a prognostic factor for breast cancer subgroups. We retrospectively identified patients in the Tokai University breast cancer database for whom IHC Ki67 data were available between January 1, 2000 and December 31, 2010. Survival curves were calculated using the Kaplan-Meier method and compared using the log-rank test. Of the 1331 primary breast cancer patients included in the study, In patients with estrogen receptor (ER)-positive and HER2-negative tumors (n = 971), high and intermediate Ki67 scores were associated with poorer relapse-free survival than low Ki67 scores (P Ki67 scores than in patients with high Ki67 scores (hazard ratio, 0.387; 95% confidence interval, 0.233-0.643; P Ki67 score was not significantly associated with PFS in the ER-positive and HER2-positive, ER-negative and HER2-positive, or ER-negative and HER2-negative subgroups. Our data demonstrated that low, intermediate, and high Ki67 scores have a prognostic value in breast cancer patients with ER-positive and HER2-negative tumors. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Strategies for developing Ki67 as a useful biomarker in breast cancer.

    Science.gov (United States)

    Denkert, Carsten; Budczies, Jan; von Minckwitz, Gunter; Wienert, Stephan; Loibl, Sibylle; Klauschen, Frederick

    2015-11-01

    Increased proliferation is a hallmark of malignant tumors. The proliferation marker Ki67 has been investigated as a breast cancer biomarker, but despite 32 years of research the best cutpoints and the best methods for determination are still under debate. This review is based on an overview on the efforts to standardize Ki67 and to optimize its performance that was presented at the St. Gallen oncology conference 2015. The clinical validity of Ki67 as a prognostic marker as well as a predictive marker (in the neoadjuvant setting) has been shown in several meta-analyses. Depending on cohort characteristics, molecular subtype and clinical setting, Ki67 is a prognostic marker, a predictive marker, or both. Many different cutpoints for Ki67 have been reported, but it is has not been possible to determine an evidence-based "optimal" cutpoint. This supports the view that Ki67 is continuous marker, reflecting the continuous variation of the proliferation rate in different tumors. We should probably stop looking for an "optimal" cutpoint for Ki67 because it simply does not exist. It is evident from the results of several ring trials that intermediate levels of Ki67 are particularly difficult for standardization. Due to the low analytical validity in the intermediate range as well as intratumoral heterogeneity, the clinical utility of intermediate Ki67 levels is limited. Clinical decisions should not be based on small differences in the intermediate range and additional molecular tests might be necessary for tumors with intermediate Ki67 levels. For the two groups of tumors with a very low or a very high Ki67 a clinical interpretation could be straightforward. Despite these limitations, the assessment of proliferation is a central parameter for tumor characterization and an important element of the pathological assessment. Copyright © 2015. Published by Elsevier Ltd.

  7. New insight into Ki67 expression at the invasive front in breast cancer.

    Science.gov (United States)

    Gong, Peng; Wang, Yingxin; Liu, Gavin; Zhang, Jing; Wang, Zhongyu

    2013-01-01

    To investigate the distribution of Ki67+ cells in breast cancer in relation to clinical-pathological parameters and prognosis. Ki67 expression status was detected in 1,086 breast cancer specimens using immunohistochemistry staining and examining the relationship between the Ki67+ cells' location. Subsequently, clinical-pathological parameters and prognosis were determined. In total, Ki67 protein expression was found in 781 (71.92%) of the 1,086 breast cancer specimens. Among the 781 Ki67+ cases, 461 were defined as diffuse type and 320 were defined as borderline type. After universal correlation analysis, significant differences were observed in age, histological grade, metastatic nodes, postoperative distant metastasis, and molecular subtype between Ki67+ and Ki67- cases (P = 0.01, 0.001, 0.001, 0.001, and 0.001, respectively). After subgroup analysis, the borderline cases were found to be characterized by a high distant metastasis rate compared to the diffuse cases as well as the Ki67- cases (P = 0.001). No differences were observed between diffuse type or Ki67- cases (P = 0.105). Multivariate analysis showed that age, tumor size, histological grade, lymph node metastasis, molecular subtype, and the Ki67 distribution pattern were observed to be related to postoperative distant metastasis (all PKi67 distribution pattern was detected as an independent prognostic factor (P = 0.001). The distribution pattern of Ki67 may be a new independent prognostic factor for breast cancer.

  8. Impact of intratumoural heterogeneity on the assessment of Ki67 expression in breast cancer.

    Science.gov (United States)

    Aleskandarany, M A; Green, A R; Ashankyty, I; Elmouna, A; Diez-Rodriguez, M; Nolan, C C; Ellis, I O; Rakha, E A

    2016-07-01

    In breast cancer (BC), the prognostic value of Ki67 expression is well-documented. Intratumoural heterogeneity (ITH) of Ki67 expression is amongst the several technical issues behind the lag of its inclusion into BC prognostic work-up. The immunohistochemical (IHC) expression of anti-Ki67 antibody (MIB1 clone) was assessed in four full-face (FF) sections from different primary tumour blocks and their matched axillary nodal (LN) metastases in a series of 55 BC. Assessment was made using the highest expression hot spots (HS), lowest expression (LS), and overall/average expression scores (AS) in each section. Heterogeneity score (Hes), co-efficient of variation, and correlation co-efficient were used to assess the levels of Ki67 ITH. Ki67 HS, LS, and AS scores were highly variable within the same section and between different sections of the primary tumour, with maximal variation observed in the LS (P Ki67 and clinicopathological and molecular variables were similar when using HS or AS, the best correlation between AS and HS was observed in tumours with high Ki67 expression only. Ki67 expression in LN deposits was less heterogeneous than in the primary tumours and was perfectly correlated with the HS Ki67 expression in the primary tumour sections (r = 0.98, P Ki67 expression using HS scoring method on a full-face BC tissue section can represent the primary tumour growth fraction that is likely to metastasise. The association between Ki67 expression pattern in the LN metastasis and the HS in the primary tumour may reflect the temporal heterogeneity through clonal expansion.

  9. Ki-67 marker useful for classification of malignant invasive ductal breast cancer

    Directory of Open Access Journals (Sweden)

    Irmawati Hassan

    2013-12-01

    Full Text Available BACKGROUND Breast cancer is an important health problem in the world. Uncontrolled cell proliferation represents a malignant characteristic of neoplasia such as breast cancer, and can be examined immunohistochemically by measuring the Ki-67 proliferative marker. The objective of this study was to determine the role of Ki-67 for classification of the degree of malignancy in women with invasive ductal breast cancer. METHODS A cross-sectional study was conducted on 20 women with invasive ductal breast cancer. The samples were immuno-histochemically tested for Ki-67 using anti-Ki-67 primary antibody. The Ki-67 proliferative index was determined by enumerating the proportion of Ki-67 positive nuclei among the total number of cells in ten areas observed at 400x magnification, using a 20% cut-off value to distinguish between low and high proliferative indices. Statistical analysis was by means of the chi-square test. RESULTS Seventy five persent of the high grade malignancies had a high Ki-67 proliferative index (>20%, while only 12.5% of the low grade malignancies had a high Ki-67 index (>20%. The difference in grade malignancy was statistically significant (p=0.022, whereas tumor size was not associated with a statistically significant difference in Ki-67 index (p=0.648. CONCLUSION The study showed that invasive ductal breast cancer with high Ki-67 index was significantly associated with high grade of malignacy. The high Ki-67 marker index can be used for classification of the grade of malignancy of invasive ductal breast cancer.

  10. KI and WU Polyomavirus detection in tonsils of immunocompetent patients

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    Massimiliano Bergallo

    2010-06-01

    Full Text Available The Polyomaviruses KI and WU have been identified in 2007 in nasopharyngeal aspirates of patients with acute respiratory tract infections.They have been further isolated in faecal samples, lymphoid tissue, bronchoalveolar lavages and blood, although their pathological associations, molecular epidemiology and tissue tropism are still not widely known.The aim of this study was to determine the presence of KIV and WUV in tonsillar tissue of immunocompetent patients to assess whether the tonsils may represent a site of infection and/or persistence.The presence of Polyomavirus BKV, JCV and SV40 was also evaluated. The presence of Polyomavirus KI,WU, BK, JC and SV40-DNA was evaluated in a prospective study on tonsillar samples obtained from 29 immunocompetent patients (adults and children undergoing tonsillectomy by a commercially available Taqman Real-time quantitative PCR (BKV Q-PCR Alert Kit, Nanogen and a home-made system (for KIV,WUV, SV40, JCV.The amplification conditions were optimized and standardized. KIV-DNA was detected in 2/29 (6.9% tonsil tissue (obtained from an adult and a child, while WU, BK, JC and SV40 were negative in all cases. Our prevalence results are consistent with those reported in the literature on samples from the respiratory tract and lymphoid tissue such as tonsils. Further studies are needed to understand the significance of the presence of KIV in tonsil tissue and assess the possibility that the virus can establish latent and/or persistent infection at this level.

  11. Higher Ki67 expression is associates with unfavorable prognostic factors and shorter survival in breast cancer.

    Science.gov (United States)

    Kilickap, Saadettin; Kaya, Yalcin; Yucel, Birsen; Tuncer, Ersin; Babacan, Nalan Akgul; Elagoz, Sahande

    2014-01-01

    The prognostic value of the Ki67 expression level is yet unclear in breast cancer. The aim of this study was to investigate the association between Ki67 expression levels and prognostic factors such as grade, Her2 and hormone receptor expression status in breast cancers. Clinical and pathological features of the patients with breast cancer were retreived from the hospital records. In this study, 163 patients with breast cancer were analyzed, with a mean age of 53.4±12.2 years. Median Ki67 positivity was 20% and Ki67-high tumors were significantly associated with high grade (pKi67 levels were significantly associated with longer median relapse-free and overall survival compared to those of higher Ki67 levels. High Ki67 expression is associated with ER negativity, Her2 positivity, higher grade and axillary lymph node involvement in breast cancers. The level of Ki67 expression is a prognostic factor predicting relapse-free and overall survival in breast cancer patients.

  12. Intratumoral heterogeneity of Ki67 expression in early breast cancers exceeds variability between individual tumours

    NARCIS (Netherlands)

    Focke, Cornelia M.; Decker, Thomas; van Diest, Paul J.

    2016-01-01

    Aims: Regional differences in proliferative activity are commonly seen within breast cancers, but little is known on the extent of intratumoral heterogeneity of Ki67 expression. Our aim was to study the intratumoral heterogeneity of Ki67 expression in early breast cancers and its association with

  13. Standardizing evaluation of sarcoma proliferation- higher Ki-67 expression in the tumor periphery than the center

    DEFF Research Database (Denmark)

    Fernebro, J; Engellau, J; Persson, A

    2007-01-01

    Soft tissue sarcomas often present as large and histopathologically heterogenous tumors. Proliferation has repeatedly been identified as a prognostic factor and immunostaining for Ki-67 represents the most commonly used proliferation marker. There is, however, a lack of consensus on how to evaluate...... of proliferation in soft tissue sarcomas should be standardized for clinical application of Ki-67 as a prognostic marker....

  14. Interest of the PET with F DOPA in the exploration of endocrine para neoplastic syndromes (E.P.S.): about four cases; Interet de la TEP a la FDOPA dans l'exploration des syndromes paraneoplasiques endocriniens (SPE): a propos de 4 cas

    Energy Technology Data Exchange (ETDEWEB)

    Moreau Triby, C.; Pina, G.; Bournaud, C. [Centre de medecine nucleaire, groupement hospitalier Est, Lyon, (France); Billotey, C. [CERMEP, Lyon, (France); Raverot, G.; Borson Chazot, F. [service d' endocrinologie, groupement hospitalier Est, Lyon, (France)

    2009-05-15

    In front an ectopic secretion of adrenocorticotropic hormone (ACTH or corticotropin) or growth hormone (GH) the existence of an endocrine tumor must be evoked. The topographical diagnosis of these tumors is often difficult. The positron computed tomography with 6-fluoro-({sup 18}F)-L-dihydroxy-phenylalanine (PET-FDOPA) showed recently a good sensitivity in the detection of well differentiated endocrine tumors. We report our experience of the PET-FDOPA in the explorations of para-neoplasic endocrine syndromes. Our experience was relatively disappointing, this examination being a little contributive for our patients. The scintigraphy of receptors with somatostatin with octreoscan keeps all this place in this indication. (N.C.)

  15. An inter-observer Ki67 reproducibility study applying two different assessment methods

    DEFF Research Database (Denmark)

    Laenkholm, Anne-Vibeke; Grabau, Dorthe; Møller Talman, Maj-Lis

    2018-01-01

    INTRODUCTION: In 2011, the St. Gallen Consensus Conference introduced the use of pathology to define the intrinsic breast cancer subtypes by application of immunohistochemical (IHC) surrogate markers ER, PR, HER2 and Ki67 with a specified Ki67 cutoff (>14%) for luminal B-like definition. Reports...... concerning impaired reproducibility of Ki67 estimation and threshold inconsistency led to the initiation of this quality assurance study (2013-2015). The aim of the study was to investigate inter-observer variation for Ki67 estimation in malignant breast tumors by two different quantification methods....... 0.84 (95% CI: 0.80-0.87) by the count method. CONCLUSION: Although the study in general showed a moderate to good inter-observer agreement according to both ICC and Lights Kappa, still major discrepancies were identified in especially the mid-range of observations. Consequently, for now Ki67...

  16. Free radical production induced by methamphetamine in rat striatal synaptosomes.

    Science.gov (United States)

    Pubill, David; Chipana, Carlos; Camins, Antonio; Pallàs, Mercè; Camarasa, Jordi; Escubedo, Elena

    2005-04-01

    The pro-oxidative effect of methamphetamine (METH) in dopamine terminals was studied in rat striatal synaptosomes. Flow cytometry analysis showed increased production of reactive oxygen species (ROS) in METH-treated synaptosomes, without reduction in the density of dopamine transporters. In synaptosomes from dopamine (DA)-depleted animals, METH did not induce ROS production. Reserpine, in vitro, completely inhibited METH-induced ROS production. These results point to endogenous DA as the main source of ROS induced by METH. Antioxidants and inhibitors of neuronal nitric oxide synthase and protein kinase C (PKC) prevented the METH-induced oxidative effect. EGTA and the specific antagonist methyllycaconitine (MLA, 50 microM) prevented METH-induced ROS production, thus implicating calcium and alpha7 nicotinic receptors in such effect. Higher concentrations of MLA (>100 microM) showed nonspecific antioxidant effect. Preincubation of synaptosomes with METH (1 microM) for 30 min reduced [(3)H]DA uptake by 0%. The METH effect was attenuated by MLA and EGTA and potentiated by nicotine, indicating that activation of alpha(7) nicotinic receptors and Ca(2+) entry are necessary and take place before DAT inhibition. From these findings, it can be postulated that, in our model, METH induces DA release from synaptic vesicles to the cytosol. Simultaneously, METH activates alpha(7) nicotinic receptors, probably inducing depolarization and an increase in intrasynaptosomal Ca(2+). This would lead to DAT inhibition and NOS and PKC activation, initiating oxidation of cytosolic DA.

  17. Reduced Striatal Dopamine Transporters in People with Internet Addiction Disorder

    Directory of Open Access Journals (Sweden)

    Haifeng Hou

    2012-01-01

    Full Text Available In recent years, internet addiction disorder (IAD has become more prevalent worldwide and the recognition of its devastating impact on the users and society has rapidly increased. However, the neurobiological mechanism of IAD has not bee fully expressed. The present study was designed to determine if the striatal dopamine transporter (DAT levels measured by T99mc-TRODAT-1 single photon emission computed tomography (SPECT brain scans were altered in individuals with IAD. SPECT brain scans were acquired on 5 male IAD subjects and 9 healthy age-matched controls. The volume (V and weight (W of bilateral corpus striatum as well as the T99mc-TRODAT-1 uptake ratio of corpus striatum/the whole brain (Ra were calculated using mathematical models. It was displayed that DAT expression level of striatum was significantly decreased and the V, W, and Ra were greatly reduced in the individuals with IAD compared to controls. Taken together, these results suggest that IAD may cause serious damages to the brain and the neuroimaging findings further illustrate IAD is associated with dysfunctions in the dopaminergic brain systems. Our findings also support the claim that IAD may share similar neurobiological abnormalities with other addictive disorders.

  18. Frontal and striatal alterations associated with psychopathic traits in adolescents

    Science.gov (United States)

    Yang, Yaling; Narr, Katherine L.; Baker, Laura A.; Joshi, Shantanu H.; Jahanshad, Neda; Raine, Adrian; Thompson, Paul M.

    2016-01-01

    Neuroimaging research has demonstrated a range of structural deficits in adults with psychopathy, but little is known about structural correlates of psychopathic tendencies in adolescents. Here we examined structural magnetic resonance imaging (sMRI) data obtained from 14-year-old adolescents (n=108) using tensor-based morphometry (TBM) to isolate global and localized differences in brain tissue volumes associated with psychopathic traits in this otherwise healthy developmental population. We found that greater levels of psychopathic traits were correlated with increased brain tissue volumes in the left putamen, left ansa peduncularis, right superiomedial prefrontal cortex, left inferior frontal cortex, right orbitofrontal cortex, and right medial temporal regions and reduced brain tissues volumes in the right middle frontal cortex, left superior parietal lobule, and left inferior parietal lobule. Post hoc analyses of parcellated regional volumes also showed putamen enlargements to correlate with increased psychopathic traits. Consistent with earlier studies, findings suggest poor decision-making and emotional dysregulation associated with psychopathy may be due, in part, to structural anomalies in frontal and temporal regions whereas striatal structural variations may contribute to sensation-seeking and reward-driven behavior in psychopathic individuals. Future studies will help clarify how disturbances in brain maturational processes might lead to the developmental trajectory from psychopathic tendencies in adolescents to adult psychopathy. PMID:25676553

  19. Ki67 expression in breast cancer. Correlation with prognostic markers and clinicopathological parameters in Saudi patients.

    Science.gov (United States)

    Elkablawy, Mohamed A; Albasri, Abdulkader M; Mohammed, Rabab A; Hussainy, Akbar S; Nouh, Magdy M; Alhujaily, Ahmed S

    2016-02-01

    To evaluate Ki67 immunoexpression pattern in Saudi breast cancer (BC) patients and investigate any possible predictive or prognostic value for Ki67. This is a retrospective study designed to quantitatively assess the Ki67 proliferative index (PI) in retrieved paraffin blocks of 115 Saudi BC patients diagnosed between January 2005 and March 2015 at the Department of Pathology, King Fahd Hospital, Al Madinah Al Munawarah, Kingdom of Saudi Arabia. The Ki67 PI was correlated with individual and combined immunoprofile data of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) with their clinicopathological parameters.   Ki67 immunoreactivity was highly expressed (greater than 25% of the tumor cells were positive) in 85 (73.9%) patients. The Ki67 PI was significantly associated with poor prognostic clinicopathological parameters including old age (p less than 0.02), high tumor grade (p less than 0.01), lymph node metastasis (p less than 0.001), and Her-2/neu positivity (p less than 0.009). However, the association with ER positivity, PR positivity, tumor size, and lymphovascular invasion were not statistically significant. The Ki67 PI was significantly associated with BC molecular subtypes that were Her2/neu positive (luminal B and HER-2) subtypes compared with the Her2/neu negative (luminal A) subtype (p less than 0.04). The Ki67 PI is significantly higher in Saudi BC patients comparing with the reported literature. Ki67 PI was highest in the HER-2 and luminal-B molecular subtypes. Along with other prognostic indicators, Ki67 PI may be useful in predicting prognosis and management of Saudi BC patients.

  20. Role of Ki67 in predicting resistance to adjuvant tamoxifen in postmenopausal breast cancer patients.

    Science.gov (United States)

    Elzawahry, Heba M; Saber, Magdy M; Mokhtar, Nadia M; Zeeneldin, Ahmed A; Ismail, Yahia M; Alieldin, Nelly H

    2013-12-01

    Breast cancer (BC) is a major health problem in Egypt and worldwide. Its prognosis depends not only on tumor stage but also on tumor biology. To correlate the expression of Ki67 with the clinical outcomes of early hormone-receptor positive postmenopausal BC patients who are receiving tamoxifen. This cohort study included 70 patients. They were followed up for a minimum of 2 years. Ki67 was assessed on paraffin-embedded blocks using immunohistochemistry methods. The median Ki67 value was 22.5% (IQR, 10%-50%). Ki67 was significantly higher in patients with HER2 positive tumors compared to HER2 negative tumors. After a median follow up period of 53 months, 22 patients (31%) developed disease recurrence either loco-regional or distant in 5.7% and 30%, respectively. Recurrent patients had significantly higher tumor stage, nodal stage and Ki67 values compared to non-recurrent cases. The 2-, 3- and 5-year overall survival (OS) and disease-free survival (DFS) rates were 100% & 91%, 98% & 84% and 77% & 59%, respectively. DFS was significantly worse with higher TNM stage, lower ER expression and higher Ki67 values. OS was significantly worse in patients with Ki67 values ≥ 30%. Ki67 ≥ 30% was an independent predictor of recurrence, poor DFS and OS. High Ki67 expression is predictive of poor prognosis and of resistance to adjuvant tamoxifen therapy in postmenopausal BC. We recommend considering Ki67 as one of the risk factors that guide adjuvant treatment decisions. Copyright © 2013. Production and hosting by Elsevier B.V.

  1. Correlation between Ki67 and histological grade in breast cancer patients treated with preoperative chemotherapy.

    Science.gov (United States)

    Petric, Militza; Martinez, Santiago; Acevedo, Francisco; Oddo, David; Artigas, Rocio; Camus, Mauricio; Sanchez, Cesar

    2014-01-01

    Breast cancer (BC) is a heterogeneous disease and cell proliferation markers may help to identify subtypes of clinical interest. We here analyzed the correlation between cell proliferation determined by Ki67 and HG in BC patients undergoing preoperative chemotherapy (PCT). We obtained clinical/pathological data from patients with invasive BC treated at our institution from 1999 until 2012. Expression of estrogen receptor (ER), progesterone receptor (PR), epidermal growth factor receptor type 2 (HER2) and Ki67 were determined by immuno-histochemistry (IHC). Clinicopathological subtypes were defined as: Luminal A, ER and/or PR positive, HER2 negative, HG 1 or 2; Luminal B, ER and/or PR positive, HER2 negative or positive and/or HG 3; triple negative (TN), ER, PR and HER2 negative independent of HG; HER2 positive, ER, PR negative and HER2 positive, independent of HG. By using Ki67, a value of 14% separated Luminal A and B tumors, independently of the histological grade. We analyzed correlations between Ki67 and HG, to define BC subtypes and their predictive value for response to PCT. 1,560 BC patients were treated in the period, 147 receiving PCT (9.5%). Some 57 had sufficient clinicopathological information to be included in the study. Median age was 52 years (26-72), with 87.7% invasive ductal carcinomas (n=50). We performed IHC for Ki67 in 40 core biopsies and 50 surgical biopsies, 37 paired samples with Ki67 before and after chemotherapy being available. There was no significant correlation between Ki67 and HG (p=0.237), both categorizing patients into different subtypes. In most cases Ki67 decreased after PCT (65.8%). Only 3 patients had pathologic complete response (cPR). In our experience we did not find associations between Ki67 and HG. Determination of clinicopathological luminal subtypes differs by using Ki67 or HG.

  2. Ki67 expression in breast cancer. Correlation with prognostic markers and clinicopathological parameters in Saudi patients

    Directory of Open Access Journals (Sweden)

    Mohamed A. Elkablawy

    2016-02-01

    Full Text Available Objectives: To evaluate Ki67 immunoexpression pattern in Saudi breast cancer (BC patients and investigate any possible predictive or prognostic value for Ki67. Methods: This is a retrospective study designed to quantitatively assess the Ki67 proliferative index (PI in retrieved paraffin blocks of 115 Saudi BC patients diagnosed between January 2005 and March 2015 at the Department of Pathology, King Fahd Hospital, Al Madinah Al Munawarah, Kingdom of Saudi Arabia. The Ki67 PI was correlated with individual and combined immunoprofile data of estrogen receptor (ER, progesterone receptor (PR, and human epidermal growth factor receptor 2 (HER2/neu with their clinicopathological parameters. Results: Ki67 immunoreactivity was highly expressed (greater than 25% of the tumor cells were positive in 85 (73.9% patients. The Ki67 PI was significantly associated with poor prognostic clinicopathological parameters including old age (p less than 0.02, high tumor grade (p less than 0.01, lymph node metastasis (p less than 0.001, and Her-2/neu positivity (p less than 0.009. However, the association with ER positivity, PR positivity, tumor size, and lymphovascular invasion were not statistically significant. The Ki67 PI was significantly associated with BC molecular subtypes that were Her2/neu positive (luminal B and HER-2 subtypes compared with the Her2/neu negative (luminal A subtype (p less than 0.04. Conclusion: The Ki67 PI is significantly higher in Saudi BC patients comparing with the reported literature. Ki67 PI was highest in the HER-2 and luminal-B molecular subtypes. Along with other prognostic indicators, Ki67 PI may be useful in predicting prognosis and management of Saudi BC patients.

  3. Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease.

    Directory of Open Access Journals (Sweden)

    Carmela Giampà

    2010-10-01

    Full Text Available Huntington's disease is a devastating neurodegenerative condition for which there is no therapy to slow disease progression. The particular vulnerability of striatal medium spiny neurons to Huntington's pathology is hypothesized to result from transcriptional dysregulation within the cAMP and CREB signaling cascades in these neurons. To test this hypothesis, and a potential therapeutic approach, we investigated whether inhibition of the striatal-specific cyclic nucleotide phosphodiesterase PDE10A would alleviate neurological deficits and brain pathology in a highly utilized model system, the R6/2 mouse.R6/2 mice were treated with the highly selective PDE10A inhibitor TP-10 from 4 weeks of age until euthanasia. TP-10 treatment significantly reduced and delayed the development of the hind paw clasping response during tail suspension, deficits in rotarod performance, and decrease in locomotor activity in an open field. Treatment prolonged time to loss of righting reflex. These effects of PDE10A inhibition on neurological function were reflected in a significant amelioration in brain pathology, including reduction in striatal and cortical cell loss, the formation of striatal neuronal intranuclear inclusions, and the degree of microglial activation that occurs in response to the mutant huntingtin-induced brain damage. Striatal and cortical levels of phosphorylated CREB and BDNF were significantly elevated.Our findings provide experimental support for targeting the cAMP and CREB signaling pathways and more broadly transcriptional dysregulation as a therapeutic approach to Huntington's disease. It is noteworthy that PDE10A inhibition in the R6/2 mice reduces striatal pathology, consistent with the localization of the enzyme in medium spiny neurons, and also cortical pathology and the formation of neuronal nuclear inclusions. These latter findings suggest that striatal pathology may be a primary driver of these secondary pathological events. More

  4. Risk Factors Associated with Discordant Ki-67 Levels between Preoperative Biopsy and Postoperative Surgical Specimens in Breast Cancers

    OpenAIRE

    Kim, Hyung Sun; Park, Seho; Koo, Ja Seung; Kim, Sanghwa; Kim, Jee Ye; Nam, Sanggeun; Park, Hyung Seok; Kim, Seung Il; Park, Byeong-Woo

    2016-01-01

    Purpose The Ki-67 labelling index is significant for the management of breast cancer. However, the concordance of Ki-67 expression between preoperative biopsy and postoperative surgical specimens has not been well evaluated. This study aimed to find the correlation in Ki-67 expression between biopsy and surgical specimens and to determine the clinicopathological risk factors associated with discordant values. Patients and Methods Ki-67 levels were immunohistochemically measured using paired b...

  5. Profile of mRNA Expression of Ki-67 in Breast Cancer Patients Pre- and Post- Chemotherapy

    OpenAIRE

    Andi Asadul Islam, Andi Asadul Islam

    2017-01-01

    Abstract: Background: Proliferation is a distinct hallmarks of cancer. Ki-67 designated as a marker of proliferation in solid tumors. The proliferative activity of tumor demonstrated by expression of Ki-67 in breast cancer has been associated with a poor prognosis. Changes in the relative proportions of Ki-67 can be observed during chemotherapy and may correlated with clinical response in breast cancer. Purpose: Evaluate changes in mRNA expression of proliferation marker Ki-67 in bre...

  6. KONSEP PEMIKIRAN PENDIDIKAN MENURUT PAULO FREIRE DAN KI HAJAR DEWANTORO

    Directory of Open Access Journals (Sweden)

    Ahmad Syaikhudin

    2012-06-01

    Full Text Available Abstract: Criticism and alternative education offered by Paulo Freire is very interesting to be used to analyze the problems of education in Indonesia. It must be admitted that the context behind the controversial issue of those educational thought is different from that of Indonesian, however, it must be very suitable. According to Paulo Freire, there should be no dichotomy between the goals of education and educational ways. The goal, the transformation that frees individual to be a real person, should be manifested in the extent to how education must be implemented. The purpose of exemption cannot be separated with the path that frees. In addition, Freire's educational theory remains significant in terms of its role in which education should bring up not only the understanding of the world, but also the transformation of the world. On the other hands, Indonesian national leaders, Ki Hajar Dewantara also has inherited a very important philosophy in our national education, that is ing ngarso sung tulodo, ing madyo mangun karso, tut wuri handayani which means that the front is setting as a good model, the middle is inspiring and in the back provides support.

  7. Cortico–Amygdala–Striatal Circuits Are Organized as Hierarchical Subsystems through the Primate Amygdala

    Science.gov (United States)

    Cho, Youngsun T.; Ernst, Monique

    2013-01-01

    The prefrontal and insula cortex, amygdala, and striatum are key regions for emotional processing, yet the amygdala's role as an interface between the cortex and striatum is not well understood. In the nonhuman primate (Macaque fascicularis), we analyzed a collection of bidirectional tracer injections in the amygdala to understand how cortical inputs and striatal outputs are organized to form integrated cortico–amygdala–striatal circuits. Overall, diverse prefrontal and insular cortical regions projected to the basal and accessory basal nuclei of the amygdala. In turn, these amygdala regions projected to widespread striatal domains extending well beyond the classic ventral striatum. Analysis of the cases in aggregate revealed a topographic colocalization of cortical inputs and striatal outputs in the amygdala that was additionally distinguished by cortical cytoarchitecture. Specifically, the degree of cortical laminar differentiation of the cortical inputs predicted amygdalostriatal targets, and distinguished three main cortico–amygdala–striatal circuits. These three circuits were categorized as “primitive,” “intermediate,” and “developed,” respectively, to emphasize the relative phylogenetic and ontogenetic features of the cortical inputs. Within the amygdala, these circuits appeared arranged in a pyramidal-like fashion, with the primitive circuit found in all examined subregions, and subsequent circuits hierarchically layered in discrete amygdala subregions. This arrangement suggests a stepwise integration of the functions of these circuits across amygdala subregions, providing a potential mechanism through which internal emotional states are managed with external social and sensory information toward emotionally informed complex behaviors. PMID:23986238

  8. Altered resting state cortico-striatal connectivity in mild to moderate stage Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Youngbin Kwak

    2010-09-01

    Full Text Available Parkinson’s disease (PD is a progressive neurodegenerative disorder that is characterized by dopamine depletion in the striatum. One consistent pathophysiological hallmark of PD is an increase in spontaneous oscillatory activity in the basal ganglia thalamocortical networks. We evaluated these effects using resting state functional connectivity MRI (fcMRI in mild to moderate stage Parkinson’s patients on and off L-DOPA and age-matched controls using six different striatal seed regions. We observed an overall increase in the strength of cortico-striatal functional connectivity in PD patients off L-DOPA compared to controls. This enhanced connectivity was down-regulated by L-DOPA as shown by an overall decrease in connectivity strength, particularly within motor cortical regions. We also performed a frequency content analysis of the BOLD signal time course extracted from the six striatal seed regions. PD off L-DOPA exhibited increased power in the frequency band 0.02 – 0.05 Hz compared to controls and to PD on L-DOPA. The L-DOPA associated decrease in the power of this frequency range modulated the L-DOPA associated decrease in connectivity strength between striatal seeds and the thalamus. In addition, the L-DOPA associated decrease in power in this frequency band also correlated with the L-DOPA associated improvement in cognitive performance. Our results demonstrate that PD and L-DOPA modulate striatal resting state BOLD signal oscillations and corticostriatal network coherence.

  9. Altered resting-state functional connectivity of striatal-thalamic circuit in bipolar disorder.

    Directory of Open Access Journals (Sweden)

    Shin Teng

    Full Text Available Bipolar disorder is characterized by internally affective fluctuations. The abnormality of inherently mental state can be assessed using resting-state fMRI data without producing task-induced biases. In this study, we hypothesized that the resting-state connectivity related to the frontal, striatal, and thalamic regions, which were associated with mood regulations and cognitive functions, can be altered for bipolar disorder. We used the Pearson's correlation coefficients to estimate functional connectivity followed by the hierarchical modular analysis to categorize the resting-state functional regions of interest (ROIs. The selected functional connectivities associated with the striatal-thalamic circuit and default mode network (DMN were compared between bipolar patients and healthy controls. Significantly decreased connectivity in the striatal-thalamic circuit and between the striatal regions and the middle and posterior cingulate cortex was observed in the bipolar patients. We also observed that the bipolar patients exhibited significantly increased connectivity between the thalamic regions and the parahippocampus. No significant changes of connectivity related to the frontal regions in the DMN were observed. The changed resting-state connectivity related to the striatal-thalamic circuit might be an inherent basis for the altered emotional and cognitive processing in the bipolar patients.

  10. Striatal lesions produce distinctive impairments in reaction time performance in two different operant chambers.

    Science.gov (United States)

    Brasted, P J; Döbrössy, M D; Robbins, T W; Dunnett, S B

    1998-08-01

    The dorsal striatum plays a crucial role in mediating voluntary movement. Excitotoxic striatal lesions in rats have previously been shown to impair the initiation but not the execution of movement in a choice reaction time task in an automated lateralised nose-poke apparatus (the "nine-hole box"). Conversely, when a conceptually similar reaction time task has been applied in a conventional operant chamber (or "Skinner box"), striatal lesions have been seen to impair the execution rather than the initiation of the lateralised movement. The present study was undertaken to compare directly these two results by training the same group of rats to perform a choice reaction time task in the two chambers and then comparing the effects of a unilateral excitotoxic striatal lesion in both chambers in parallel. Particular attention was paid to adopting similar parameters and contingencies in the control of the task in the two test chambers. After striatal lesions, the rats showed predominantly contralateral impairments in both tasks. However, they showed a deficit in reaction time in the nine-hole box but an apparent deficit in response execution in the Skinner box. This finding confirms the previous studies and indicates that differences in outcome are not simply attributable to procedural differences in the lesions, training conditions or tasks parameters. Rather, the pattern of reaction time deficit after striatal lesions depends critically on the apparatus used and the precise response requirements for each task.

  11. High Ki67/BCL2 index is associated with worse outcome in early stage breast cancer.

    Science.gov (United States)

    Min, Kyueng-Whan; Kim, Dong-Hoon; Do, Sung-Im; Pyo, Jung-Soo; Chae, Seoung Wan; Sohn, Jin Hee; Kim, Kyungeun; Lee, Hyun Joo; Kim, Dong Hyun; Oh, Sukjoong; Choi, Seon Hyeong; Park, Yong Lai; Park, Chan Heun; Kwon, Mi Jung; Moon, Kyoung Min

    2016-12-01

    Breast cancers are heterogeneous, making it essential to recognise several biomarkers for cancer outcome predictions. Ki67 proliferation index and B cell lymphoma 2 (BCL2) proteins are widely used as prognostic indicators in many types of malignancies. While Ki67 is a marker of normal or tumour cell proliferation, BCL2 plays a central role in antiproliferative activities. A combination of these two biomarkers with contrary purposes can provide enhanced prognostic accuracy than an analysis using a single biomarker. We evaluated Ki67 and BCL2 expression with 203 cases of breast cancer. The relative expression of each biomarker named as Ki67/BCL2 index was divided into two groups (low vs high) with the use of area under receiver operating characteristic curves. There were significant correlations between Ki67/BCL2 index and clinicopathological findings such as age, tumour stage, size and necrosis, histological grade, extensive intraductal component, lymphatic and vascular invasion, oestrogen receptor, progesterone receptor, human epithelial growth factor receptor 2 and p53 expression (all pKi67/BCL2 index correlated with shorter disease-free survival and overall survival in patients with early stage invasive ductal carcinoma (all pKi67/BCL2 index should be considered as a prognostic predictor in patients with early stage invasive ductal carcinoma. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  12. Phosphohistone H3 outperforms Ki67 as a marker of outcome for breast cancer patients.

    Science.gov (United States)

    Gerring, Zac; Pearson, John F; Morrin, Helen R; Robinson, Bridget A; Harris, Gavin C; Walker, Logan C

    2015-10-01

    The proliferation marker Ki67 has been extensively investigated as a prognostic factor in breast cancer, but has not gained widespread clinical acceptance. Phosphohistone H3 is a new immunohistochemical marker for quantifying mitoses; however, there is limited information on its prognostic value in breast cancer. In this study, we performed a head-to-head comparison of Ki67 and phosphohistone H3 to establish the marker with the greatest prognostic value. Tissue microarrays from 108 breast cancer patients were immunohistochemically stained for Ki67 and phosphohistone H3. Our results showed that phosphohistone H3 had a greater prognostic value than Ki67 in a multivariable model that adjusted for traditional prognostic variables in breast cancer. Phosphohistone H3 staining was a stronger predictor of survival at 5 years after diagnosis [hazard ratio (HR) 4.35, P Ki67 (HR 2.44, P = 0.004), and better separated the risk of death in patients aged >45 years. Importantly, phosphohistone H3 consistently showed strong unequivocal staining, in contrast to the variable staining intensities associated with Ki67. Our study suggests that phosphohistone H3 staining is a stronger and more robust prognostic indicator than Ki67 staining in breast cancer patients, and has the potential for use in routine diagnostic laboratories. © 2015 John Wiley & Sons Ltd.

  13. Radiomic features predict Ki-67 expression level and survival in lower grade gliomas.

    Science.gov (United States)

    Li, Yiming; Qian, Zenghui; Xu, Kaibin; Wang, Kai; Fan, Xing; Li, Shaowu; Liu, Xing; Wang, Yinyan; Jiang, Tao

    2017-11-01

    To investigate the radiomic features associated with Ki-67 expression in lower grade gliomas and assess the prognostic values of these features. Patients with lower grade gliomas (n = 117) were randomly assigned into the training (n = 78) and validation (n = 39) sets. A total of 431 radiological features were extracted from each patient. Differential radiological features between the low and high Ki-67 expression groups were screened by significance analysis of microarrays. Then, generalized linear analysis was performed to select features that could predict the Ki-67 expression level. Predictive efficiencies were further evaluated in the validation set. Cox regression analysis was performed to investigate the prognostic values of Ki-67 expression level and Ki-67-related radiological features. A group of nine radiological features were screened for prediction of Ki-67 expression status; these achieved accuracies of 83.3% and 88.6% (areas under the curves, 0.91 and 0.93) in the training and validation sets, respectively. Of these features, only spherical disproportion (SD) was found to be a prognostic factor. Patients in the high SD group exhibited worse outcomes in the whole cohort (overall survival, p level and SD were independent prognostic factors in the multivariate Cox regression analysis. This study identified a radiomic signature for prediction of Ki-67 expression level as well as a prognostic radiological feature in patients with lower grade gliomas.

  14. Prognostic Value of Ki-67 Labeling Index and Postoperative Radiotherapy in WHO Grade II Meningioma.

    Science.gov (United States)

    Choi, Yunseon; Lim, Do Hoon; Yu, Jeong Il; Jo, Kyungil; Nam, Do-Hyun; Seol, Ho Jun; Lee, Jung-Il; Kong, Doo-Sik; Suh, Yeon-Lim; Nam, Heerim

    2018-01-01

    This study was performed to determine the clinical significance of the Ki-67 labeling index (LI) for local control (LC) in patients with World Health Organization (WHO) grade II meningioma. We also tried to discern the effect of postoperative radiotherapy (PORT) on LC depending upon the Ki-67 LI value. The medical records and values of Ki-67 LIs were retrospectively reviewed for 50 patients who underwent surgical resection of intracranial WHO grade II meningiomas at Samsung Medical Center from May 2001 to December 2012. Forty-three patients (86%) were treated with immediate PORT. The median total radiation dose was 60 Gy (range, 54 to 60 Gy). The median follow-up was 47.4 months. The mean Ki-67 LI was 13% (range, 1% to 47%). Twelve patients (24.0%) showed local failure, and 8 patients (16.0%) experienced local failure even after PORT. The mean Ki-67 LI was 15% in patients with local failure (n=12) and 12% in patients without local failure (n=38). The 3-year actuarial LC was 80.5%. The 3-year overall survival was 89.5%. Ki-67 LI>13% and PORT were significant prognostic factors for LC (P=0.015 and 0.009, respectively). In patients with Ki-67 LI>13% (n=17), PORT (n=14) improved LC (P13%, PORT should be recommended to improve LC.

  15. A study of Ki-67 expression and its clinicopathological determinants in nondysplastic oral leukoplakia

    Directory of Open Access Journals (Sweden)

    Krishnendu Mondal

    2016-01-01

    Full Text Available Context: Oral cancer is the third most prevalent malignancy in India. Leukoplakia is its most common precursor lesion. Aims: This study aimed at evaluation of the Ki-67 expression and thereby detection of the dysplastic potential in histopathologically nondysplastic oral leukoplakia (OL. Secondarily, another purpose was to correlate various clinicopathological factors with the labeling indices (LIs of Ki-67 in those cases as well. Settings and Design: In total, 97 OL cases were examined. Relevant clinical and demographic information was retrieved from the pro forma, prefilled by the patients themselves during their first visit. Subjects and Methods: Ki-67 immunohistochemical staining was performed on paraffin-embedded tissue samples. Its LIs were calculated and correlated with different clinicopathological parameters using statistical software SPSS version 16.0. Results: 58.8% (57 cases lesions exhibited a Ki-67 positivity of ≤5%, and 25.8% (25 cases lesions exhibited it in the range of 6%–25%. Only 15 (15.4% patches were stained positively between 26% and 60%. Patients' age beyond 50 years, nonhomogeneous leukoplakia, and tobacco addiction were the significant risk factors for high Ki-67 scores (P < 0.05. Conclusions: Ki-67 is an essential immunohistochemical marker for epithelial dysplasia in OL, especially when the conventional histopathology fails to appreciate the same. In this purpose, Ki-67 labeling on a routine basis delivers the most convenient results for patients aged above 50 years, and/or addicted to tobacco products, and/or suffering from nonhomogeneous patches.

  16. Application of DWIBS in malignant lymphoma: correlation between ADC values and Ki-67 index.

    Science.gov (United States)

    Sun, Mengtian; Cheng, Jingliang; Zhang, Yong; Bai, Jie; Wang, Feifei; Meng, Yun; Li, Zhenqian

    2018-04-01

    We investigated the correlation between the apparent diffusion coefficient (ADC) and Ki-67 index using diffusion-weighted whole-body imaging with background body signal suppression (DWIBS), and their utility in evaluating malignant lymphoma cell proliferation. Seventy-four patients with malignant lymphoma underwent DWIBS within 1 week before pathological confirmation. The ADC value was measured at the site of the pathological examination, and specimens were also stained with Ki-67. The ADC values and Ki-67 indices in aggressive non-Hodgkin's lymphoma (NHL), indolent NHL, and Hodgkin's lymphoma (HL) were compared using Spearman's rank correlation coefficient and the Kruskal-Wallis test. The Ki-67 indices and ADC values were inversely correlated (r = -0.289, p = 0.0125); the differences in the Ki-67 index between aggressive NHL, indolent NHL, and HL were significant (p values were significantly different between the types of lymphoma (p = 0.013); the Nemenyi test showed a significant difference only between aggressive NHL and HL. The Ki-67 indices and ADC values are inversely correlated in patients with lymphoma, combining DWIBS and ADC values can evaluate the proliferation level of malignant lymphoma cells noninvasively. • By using DWIBS, malignant lymphoma cell proliferation can be assessed noninvasively. • The ADC value and Ki-67 index are significantly and inversely correlated. • The ADC values were lower in aggressive NHL than in HL. • The ADC values of aggressive and indolent NHL were not significantly different.

  17. Reliability of the Ki67-Labelling Index in Core Needle Biopsies of Luminal Breast Cancers is Unaffected by Biopsy Volume

    NARCIS (Netherlands)

    Focke, C. M.|info:eu-repo/dai/nl/413647927; Decker, T.; van Diest, P. J.|info:eu-repo/dai/nl/075281775

    Background: Assessing prognostic and predictive factors like the Ki67 labelling index (Ki67-LI) in breast cancer core needle biopsies (CNB) may be hampered by undersampling. Our aim was to arrive at a representative assessment of Ki67-LI in CNB of luminal breast cancers by defining optimal cutoffs

  18. Prognostic value of automated KI67 scoring in breast cancer: A centralised evaluation of 8088 patients from 10 study groups

    NARCIS (Netherlands)

    Abubakar, M. (Mustapha); N. Orr (Nick); F. Daley (Frances); P. Coulson (Penny); H.R. Ali (Hamid Raza); Blows, F. (Fiona); J. Benítez (Javier); R.L. Milne (Roger); H. Brenner (Hermann); C. Stegmaier (Christa); A. Mannermaa (Arto); J. Chang-Claude (Jenny); Rudolph, A. (Anja); P. Sinn (Peter); F.J. Couch (Fergus); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); C.M. Seynaeve (Caroline); J.D. Figueroa (Jonine); M.E. Sherman (Mark); J. Lissowska (Jolanta); S.M. Hewitt (Stephen); D. Eccles (Diana); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); J.W.M. Martens (John); C.H.M. van Deurzen (Carolien); Investigators, C.F. (kConFab); M.K. Bolla (Manjeet K.); Wang, Q. (Qin); M. Jones (Michael); M. Schoemaker (Minouk); J. Wesseling (Jelle); F.E. van Leeuwen (F.); L.J. van 't Veer (Laura); D.F. Easton (Douglas); A.J. Swerdlow (Anthony ); M. Dowsett (Mitch); P.D.P. Pharoah (Paul); M.K. Schmidt (Marjanka); M. García-Closas (Montserrat)

    2016-01-01

    textabstractBackground: The value of KI67 in breast cancer prognostication has been questioned due to concerns on the analytical validity of visual KI67 assessment and methodological limitations of published studies. Here, we investigate the prognostic value of automated KI67 scoring in a large,

  19. VizieR Online Data Catalog: KiDS-ESO-DR3 multi-band source catalog (de Jong+, 2017)

    NARCIS (Netherlands)

    de Jong, J. T. A.; Verdoes Kleijn, G. A.; Erben, T.; Hildebrandt, H.; Kuijken, K.; Sikkema, G.; Brescia, M.; Bilicki, M.; Napolitano, N. R.; Amaro, V.; Begeman, K. G.; Boxhoorn, D. R.; Buddelmeijer, H.; Cavuoti, S.; Getman, F.; Grado, A.; Helmich, E.; Huang, Z.; Irisarri, N.; La Barbera, F.; Longo, G.; McFarland, J. P.; Nakajima, R.; Paolillo, M.; Puddu, E.; Radovich, M.; Rifatto, A.; Tortora, C; Valentijn, E. A.; Vellucci, C.; Vriend, W-J.; Amon, A.; Blake, C.; Choi, A.; Fenech Conti, I.; Herbonnet, R.; Heymans, C.; Hoekstra, H.; Klaes, D.; Merten, J.; Miller, L.; Schneider, P.; Viola, M.

    2017-01-01

    KiDS-ESO-DR3 contains a multi-band source catalogue encompassing all publicly released tiles, a total of 440 survey tiles including the coadded images, weight maps, masks and source lists of 292 survey tiles of KiDS-ESO-DR3, adding to the 148 tiles released previously (50 in KiDS-ESO-DR1 and 98 in

  20. An interobserver reproducibility analysis of Ki67 visual assessment in breast cancer.

    Directory of Open Access Journals (Sweden)

    Ruohong Shui

    Full Text Available Ki67 labeling index (LI is used as a predictive marker and is associated with prognosis in breast cancer. However, standardised methodologies for measurement are lacking which has limited its application in clinical practice. In this study, we evaluated the interobserver concordance of visual assessment of Ki67 LI in breast cancer.Ki67-immunostained slides of 160 cases of primary invasive breast cancer were visual assessed by five breast pathologists with two different methods to choose the scoring fields: (1 hot-spot score, (2 average score. Proportions of positive invasive tumor cells at 10 % intervals were scored. The intra-class correlation coefficient (ICC was used to assess the interobserver reproducibility.(1 A perfect concordance of Ki67 LI was demonstrated according to both score methods (P30% Ki-67 LI. The concordance was relatively low in intermediate Ki67 LI group compared with low and high Ki67 LI groups. (3 All cases were classified into three groups by paired-difference (d between means of hot-spot score and average score (d<5, 5≤d<10, d≥10. The consistency was observed to decrease with increasing paired-difference according to both methods.Visual assessment of Ki67 LI at 10 % intervals is a candidate for a standard method in breast cancer clinical practice. Average score and hot-spot score of visual assessment both demonstrated a perfect concordance, and an overall average assessment across the whole section including hot spots may be a better method. Interobserver concordance of intermediate Ki67 LI in which most cutoffs are located for making clinical decisions was relatively low.

  1. Identifying tumor in pancreatic neuroendocrine neoplasms from Ki67 images using transfer learning.

    Science.gov (United States)

    Niazi, Muhammad Khalid Khan; Tavolara, Thomas Erol; Arole, Vidya; Hartman, Douglas J; Pantanowitz, Liron; Gurcan, Metin N

    2018-01-01

    The World Health Organization (WHO) has clear guidelines regarding the use of Ki67 index in defining the proliferative rate and assigning grade for pancreatic neuroendocrine tumor (NET). WHO mandates the quantification of Ki67 index by counting at least 500 positive tumor cells in a hotspot. Unfortunately, Ki67 antibody may stain both tumor and non-tumor cells as positive depending on the phase of the cell cycle. Likewise, the counter stain labels both tumor and non-tumor as negative. This non-specific nature of Ki67 stain and counter stain therefore hinders the exact quantification of Ki67 index. To address this problem, we present a deep learning method to automatically differentiate between NET and non-tumor regions based on images of Ki67 stained biopsies. Transfer learning was employed to recognize and apply relevant knowledge from previous learning experiences to differentiate between tumor and non-tumor regions. Transfer learning exploits a rich set of features previously used to successfully categorize non-pathology data into 1,000 classes. The method was trained and validated on a set of whole-slide images including 33 NETs subject to Ki67 immunohistochemical staining using a leave-one-out cross-validation. When applied to 30 high power fields (HPF) and assessed against a gold standard (evaluation by two expert pathologists), the method resulted in a high sensitivity of 97.8% and specificity of 88.8%. The deep learning method developed has the potential to reduce pathologists' workload by directly identifying tumor boundaries on images of Ki67 stained slides. Moreover, it has the potential to replace sophisticated and expensive imaging methods which are recently developed for identification of tumor boundaries in images of Ki67-stained NETs.

  2. Sjenički sir kao nematerijalno kulturno nasleđe: Antropološki pristup problemu

    Directory of Open Access Journals (Sweden)

    Ljiljana Gavrilović

    2017-01-01

    Full Text Available U radu se raspravlja o tradicionalnim tehnologijama kao nematerijalnom kulturnom nasleđu i iznosi se etnografija koja je rezultat rada na projektu pripreme dokumentacije za predlog upisa tehnologije proizvodnje sjeničkog sira u nacinalnu Listu nematerijalnih kulturnih dobara. U okviru toga razmotrena je tradicionalna tehnologija proizvodnje sjeničkog sira, kao i nastojanja lokalnih aktera da tu tehnologiju zaštite i sačuvaju. Zatim sledi analiza građe prikupljene u razgovorima s ispitanicima, pripadnicima lokalne zajednice – od samih proizvođača, pa do pojedinaca koji zauzimaju različite upravljačke pozicije. U ovom segmentu fokus je stavljen na svest i spoznaju koju sami lokalni akteri imaju o značaju proizvoda koji nastoje da zaštite i, kako oni sami kažu, „brendiraju“, ali pre svega na probleme sa kojima se suočavaju u tom procesu. Na kraju, analizirane su potencijalne mogućnosti realizacije projekta izrade aplikacije na osnovu koje bi sjenički sir bio upisan na Nacionalnu listu nematerijalnog kulturnog nasleđa. U tom segmentu, fokus je stavljen na delovanje menadžmenta lokalne zajednice, kao i mogućnosti profesionalnih antropologa da pomognu u realizaciji tog procesa.

  3. Decreased spontaneous eye blink rates in chronic cannabis users: evidence for striatal cannabinoid-dopamine interactions.

    Directory of Open Access Journals (Sweden)

    Mikael A Kowal

    Full Text Available Chronic cannabis use has been shown to block long-term depression of GABA-glutamate synapses in the striatum, which is likely to reduce the extent to which endogenous cannabinoids modulate GABA- and glutamate-related neuronal activity. The current study aimed at investigating the effect of this process on striatal dopamine levels by studying the spontaneous eye blink rate (EBR, a clinical marker of dopamine level in the striatum. 25 adult regular cannabis users and 25 non-user controls matched for age, gender, race, and IQ were compared. Results show a significant reduction in EBR in chronic users as compared to non-users, suggesting an indirect detrimental effect of chronic cannabis use on striatal dopaminergic functioning. Additionally, EBR correlated negatively with years of cannabis exposure, monthly peak cannabis consumption, and lifetime cannabis consumption, pointing to a relationship between the degree of impairment of striatal dopaminergic transmission and cannabis consumption history.

  4. Immunohistochemical Ki-67/KL1 double stains increase accuracy of Ki-67 indices in breast cancer and simplify automated image analysis

    DEFF Research Database (Denmark)

    Nielsen, Patricia S; Bentzer, Nina K; Jensen, Vibeke

    2014-01-01

    observers and automated image analysis. RESULTS: Indices were predominantly higher for single stains than double stains (P≤0.002), yet the difference between observers was statistically significant (Pmanual and automated indices ranged from 0...... by digital image analysis. This study aims to detect the difference in accuracy and precision between manual indices of single and double stains, to develop an automated quantification of double stains, and to explore the relation between automated indices and tumor characteristics when quantified...... in different regions: hot spots, global tumor areas, and invasive fronts. MATERIALS AND METHODS: Paraffin-embedded, formalin-fixed tissue from 100 consecutive patients with invasive breast cancer was immunohistochemically stained for Ki-67 and Ki-67/KL1. Ki-67 was manually scored in different regions by 2...

  5. Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of SKF38393.

    NARCIS (Netherlands)

    Saigusa, T.; Aono, Y.; Sekino, R.; Uchida, T.; Takada, K.; Oi, Y.; Koshikawa, N.; Cools, A.R.

    2009-01-01

    Like dexamphetamine, SKF38393 induces an increase in striatal dopamine efflux which is insensitive for tetrodotoxin, Ca(2+) independent and prevented by a dopamine transporter inhibitor. The dexamphetamine-induced striatal dopamine efflux originates from both the reserpine-sensitive vesicular

  6. Striatal dopamine in Parkinson disease: A meta-analysis of imaging studies.

    Science.gov (United States)

    Kaasinen, Valtteri; Vahlberg, Tero

    2017-12-01

    A meta-analysis of 142 positron emission tomography and single photon emission computed tomography studies that have investigated striatal presynaptic dopamine function in Parkinson disease (PD) was performed. Subregional estimates of striatal dopamine metabolism are presented. The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter and vesicular monoamine transporter 2 defects, suggesting upregulation of AADC function in PD. The correlation between disease severity and dopamine loss appears linear, but the majority of longitudinal studies point to a negative exponential progression pattern of dopamine loss in PD. Ann Neurol 2017;82:873-882. © 2017 American Neurological Association.

  7. Proteostasis in striatal cells and selective neurodegeneration in Huntington’s disease

    Science.gov (United States)

    Margulis, Julia; Finkbeiner, Steven

    2014-01-01

    Selective neuronal loss is a hallmark of neurodegenerative diseases, including Huntington’s disease (HD). Although mutant huntingtin, the protein responsible for HD, is expressed ubiquitously, a subpopulation of neurons in the striatum is the first to succumb. In this review, we examine evidence that protein quality control pathways, including the ubiquitin proteasome system, autophagy, and chaperones, are significantly altered in striatal neurons. These alterations may increase the susceptibility of striatal neurons to mutant huntingtin-mediated toxicity. This novel view of HD pathogenesis has profound therapeutic implications: protein homeostasis pathways in the striatum may be valuable targets for treating HD and other misfolded protein disorders. PMID:25147502

  8. Beebitoidu müüki hakkab korraldama range koodeks / Eha Laanepere

    Index Scriptorium Estoniae

    Laanepere, Eha, 1963-

    1995-01-01

    Rinnapiima asendajate reklaami ja müüki reguleerivast rahvusvahelisest koodeksist International Baby Food Action Network (IBFAN), mis on vastu võetud 1982. aastal, selle seadustiku vajalikkusest Eestis

  9. Expression of Oestrogen and progesterone receptors, Ki-67,p53 and ...

    African Journals Online (AJOL)

    Expression of Oestrogen and progesterone receptors, Ki-67,p53 and bcl-2 proteins, cathepsin D, urokinase plasminogen activator and urokinase plasminogen activator-receptors in carcinomas of the female breast in an African population.

  10. Heat enhancement of radiation resistivity of evaporated CsI, KI and KBr photocathodes

    CERN Document Server

    Tremsin, A S

    2000-01-01

    The photoemissive stability of as-deposited and heat-treated CsI, KI and KBr evaporated thin films under UV radiation is examined in this paper. After the deposition, some photocathodes were annealed for several hours at 90 deg. C in vacuum and their performance was then compared to the performance of non-heated samples. We observed that the post-evaporation thermal treatment not only increases the photoyield of CsI and KI photocathodes in the spectral range of 115-190 nm, but also reduces CsI, KI and KBr photocurrent degradation that occurs after UV irradiation. KBr evaporated layers appeared to be more radiation-resistant than CsI and KI layers. Post-deposition heat treatment did not result in any significant variation of KBr UV sensitivity.

  11. Striatal lesions in delusional parasitosis revealed by magnetic resonance imaging.

    Science.gov (United States)

    Huber, Markus; Karner, Martin; Kirchler, Erwin; Lepping, Peter; Freudenmann, Roland W

    2008-12-12

    Delusional parasitosis (DP) is a syndrome characterized by the firm conviction that small living beings infest the skin. The etiology can be primary and secondary. Structural brain abnormalities in DP have only been reported in case reports often subcortical vascular encephalopathy and right-hemisphere strokes in the temporo-parietal cortex. Systematic brain imaging studies are lacking. We aimed to identify a brain region with structural lesions in patients with DP in order to better understand the pathophysiology of DP. Nine consecutive patients with DP in a psychiatric outpatient department were assessed clinically and by means of cranial magnetic resonance imaging (MRI). Five of the nine cases were diagnosed as having DP as psychotic disorders due to a general medical condition while three had DP arising from pre-existing psychiatric illness and one suffered from a delusional disorder, somatic type (primary form). Four of the five DP cases secondary to a general medical condition (one case could not be analyzed) had striatal lesions predominantly in the putamen. Thalamic or cortical lesions were found in one case, respectively. In the primary DP case and all cases secondary to another psychiatric disorder basal ganglia and subcortical gray matter lesions were absent. In all medical (secondary) DP cases subcortical white matter lesions were found mainly in the centrum semiovale. Three of the five medical DP cases showed severe generalized brain atrophy which was absent in the primary DP case and in the cases secondary to other psychiatric disorders. We present the findings of the first structural MRI study in DP. Our results suggest a possible relevance of structural lesions in the striatum, predominantly the putamen, in the medical (secondary) DP-subgroup. Our findings are in line with other studies demonstrating that the putamen, in addition to its role in motor regulation, represents a brain area that mediates visuo-tactile perception. Disturbed functioning of

  12. An assessment of ECC ozonesondes operated using 1% and 0.5% KI cathode solutions at Lauder, New Zealand

    Science.gov (United States)

    Boyd, Ian S.; Bodeker, Greg E.; Connor, Brian J.; Swart, Daan P. J.; Brinksma, Ellen J.

    The effects of reducing the concentration of the potassium iodide (KI) cathode electrolyte from 1% to 0.5% in electrochemical concentration cell (ECC) ozonesondes flown at Lauder, New Zealand (45° S, 170° E) have been investigated. Four studies were made to assess these effects: 1% and 0.5% KI ozonesonde performance was compared directly in three dual flights, one year of 1% KI and one year of 0.5% KI ozonesonde profiles were compared with near-simultaneous lidar profiles, integrated ozonesonde profiles were compared with Dobson spectrophotometer measurements over the same period, and ascent and descent profiles were compared for both KI concentrations. Ozonesondes flown with a 1% KI solution showed positive differences of 3% to 8% in the ozone profile and ∼5% in the ozone column compared with the 0.5% KI ozonesondes, which also showed better agreement in profiles and ozone column compared with the lidar and Dobson spectrophotometer measurements respectively.

  13. Expression and significance of VEGF, CD34, Ki-67 and p21 in pterygium

    Directory of Open Access Journals (Sweden)

    Li-Bo Wang

    2014-07-01

    Full Text Available AIM: To investigate the expression of VEGF, CD34, Ki-67 and p21 in pterygium as well as the correlation between their expression and clinical pathological characteristics; explore its pathogenesis. METHODS: Immunohistochemical S-P staining method was adopted in detecting the expression of VEGF, CD34, Ki-67 and p21 in 62 cases of pterygia and 20 cases of normal conjunctival tissues. Relationship between these markers and clinical pathological characteristics was analyzed. RESULTS:(1The positive expression of VEGF, CD34, Ki-67 and p21 in 62 cases of pterygia was 74.2%(46/62, 77.4%(48/62, 66.1%(41/62and 40.3%(25/62respectively. The differences were statistically significant compared with normal conjunctival tissues(PPP>0.05; the expression of Ki-67 was correlated with clinical stages(PP>0.05; the expression of p21 was correlated with clinical stages and pterygium characters(PP>0.05.(3Spearman correlation showed that there was a positive correlation between VEGF and Ki-67(r=0.279, Pr=0.299, Pr=-0.267, PP>0.05.CONCLUSION:(1Overexpression of VEGF, Ki-67, CD34 and low expression of p21 suggest that these markers are concerned with the development and progression of pterygium.(2Expression of VEGF and CD34 increases along with the increase of clinical types and stages, expression of Ki-67 increases along with the increase of clinical stages, and expression of p21 decreases along with the improvement of clinical types or stages; they suggest that these markers may play important roles in the development and recurrence of pterygium.(3There is positive correlation between VEGF and Ki-67, VEGF and CD34 as well as negative correlation between VEGF and p21. They suggest that there may be synergistic action between two factors during the development and progression of pterygium.

  14. Decrease in specific micronutrient intake in colorectal cancer patients with tumors presenting Ki-ras mutation

    OpenAIRE

    JORDI SALAS; NURIA LASO; SERGI MAS; M. JOSE LAFUENTE; XAVIER CASTERAD; MANUEL TRIAS; ANTONIO BALLESTA; RAFAEL MOLINA; CARLOS ASCASO; SHICHUN ZHENG; JOHN K. WIENCKE; AMALIA LAFUENTE

    2004-01-01

    Decrease in specific micronutrient intake in colorectal cancer patients with tumors presenting Ki-ras mutation BACKGROUND: The diversity of the Mediterranean diet and the heterogeneity of acquired genetic alterations in colorectal cancer (CRC) led us to examine the possible association between dietary factors and mutations, such as Ki-ras mutations, in genes implicated in the pathogenesis of these neoplasms. PATIENTS AND METHODS: The study was based on 246 cases and 296 controls. For th...

  15. Transformation in Dang-ki Healing: The Embodied Self and Perceived Legitimacy.

    Science.gov (United States)

    Lee, Boon-Ooi

    2016-09-01

    Since spirit possession in mediumship and shamanism resembles psychotic symptoms, early researchers perceived spirit mediums and shamans as psychiatric patients whose psychopathology was culturally sanctioned. However, other researchers have not only challenged this assumption, but also proposed that spirit possession has transformative benefits. The idiom of spirit possession provides cultural meanings for spirit mediums and shamans to express and transform their personal experiences. The present case study focuses on dang-ki healing, a form of Chinese mediumship practiced in Singapore, in which a deity possesses a human (i.e., dang-ki) to offer aid to supplicants. This study seeks to explore whether involvement in dang-ki healing is transformative; and if so, how the dang-ki's transformation is related to his self and the perceived legitimacy of his mediumship. At a shrine, I interviewed 20 participants, including a male dang-ki, 10 temple assistants, and nine clients. The results obtained were supportive of the therapeutic nature of spirit possession. First, there is a relationship between his self-transformation and the perceived legitimacy of his mediumship. As his clients and community have recognized his spirit possession as genuine, and the healing power of his possessing god, he is able to make use of mediumship as a means for spiritual development. Second, he has developed his spirituality by internalizing his god's positive traits (e.g., compassion). Deities worshipped in dang-ki healing can be conceptualized as ideal selves who represent a wide range of positive traits and moral values of Chinese culture. Thus, the possession of a deity is the embodiment of an ideal self. Finally, the dang-ki's transformation may run parallel to his god's transformation. In Chinese religions, gods have to constantly develop their spirituality even though they are already gods. An understanding of the god's spiritual development further sheds light on the dang-ki's self-transformation.

  16. Up-regulation of striatal adenosine A2A receptors with iron deficiency in rats. Effects on locomotion and cortico-striatal neurotransmission

    Science.gov (United States)

    Quiroz, César; Pearson, Virginia; Gulyani, Seema; Allen, Richard; Earley, Christopher; Ferré, Sergi

    2010-01-01

    Brain iron deficiency leads to altered dopaminergic function in experimental animals, which can provide a mechanistic explanation for iron deficiency-related human sensory-motor disorders, such as Restless Legs Syndrome (RLS). However, mechanisms linking both conditions have not been determined. Considering the strong modulation exerted by adenosine on dopamine signaling, one connection could involve changes in adenosine receptor expression or function. In the striatum, presynaptic A2A receptors are localized in glutamatergic terminals contacting GABAergic dynorphinergic neurons and their function can be analyzed by the ability of A2A receptor antagonists to block the motor output induced by cortical electrical stimulation. Postsynaptic A2A receptors are localized in the dendritic field of GABAergic enkephalinergic neurons and their function can be analyzed by studying the ability of A2A receptor antagonists to produce locomotor activity and to counteract striatal ERK1/2 phosphorylation induced by cortical electrical stimulation. Increased density of striatal A2A receptors was found in rats fed during three weeks with an iron-deficient diet during the post-weaning period. In iron-deficient rats, the selective A2A receptor antagonist MSX-3, at doses of 1 and 3 mg/kg, was more effective at blocking motor output induced by cortical electrical stimulation (presynaptic A2A receptor-mediated effect) and at enhancing locomotor activation and blocking striatal ERK phosphorylation induced by cortical electrical stimulation (postsynaptic A2A receptor-mediated effects). These results indicate that brain iron deficiency induces a functional up-regulation of both striatal pre- and postsynaptic A2A receptor, which could be involved in sensory-motor disorders associated with iron deficiency such as RLS. PMID:20385128

  17. Up-regulation of striatal adenosine A(2A) receptors with iron deficiency in rats: effects on locomotion and cortico-striatal neurotransmission.

    Science.gov (United States)

    Quiroz, César; Pearson, Virginia; Gulyani, Seema; Allen, Richard; Earley, Christopher; Ferré, Sergi

    2010-07-01

    Brain iron deficiency leads to altered dopaminergic function in experimental animals, which can provide a mechanistic explanation for iron deficiency-related human sensory-motor disorders, such as Restless Legs Syndrome (RLS). However, mechanisms linking both conditions have not been determined. Considering the strong modulation exerted by adenosine on dopamine signaling, one connection could involve changes in adenosine receptor expression or function. In the striatum, presynaptic A(2A) receptors are localized in glutamatergic terminals contacting GABAergic dynorphinergic neurons and their function can be analyzed by the ability of A(2A) receptor antagonists to block the motor output induced by cortical electrical stimulation. Postsynaptic A(2A) receptors are localized in the dendritic field of GABAergic enkephalinergic neurons and their function can be analyzed by studying the ability of A(2A) receptor antagonists to produce locomotor activity and to counteract striatal ERK1/2 phosphorylation induced by cortical electrical stimulation. Increased density of striatal A(2A) receptors was found in rats fed during 3 weeks with an iron-deficient diet during the post-weaning period. In iron-deficient rats, the selective A(2A) receptor antagonist MSX-3, at doses of 1 and 3 mg/kg, was more effective at blocking motor output induced by cortical electrical stimulation (presynaptic A(2A) receptor-mediated effect) and at enhancing locomotor activation and blocking striatal ERK phosphorylation induced by cortical electrical stimulation (postsynaptic A(2A) receptor-mediated effects). These results indicate that brain iron deficiency induces a functional up-regulation of both striatal pre- and postsynaptic A(2A) receptor, which could be involved in sensory-motor disorders associated with iron deficiency such as RLS. Copyright 2010. Published by Elsevier Inc.

  18. Quantum dots-based double imaging combined with organic dye imaging to establish an automatic computerized method for cancer Ki67 measurement

    Science.gov (United States)

    Wang, Lin-Wei; Qu, Ai-Ping; Liu, Wen-Lou; Chen, Jia-Mei; Yuan, Jing-Ping; Wu, Han; Li, Yan; Liu, Juan

    2016-02-01

    As a widely used proliferative marker, Ki67 has important impacts on cancer prognosis, especially for breast cancer (BC). However, variations in analytical practice make it difficult for pathologists to manually measure Ki67 index. This study is to establish quantum dots (QDs)-based double imaging of nuclear Ki67 as red signal by QDs-655, cytoplasmic cytokeratin (CK) as yellow signal by QDs-585, and organic dye imaging of cell nucleus as blue signal by 4‧,6-diamidino-2-phenylindole (DAPI), and to develop a computer-aided automatic method for Ki67 index measurement. The newly developed automatic computerized Ki67 measurement could efficiently recognize and count Ki67-positive cancer cell nuclei with red signals and cancer cell nuclei with blue signals within cancer cell cytoplasmic with yellow signals. Comparisons of computerized Ki67 index, visual Ki67 index, and marked Ki67 index for 30 patients of 90 images with Ki67 ≤ 10% (low grade), 10% Ki67 Ki67 ≥ 50% (high grade) showed computerized Ki67 counting is better than visual Ki67 counting, especially for Ki67 low and moderate grades. Based on QDs-based double imaging and organic dye imaging on BC tissues, this study successfully developed an automatic computerized Ki67 counting method to measure Ki67 index.

  19. Ki67--no evidence for its use in node-positive breast cancer.

    Science.gov (United States)

    Andre, Fabrice; Arnedos, Monica; Goubar, Aicha; Ghouadni, Amal; Delaloge, Suzette

    2015-05-01

    The expression of Ki67 in breast cancer has been associated with the luminal B phenotype, a high risk of relapse, and likelihood of good response to neoadjuvant chemotherapy. Several guidelines propose assays to determine Ki67 expression levels to select which patients with early stage breast cancer and 1-3 positive axillary nodes should not receive adjuvant chemotherapy. We discuss why oncologists should not rely on the use of this biomarker for patients with early stage breast cancer and only 1-3 positive axillary nodes. First, Ki67 staining lacks analytical validity. Second, the performance of the biomarker for prognostic purposes is poor, with no compelling evidence to indicate that patients with oestrogen receptor (ER)-positive disease, low Ki67 expression and 1-3 positive axillary nodes have a very low risk of disease relapse. Finally, no robust evidence indicates that Ki67 staining predicts the efficacy of adjuvant chemotherapy. Overall, evidence does not support withholding adjuvant chemotherapy in patients with ER-positive, Ki67-low breast cancer and 1-3 positive nodes without risk in daily practice.

  20. Teacher factors contributing to dosage of the KiVa anti-bullying program.

    Science.gov (United States)

    Swift, Lauren E; Hubbard, Julie A; Bookhout, Megan K; Grassetti, Stevie N; Smith, Marissa A; Morrow, Michael T

    2017-12-01

    The KiVa Anti-Bullying Program (KiVa) seeks to meet the growing need for anti-bullying programming through a school-based, teacher-led intervention for elementary school children. The goals of this study were to examine how intervention dosage impacts outcomes of KiVa and how teacher factors influence dosage. Participants included 74 teachers and 1409 4th- and 5th-grade students in nine elementary schools. Teachers and students completed data collection at the beginning and end of the school year, including measures of bullying and victimization, correlates of victimization (depression, anxiety, peer rejection, withdrawal, and school avoidance), intervention cognitions/emotions (anti-bullying attitudes, and empathy toward victims), bystander behaviors, and teacher factors thought to relate to dosage (self-efficacy for teaching, professional burnout, perceived principal support, expected effectiveness of KiVa, perceived feasibility of KiVa). The dosage of KiVa delivered to classrooms was measured throughout the school year. Results highlight dosage as an important predictor of change in bullying, victimization, correlates of victimization, bystander behavior, and intervention cognitions/emotions. Of the teacher factors, professional burnout uniquely predicted intervention dosage. A comprehensive structural equation model linking professional burnout to dosage and then to child-level outcomes demonstrated good fit. Implications for intervention design and implementation are discussed. Copyright © 2017 Society for the Study of School Psychology. Published by Elsevier Ltd. All rights reserved.

  1. Cyclooxygenase-2 and Ki67 Expression in Oral Leukoplakia: a Clinicopathological Study

    Directory of Open Access Journals (Sweden)

    Alper Sinanoglu

    2015-06-01

    Full Text Available Objectives: Oral leukoplakia is a precancerous lesion of the oral mucosa. The upregulation of Ki67 and cyclooxygenase-2 has been reported in both dysplastic and non-dysplastic tissues. The aim of this clinicopathological study was to investigate the prognostic value of Ki67 and cyclooxygenase-2 expression for oral leukoplakia. Material and Methods: A total of 50 samples were investigated and the study group consisted of 30 oral leukoplakia samples. Samples of 10 intact oral mucosa and 10 squamous cell carcinoma were included as negative and positive control groups, respectively. Epithelial dysplasia was defined as oral intraepithelial neoplasia (OIN and classified into subgroups 1 - 3. Tissue samples were assessed immunohistochemically for Ki67 and cyclooxygenase-2 expression. Clinicopathological correlations of oral leukoplakia patients were also investigated. Results: All OIN 3 patients were non-smokers (P < 0.05, and homogeneous oral leukoplakia lesions also presented OIN. Both cyclooxygenase-2 and Ki67 expression increased with the severity of lesions, which defined different subgroups (P < 0.05, except there was no significant difference between the hyperkeratosis and OIN groups for Ki67 expression. Conclusions: Cyclooxygenase-2 and Ki67 expression may have a prognostic value for the malignant transformation of oral leukoplakia.

  2. The region-of-interest size impacts on Ki67 quantification by computer-assisted image analysis in breast cancer.

    Science.gov (United States)

    Christgen, Matthias; von Ahsen, Sabrina; Christgen, Henriette; Länger, Florian; Kreipe, Hans

    2015-09-01

    Therapeutic decision-making in breast cancer depends on histopathologic biomarkers and is influenced by the Ki67 proliferation index. Computer-assisted image analysis (CAIA) promises to improve Ki67 quantification. Several commercial applications have been developed for semiautomated CAIA-based Ki67 quantification, many of which rely on measurements in user-defined regions of interest (ROIs). Because of intratumoral proliferative heterogeneity, definition of the ROI is an important step in the analytical procedure. This study explores the ROI size impacts on Ki67 quantification. Whole-slide sections of 100 breast cancers were immunostained with the anti-Ki67 antibody 30-9 and were analyzed on the iScan Coreo digital pathology platform using a Food and Drug Administration-cleared Ki67 quantification software version v5.3 (Virtuoso; Ventana, Tucson, TX). For each case, the Ki67 labeling index (LI) was determined in multiple ROIs of gradually increasing size centered around a high-proliferation area. The spatial Ki67 decline was modeled with nonlinear regression. Depending on the ROI size, the median Ki67 LI varied between 55% and 15%. The proportion of tumors classified as Ki67 low according to the St Gallen 2013/2015 cutoff increased from 2% to 56%, as the ROI size increased from 50 to 10,000 cells captured. The interrater reliability of conventional Ki67 assessment versus CAIA-based Ki67 quantification was also dependent on the ROI size and varied between slight and almost perfect agreement (Cohen κ = 0.06-0.85). In conclusion, the ROI size is a critically important parameter for semiautomated Ki67 quantification by CAIA. Ki67 LIs determined on platforms like iScan Coreo/Virtuoso require an ROI size adjustment, for which we offer a downloadable data transformation tool. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Logistički informacioni sistem / Logistics information system

    Directory of Open Access Journals (Sweden)

    Marko D. Andrejić

    2010-01-01

    Full Text Available Logistički automatizovani informacioni sistem treba razvijati kao deo jedinstvenog automatizovanog informacionog sistema (JAIS-a. Da bi se logistički automatizovani informacioni sistem uspešno razvijao i primenjivao u operativnoj praksi, neophodno je slediti globalni koncept razvoja JAIS-a i u razvoju više primenjivati timski rad profesionalnog informatičara i poznavaoca realnog logističkog sistema. Bitan uslov za razvoj kvalitetnog logističkog informacionog sistema jeste definisanje informacionih potreba o pojedinim objektima koje tretira logistički informacioni sistem. Zadatak logističkog automatizovanog informacionog sistema jeste da obezbedi: stalni uvid u stanje logističkog sistema; ukazivanje na potrebne i moguće mere poboljšanja; bolje planiranje i upravljanje radom realnog sistema; informisanje ljudstva o stanju realnog sistema i ukazivanje na pravce daljeg razvoja informacionih sistema. Logistički informacioni sistem treba razvijati vodeći računa i o kompatibilnosti sa budućim saveznicima i partnerima. / A logistics automated information system should be developed as a part of a unified automated information system (JAIS. In order to develop a logistics automated information system and to apply it successfully in operational use, it is necessary to follow the JAIS global development concept and rely more on teamwork of IT experts and specialists in real logistics systems. An important condition for the development of a high-quality logistics information system is to define information needs for particular objects treated by a logistics information system. The task of such a system is to provide: permanent insight into the logistics system, pointing to the necessary and possible measures for improvement, better real system planning and management activities, personnel information about the state of the real system, pointing to the directions of further system development. A logistics information system should be developed

  4. Ki67 Changes Identify Worse Outcomes in Residual Breast Cancer Tumors After Neoadjuvant Chemotherapy.

    Science.gov (United States)

    Cabrera-Galeana, Paula; Muñoz-Montaño, Wendy; Lara-Medina, Fernando; Alvarado-Miranda, Alberto; Pérez-Sánchez, Victor; Villarreal-Garza, Cynthia; Quintero, R Marisol; Porras-Reyes, Fany; Bargallo-Rocha, Enrique; Del Carmen, Ignacio; Mohar, Alejandro; Arrieta, Oscar

    2018-02-28

    Several breast cancer (BC) trials have adopted pathological complete response (pCR) as a surrogate marker of long-term treatment efficacy. In patients with luminal subtype, pCR seems less important for outcome prediction. BC is a heterogeneous disease, which is evident in residual tumors after neoadjuvant-chemotherapy (NAC). This study evaluates changes in Ki67 in relation to disease-free survival (DFS) and overall survival (OS) in patients without pCR. Four hundred thirty-five patients with stage IIA-IIIC BC without pCR after standard NAC with anthracycline and paclitaxel were analyzed. We analyzed the decrease or lack of decrease in the percentage of Ki67-positive cells between core biopsy samples and surgical specimens and correlated this value with outcome. Twenty-five percent of patients presented with luminal A-like tumors, 45% had luminal B-like tumors, 14% had triple-negative BC, 5% had HER2-positive BC, and 11% had triple-positive BC. Patients were predominantly diagnosed with stage III disease (52%) and high-grade tumors (46%). Median Ki67 level was 20% before NAC, which decreased to a median of 10% after NAC. Fifty-seven percent of patients had a decrease in Ki67 percentage. Ki67 decrease significantly correlated with better DFS and OS compared with no decrease, particularly in the luminal B subgroup. Multivariate analysis showed that nonreduction of Ki67 significantly increased the hazard ratio of recurrence and death by 3.39 (95% confidence interval [CI] 1.8-6.37) and 7.03 (95% CI 2.6-18.7), respectively. Patients without a decrease in Ki67 in residual tumors after NAC have poor prognosis. This warrants the introduction of new therapeutic strategies in this setting. This study evaluates the change in Ki67 percentage before and after neoadjuvant chemotherapy (NAC) and its relationship with survival outcomes in patients with breast cancer who did not achieve complete pathological response (pCR). These patients, a heterogeneous group with diverse

  5. Fronto-striatal glutamate in children with Tourette's disorder and attention-deficit/hyperactivity disorder

    Directory of Open Access Journals (Sweden)

    Jilly Naaijen

    2017-01-01

    Conclusion: We found no evidence for glutamatergic neuropathology in TD or ADHD within the fronto-striatal circuits. However, the correlation of OC-symptoms with ACC glutamate concentrations suggests that altered glutamatergic transmission is involved in OC-symptoms within TD, but this needs further investigation.

  6. Agonist-selective effects of opioid receptor ligands on cytosolic calcium concentration in rat striatal neurons.

    Science.gov (United States)

    Brailoiu, G Cristina; Deliu, Elena; Hooper, Robert; Dun, Nae J; Undieh, Ashiwel S; Adler, Martin W; Benamar, Khalid; Brailoiu, Eugen

    2012-06-01

    Buprenorphine is an opioid receptor ligand whose mechanism of action is incompletely understood. Using Ca(2+) imaging, we assessed the effects of buprenorphine, β-endorphin, and morphine on cytosolic Ca(2+) concentration [Ca(2+)](i), in rat striatal neurons. Buprenorphine (0.01-1 μM) increased [Ca(2+)](i) in a dose-dependent manner in a subpopulation of rat striatal neurons. The effect of buprenorphine was largely reduced by naloxone, a non-selective opioid receptor antagonist, but not by μ, κ, δ or NOP-selective antagonists. β-Endorphin (0.1 μM) increased [Ca(2+)](i) with a lower amplitude and slower time course than buprenorphine. Similar to buprenorphine, the effect of β-endorphin was markedly decreased by naloxone, but not by opioid-selective antagonists. Morphine (0.1-10 μM), did not affect [Ca(2+)](i) in striatal neurons. Our results suggest that buprenorphine and β-endorphin act on a distinct type/subtype of plasmalemmal opioid receptors or activate intracellular opioid-like receptor(s) in rat striatal neurons. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  7. Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson's disease.

    Science.gov (United States)

    Singh, Arun; Mewes, Klaus; Gross, Robert E; DeLong, Mahlon R; Obeso, José A; Papa, Stella M

    2016-08-23

    Circuitry models of Parkinson's disease (PD) are based on striatal dopamine loss and aberrant striatal inputs into the basal ganglia network. However, extrastriatal mechanisms have increasingly been the focus of attention, whereas the status of striatal discharges in the parkinsonian human brain remains conjectural. We now report the activity pattern of striatal projection neurons (SPNs) in patients with PD undergoing deep brain stimulation surgery, compared with patients with essential tremor (ET) and isolated dystonia (ID). The SPN activity in ET was very low (2.1 ± 0.1 Hz) and reminiscent of that found in normal animals. In contrast, SPNs in PD fired at much higher frequency (30.2 ± 1.2 Hz) and with abundant spike bursts. The difference between PD and ET was reproduced between 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated and normal nonhuman primates. The SPN activity was also increased in ID, but to a lower level compared with the hyperactivity observed in PD. These results provide direct evidence that the striatum contributes significantly altered signals to the network in patients with PD.

  8. Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease

    NARCIS (Netherlands)

    van Oostrom, JCH; Maguire, RP; Verschuuren-Bemelmans, CC; van der Duin, LV; Pruim, J; Roos, RAC; Leenders, KL

    2005-01-01

    Among 27 preclinical carriers of the Huntington disease mutation (PMC), the authors found normal striatal values for MRI volumetry in 88% and for fluorodesoxyglucose PET metabolic index in 67%. Raclopride PET binding potential (RAC-BP) was decreased in 50% and correlated with increases in the

  9. Reduced striatal dopamine D2/3 receptor availability in Body Dysmorphic Disorder

    NARCIS (Netherlands)

    Vulink, Nienke C; Planting, Robin S; Figee, Martijn; Booij, Jan; Denys, D.

    Though the dopaminergic system is implicated in Obsessive Compulsive and Related Disorders (OCRD), the dopaminergic system has never been investigated in-vivo in Body Dysmorphic Disorder (BDD). In line with consistent findings of reduced striatal dopamine D2/3 receptor availability in Obsessive

  10. Reduced striatal dopamine D2/3 receptor availability in Body Dysmorphic Disorder

    NARCIS (Netherlands)

    Vulink, Nienke C.; Planting, Robin S.; Figee, Martijn; Booij, Jan; Denys, Damiaan

    2016-01-01

    Though the dopaminergic system is implicated in Obsessive Compulsive and Related Disorders (OCRD), the dopaminergic system has never been investigated in-vivo in Body Dysmorphic Disorder (BDD). In line with consistent findings of reduced striatal dopamine D2/3 receptor availability in Obsessive

  11. Synthesis and binding to striatal membranes of non carrier added I-123 labeled 4'-iodococaine

    International Nuclear Information System (INIS)

    Metwally, S.A.M.; Gatley, S.J.; Wolf, A.P.; Yu, D.-W.

    1992-01-01

    An 123 I labeled cocaine analog, 4'-[ 123 I]iodococaine, has been prepared by oxidative destannylation of the tributyltin analog and shown to interact with cocaine binding sites in rat brain striatal membranes. It may thus be a suitable SPECT radiotracer for studies of the dopamine reuptake site in neurodegenerative diseases. (Author)

  12. Repeated cocaine administration results in supersensitivity of striatal D-2 dopamine autoreceptors to pergolide

    International Nuclear Information System (INIS)

    Dwoskin, L.P.; Peris, J.; Yasuda, R.P.; Philpott, K.; Zahniser, N.R.

    1988-01-01

    Groups of rats administered cocaine-HCl (10 mg/kg, i.p.) or saline either acutely or once daily for 8 or 14 days were killed 24 hrs after the last dose. In striatal slices prelabelled with [ 3 H]DA, modulation of [ 3 H]-overflow by pergolide was used to measure D-2 autoreceptor activity. Compared to the contemporaneous control group pergolide produced a greater inhibition only in striatal slices from rats treated repeatedly with cocaine. In radioligand binding studies using striatal membranes from control rats, pergolide had a 500-fold greater affinity for the D-2, as opposed to the D-1, dopamine (DA) receptor subtype. These results indicate that repeated treatment with cocaine produces supersensitive striatal D-2 release-modulating autoreceptors consistent with a compensatory change to diminish the effect of elevated synaptic concentrations of DA produced by cocaine. In contrast, supersensitivity of D-2 receptors was not detected in [ 3 H]spiperone binding assays. 31 references, 2 figures, 1 table

  13. Ciliary neurotrophic factor protects striatal neurons against excitotoxicity by enhancing glial glutamate uptake.

    Directory of Open Access Journals (Sweden)

    Corinne Beurrier

    Full Text Available Ciliary neurotrophic factor (CNTF is a potent neuroprotective cytokine in different animal models of glutamate-induced excitotoxicity, although its action mechanisms are still poorly characterized. We tested the hypothesis that an increased function of glial glutamate transporters (GTs could underlie CNTF-mediated neuroprotection. We show that neuronal loss induced by in vivo striatal injection of the excitotoxin quinolinic acid (QA was significantly reduced (by approximately 75% in CNTF-treated animals. In striatal slices, acute QA application dramatically inhibited corticostriatal field potentials (FPs, whose recovery was significantly higher in CNTF rats compared to controls (approximately 40% vs. approximately 7%, confirming an enhanced resistance to excitotoxicity. The GT inhibitor DL-threo-beta-benzyloxyaspartate greatly reduced FP recovery in CNTF rats, supporting the role of GT in CNTF-mediated neuroprotection. Whole-cell patch-clamp recordings from striatal medium spiny neurons showed no alteration of basic properties of striatal glutamatergic transmission in CNTF animals, but the increased effect of a low-affinity competitive glutamate receptor antagonist (gamma-D-glutamylglycine also suggested an enhanced GT function. These data strongly support our hypothesis that CNTF is neuroprotective via an increased function of glial GTs, and further confirms the therapeutic potential of CNTF for the clinical treatment of progressive neurodegenerative diseases involving glutamate overflow.

  14. Striatal Dopamine Transporter Binding Does Not Correlate with Clinical Severity in Dementia with Lewy Bodies

    DEFF Research Database (Denmark)

    Ziebell, Morten; Andersen, Birgitte B; Pinborg, Lars H

    2013-01-01

    cognitively evaluated with the Mini Mental State Examination. RESULTS: There was no correlation between Mini Mental State Examination, Hoehn and Yahr score, fluctuations or hallucinations, and striatal DAT availability as measured with (123)I-PE2I and SPECT. CONCLUSION: In patients with newly diagnosed DLB...

  15. Aberrant local striatal functional connectivity in attention-deficit/hyperactivity disorder

    NARCIS (Netherlands)

    Rhein, D.T. von; Oldehinkel, M.; Beckmann, C.F.; Oosterlaan, J.; Heslenfeld, D.; Hartman, C.A.; Hoekstra, P.J.; Franke, B.; Cools, R.; Buitelaar, J.K.; Mennes, M.

    2016-01-01

    BACKGROUND: Task-based and resting-state functional Magnetic Resonance Imaging (fMRI) studies report attention-deficit/hyperactivity disorder (ADHD)-related alterations in brain regions implicated in cortico-striatal networks. We assessed whether ADHD is associated with changes in the brain's global

  16. Aberrant local striatal functional connectivity in attention-deficit/hyperactivity disorder

    NARCIS (Netherlands)

    von Rhein, Daniel; Oldehinkel, Marianne; Beckmann, Christian F.; Oosterlaan, Jaap; Heslenfeld, Dirk; Hartman, Catharina A.; Hoekstra, Pieter J.; Franke, Barbara; Cools, Roshan; Buitelaar, Jan K.; Mennes, Maarten

    Background: Task-based and resting-state functional Magnetic Resonance Imaging (fMRI) studies report attention-deficit/hyperactivity disorder (ADHD)-related alterations in brain regions implicated in cortico-striatal networks. We assessed whether ADHD is associated with changes in the brain's global

  17. Fronto-striatal glutamate in autism spectrum disorder and obsessive compulsive disorder

    NARCIS (Netherlands)

    Naaijen, Jilly; Zwiers, Marcel P.; Amiri, Houshang; Williams, Steven C R; Durston, Sarah; Oranje, Bob; Brandeis, Daniel; Boecker-Schlier, Regina; Ruf, Matthias; Wolf, Isabella; Banaschewski, Tobias; Glennon, Jeffrey C.; Franke, Barbara; Buitelaar, Jan K.; Lythgoe, David J

    2017-01-01

    Autism spectrum disorders (ASDs) and obsessive compulsive disorder (OCD) are often comorbid with the overlap based on compulsive behaviors. Although previous studies suggest glutamatergic deficits in fronto-striatal brain areas in both disorders, this is the first study to directly compare the

  18. Fronto-striatal glutamate in children with Tourette's disorder and attention-deficit/hyperactivity disorder

    NARCIS (Netherlands)

    Naaijen, J.; Forde, N.J.; Lythgoe, D.J.; Akkermans, S.E.A.; Openneer, T.J.; Dietrich, A.; Zwiers, M.P.; Hoekstra, P.J.; Buitelaar, J.K.

    2017-01-01

    OBJECTIVE: Both Tourette's disorder (TD) and attention-deficit/hyperactivity disorder (ADHD) have been related to abnormalities in glutamatergic neurochemistry in the fronto-striatal circuitry. TD and ADHD often co-occur and the neural underpinnings of this co-occurrence have been insufficiently

  19. Fronto-striatal glutamate in children with Tourette's disorder and attention-deficit/hyperactivity disorder

    NARCIS (Netherlands)

    Naaijen, Jilly; Forde, Natalie J.; Lythgoe, David J.; Akkermans, Sophie E. A.; Openneer, Thaira J. C.; Dietrich, Andrea; Zwiers, Marcel P.; Hoekstra, Pieter J.; Buitelaar, Jan K.

    2017-01-01

    Objective: Both Tourette's disorder (TD) and attention-deficit/hyperactivity disorder (ADHD) have been related to abnormalities in glutamatergic neurochemistry in the fronto-striatal circuitry. TD and ADHD often co-occur and the neural underpinnings of this co-occurrence have been insufficiently

  20. De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions

    NARCIS (Netherlands)

    Mencacci, N.E.; Kamsteeg, E.J.; Nakashima, K.; R'Bibo, L.; Lynch, D.S.; Balint, B.; Willemsen, M.A.A.P.; Adams, M.E.; Wiethoff, S.; Suzuki, K.; Davies, C.H.; Ng, J.; Meyer, E.; Veneziano, L.; Giunti, P.; Hughes, D.; Raymond, F.L.; Carecchio, M.; Zorzi, G.; Nardocci, N.; Barzaghi, C.; Garavaglia, B.; Salpietro, V.; Hardy, J.; Pittman, A.M.; Houlden, H.; Kurian, M.A.; Kimura, H.; Vissers, L.E.L.M.; Wood, N.W.; Bhatia, K.P.

    2016-01-01

    Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very

  1. Cannabinoid-1 receptor antagonist rimonabant (SR141716) increases striatal dopamine D2 receptor availability

    NARCIS (Netherlands)

    Crunelle, Cleo L.; van de Giessen, Elsmarieke; Schulz, Sybille; Vanderschuren, Louk J. M. J.; de Bruin, Kora; van den Brink, Wim; Booij, Jan

    2013-01-01

    The cannabinoid 1 receptor antagonist rimonabant (SR141716) alters rewarding properties and intake of food and drugs. Additionally, striatal dopamine D2 receptor (DRD2) availability has been implicated in reward function. This study shows that chronic treatment of rats with rimonabant (1.0 and

  2. Writer's cramp: restoration of striatal D2-binding after successful biofeedback-based sensorimotor training.

    NARCIS (Netherlands)

    Berger, H.J.C.; Werf, S.P. van der; Horstink, C.A.; Cools, A.R.; Oyen, W.J.G.; Horstink, M.W.I.M.

    2007-01-01

    INTRODUCTION: Previous studies of writer's cramp have detected cerebral sensorimotor abnormalities in this disorder and, more specifically, a reduced striatal D2-binding as assessed by [(123)I]IBZM SPECT. However, empirical data were lacking about the influence of effective biofeedback-based

  3. Apathy and striatal dopamine defects in non-demented patients with Parkinson's disease.

    Science.gov (United States)

    Chung, Su Jin; Lee, Jae Jung; Ham, Jee Hyun; Lee, Phil Hyu; Sohn, Young H

    2016-02-01

    Apathy is a common, disabling symptom in Parkinson's disease (PD). The mechanisms underlying apathy in PD are still unclear, although they may be related to dysfunction in the meso-cortico-limbic circuit, including the ventral striatum. Thus, we performed this study to investigate whether dopamine depletion in the ventral striatum contributes to apathy in PD. We conducted a survey of the degree of apathy (using the Korean version of the Apathy Evaluation Scale, AES-S) in 108 non-demented patients with PD who underwent dopamine transporter (DAT) positron emission tomography scans as an initial diagnostic work-up. Patients with AES-S scores of 37 or higher were defined as having apathetic PD. The Beck Depression Inventory (BDI) was administered to assess the severity of depression. Patients with BDI scores of 15 or higher were regarded as having depression. Apathetic patients (n = 34) tended to exhibit higher BDI scores than non-apathetic patients (n = 74); however, other clinical variables were comparable between the two groups. DAT activity in the striatal sub-regions was also similar between the two groups. Selecting only non-depressed patients, including 20 apathetic and 47 non-apathetic patients, did not alter the results. This study demonstrated that the pattern of striatal dopamine depletion does not contribute to the degree of apathy in early PD. Apathy in PD may be associated with extra-striatal lesions that accompany PD rather than striatal dopaminergic deficits. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Apathy and striatal dopamine transporter levels in de-novo, untreated Parkinson's disease patients.

    Science.gov (United States)

    Santangelo, Gabriella; Vitale, Carmine; Picillo, Marina; Cuoco, Sofia; Moccia, Marcello; Pezzella, Domenica; Erro, Roberto; Longo, Katia; Vicidomini, Caterina; Pellecchia, Maria Teresa; Amboni, Marianna; Brunetti, Arturo; Salvatore, Marco; Barone, Paolo; Pappatà, Sabina

    2015-05-01

    Apathy is a neuropsychiatric symptom in Parkinson's Disease (PD) which has a negative impact on quality of life and might be related in part to damage of presynaptic dopaminergic system. Little is known about relationship between striatal dopamine levels and apathy in PD patients without dementia and/or depression. The aim of the present study was to investigate the relationship between "pure apathy" and striatal dopamine uptake in untreated, drug-naïve PD patients without clinically significant dementia and/or depression. Fourteen PD patients with pure apathy and 14 PD patients without apathy, matched for age, side of motor symptoms at onset, motor disability and disease duration, underwent both neuropsychological and behavioral examination including self-rated version of the Apathy Evaluation Scale (AES-S). All patients underwent 123 I-FP-CIT (DaT-SCAN) SPECT to assess dopamine transporter (DAT) striatal uptake. PD patients with apathy showed lower DAT levels in the striatum than non-apathetic patients. After Bonferroni correction the difference between groups was significant in the right caudate. Apathy is associated with reduced striatal dopamine transporter levels, independent of motor disability and depression in non-demented PD patients. These findings suggest that dysfunction of dopaminergic innervation in the striatum and particularly in the right caudate may contribute to development of apathy in early PD. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Frizzled3 controls axonal polarity and intermediate target entry during striatal pathway development

    NARCIS (Netherlands)

    Morello, Francesca; Prasad, Asheeta A.; Rehberg, Kati; Baptista Vieira de Sá, Renata; Antón-Bolaños, Noelia; Leyva-Diaz, Eduardo; Adolfs, Youri; Tissir, Fadel; López-Bendito, Guillermina; Pasterkamp, R. Jeroen

    2015-01-01

    The striatum is a large brain nucleus with an important role in the control of movement and emotions.Mediumspiny neurons (MSNs) are striatal output neurons forming prominent descending axon tracts that target different brain nuclei. However, how MSN axon tracts in the forebrain develop remains

  6. Environmental enrichment enhances synaptic plasticity by internalization of striatal dopamine transporters

    Science.gov (United States)

    Kim, Myung-Sun; Yu, Ji Hea; Kim, Chul Hoon; Choi, Jae Yong; Seo, Jung Hwa; Lee, Min-Young; Yi, Chi Hoon; Choi, Tae Hyun; Ryu, Young Hoon; Lee, Jong Eun; Lee, Bae Hwan; Kim, Hyongbum

    2015-01-01

    Environmental enrichment (EE) with a complex combination of physical, cognitive and social stimulations enhances synaptic plasticity and behavioral function. However, the mechanism remains to be elucidated in detail. We aimed to investigate dopamine-related synaptic plasticity underlying functional improvement after EE. For this, six-week-old CD-1 mice were randomly allocated to EE or standard conditions for two months. EE significantly enhanced behavioral functions such as rotarod and ladder walking tests. In a [18F]FPCIT positron emission tomography scan, binding values of striatal DAT were significantly decreased approximately 18% in the EE mice relative to the control mice. DAT inhibitor administrated to establish the relationship of the DAT down-regulation to the treatment effects also improved rotarod performances, suggesting that DAT inhibition recapitulated EE-mediated treatment benefits. Next, EE-induced internalization of DAT was confirmed using a surface biotinylation assay. In situ proximity ligation assay and immunoprecipitation demonstrated that EE significantly increased the phosphorylation of striatal DAT as well as the levels of DAT bound with protein kinase C (PKC). In conclusion, we suggest that EE enables phosphorylation of striatal DAT via a PKC-mediated pathway and causes DAT internalization. This is the first report to suggest an EE-mediated mechanism of synaptic plasticity by internalization of striatal DAT. PMID:26661218

  7. Different correlation patterns of cholinergic and GABAergic interneurons with striatal projection neurons

    Directory of Open Access Journals (Sweden)

    Avital eAdler

    2013-09-01

    Full Text Available The striatum is populated by a single projection neuron group, the medium spiny neurons (MSNs, and several groups of interneurons. Two of the electrophysiologically well-characterized striatal interneuron groups are the tonically active neurons (TANs, which are presumably cholinergic interneurons, and the fast spiking interneurons (FSIs, presumably parvalbumin (PV expressing GABAergic interneurons. To better understand striatal processing it is thus crucial to define the functional relationship between MSNs and these interneurons in the awake and behaving animal. We used multiple electrodes and standard physiological methods to simultaneously record MSN spiking activity and the activity of TANs or FSIs from monkeys engaged in a classical conditioning paradigm. All three cell populations were highly responsive to the behavioral task. However, they displayed different average response profiles and a different degree of response synchronization (signal correlation. TANs displayed the most transient and synchronized response, MSNs the most diverse and sustained response and FSIs were in between on both parameters. We did not find evidence for direct monosynaptic connectivity between the MSNs and either the TANs or the FSIs. However, while the cross correlation histograms of TAN to MSN pairs were flat, those of FSI to MSN displayed positive asymmetrical broad peaks. The FSI-MSN correlogram profile implies that the spikes of MSNs follow those of FSIs and both are driven by a common, most likely cortical, input. Thus, the two populations of striatal interneurons are probably driven by different afferents and play complementary functional roles in the physiology of the striatal microcircuit.

  8. Glutamine triggers long-lasting increase in striatal network activity in vitro.

    Science.gov (United States)

    Fleischer, Wiebke; Theiss, Stephan; Schnitzler, Alfons; Sergeeva, Olga

    2017-04-01

    Accumulation of ammonium and glutamine in blood and brain is a key factor in hepatic encephalopathy (HE) - a neuropsychiatric syndrome characterized by various cognitive and motor deficits. MRI imaging identified abnormalities notably in the basal ganglia of HE patients, including its major input station, the striatum. While neurotoxic effects of ammonia have been extensively studied, glutamine is primarily perceived as "detoxified" form of ammonia. We applied ammonium and glutamine to striatal and cortical cells from newborn rats cultured on microelectrode arrays. Glutamine, but not ammonium significantly increased spontaneous spike rate with a long-lasting excitation outlasting washout. This effect was more prominent in striatal than in cortical cultures. Calcium imaging revealed that glutamine application caused a rise in intracellular calcium that depended both on system A amino acid transport and activation of ionotropic glutamate receptors. This pointed to downstream glutamate release that was triggered by intracellular glutamine. Using an enzymatic assay kit we confirmed glutamine-provoked glutamate release from striatal cells. Real-time PCR and immunocytochemistry demonstrated the presence of vesicular glutamate transporters (VGLUT1 and VGLUT2) necessary for synaptic glutamate release in striatal neurons. We conclude that extracellular glutamine is taken up by neurons, triggers synaptic release of glutamate which is then taken up by astrocytes and again converted to glutamine. This feedback-loop causes a sustained long-lasting excitation of network activity. Thus, apart from ammonia also its "detoxified" form glutamine might be responsible for the neuropsychiatric symptoms in HE. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Creative cognition and dopaminergic modulation of fronto-striatal networks: Integrative review and research agenda.

    Science.gov (United States)

    Boot, Nathalie; Baas, Matthijs; van Gaal, Simon; Cools, Roshan; De Dreu, Carsten K W

    2017-07-01

    Creative cognition is key to human functioning yet the underlying neurobiological mechanisms are sparsely addressed and poorly understood. Here we address the possibility that creative cognition is a function of dopaminergic modulation in fronto-striatal brain circuitries. It is proposed that (i) creative cognition benefits from both flexible and persistent processing, (ii) striatal dopamine and the integrity of the nigrostriatal dopaminergic pathway is associated with flexible processing, while (iii) prefrontal dopamine and the integrity of the mesocortical dopaminergic pathway is associated with persistent processing. We examine this possibility in light of studies linking creative ideation, divergent thinking, and creative problem-solving to polymorphisms in dopamine receptor genes, indirect markers and manipulations of the dopaminergic system, and clinical populations with dysregulated dopaminergic activity. Combined, studies suggest a functional differentiation between striatal and prefrontal dopamine: moderate (but not low or high) levels of striatal dopamine benefit creative cognition by facilitating flexible processes, and moderate (but not low or high) levels of prefrontal dopamine enable persistence-driven creativity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Diversity in Long-Term Synaptic Plasticity at Inhibitory Synapses of Striatal Spiny Neurons

    Science.gov (United States)

    Rueda-Orozco, Pavel E.; Mendoza, Ernesto; Hernandez, Ricardo; Aceves, Jose J.; Ibanez-Sandoval, Osvaldo; Galarraga, Elvira; Bargas, Jose

    2009-01-01

    Procedural memories and habits are posited to be stored in the basal ganglia, whose intrinsic circuitries possess important inhibitory connections arising from striatal spiny neurons. However, no information about long-term plasticity at these synapses is available. Therefore, this work describes a novel postsynaptically dependent long-term…

  11. Impaired dual tasking in Parkinson's disease is associated with reduced focusing of cortico-striatal activity.

    Science.gov (United States)

    Nieuwhof, Freek; Bloem, Bastiaan R; Reelick, Miriam F; Aarts, Esther; Maidan, Inbal; Mirelman, Anat; Hausdorff, Jeffrey M; Toni, Ivan; Helmich, Rick C

    2017-05-01

    See Bell et al. (doi:10.1093/awx063) for a scientific commentary on this article. Impaired dual tasking, namely the inability to concurrently perform a cognitive and a motor task (e.g. 'stops walking while talking'), is a largely unexplained and frequent symptom of Parkinson's disease. Here we consider two circuit-level accounts of how striatal dopamine depletion might lead to impaired dual tasking in patients with Parkinson's disease. First, the loss of segregation between striatal territories induced by dopamine depletion may lead to dysfunctional overlaps between the motor and cognitive processes usually implemented in parallel cortico-striatal circuits. Second, the known dorso-posterior to ventro-anterior gradient of dopamine depletion in patients with Parkinson's disease may cause a funnelling of motor and cognitive processes into the relatively spared ventro-anterior putamen, causing a neural bottleneck. Using functional magnetic resonance imaging, we measured brain activity in 19 patients with Parkinson's disease and 26 control subjects during performance of a motor task (auditory-cued ankle movements), a cognitive task (implementing a switch-stay rule), and both tasks simultaneously (dual task). The distribution of task-related activity respected the known segregation between motor and cognitive territories of the putamen in both groups, with motor-related responses in the dorso-posterior putamen and task switch-related responses in the ventro-anterior putamen. During dual task performance, patients made more motor and cognitive errors than control subjects. They recruited a striatal territory (ventro-posterior putamen) not engaged during either the cognitive or the motor task, nor used by controls. Relatively higher ventro-posterior putamen activity in controls was associated with worse dual task performance. These observations suggest that dual task impairments in Parkinson's disease are related to reduced spatial focusing of striatal activity. This

  12. Standardized Ki67 Diagnostics Using Automated Scoring--Clinical Validation in the GeparTrio Breast Cancer Study.

    Science.gov (United States)

    Klauschen, Frederick; Wienert, Stephan; Schmitt, Wolfgang D; Loibl, Sibylle; Gerber, Bernd; Blohmer, Jens-Uwe; Huober, Jens; Rüdiger, Thomas; Erbstößer, Erhard; Mehta, Keyur; Lederer, Bianca; Dietel, Manfred; Denkert, Carsten; von Minckwitz, Gunter

    2015-08-15

    Scoring proliferation through Ki67 immunohistochemistry is an important component in predicting therapy response to chemotherapy in patients with breast cancer. However, recent studies have cast doubt on the reliability of "visual" Ki67 scoring in the multicenter setting, particularly in the lower, yet clinically important, proliferation range. Therefore, an accurate and standardized Ki67 scoring is pivotal both in routine diagnostics and larger multicenter studies. We validated a novel fully automated Ki67 scoring approach that relies on only minimal a priori knowledge on cell properties and requires no training data for calibration. We applied our approach to 1,082 breast cancer samples from the neoadjuvant GeparTrio trial and compared the performance of automated and manual Ki67 scoring. The three groups of autoKi67 as defined by low (≤ 15%), medium (15.1%-35%), and high (>35%) automated scores showed pCR rates of 5.8%, 16.9%, and 29.5%, respectively. AutoKi67 was significantly linked to prognosis with overall and progression-free survival P values P(OS) Ki67 scoring. Moreover, automated Ki67 scoring was an independent prognosticator in the multivariate analysis with P(OS) = 0.002, P(PFS) = 0.009 (autoKi67) versus P(OS) = 0.007, PPFS = 0.004 (manual Ki67). The computer-assisted Ki67 scoring approach presented here offers a standardized means of tumor cell proliferation assessment in breast cancer that correlated with clinical endpoints and is deployable in routine diagnostics. It may thus help to solve recently reported reliability concerns in Ki67 diagnostics. ©2014 American Association for Cancer Research.

  13. Striatal dopamine transmission is subtly modified in human A53Tα-synuclein overexpressing mice.

    Directory of Open Access Journals (Sweden)

    Nicola J Platt

    Full Text Available Mutations in, or elevated dosage of, SNCA, the gene for α-synuclein (α-syn, cause familial Parkinson's disease (PD. Mouse lines overexpressing the mutant human A53Tα-syn may represent a model of early PD. They display progressive motor deficits, abnormal cellular accumulation of α-syn, and deficits in dopamine-dependent corticostriatal plasticity, which, in the absence of overt nigrostriatal degeneration, suggest there are age-related deficits in striatal dopamine (DA signalling. In addition A53Tα-syn overexpression in cultured rodent neurons has been reported to inhibit transmitter release. Therefore here we have characterized for the first time DA release in the striatum of mice overexpressing human A53Tα-syn, and explored whether A53Tα-syn overexpression causes deficits in the release of DA. We used fast-scan cyclic voltammetry to detect DA release at carbon-fibre microelectrodes in acute striatal slices from two different lines of A53Tα-syn-overexpressing mice, at up to 24 months. In A53Tα-syn overexpressors, mean DA release evoked by a single stimulus pulse was not different from wild-types, in either dorsal striatum or nucleus accumbens. However the frequency responsiveness of DA release was slightly modified in A53Tα-syn overexpressors, and in particular showed slight deficiency when the confounding effects of striatal ACh acting at presynaptic nicotinic receptors (nAChRs were antagonized. The re-release of DA was unmodified after single-pulse stimuli, but after prolonged stimulation trains, A53Tα-syn overexpressors showed enhanced recovery of DA release at old age, in keeping with elevated striatal DA content. In summary, A53Tα-syn overexpression in mice causes subtle changes in the regulation of DA release in the striatum. While modest, these modifications may indicate or contribute to striatal dysfunction.

  14. The basal ganglia matching tools package for striatal uptake semi-quantification: description and validation

    International Nuclear Information System (INIS)

    Calvini, Piero; Rodriguez, Guido; Nobili, Flavio; Inguglia, Fabrizio; Mignone, Alessandro; Guerra, Ugo P.

    2007-01-01

    To design a novel algorithm (BasGan) for automatic segmentation of striatal 123 I-FP-CIT SPECT. The BasGan algorithm is based on a high-definition, three-dimensional (3D) striatal template, derived from Talairach's atlas. A blurred template, obtained by convolving the former with a 3D Gaussian kernel (FWHM = 10 mm), approximates striatal activity distribution. The algorithm performs translations and scale transformation on the bicommissural aligned image to set the striatal templates with standard size in an appropriate initial position. An optimization protocol automatically performs fine adjustments in the positioning of blurred templates to best match the radioactive counts, and locates an occipital ROI for background evaluation. Partial volume effect correction is included in the process of uptake computation of caudate, putamen and background. Experimental validation was carried out by means of six acquisitions of an anthropomorphic striatal phantom. The BasGan software was applied to a first set of patients with Parkinson's disease (PD) versus patients affected by essential tremor. A highly significant correlation was achieved between true binding potential and measured 123 I activity from the phantom. 123 I-FP-CIT uptake was significantly lower in all basal ganglia in the PD group versus controls with both BasGan and a conventional ROI method used for comparison, but particularly with the former. Correlations with the motor UPDRS score were far more significant with the BasGan. The novel BasGan algorithm automatically performs the 3D segmentation of striata. Because co-registered MRI is not needed, it can be used by all nuclear medicine departments, since it is freely available on the Web. (orig.)

  15. Youth at risk for obesity show greater activation of striatal and somatosensory regions to food.

    Science.gov (United States)

    Stice, Eric; Yokum, Sonja; Burger, Kyle S; Epstein, Leonard H; Small, Dana M

    2011-03-23

    Obese humans, compared with normal-weight humans, have less striatal D2 receptors and striatal response to food intake; weaker striatal response to food predicts weight gain for individuals at genetic risk for reduced dopamine (DA) signaling, consistent with the reward-deficit theory of obesity. Yet these may not be initial vulnerability factors, as overeating reduces D2 receptor density, D2 sensitivity, reward sensitivity, and striatal response to food. Obese humans also show greater striatal, amygdalar, orbitofrontal cortex, and somatosensory region response to food images than normal-weight humans do, which predicts weight gain for those not at genetic risk for compromised dopamine signaling, consonant with the reward-surfeit theory of obesity. However, after pairings of palatable food intake and predictive cues, DA signaling increases in response to the cues, implying that eating palatable food contributes to increased responsivity. Using fMRI, we tested whether normal-weight adolescents at high- versus low-risk for obesity showed aberrant activation of reward circuitry in response to receipt and anticipated receipt of palatable food and monetary reward. High-risk youth showed greater activation in the caudate, parietal operculum, and frontal operculum in response to food intake and in the caudate, putamen, insula, thalamus, and orbitofrontal cortex in response to monetary reward. No differences emerged in response to anticipated food or monetary reward. Data indicate that youth at risk for obesity show elevated reward circuitry responsivity in general, coupled with elevated somatosensory region responsivity to food, which may lead to overeating that produces blunted dopamine signaling and elevated responsivity to food cues.

  16. Functional role for cortical-striatal circuitry in modulating alcohol self-administration.

    Science.gov (United States)

    Jaramillo, Anel A; Randall, Patrick A; Stewart, Spencer; Fortino, Brayden; Van Voorhies, Kalynn; Besheer, Joyce

    2018-03-01

    The cortical-striatal brain circuitry is heavily implicated in drug-use. As such, the present study investigated the functional role of cortical-striatal circuitry in modulating alcohol self-administration. Given that a functional role for the nucleus accumbens core (AcbC) in modulating alcohol-reinforced responding has been established, we sought to test the role of cortical brain regions with afferent projections to the AcbC: the medial prefrontal cortex (mPFC) and the insular cortex (IC). Long-Evans rats were trained to self-administer alcohol (15% alcohol (v/v)+2% sucrose (w/v)) during 30 min sessions. To test the functional role of the mPFC or IC, we utilized a chemogenetic technique (hM4D i -Designer Receptors Activation by Designer Drugs) to silence neuronal activity prior to an alcohol self-administration session. Additionally, we chemogenetically silenced mPFC→AcbC or IC→AcbC projections, to investigate the role of cortical-striatal circuitry in modulating alcohol self-administration. Chemogenetically silencing the mPFC decreased alcohol self-administration, while silencing the IC increased alcohol self-administration, an effect absent in mCherry-Controls. Interestingly, silencing mPFC→AcbC projections had no effect on alcohol self-administration. In contrast, silencing IC→AcbC projections decreased alcohol self-administration, in a reinforcer-specific manner as there was no effect in rats trained to self-administer sucrose (0.8%, w/v). Additionally, no change in self-administration was observed in the mCherry-Controls. Together these data demonstrate the complex role of the cortical-striatal circuitry while implicating a role for the insula-striatal circuit in modulating ongoing alcohol self-administration. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Prognostic significance of pathologic complete response and Ki67 expression after neoadjuvant chemotherapy in breast cancer.

    Science.gov (United States)

    Yoshioka, Tatsuya; Hosoda, Mitsuchika; Yamamoto, Mitsugu; Taguchi, Kazunori; Hatanaka, Kanako C; Takakuwa, Emi; Hatanaka, Yutaka; Matsuno, Yoshihiro; Yamashita, Hiroko

    2015-03-01

    Recent studies have indicated that response to chemotherapy and the prognostic impact of a pathologic complete response (pCR) after neoadjuvant chemotherapy differ among breast cancer subtypes. Women with Stage I to III breast cancer treated with anthracycline and taxane-based neoadjuvant chemotherapy (four cycles of docetaxel every 3 weeks followed by four cycles of FEC every 3 weeks) between 2006 and 2011 were retrospectively analyzed. Trastuzumab was concurrently added to docetaxel for HER2-positive breast cancer. Expression of estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens. Predictive factors for neoadjuvant chemotherapy and prognosis were analyzed by breast cancer subtype. Of 64 patients, 30 (47 %) were ER-positive (ER+) HER2-negative (HER2-), including eight as luminal A (Ki67 labeling index (LI) Ki67 LI ≥ 14 %) subtypes, 11 (17 %) were ER+ HER2-positive (HER2+), 12 (19 %) were ER-negative (ER-) HER2+, and 11 (17 %) were ER- HER2-. The clinical response rates were significantly higher in luminal B, ER+ HER2+, and ER- HER2+ subtypes compared with luminal A subtype. Patients whose tumors contained high Ki67 expression effectively responded to neoadjuvant chemotherapy. Ki67 LI was a predictive marker for pCR, and all patients whose tumors achieved pCR are currently disease-free. Furthermore, high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free and overall survival regardless of subtype. It is necessary to establish additional strategies to improve survival for patients whose residual tumors show high Ki67 expression after neoadjuvant chemotherapy.

  18. Screening for precancerous anal lesions with P16/Ki67 immunostaining in HIV-infected MSM.

    Directory of Open Access Journals (Sweden)

    Sergio Serrano-Villar

    Full Text Available Screening of anal cancer in HIV-infected MSM with anal cytology results in high rates of false positive results and elevated burden of high-resolution anoscopies. High-risk HPV up-regulates p16 and Ki67 expression in epithelial cells. We assessed the usefulness of P16/Ki-67 immunostaining cytology for the diagnosis of precancerous anal lesions.Cross-sectional multicenter study. Concomitant anal liquid cytology with p16/Ki-67 immunostaining and HRA with biopsy of acetowhite lugol-negative lesions was performed in HIV-infected MSM. We compared the diagnostic performance of an abnormal anal cytology and p16/Ki-67 immunostaining relative to HRA-guided biopsy by logistic regression and comparison of ROC areas.We included 328 HIV-infected MSM. HSIL was histologically diagnosed in 72 subjects (25.1%, and 2 (0.6% were diagnosed with anal cancer. An abnormal cytology showed a sensitivity of 95.6% and a specificity of 58.8% for the diagnosis of biopsy-proven HSIL. P16/Ki67 positivity was associated with the presence of biopsy-proven HSIL (P trend = 0.004 but with low sensitivity (41.2% and specificity (71%. The combination of standard cytology with P16/Ki67 immunostaining did not increment the predictive value of standard cytology alone (AUC 0.685 vs. 0.673, respectively, P = 0.688.In HIV-infected MSM P16/Ki67 immunostaining does not improve the diagnostic accuracy of anal cytology, which shows a high sensitivity yet poor specificity. Other approaches aimed at improving the diagnostic accuracy of current techniques for the diagnostic of precancerous HSIL are warranted.

  19. Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection.

    Science.gov (United States)

    Beuschlein, Felix; Weigel, Jens; Saeger, Wolfgang; Kroiss, Matthias; Wild, Vanessa; Daffara, Fulvia; Libé, Rosella; Ardito, Arianna; Al Ghuzlan, Abir; Quinkler, Marcus; Oßwald, Andrea; Ronchi, Cristina L; de Krijger, Ronald; Feelders, Richard A; Waldmann, Jens; Willenberg, Holger S; Deutschbein, Timo; Stell, Anthony; Reincke, Martin; Papotti, Mauro; Baudin, Eric; Tissier, Frédérique; Haak, Harm R; Loli, Paola; Terzolo, Massimo; Allolio, Bruno; Müller, Hans-Helge; Fassnacht, Martin

    2015-03-01

    Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently. The aim of this study was to identify markers with prognostic value for patients in this clinical setting. From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I-III were identified. As an independent validation cohort, 250 patients from three European countries were included. Clinical, histological, and immunohistochemical markers were correlated with recurrence-free (RFS) and overall survival (OS). Although univariable analysis within the German cohort suggested several factors with potential prognostic power, upon multivariable adjustment only a few including age, tumor size, venous tumor thrombus (VTT), and the proliferation marker Ki67 retained significance. Among these, Ki67 provided the single best prognostic value for RFS (hazard ratio [HR] for recurrence, 1.042 per 1% increase; P < .0001) and OS (HR for death, 1.051; P < .0001) which was confirmed in the validation cohort. Accordingly, clinical outcome differed significantly between patients with Ki67 <10%, 10-19%, and ≥20% (for the German cohort: median RFS, 53.2 vs 31.6 vs 9.4 mo; median OS, 180.5 vs 113.5 vs 42.0 mo). Using the combined cohort prognostic scores including tumor size, VTT, and Ki67 were established. Although these scores discriminated slightly better between subgroups, there was no clinically meaningful advantage in comparison with Ki67 alone. This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.

  20. The expression and significance of p53 protein and Ki-67 protein in pterygium

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    Ljubojević Vesna

    2016-01-01

    Full Text Available Background/Aim. Pterygium is considered to be a degenerative disease of the conjunctiva, however, the presence of tumor markers in pterygium reinforces the hypothesis that this lesion is similar to tumor. Inactivation of p53 function removes an obstacle to increased proliferation. Factors affecting the prevalence of p53 expression in pterygium deserve investigation. The aim of the study was to investigate the expression of p53 and Ki-67 proteins in pterygium and normal conjunctiva, the effects of gender and age on p53 expression, and the relationship between the expression of p53 and Ki-67 proteins. Methods. A total of 34 samples of pterygium and 34 samples of the normal conjunctiva were analyzed. The samples were studied by immunohistochemistry using antibodies against p53 and Ki-67. Results. Totally 15 (44% samples of pterygia were p53 positive. Correlations between the expression of p53 protein and sex, and age were not established. The number of Ki-67 positive cells in pterygium (9.74% was significantly higher than the number of Ki-67 positive cells in the normal conjunctiva (1.74%, (p = 0.001. Between the expression of p53 protein and Ki-67 protein in pterygium there was a significant positive correlation (p = 0.000. Conclusion. The prevalence of p53 positive samples of pterygium was 44%. The influence of sex and age on p53 protein expression in pterygium was not found. The increased proliferative acivity was present in the epithelium of pterygium. The expression of Ki-67 protein is associated with the expression of p53 protein in pterygium. The findings of our study support the thesis of pterygium as tissue growth disorder.

  1. Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment

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    Fasching Peter A

    2011-11-01

    Full Text Available Abstract Background The pathological complete response (pCR after neoadjuvant chemotherapy is a surrogate marker for a favorable prognosis in breast cancer patients. Factors capable of predicting a pCR, such as the proliferation marker Ki67, may therefore help improve our understanding of the drug response and its effect on the prognosis. This study investigated the predictive and prognostic value of Ki67 in patients with invasive breast cancer receiving neoadjuvant treatment for breast cancer. Methods Ki67 was stained routinely from core biopsies in 552 patients directly after the fixation and embedding process. HER2/neu, estrogen and progesterone receptors, and grading were also assessed before treatment. These data were used to construct univariate and multivariate models for predicting pCR and prognosis. The tumors were also classified by molecular phenotype to identify subgroups in which predicting pCR and prognosis with Ki67 might be feasible. Results Using a cut-off value of > 13% positively stained cancer cells, Ki67 was found to be an independent predictor for pCR (OR 3.5; 95% CI, 1.4, 10.1 and for overall survival (HR 8.1; 95% CI, 3.3 to 20.4 and distant disease-free survival (HR 3.2; 95% CI, 1.8 to 5.9. The mean Ki67 value was 50.6 ± 23.4% in patients with pCR. Patients without a pCR had an average of 26.7 ± 22.9% positively stained cancer cells. Conclusions Ki67 has predictive and prognostic value and is a feasible marker for clinical practice. It independently improved the prediction of treatment response and prognosis in a group of breast cancer patients receiving neoadjuvant treatment. As mean Ki67 values in patients with a pCR were very high, cut-off values in a high range above which the prognosis may be better than in patients with lower Ki67 values may be hypothesized. Larger studies will be needed in order to investigate these findings further.

  2. Ki-67 labeling index as an adjunct in the diagnosis of serous tubal intraepithelial carcinoma.

    Science.gov (United States)

    Kuhn, Elisabetta; Kurman, Robert J; Sehdev, Ann Smith; Shih, Ie-Ming

    2012-09-01

    There is mounting evidence that serous tubal intraepithelial carcinoma (STIC) may be the immediate precursor of ovarian high-grade serous carcinoma (HGSC) but the criteria for its diagnosis are not well established as highlighted in a recent study showing that interobserver reproducibility, even among expert gynecologic pathologists, was moderate at best. Given the clinical significance of a diagnosis of STIC in a patient who has no other evidence of ovarian carcinoma, this is a serious issue that we felt needed to be addressed. Although it is not clear, at this time, whether such a patient should or should not be treated, the importance of an accurate and reproducible diagnosis of precursors of ovarian carcinoma cannot be underestimated. We hypothesized that an elevated Ki-67 labeling index may aid the diagnosis of STIC. Accordingly, we compared the Ki-67 index of STIC and HGSC to normal fallopian tube epithelium (FTE) in the same patients and to a control group of patients without carcinoma, matched for age. A total of 41 STICs were analyzed, of which 35 were associated with a concurrent HGSC. In FTE, immunoreactivity for Ki-67 was restricted to a few scattered cells (mean 2.0%). No statistically significant difference was found between patients with and without HGSC (P>0.05). However, both STICs and HGSC had significantly higher Ki-67 indices than normal FTE (PSTICs uniformly had an elevated Ki-67 labeling index that ranged from 11.7% to 71.1% (average 35.6%). There was no correlation of the Ki-67 labeling index in the STICs and the associated HGSC, as the labeling index was lower in STIC in 18/35 (51.4%) whereas it was higher in 17/35 (48.6%) (P=0.86). In conclusion, the findings in this study indicate that compared with FTE, STICs have a significantly higher Ki-67 index similar to HGSC. Accordingly, the Ki-67 index can aid the diagnosis of intraepithelial tubal proliferations suspicious for STIC. Therefore, we propose that a Ki-67 index of 10% is a useful

  3. Analysis of clinically relevant values of Ki-67 labeling index in Japanese breast cancer patients.

    Science.gov (United States)

    Tamaki, Kentaro; Ishida, Takanori; Tamaki, Nobumitsu; Kamada, Yoshihiko; Uehara, Kanou; Miyashita, Minoru; Amari, Masakazu; Tadano-Sato, Akiko; Takahashi, Yayoi; Watanabe, Mika; McNamara, Keely; Ohuchi, Noriaki; Sasano, Hironobu

    2014-05-01

    It has become important to standardize the methods of Ki-67 evaluation in breast cancer patients, especially those used in the interpretation and scoring of immunoreactivity. Therefore, in this study, we examined the Ki-67 immunoreactivity of breast cancer surgical specimens processed and stained in the same manner in one single Japanese institution by counting nuclear immunoreactivity in the same fashion. We examined 408 Japanese breast cancers with invasive ductal carcinoma and studied the correlation between Ki-67 labeling index and ER/HER2 status and histological grade of breast cancer. We also analyzed overall survival (OS) and disease-free survival (DFS) of these patients according to individual Ki-67 labeling index. There were statistically significant differences of Ki-67 labeling index between ER positive/HER2 negative and ER positive/HER2 positive, ER negative/HER2 positive or ER negative/HER2 negative, and ER positive/HER2 positive and ER negative/HER2 negative groups (all P < 0.001). There were also statistically significant differences of Ki-67 labeling index among each histological grade (P < 0.001, respectively). As for multivariate analyses, Ki-67 labeling index was strongly associated with OS (HR 39.12, P = 0.031) and DFS (HR 10.85, P = 0.011) in ER positive and HER2 negative breast cancer patients. In addition, a statistically significant difference was noted between classical luminal A group and "20 % luminal A" in DFS (P = 0.039) but not between classical luminal A group and "25 % luminal A" (P = 0.105). A significant positive correlation was detected between Ki-67 labeling index and ER/HER2 status and histological grades of the cases examined in our study. The suggested optimal cutoff point of Ki-67 labeling index is between 20 and 25 % in ER positive and HER2 negative breast cancer patients.

  4. [Unintentional injuries in childhood and adolescence: current prevalence, determinants, and trends: results of the KiGGS study: first follow-up (KiGGS Wave 1)].

    Science.gov (United States)

    Saß, Anke-Christine; Poethko-Müller, C; Rommel, A

    2014-07-01

    In Germany and worldwide, unintentional injuries (UI) are a major health threat for children and adolescents. The first follow-up of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS Wave 1, 2009-2012) continued the national UI monitoring that started with the KiGGS baseline study (2003-2006). The present analysis provides updated information and for the first time gives indications on time trends. KiGGS Wave 1 is a combined nationwide cross-sectional and longitudinal survey by the Robert Koch Institute (RKI) providing information about 12,368 participating children and adolescents (0-17 years old; response rates: 38.8% first time invited, 72.9% reinvited). Parents were asked about their children's UI and poisonings via telephone interviews. Information on UI is available for 11,665 children and adolescents (1-17 years old). The 12-month prevalence rate and 95% confidence interval were calculated, and KiGGS Wave 1 was compared with the KiGGS baseline study. The Rao-Scott chi-square test corrected over the F distribution was used to test for the statistical significance of subgroup differences and trend effects. Within the previous 12 months, 15.5% of all children and adolescents aged 1-17 years were medically treated for UI. UI were significantly more prevalent among boys (17.0%) than among girls (14.0%), and 3.4% of the subjects had more than one accident leading to UI. One in eight children and adolescents who suffered UI stayed in hospital (12.3%) for inpatient treatment for at least one night. The home, childcare and educational institutions, and sports facilities/playgrounds were the predominant accident locations. Compared to the baseline study, neither the overall prevalence of UI nor the gender- and age-specific patterns changed significantly. Since a large proportion of UI is avoidable, knowledge of high-risk subgroups and accident locations is of particular use for prevention. KiGGS Wave 1 makes an important

  5. Ki67/KIT double immunohistochemical staining in cutaneous mast cell tumors from Boxer dogs.

    Science.gov (United States)

    Fonseca-Alves, Carlos Eduardo; Bento, Daniel Diola; Torres-Neto, Rafael; Werner, Juliana; Kitchell, Barbara; Laufer-Amorim, Renée

    2015-10-01

    Cutaneous mast cell tumors (MCTs) are among the most frequent malignant tumors in dogs and Boxer breed dogs have a higher incidence of this disease. Ki67 staining and KIT staining are widely used to predict natural behavior in canine MCT but no previous study has evaluated double staining of these proteins as a prognostic factor. Based on biological behavior predictors in canine MCT, the purpose of this study was to determine the Ki67 proliferative index in KIT positive cells using double stain immunohistochemistry technique. Sixty-nine MCTs from Boxer dogs were selected and a tissue microarray was constructed for the double stained immunohistochemistry. Double positivity (Ki67(+)/KIT(+)) was observed in 20/69 (29%) MCT, with a mean of 9.06 double positive cells per tissue core (range 0.48%-43.97%) and Ki67(-)/KIT(+) animals had a longer survival time than Ki67(+)/KIT(+) animals (p=0.03). Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. PENDIDIKAN KARAKTER KI HADJAR DEWANTARA: STUDI KRITIS PEMIKIRAN KARAKTER DAN BUDI PEKERTI DALAM TINJAUAN ISLAM

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    Muthoifin Muthoifin

    2015-12-01

    Full Text Available What an importance of character, Ki Hadjar makes it as a soul from the concept of his education. Even the government admitted, almost all national educational concepts referring to his idea. the focus of this issue is how the concept of Ki Hadjar's character in the Islamic view. The method used is historical approach, by the technique of content analysis, descriptive and comparative. The data is analyzed to be conclusion from the existing phenomenon. The results of the study, Ki Hadjar's idea about the character is not found the base that is closely related to faith, but rather stands on a universal national identity, it can be seen that the Ki Hadjar wants the Indonesian nation has a good attitude and personality and remain to stand on the personality of the Indonesian nation that has a distinctive culture and personality. While the characters in Islam can not be separated with monotheism and faith.   Keywords: character; Ki Hadjar Dewantara; budi pekerti; Islam.

  7. Automatic Ki-67 counting using robust cell detection and online dictionary learning.

    Science.gov (United States)

    Xing, Fuyong; Su, Hai; Neltner, Janna; Yang, Lin

    2014-03-01

    Ki-67 proliferation index is a valid and important biomarker to gauge neuroendocrine tumor (NET) cell progression within the gastrointestinal tract and pancreas. Automatic Ki-67 assessment is very challenging due to complex variations of cell characteristics. In this paper, we propose an integrated learning-based framework for accurate automatic Ki-67 counting for NET. The main contributions of our method are: 1) A robust cell counting and boundary delineation algorithm that is designed to localize both tumor and nontumor cells. 2) A novel online sparse dictionary learning method to select a set of representative training samples. 3) An automated framework that is used to differentiate tumor from nontumor cells (such as lymphocytes) and immunopositive from immunonegative tumor cells for the assessment of Ki-67 proliferation index. The proposed method has been extensively tested using 46 NET cases. The performance is compared with pathologists' manual annotations. The automatic Ki-67 counting is quite accurate compared with pathologists' manual annotations. This is much more accurate than existing methods.

  8. Ki67 Heterogeneity in Estrogen Receptor-Positive Breast Cancers: Which Tumor Type Has the Most Heterogeneity?

    Science.gov (United States)

    Himuro, Takanori; Horimoto, Yoshiya; Arakawa, Atsushi; Tanabe, Masahiko; Saito, Mitsue

    2016-04-01

    Heterogeneity of Ki67 expression, often seen in breast cancer, can make evaluation of the expression of this marker difficult and give rise to confusion when considering adjuvant treatments for patients. Herein, we investigated estrogen receptor-positive breast cancers to reveal the tumor characteristics associated with Ki67 heterogeneity. Surgical specimens from 85 invasive ductal carcinomas of no special type and 13 invasive lobular carcinomas were examined. We first calculated the differences between Ki67 expression in a hot spot and those in 4 random fields on the same slide. We then evaluated Ki67 heterogeneity within the tumor, based on these differences. Among clinicopathological factors, solid-tubular carcinoma, an architectural growth pattern subtype of invasive ductal carcinoma, correlated with high Ki67 heterogeneity (P Ki67 expression. © The Author(s) 2015.

  9. A comparison of Ki-67 counting methods in luminal Breast Cancer: The Average Method vs. the Hot Spot Method.

    Directory of Open Access Journals (Sweden)

    Min Hye Jang

    Full Text Available In spite of the usefulness of the Ki-67 labeling index (LI as a prognostic and predictive marker in breast cancer, its clinical application remains limited due to variability in its measurement and the absence of a standard method of interpretation. This study was designed to compare the two methods of assessing Ki-67 LI: the average method vs. the hot spot method and thus to determine which method is more appropriate in predicting prognosis of luminal/HER2-negative breast cancers. Ki-67 LIs were calculated by direct counting of three representative areas of 493 luminal/HER2-negative breast cancers using the two methods. We calculated the differences in the Ki-67 LIs (ΔKi-67 between the two methods and the ratio of the Ki-67 LIs (H/A ratio of the two methods. In addition, we compared the performance of the Ki-67 LIs obtained by the two methods as prognostic markers. ΔKi-67 ranged from 0.01% to 33.3% and the H/A ratio ranged from 1.0 to 2.6. Based on the receiver operating characteristic curve method, the predictive powers of the KI-67 LI measured by the two methods were similar (Area under curve: hot spot method, 0.711; average method, 0.700. In multivariate analysis, high Ki-67 LI based on either method was an independent poor prognostic factor, along with high T stage and node metastasis. However, in repeated counts, the hot spot method did not consistently classify tumors into high vs. low Ki-67 LI groups. In conclusion, both the average and hot spot method of evaluating Ki-67 LI have good predictive performances for tumor recurrence in luminal/HER2-negative breast cancers. However, we recommend using the average method for the present because of its greater reproducibility.

  10. Profile of mRNA Expression of Ki-67 in Breast Cancer Patients Pre- and Post- Chemotherapy

    OpenAIRE

    Prihantono, Prihantono; Hatta, Mochammad; Sampepajung, Daniel; Islam, Andi Asadul

    2017-01-01

    Journal International Prihantono Abstract: Background: Proliferation is a distinct hallmarks of cancer. Ki-67 designated as a marker of proliferation in solid tumors. The proliferative activity of tumor demonstrated by expression of Ki-67 in breast cancer has been associated with a poor prognosis. Changes in the relative proportions of Ki-67 can be observed during chemotherapy and may correlated with clinical response in breast cancer. Purpose: Evaluate changes in mRNA expression ...

  11. Clinical relevance of Ki67 gene expression analysis using formalin-fixed paraffin-embedded breast cancer specimens.

    Science.gov (United States)

    Yamamoto, Satoko; Ibusuki, Mutsuko; Yamamoto, Yutaka; Fu, Peifen; Fujiwara, Saori; Murakami, Keiichi; Iwase, Hirotaka

    2013-07-01

    Ki67 is a protein associated with cell cycle activity and shows a good correlation with the growth fraction, which has been proposed as a prognostic or predictive marker in breast cancer. In this study, we aimed to analyze the expression levels of Ki67 (MKI67) messenger RNA (mRNA) derived from formalin-fixed paraffin-embedded (FFPE) tissues for comparison with the immunohistochemical Ki67 labeling index, and investigate the correlation coefficients with clinical outcomes. We analyzed the data of Ki67 mRNA from FFPE and matched fresh-frozen (FF) tissues based on a real-time quantitative reverse-transcription polymerase chain reaction (RT-qPCR) assay system in 203 cases of primary invasive breast cancer. The correlation between Ki67 mRNA expression of either FFPE or FF specimens and Ki67 labeling index was positive, as was the correlation between the FFPE and FF results (P Ki67 mRNA expression of FFPE specimens was significantly associated with clinicopathological characteristics: tumor size, lymph node status, nuclear grade, hormone receptors, human epidermal growth factor receptor 2 (Her2) status, and tumor subtype. In prognostic results, Ki67 gene expression in the FFPE specimens revealed almost similar patterns of significance in Kaplan-Meier curves and univariate and multivariate relapse-free survival results as the Ki67 labeling index. Gene expression analysis of Ki67 of FFPE specimens could be successfully performed using RT-qPCR, closely resembling the significant clinical characteristics of Ki67 labeling index. These results confirm that Ki67 gene expression of FFPE specimens has potential for evaluation of cell cycle activity of breast cancer specimens.

  12. Surgery time interval and molecular subtype may influence Ki67 change after core needle biopsy in breast cancer patients.

    Science.gov (United States)

    Chen, Xiaosong; Zhu, Siji; Fei, Xiaochun; Garfield, David H; Wu, Jiayi; Huang, Ou; Li, Yafen; Zhu, Li; He, Jianrong; Chen, Weiguo; Jin, Xiaolong; Shen, Kunwei

    2015-10-30

    To investigate the accuracy of core needle biopsy (CNB) in evaluating breast cancer estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 status and to identify factors which might be associated with Ki67 value change after CNB. A retrospective study was carried out on 276 patients with paired CNB and surgically removed samples (SRS). Clinico-pathological factors as well as the surgery time interval (STI) between CNB and surgery were analyzed to determine whether there were factors associated with Ki67 value change after CNB. Five tumor subtypes were classified as follows: Luminal A, Luminal B-HER2-, Luminal B-HER2+, Triple Negative (TN), and HER2+. Ki67 value change was calculated as SRS minus CNB. Mean STI after CNB was 4.5 (1-37) days. Good agreement was achieved for ER, PR, and HER2 evaluation between CNB and SRS. However, Ki67 expression level was significantly higher in SRS compared with CNB samples: 29.1 % vs. 26.2 % (P Ki67 change after CNB. Luminal A tumors experienced more Ki67 elevation than Luminal B-HER2- diseases (6.2 % vs -0.1 %, P = 0.014). Patients with longer STI after CNB had a higher Ki67 increase: -1.1 % within 1-2 days, 2.1 % with 3-4 days, and 5.6 % more than 4 days, respectively (P = 0.007). For TN and HER2+ tumors, the Ki67 change was apt to be 0 with STI ≤ 4 days, while a >7 % Ki67 increase was noticed in patients with STI ≥ 5 days. CNB was accurate in evaluating ER, PR, HER2, and molecular subtype status. Ki67 value significantly increased after CNB, which was associated with STI and molecular subtype. Further translational research needs to consider Ki67 changes following CNB among different breast cancer molecular subtypes.

  13. The satisfactory reproducibility of the Ki-67 index in breast carcinoma, and it′s correlation with the recurrence score

    OpenAIRE

    Varsha Manucha; Xinmin Zhang; Rebecca M. Thomas

    2014-01-01

    Objective: The clinical utility of Ki-67 in predicting response to neoadjuvant chemotherapy is limited by lack of an accepted validated method of assessment of Ki-67 and wide variations in the cut-offs. In this study, the interobserver variability in the estimation of Ki-67 proliferation index (PI) and its association with recurrence score (RS) was assessed. Materials and Methods: The interobserver variability was assessed between 3 pathologists in 27 invasive breast carcinomas that had also ...

  14. Reliability of the Ki67-Labelling Index in Core Needle Biopsies of Luminal Breast Cancers is Unaffected by Biopsy Volume.

    Science.gov (United States)

    Focke, C M; Decker, T; van Diest, P J

    2017-05-01

    Assessing prognostic and predictive factors like the Ki67 labelling index (Ki67-LI) in breast cancer core needle biopsies (CNB) may be hampered by undersampling. Our aim was to arrive at a representative assessment of Ki67-LI in CNB of luminal breast cancers by defining optimal cutoffs and establishing the minimum CNB volume needed for highest concordance of Ki67-LI between CNB and subsequent surgical excision biopsy (SEB). We assessed the Ki67-LI in CNB and subsequent SEB of 170 luminal breast cancers according to two counting methods recommended by the International Ki67 in Breast Cancer Working Group and applied the cutoffs to distinguish low and high proliferation given by the St Gallen 2013 and 2015 consensus, respectively. We then compared CNB volume characteristics for cases with concordant and discordant Ki67-LI between CNB versus SEB. Highest concordance (75%, κ = 0.44) between CNB and SEB was achieved using the method that assesses the average tumor Ki67-LI and a cutoff of 20%. No significant differences were found between cases with concordant and discordant Ki67-LI in CNB versus SEB for number of biopsy cores, total core length, tumor tissue length, or total CNB or tumor tissue area size in the CNB for two various cutoffs. A concordance of 75% between CNB and SEB can be achieved for the Ki67-LI using a method assessing average Ki67-LI at the threshold of 20%. Increasing CNB volume did not result in improved agreement rates, indicating that reliability of Ki67 levels in CNB of luminal breast cancers is unaffected by CNB volume.

  15. Separation of KI and KIO3 using 1,4 dioxane

    International Nuclear Information System (INIS)

    Hull, D.R.; Owens, C.W.

    1975-01-01

    A simple and quick procedure was elaborated for the separation of KI and KIO 3 and subsequent scintillation counting. KI-KIO 3 mixture was dissolved in one ml ammoniacal water (pH 8) and 6.5 ml carefully purified 1,4-dioxane was added. The mixture was thoroughly shaken, allowed to stand for several minutes, then centrifuged 3-5 minutes. The supernatant solution (containg KI) was decanted and the KIO 3 precipitate was redissolved by adding one ml ammoniacal water. Again 1.4-dioxane was added. The supernate is added to the first decanted solution. The combined supernates permits determination of the iodide-radioactivity by liquid scintillation counting. The iodate radioactivity may be similarly determined by dissolving the residual KIO 3 in ammoniacal water. (F.Gy.)

  16. Typical and atypical bronchopulmonary carcinoid tumors: a clinicopathologic and KI-67-labeling study.

    Science.gov (United States)

    Costes, V; Marty-Ané, C; Picot, M C; Serre, I; Pujol, J L; Mary, H; Baldet, P

    1995-07-01

    Expression of a proliferating antigen by KI-67 immunohistochemistry was analyzed with a SAMBA 2005 computer-assisted image processor (Traitement de l'Information for des Techniques Nouvelles, Grenoble, France) in 47 surgically resected bronchopulmonary carcinoids embedded in paraffin. The clinicopathologic characteristics and KI-67 labeling, expressed in percentage of stained nuclear surface relative to the total nuclear surface, of 31 typical carcinoids and 16 atypical carcinoids were compared and assessed with respect to patient survival. The proliferation status was significantly higher in histologically atypical than in typical carcinoids. Moreover, using a 4% cutoff, we observed a significant difference for the 4-year overall survival rate. Semiquantitative analysis of the proliferation index by KI-67 immunostaining seemed to be an effective means of identifying high risk subsets among patients with histologically atypical carcinoids and for whom adjuvant chemotherapy could be proposed.

  17. Imaging of striatal dopamine transporters in rat brain with single pinhole SPECT and co-aligned MRI is highly reproducible

    International Nuclear Information System (INIS)

    Booij, Jan; Bruin, Kora de; Win, Maartje M.L. de; Lavini, Cristina Mphil; Heeten, Gerard J. den; Habraken, Jan

    2003-01-01

    A recently developed pinhole high-resolution SPECT system was used to measure striatal to non-specific binding ratios in rats (n = 9), after injection of the dopamine transporter ligand 123 I-FP-CIT, and to assess its test/retest reproducibility. For co-alignment purposes, the rat brain was imaged on a 1.5 Tesla clinical MRI scanner using a specially developed surface coil. The SPECT images showed clear striatal uptake. On the MR images, cerebral and extra-cerebral structures could be easily delineated. The mean striatal to non-specific [ 123 I]FP-CIT binding ratios of the test/retest studies were 1.7 ± 0.2 and 1.6 ± 0.2, respectively. The test/retest variability was approximately 9%. We conclude that the assessment of striatal [ 123 I]FP-CIT binding ratios in rats is highly reproducible

  18. Gain in Body Fat Is Associated with Increased Striatal Response to Palatable Food Cues, whereas Body Fat Stability Is Associated with Decreased Striatal Response

    Science.gov (United States)

    Yokum, Sonja

    2016-01-01

    Cross-sectional brain-imaging studies reveal that obese versus lean humans show greater responsivity of reward and attention regions to palatable food cues, but lower responsivity of reward regions to palatable food receipt. However, these individual differences in responsivity may result from a period of overeating. We conducted a repeated-measures fMRI study to test whether healthy weight adolescent humans who gained body fat over a 2 or 3 year follow-up period show an increase in responsivity of reward and attention regions to a cue signaling impending milkshake receipt and a simultaneous decrease in responsivity of reward regions to milkshake receipt versus adolescents who showed stability of or loss of body fat. Adolescents who gained body fat, who largely remained in a healthy weight range, showed increases in activation in the putamen, mid-insula, Rolandic operculum, and precuneus to a cue signaling impending milkshake receipt versus those who showed stability of or loss of body fat, though these effects were partially driven by reductions in responsivity among the latter groups. Adolescents who gained body fat reported significantly greater milkshake wanting and milkshake pleasantness ratings at follow-up compared to those who lost body fat. Adolescents who gained body fat did not show a reduction in responsivity of reward regions to milkshake receipt or changes in responsivity to receipt and anticipated receipt of monetary reward. Data suggest that initiating a prolonged period of overeating may increase striatal responsivity to food cues, and that maintaining a balance between caloric intake and expenditure may reduce striatal, insular, and Rolandic operculum responsivity. SIGNIFICANCE STATEMENT This novel, repeated-measures brain-imaging study suggests that adolescents who gained body fat over our follow-up period experienced an increase in striatal responsivity to cues for palatable foods compared to those who showed stability of or loss of body fat

  19. Expression of Progestrone Receptor and Proliferative Marker ki 67, in Various Grades of Meningioma

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    Nasrin Shayanfar

    2010-05-01

    Full Text Available Meningiomas are slow-growing neoplasms which recur locally, their morphologic grading is simple but do not always correlate with patient outcome. The aim of present study is to evaluate the status of progesterone receptor (PR and proliferation marker Ki67 in various grades of meningioma in a group of Iranian patients. 78 cases of meningioma were selected from the file of a hospital university. All archival H&E stained sections were reviewed and regraded according to WHO criteria. Immunohistochemical analysis for PR and Ki67 was performed on formalin- fixed, paraffin- embedded samples. PR status considered positive if > 10% of tumor cell's nuclei were strongly immunoreactive, or if > 50% of nuclei were stained with medium intensity. The Ki67 labeling index (LI is defined as the percentage area with strongest immunostaining. PR were positive in 61/63(96.8% of grade I tumors,2/10(20% of grade II,and 0/5(0% of grade III tumors.Ki67 LI was %2.98±2.27 in grade I tumors, %9.30±5.79 in grade II tumors and %34.00±5.47 in grade III tumors. For both markers, differences between grade I,II and III tumors were significant(P<0.001.There was a reverse relationship between mean of Ki67 LI and PR status,with increasing grade of tumor. Evaluation of PR status and Ki67 LI together with conventional histologic evaluation can help in providing more information about the biologic behaviour of meningiomas,especially for those that histological grading is not straightforward.

  20.  Immunohistochemical Expression of ki-67 and p53 in Colorectal Adenomas: A Clinicopathological Study

    Directory of Open Access Journals (Sweden)

    Hussam Hasson Ali

    2011-07-01

    Full Text Available  Objectives: To evaluate the significance of P53 and Ki-67 expression as immunohistochemical markers in early detection of premalignant changes in different types of colorectal adenomas. Also, to correlate immunohistochemical expression of the two markers with different clinicopathological parameters including; age, and sex of the patient, type, site, size and grade of dysplasia of colorectal adenomas.Methods: Forty-seven polypectomy specimens of colorectal adenomas were retrieved from the archival materials of the Gastrointestinal and Hepatic Diseases Teaching Hospital in Baghdad from 2009 - 2010. Four µm section specimens were stained by immunohistochemical technique with Ki-67 and P53 tumor markers. P-values <0.05 were considered statistically significant.Results: Immunohistochemical expressions of Ki-67 and P53 had a significant correlation with the size and grade of dysplasia in colorectal adenomas. However, there was no significant correlation among the immunohistochemical expression of Ki-67 and P53 with the age and gender of the patient, and the type and site of colorectal adenomas. There was no significant correlation between Ki-67 and P53 expressions in colorectal adenomas. Villous adenomas of colorectum showed a significant correlation with the grade of dysplasia, while there was no significant correlation between size and site of colorectal adenoma with the grade of dysplasia.Conclusion: High grade dysplasia with significant positive immunohistochemical markers of Ki-67 and P53 could be valuable parameters for selecting from the total colorectal adenoma population, those most deserving of close surveillance in follow-up cancer prevention programs. It is closely linked with increasing age particularly in patients with a large size adenoma of villous component in their histology.

  1. Effects of the KiVa antibullying program on cyberbullying and cybervictimization frequency among Finnish youth.

    Science.gov (United States)

    Williford, Anne; Elledge, L Christian; Boulton, Aaron J; DePaolis, Kathryn J; Little, Todd D; Salmivalli, Christina

    2013-01-01

    Cyberbullying among school-aged children has received increased attention in recent literature. However, no empirical evidence currently exists on whether existing school-based antibullying programs are effective in targeting the unique aspects of cyberbullying. To address this important gap, the present study investigates the unique effects of the KiVa Antibullying Program on the frequency of cyberbullying and cybervictimization among elementary and middle school youth. Using data from a group randomized controlled trial, multilevel ordinal regression analyses were used to examine differences in the frequencies of cyberbullying and cybervictimization between intervention (N = 9,914) and control students (N = 8,498). The effects of age and gender on frequencies of cyber behaviors were also assessed across conditions. Results revealed a significant intervention effect on the frequency of cybervictimization; KiVa students reported lower frequencies of cybervictimization at posttest than students in a control condition. The effect of condition on the perpetration of cyberbullying was moderated by age. When student age was below the sample mean, KiVa students reported lower frequencies of cyberbullying than students in the control condition. We also found evidence of classroom level variation in cyberbullying and cybervictimization, suggesting cyberbullying is in part a classroom-level phenomenon. KiVa appears to be an efficacious program to address cyber forms of bullying and victimization. We discuss several unique aspects of KiVa that may account for the significant intervention effects. Results suggest that KiVa is an intervention option for schools concerned with reducing cyberbullying behavior and its deleterious effects on children's adjustment.

  2. Typhonium flagelliforme decreases tyrosine kinase and Ki67 expression in mice

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    Chodidjah Chodidjah

    2015-12-01

    Full Text Available Background Worldwide, breast cancer is the most frequent cancer in women after lung cancer. Treatments include surgery, radiation, immunotherapy and chemotherapy, but are not effective. Tyrosine kinase and Ki67 protein are markers of proliferation. Typhonium flagelliforme ethanol extract (TFEE has been shown to inhibit proliferation of Michigan Cancer Foundation-7 (MCF7 cells in culture. The aim of the present study was to examine the effect of administration of TFEE on tyrosine kinase and Ki67 expression in mice. Methods This experimental study using post test randomized design with control group was conducted in 24 tumor-bearing CH3 mice. They were randomly divided into 4 groups, consisting of one control and 3 treatment groups (TI, T2, T3 treated daily for 30 days with 0.2 ml TFEE at dosages of 200, 400, and 800 mg/kgBW, respectively. On day 31 the tumor tissues were collected and their tyrosine kinase and Ki67 expression were levels assessed using ELISA and immunohistochemical staining, respectively. Tyrosine kinase and Ki67 expression levels were analyzed, respectively using Kruskal Wallis test and one-way Anova followed by Bonferroni post hoc test. Results Mean tyrosine kinase level was highest in the control group, followed by T3, T2 and T1 (p=0.019. Mean level of Ki 67 expression was highest in the control group, followed by T2, T3 and T1 (p=0.000. Conclussions Oral administration of TFEE at a dose of 200 mg/kgBW decreases tyrosine kinase levels and Ki 67 expression.

  3. Immunohistochemicai study of Ki- 67 expression in unicystic Ameloblastoma and Dentigerous cyst

    Directory of Open Access Journals (Sweden)

    Eslami M.

    2004-06-01

    Full Text Available Statement of Problem: Differentiation of dentigerous cyst from unicystic ameloblastoma, discovering any initial ameloblastic changes in lining epithelium of dentigerous cyst at early stage, and differentiation between hyperplastic odontogenic epithelium in fibrous capsule of dentigerous cyst from ameloblastic proliferation, need to an accurate and reliable technique."nPurpose: The aim of this study was to determine and compare Ki-67 immunoreactivity in various locations of the epithelium of Dentigerous cyst and Unicystic Ameloblastoma."nMaterials and Methods: In this historical Cohort study, 15 cases of dentigerous cyst and 9 cases of unicystic ameloblastoma were selected. Immunohistochemistry staining was performed by M1B-1 (murine monoclonal antibody against Ki-67. The stained nucleous were counted in basal and suprabasal layer of lining epithelium of both lesions in 3000 epithelial cells. Finally, the percentage of positive cells (presented as labeling index was calculated, t- student test was used to analyze the related data."nResults: Ki-67 (LI in basal layer of Dentigerous cyst (2.59±1.66 and Unicystic Ameloblastoma (3.76±79 had no significant differences, but Ki-67 (LI in suprabasal layer of unicystic ameloblastoma (2.15±0.69 was significantly higher than dentigerous cyst (0.77±0.55 P=0.003."nThe difference between the average numbers of positive cells for Ki-67 (LI in these two lesions was statistically significant (P<0.05 and it was higher in Unicystic Ameloblastoma than Dentigerous cyst."nConclusion: Based on the findings of this study, it is suggested that Ki-67 (LI in suprabasal layer or throughout the epithelium can be considered as a useful marker for differential diagnosis between dentigerous cyst and unicystic ameloblastoma.

  4. HORISONTAALISEN WEB-SIVUN SUUNNITTELU : Esimerkkinä Virtuaalikärsämäki

    OpenAIRE

    Tiri, Erkki

    2012-01-01

    Opinnäytetyön aiheena oli suunnitella ja tehdä Kärsämäen kunnalle web-sivu, joka toisi erillä tavalla esille mitä kunnalla tapahtuu. Virtuaalikärsämäki on suunniteltu toimimaan usealla selaimella. Opinnäytteessä tutkittiin, miten voisi suunnitella horisontaalisesti toimivan sivuston, nor-maalin vertikaalin sijaan. Tuloksena oli toimiva, visuaalinen ja asiakasta miellyttävä web-sivusto. Topic of thesis was to desing a web page for the municipality of Kärsämäki. The page should bring...

  5. EKOLOŠKI IZAZOVI TRGOVINSKOM MENADŽMENTU U GLOBALNOM OKRUŽENJU

    OpenAIRE

    Ćuzović, Sreten; Ćuzović, Đorđe

    2009-01-01

    Trgovinu ne bi trebalo promatrati izvan prostora i vremena. Naprotiv, ugrožavanjem prirodne sredine (po Kotleru fizičke okoline) dolazi do približavanja marketinga i ekologije. Po tom osnovu dobiva pravo građanstva tzv. ekološki marketing, ekotrgovina i sl. Ekolozi nisu protiv marketinga i trgovine. Oni traže da se više uvažavaju ekološki principi. Smatraju da bi se zadatak marketinga i trgovine trebao sastojati u maksimiziranju profita, ali uz očuvanje prirode i životne sredine. Kotler skreć...

  6. Construction of the subtracted cDNA library of striatal neurons treated with long-term morphine.

    Science.gov (United States)

    Bai, Bo; Liu, Hai-qing; Chen, Jing; Li, Ya-lin; Du, Hui; Lu, Hai; Yu, Peng-li

    2011-03-01

    To construct a morphine tolerance model in primarily cultured striatal neurons, and screen the differentially expressed genes in this model using suppression subtractive hybridization (SSH). Sbtracted cDNA libraries were constructed using SSH from normal primarily cultured striatal neurons and long-term morphine treated striatal neurons (10-5 mol/L for 72 hours). To check reliability of the cell culture model, RT-PCR was performed to detect the cAMP-responsive element-binding protein (CREB) mRNA expression. The subtracted clones were prescreened by PCR. The clones containing inserted fragments from forward libraries were sequenced and submitted to GenBank for homology analysis. And the expression levels of genes of interest were confirmed by RT-PCR. Results CREB mRNA expression showed a significant increase in morphine treated striatal neurons (62.85 ± 1.98) compared with normal striatal neurons (28.43 ± 1.46, P library of striatal neurons treated with long-term morphine is constructed. Mtch1 and Akt1 might be the candidate genes for the development of morphine tolerance.

  7. Populations of striatal medium spiny neurons encode vibrotactile frequency in rats: modulation by slow wave oscillations.

    Science.gov (United States)

    Hawking, Thomas G; Gerdjikov, Todor V

    2013-01-01

    Dorsolateral striatum (DLS) is implicated in tactile perception and receives strong projections from somatosensory cortex. However, the sensory representations encoded by striatal projection neurons are not well understood. Here we characterized the contribution of DLS to the encoding of vibrotactile information in rats by assessing striatal responses to precise frequency stimuli delivered to a single vibrissa. We applied stimuli in a frequency range (45-90 Hz) that evokes discriminable percepts and carries most of the power of vibrissa vibration elicited by a range of complex fine textures. Both medium spiny neurons and evoked potentials showed tactile responses that were modulated by slow wave oscillations. Furthermore, medium spiny neuron population responses represented stimulus frequency on par with previously reported behavioral benchmarks. Our results suggest that striatum encodes frequency information of vibrotactile stimuli which is dynamically modulated by ongoing brain state.

  8. Striatal μ-opioid receptor availability predicts cold pressor pain threshold in healthy human subjects

    DEFF Research Database (Denmark)

    Hagelberg, Nora; Aalto, Sargo; Tuominen, Lauri

    2012-01-01

    the potential associations between μ-opioid receptor BP(ND) and psychophysical measures. The results show that striatal μ-opioid receptor BP(ND) predicts cold pressor pain threshold, but not cold pressor pain tolerance or tactile sensitivity. This finding suggests that striatal μ-opioid receptor density......Previous PET studies in healthy humans have shown that brain μ-opioid receptor activation during experimental pain is associated with reductions in the sensory and affective ratings of the individual pain experience. The aim of this study was to find out whether brain μ-opioid receptor binding...... at the resting state, in absence of painful stimulation, can be a long-term predictor of experimental pain sensitivity. We measured μ-opioid receptor binding potential (BP(ND)) with μ-opioid receptor selective radiotracer [(11)C]carfentanil and positron emission tomography (PET) in 12 healthy male subjects...

  9. Overeating Behavior and Striatal Dopamine with 6-[18F]-Fluoro-L--Tyrosine PET

    Directory of Open Access Journals (Sweden)

    Claire E. Wilcox

    2010-01-01

    Full Text Available Eating behavior may be affected by dopamine synthesis capacity. In this study, 6-[18F]-fluoro-L--tyrosine (FMT positron emission tomography (PET uptake in striatal subregions was correlated with BMI (kg/m2 and an estimate of the frequency of prior weight loss attempts in 15 healthy subjects. BMI was negatively correlated with FMT uptake in the dorsal caudate. Although the association between BMI and FMT uptake in the dorsal caudate was not significant upon correction for age and sex, the association fell within the range of a statistical trend. Weight loss attempts divided by years trying was also negatively correlated with FMT uptake in the dorsal putamen (=.05. These results suggest an association between low dorsal striatal presynaptic dopamine synthesis capacity and overeating behavior.

  10. Effects of the modern food environment on striatal function, cognition and regulation of ingestive behavior.

    Science.gov (United States)

    Burke, Mary V; Small, Dana M

    2016-06-01

    Emerging evidence from human and animal studies suggest that consumption of palatable foods rich in fat and/or carbohydrates may produce deleterious influences on brain function independently of body weight or metabolic disease. Here we consider two mechanisms by which diet can impact striatal circuits to amplify food cue reactivity and impair inhibitory control. First, we review findings demonstrating that the energetic properties of foods regulate nucleus accumbens food cue reactivity, a demonstrated predictor of weight gain susceptibility, which is then sensitized by chronic consumption of an energy dense diet. Second, we consider evidence for diet-induced adaptations in dorsal striatal dopamine signaling that is associated with impaired inhibitory control and negative outcome learning.

  11. St Gallen 2015 subtyping of luminal breast cancers: impact of different Ki67-based proliferation assessment methods.

    Science.gov (United States)

    Focke, Cornelia M; van Diest, Paul J; Decker, Thomas

    2016-09-01

    Ki67 has been proposed as prognostic proliferation marker in luminal breast cancer (BC), but little is known on the influence of Ki67 assessment methods on subtyping into luminal A- and B-like tumors. Our aim was to study the influence of different Ki67-labeling index (Ki67-LI) assessment methods on the proportion of BCs classified as luminal A-like. 280 early BCs were subtyped according to the St Gallen 2015 definitions into 71 % luminal (HER2 negative), 6 % luminal B-like (HER2 positive), 13 % triple negative, 1 % HER2 positive (nonluminal), and 9 % special type. Digitized whole slides were counted manually on the screen. We used nine defined counting methods to assess the Ki67-LI (including the International Ki67 in Breast Cancer Working Group recommendations), and compared the resulting medians and the proportions of cancers classified as luminal A-like according to the formerly used cut-off Ki67-LI medians than those measuring an average proliferation (27.45 % vs 16.96 %, p Ki67-LI were found when assessing 1020 compared to counting 100, 200, 300 cells (17.65 vs 33 %, vs 28 %, vs 24.33 %, respectively; p Ki67-LI cut-off cancers varied between 13 and 44 %. The proportion of BCs classified as luminal A-like is highly influenced by the Ki67-LI assessment method. As a consequence, the selection of a specific Ki67-LI assessment method may have a direct effect on the proportion of patients considered having low-risk disease and thus influence therapeutic decision making. This calls for a standardized assessment method.

  12. Predictive value of Ki67 for adjuvant chemotherapy in node-negative, hormone receptor-positive breast cancer.

    Science.gov (United States)

    Sutepvarnon, Apisada; Warnnissorn, Malee; Srimuninnimit, Vichien

    2013-02-01

    Ki67 labeling index (Ki67 LI) is a measure of tumor proliferation. In breast cancer, evidence supporting its prognostic value is clear and its predictive value for response to treatment finds some benefits. However studies of Ki67 LI as a predictive marker in early breast cancer are still limited worldwide and there is no data in Thailand. To assess the predictive value of Ki67 expression for adjuvant chemotherapy in patients with node-negative, hormone receptor-positive breast cancer The authors retrospectively evaluated 127 diagnosed early breast cancer with node-negative, hormone receptor-positive patients and receiving adjuvant systemic treatment at Siriraj hospital. Disease free survival (DFS) was compared with the log-rank test according to Ki67 LI and adjuvant systemic treatment (chemoendocrine therapy and endocrine therapy alone). At a median follow-up of 3.3 years. The 5-year DFS rate was 79% for patients with low Ki67 expression and 75% for patients with high Ki67 expression. Of the 127 patients, 56 (44.1%) received chemoendocrine therapy and 71 (55.9%) were treated with endocrine therapy alone. There was no different effect of DFS among those receiving adjuvant endocrine therapy alone and those receiving adjuvant chemoendocrine therapy depending on Ki67 expression. Among patients with node-negative, hormone receptor-positive breast cancer, a high Ki67 LI had worse DFS trend than a low Ki67 LI but the Ki67 LI did not predict the efficacy of adjuvant chemotherapy.

  13. Assessment of Ki67 expression for breast cancer subtype classification and prognosis in the Nurses' Health Study.

    Science.gov (United States)

    Healey, Megan A; Hirko, Kelly A; Beck, Andrew H; Collins, Laura C; Schnitt, Stuart J; Eliassen, A Heather; Holmes, Michelle D; Tamimi, Rulla M; Hazra, Aditi

    2017-11-01

    Ki67 is a proliferation marker commonly assessed by immunohistochemistry in breast cancer, and it has been proposed as a clinical marker for subtype classification, prognosis, and prediction of therapeutic response. However, the clinical utility of Ki67 is limited by the lack of consensus on the optimal cut point for each application. We assessed Ki67 by immunohistochemistry using Definiens digital image analysis (DIA) in 2653 cases of incident invasive breast cancer diagnosed in the Nurses' Health Study from 1976 to 2006. Ki67 was scored as continuous percentage of positive tumor cells, and dichotomized at various cut points. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models for distant recurrence, breast cancer-specific mortality and overall mortality in relation to luminal subtypes defined with various Ki67 cut points, adjusting for breast cancer prognostic factors, clinico-pathologic features and treatment. DIA was highly correlated with manual scoring of Ki67 (Spearman correlation ρ = 0.86). Mean Ki67 score was higher in grade-defined luminal B (12.6%), HER2-enriched (17.9%) and basal-like (20.6%) subtypes compared to luminal A (8.9%). In multivariable-adjusted models, luminal B tumors had higher breast cancer-specific mortality compared to luminal A cancer classified using various cut points for Ki67 positivity including the 14% cut point routinely reported in the literature (HR 1.38, 95% CI 1.11-1.72, p = 0.004). There was no significant difference in clinical outcomes for ER- tumors according to Ki67 positivity defined at various cut points. Assessment of Ki67 in breast tumors by DIA was a robust and quantitative method. Results from this large prospective cohort study provide support for the clinical relevance of using Ki67 at the 14% cut point for luminal subtype classification and breast cancer prognosis.

  14. Clinicopathological and Prognostic Value of Ki-67 Expression in Bladder Cancer: A Systematic Review and Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Yuejun Tian

    Full Text Available Ki-67 is an established marker of cell proliferation, and the Ki-67 index correlates with the clinical course of several cancer types, including bladder cancer (BC. However, the clinicopathological and prognostic significance of Ki-67 in bladder cancer remains unclear. Therefore, we performed a systematic review and meta-analysis to clarify this relationship.A comprehensive literature search for relevant studies published up to February 1, 2016, was performed using PubMed, Cochrane Library, Embase and ISI Web of Knowledge. The effects of Ki-67 expression on survival outcome in patients with BC and BC subtypes were evaluated. Furthermore, the relationship between Ki-67 expression and the clinicopathological features of BC were assessed.Thirty-one studies with 5147 bladder cancer patients were selected for evaluation. Ki-67 expression was significantly associated with shorter recurrence-free (HR 1.69, 95% CI: 1.33-2.14, progression-free (HR 1.89, 95% CI: 1.43-2.51, overall (HR 2.03, 95% CI: 1.31-3.16, and cancer-specific (HR 1.69, 95% CI: 1.47-1.95 survival. Moreover, whereas high expression was more common in high tumor stage, recurrence status, tumor size, there was no correlation between high Ki-67 expression and age, gender, smoking habits, and tumor number. Importantly, analysis of the different subgroups of BC suggested that significant correlations between high Ki-67 expression and survival outcome (recurrence-free/progression-free/overall/cancer-specific survival are present only in European-American patients.The present results indicate that over-expression of Ki-67 is distinctly correlated with poor patient survival. Ki-67 may serve as a valuable biomarker for prognosis in BC patients, particularly in non-Asian BC patients. The results suggest no significant association between Ki-67 expression and BC prognosis in Asian patients. Further efforts are needed to fully clarify this relationship.

  15. Prolonged striatal disinhibition as a chronic animal model of tic disorders.

    Science.gov (United States)

    Vinner, Esther; Israelashvili, Michal; Bar-Gad, Izhar

    2017-12-01

    Experimental findings and theoretical models have associated Tourette syndrome with abnormal striatal inhibition. The expression of tics, the hallmark symptom of this disorder, has been transiently induced in non-human primates and rodents by the injection of GABA A antagonists into the striatum, leading to temporary disinhibition. The novel chronic model of tic expression utilizes mini-osmotic pumps implanted subcutaneously in the rat's back for prolonged infusion of bicuculline into the dorsolateral striatum. Tics were expressed on the contralateral side to the infusion over a period of multiple days. Tic expression was stable, and maintained similar properties throughout the infusion period. Electrophysiological recordings revealed the existence of tic-related local field potential spikes and individual neuron activity changes that remained stable throughout the infusion period. The striatal disinhibition model provides a unique combination of face validity (tic expression) and construct validity (abnormal striatal inhibition) but is limited to sub-hour periods. The new chronic model extends the period of tic expression to multiple days and thus enables the study of tic dynamics and the effects of behavior and pharmacological agents on tic expression. The chronic model provides similar behavioral and neuronal correlates of tics as the acute striatal disinhibition model but over prolonged periods of time, thus providing a unique, basal ganglia initiated model of tic expression. Chronic expression of symptoms is the key to studying the time varying properties of Tourette syndrome and the effects of multiple internal and external factors on this disorder. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Chronic exposure to dopamine agonists affects the integrity of striatal D2 receptors in Parkinson's patients

    Directory of Open Access Journals (Sweden)

    Marios Politis

    2017-01-01

    Full Text Available We aimed to investigate the integrity and clinical relevance of striatal dopamine receptor type-2 (D2R availability in Parkinson's disease (PD patients. We studied 68 PD patients, spanning from early to advanced disease stages, and 12 healthy controls. All participants received one [11C]raclopride PET scan in an OFF medication condition for quantification of striatal D2R availability in vivo. Parametric images of [11C]raclopride non-displaceable binding potential were generated from the dynamic [11C]raclopride scans using implementation of the simplified reference tissue model with cerebellum as the reference tissue. PET data were interrogated for correlations with clinical data related to disease burden and dopaminergic treatment. PD patients showed a mean 16.7% decrease in caudate D2R and a mean 3.5% increase in putaminal D2R availability compared to healthy controls. Lower caudate [11C]raclopride BPND correlated with longer PD duration. PD patients on dopamine agonist treatment had 9.2% reduced D2R availability in the caudate and 12.8% in the putamen compared to PD patients who never received treatment with dopamine agonists. Higher amounts of lifetime dopamine agonist therapy correlated with reduced D2Rs availability in both caudate and putamen. No associations between striatal D2R availability and levodopa treatment and dyskinesias were found. In advancing PD the caudate and putamen D2R availability are differentially affected. Chronic exposure to treatment with dopamine agonists, but no levodopa, suppresses striatal D2R availability, which may have relevance to output signaling to frontal lobes and the occurrence of executive deficits, but not dyskinesias.

  17. Basal ganglia disorders associated with imbalances in the striatal striosome and matrix compartments

    Directory of Open Access Journals (Sweden)

    Jill R. Crittenden

    2011-09-01

    Full Text Available The striatum is composed principally of GABAergic, medium spiny projection neurons (MSNs that can be categorized based on their gene expression, electrophysiological profiles and input-output circuits. Major subdivisions of MSN populations include 1 those in ventromedial and dorsolateral striatal regions, 2 those giving rise to the direct and indirect pathways, and 3 those that lie in the striosome and matrix compartments. The first two classificatory schemes have enabled advances in understanding of how basal ganglia circuits contribute to disease. However, despite the large number of molecules that are differentially expressed in the striosomes or the extra-striosomal matrix, and the evidence that these compartments have different input-output connections, our understanding of how this compartmentalization contributes to striatal function is still not clear. A broad view is that the matrix contains the direct and indirect pathway MSNs that form parts of sensorimotor and associative circuits, whereas striosomes contain MSNs that receive input from parts of limbic cortex and project directly or indirectly to the dopamine-containing neurons of the substantia nigra, pars compacta. Striosomes are widely distributed within the striatum and are thought to exert global, as well as local, influences on striatal processing by exchanging information with the surrounding matrix, including through interneurons that send processes into both compartments. It has been suggested that striosomes exert and maintain limbic control over behaviors driven by surrounding sensorimotor and associative parts of the striatal matrix. Consistent with this possibility, imbalances between striosome and matrix functions have been reported in relation to neurological disorders, including Huntington’s disease, L-DOPA-induced dyskinesias, dystonia and drug addiction. Here, we consider how signaling imbalances between the striosomes and matrix might relate to symptomatology in

  18. Distinct roles for direct and indirect pathway striatal neurons in reinforcement.

    Science.gov (United States)

    Kravitz, Alexxai V; Tye, Lynne D; Kreitzer, Anatol C

    2012-06-01

    Dopamine signaling is implicated in reinforcement learning, but the neural substrates targeted by dopamine are poorly understood. We bypassed dopamine signaling itself and tested how optogenetic activation of dopamine D1 or D2 receptor–expressing striatal projection neurons influenced reinforcement learning in mice. Stimulating D1 receptor–expressing neurons induced persistent reinforcement, whereas stimulating D2 receptor–expressing neurons induced transient punishment, indicating that activation of these circuits is sufficient to modify the probability of performing future actions.

  19. Quinolinic acid induces disrupts cytoskeletal homeostasis in striatal neurons. Protective role of astrocyte-neuron interaction.

    Science.gov (United States)

    Pierozan, Paula; Ferreira, Fernanda; de Lima, Bárbara Ortiz; Pessoa-Pureur, Regina

    2015-02-01

    Quinolinic acid (QUIN) is an endogenous metabolite of the kynurenine pathway involved in several neurological disorders. Among the several mechanisms involved in QUIN-mediated toxicity, disruption of the cytoskeleton has been demonstrated in striatally injected rats and in striatal slices. The present work searched for the actions of QUIN in primary striatal neurons. Neurons exposed to 10 µM QUIN presented hyperphosphorylated neurofilament (NF) subunits (NFL, NFM, and NFH). Hyperphosphorylation was abrogated in the presence of protein kinase A and protein kinase C inhibitors H89 (20 μM) and staurosporine (10 nM), respectively, as well as by specific antagonists to N-methyl-D-aspartate (50 µM DL-AP5) and metabotropic glutamate receptor 1 (100 µM MPEP). Also, intra- and extracellular Ca(2+) chelators (10 µM BAPTA-AM and 1 mM EGTA, respectively) and Ca(2+) influx through L-type voltage-dependent Ca(2+) channel (10 µM verapamil) are implicated in QUIN-mediated effects. Cells immunostained for the neuronal markers βIII-tubulin and microtubule-associated protein 2 showed altered neurite/neuron ratios and neurite outgrowth. NF hyperphosphorylation and morphological alterations were totally prevented by conditioned medium from QUIN-treated astrocytes. Cocultured astrocytes and neurons interacted with one another reciprocally, protecting them against QUIN injury. Cocultured cells preserved their cytoskeletal organization and cell morphology together with unaltered activity of the phosphorylating system associated with the cytoskeleton. This article describes cytoskeletal disruption as one of the most relevant actions of QUIN toxicity in striatal neurons in culture with soluble factors secreted by astrocytes, with neuron-astrocyte interaction playing a role in neuroprotection. © 2014 Wiley Periodicals, Inc.

  20. The hippocampal-striatal circuit for goal-directed and habitual choice

    OpenAIRE

    Chersi, Fabian

    2014-01-01

    It is now widely accepted that one of the roles of the hippocampus is to maintain episodic spatial representations, while parallel striatal pathways contribute to both declarative and procedural value computations by encoding different input-specific outcome predictions. In this paper we investigate the use of these brain mechanisms for action selection, linking them to model-based and model-free controllers for decision making. To this aim we propose a biologically inspired computational mod...

  1. Liquid computing on and off the edge of chaos with a striatal microcircuit

    Directory of Open Access Journals (Sweden)

    Carlos eToledo-Suárez

    2014-11-01

    Full Text Available In reinforcement learning theories of the basal ganglia, there is a need for the expected rewards corresponding to relevant environmental states to be maintained and modified during the learning process. However, the representation of these states that allows them to be associated with reward expectations remains unclear. Previous studies have tended to rely on pre-defined partitioning of states encoded by disjunct neuronal groups or sparse topological drives. A more likely scenario is that striatal neurons are involved in the encoding of multiple different states through their spike patterns, and that an appropriate partitioning of an environment is learned on the basis of task constraints, thus minimizing the number of states involved in solving a particular task. Here we show that striatal activity is sufficient to implement a liquid state, an important prerequisite for such a computation, whereby transient patterns of striatal activity are mapped onto the relevant states. We develop a simple small scale model of the striatum which can reproduce key features of the experimentally observed activity of the major cell types of the striatum. We then use the activity of this network as input for the supervised training of four simple linear readouts to learn three different functions on a plane, where the network is stimulated with the spike coded position of the agent. We discover that the network configuration that best reproduces striatal activity statistics lies on the edge of chaos and has good performance on all three tasks, but that in general, the edge of chaosis a poor predictor of network performance.

  2. The Fast Spiking Subpopulation of Striatal Neurons Coding for Temporal Cognition of Movements

    Directory of Open Access Journals (Sweden)

    Bo Shen

    2017-12-01

    Full Text Available Background: Timing dysfunctions occur in a number of neurological and psychiatric disorders such as Parkinson’s disease, obsessive-compulsive disorder, autism and attention-deficit-hyperactivity disorder. Several lines of evidence show that disrupted timing processing is involved in specific fronto-striatal abnormalities. The striatum encodes reinforcement learning and procedural motion, and consequently is required to represent temporal information precisely, which then guides actions in proper sequence. Previous studies highlighted the temporal scaling property of timing-relevant striatal neurons; however, it is still unknown how this is accomplished over short temporal latencies, such as the sub-seconds to seconds range.Methods: We designed a task with a series of timing behaviors that required rats to reproduce a fixed duration with robust action. Using chronic multichannel electrode arrays, we recorded neural activity from dorso-medial striatum in 4 rats performing the task and identified modulation response of each neuron to different events. Cell type classification was performed according to a multi-criteria clustering analysis.Results: Dorso-medial striatal neurons (n = 557 were recorded, of which 113 single units were considered as timing-relevant neurons, especially the fast-spiking subpopulation that had trial–to–trial ramping up or ramping down firing modulation during the time estimation period. Furthermore, these timing-relevant striatal neurons had to calibrate the spread of their firing pattern by rewarded experience to express the timing behavior accurately.Conclusion: Our data suggests that the dynamic activities of timing-relevant units encode information about the current duration and recent outcomes, which is needed to predict and drive the following action. These results reveal the potential mechanism of time calibration in a short temporal resolution, which may help to explain the neural basis of motor coordination

  3. DISC1 and striatal volume: a potential risk phenotype for mental illness

    Directory of Open Access Journals (Sweden)

    M. Mallar eChakravarty

    2012-06-01

    Full Text Available Disrupted-in-schizophrenia 1 was originally discovered in a large Scottish family with abnormally high rates of severe mental illness, including schizophrenia, bipolar disorder, and depression. An accumulating body of evidence from genetic, postmortem, and animal data supports a role for DISC1 in different forms of mental illness. DISC1 may play an important role in determining structure and function of several brain regions. One brain region of particular importance for several mental disorders is the striatum, and DISC1 mutant mice have demonstrated an increase in dopamine (D2 receptors in this structure. However, association between DISC1 functional polymorphisms and striatal structure have not been examined in humans to our knowledge. We, therefore hypothesized that there would be a relationship between human striatal volume and DISC1 genotype, specifically in the Leu607Phe (rs6675281 and Ser704Cys (rs821618 single nucleotide polymorphisms. We tested our hypothesis by automatically identifying the striatum in fifty-four healthy volunteers recruited for this study. We also performed an exploratory analysis of cortical thickness, cortical surface area, and structure volume. Our results demonstrate that Phe allele carriers have larger striatal volume bilaterally (left striatum: p=0.017; right striatum: p=0.016. From the exploratory analyses we found that Phe carriers also had larger right hemisphere volumes and right occipital lobe surface area (p=0.014 compared to LeuLeu homozygotes (p=0.0074. However, these exploratory findings do not survive a conservative correction for multiple comparisons. Our findings demonstrate that a functional DISC1 variant influences striatal volumes. Taken together with animal data that this gene influences D2 receptor levels in striatum, a key risk pathway for mental illnesses such as schizophrenia and bipolar disorder may be conferred via DISC1’s effects on the striatum .

  4. A direct ROI quantification method for inherent PVE correction: accuracy assessment in striatal SPECT measurements

    Energy Technology Data Exchange (ETDEWEB)

    Vanzi, Eleonora; De Cristofaro, Maria T.; Sotgia, Barbara; Mascalchi, Mario; Formiconi, Andreas R. [University of Florence, Clinical Pathophysiology, Florence (Italy); Ramat, Silvia [University of Florence, Neurological and Psychiatric Sciences, Florence (Italy)

    2007-09-15

    The clinical potential of striatal imaging with dopamine transporter (DAT) SPECT tracers is hampered by the limited capability to recover activity concentration ratios due to partial volume effects (PVE). We evaluated the accuracy of a least squares method that allows retrieval of activity in regions of interest directly from projections (LS-ROI). An Alderson striatal phantom was filled with striatal to background ratios of 6:1, 9:1 and 28:1; the striatal and background ROIs were drawn on a coregistered X-ray CT of the phantom. The activity ratios of these ROIs were derived both with the LS-ROI method and with conventional SPECT EM reconstruction (EM-SPECT). Moreover, the two methods were compared in seven patients with motor symptoms who were examined with N-3-fluoropropyl-2-{beta}-carboxymethoxy-3-{beta}-(4-iodophenyl) (FP-CIT) SPECT, calculating the binding potential (BP). In the phantom study, the activity ratios obtained with EM-SPECT were 3.5, 5.3 and 17.0, respectively, whereas the LS-ROI method resulted in ratios of 6.2, 9.0 and 27.3, respectively. With the LS-ROI method, the BP in the seven patients was approximately 60% higher than with EM-SPECT; a linear correlation between the LS-ROI and the EM estimates was found (r = 0.98, p = 0.03). The LS-ROI PVE correction capability is mainly due to the fact that the ill-conditioning of the LS-ROI approach is lower than that of the EM-SPECT one. The LS-ROI seems to be feasible and accurate in the examination of the dopaminergic system. This approach can be fruitful in monitoring of disease progression and in clinical trials of dopaminergic drugs. (orig.)

  5. Cortico-striatal spike-timing dependent plasticity after activation of subcortical pathways

    Directory of Open Access Journals (Sweden)

    Jan M Schulz

    2010-07-01

    Full Text Available Cortico-striatal spike-timing dependent plasticity (STDP is modulated by dopamine in vitro. The present study investigated STDP in vivo using alternative procedures for modulating dopaminergic inputs. Postsynaptic potentials (PSP were evoked in intracellularly recorded spiny neurons by electrical stimulation of the contralateral motor cortex. PSPs often consisted of up to three distinct components, likely representing distinct cortico-striatal pathways. After baseline recording, bicuculline (BIC was ejected into the superior colliculus (SC to disinhibit visual pathways to the dopamine cells and striatum. Repetitive cortical stimulation (~60; 0.2 Hz was then paired with postsynaptic spike discharge induced by an intracellular current pulse, with each pairing followed 250 ms later by a light flash to the contralateral eye (n=13. Changes in PSPs, measured as the maximal slope normalised to 5 min pre, ranged from potentiation (~120% to depression (~80%. The determining factor was the relative timing between PSP components and spike: PSP components coinciding or closely following the spike tended towards potentiation, whereas PSP components preceding the spike were depressed. Importantly, STDP was only seen in experiments with successful BIC-mediated disinhibition (n=10. Cortico-striatal high-frequency stimulation (50 pulses at 100 Hz followed 100 ms later by a light flash did not induce more robust synaptic plasticity (n=9. However, an elevated post-light spike rate correlated with depression across plasticity protocols (R2=0.55, p=0.009, n=11 active neurons. These results confirm that the direction of cortico-striatal plasticity is determined by the timing of pre- and postsynaptic activity and that synaptic modification is dependent on the activation of additional subcortical inputs.

  6. Striatal connectivity changes following gambling wins and near-misses: Associations with gambling severity

    Directory of Open Access Journals (Sweden)

    Ruth J. van Holst

    2014-01-01

    These findings corroborate the ‘non-categorical’ nature of reward processing in gambling: near-misses and full-misses are objectively identical outcomes that are processed differentially. Ventral striatal connectivity with the insula correlated positively with gambling severity in the illusion of control contrast, which could be a risk factor for the cognitive distortions and loss-chasing that are characteristic of problem gambling.

  7. Striatal activation by optogenetics induces dyskinesias in the 6-hydroxydopamine rat model of Parkinson disease.

    Science.gov (United States)

    F Hernández, Ledia; Castela, Ivan; Ruiz-DeDiego, Irene; Obeso, Jose A; Moratalla, Rosario

    2017-04-01

    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.

  8. Increased TRPC5 glutathionylation contributes to striatal neuron loss in Huntington's disease.

    Science.gov (United States)

    Hong, Chansik; Seo, Hyemyung; Kwak, Misun; Jeon, Jeha; Jang, Jihoon; Jeong, Eui Man; Myeong, Jongyun; Hwang, Yu Jin; Ha, Kotdaji; Kang, Min Jueng; Lee, Kyu Pil; Yi, Eugene C; Kim, In-Gyu; Jeon, Ju-Hong; Ryu, Hoon; So, Insuk

    2015-10-01

    Aberrant glutathione or Ca(2+) homeostasis due to oxidative stress is associated with the pathogenesis of neurodegenerative disorders. The Ca(2+)-permeable transient receptor potential cation (TRPC) channel is predominantly expressed in the brain, which is sensitive to oxidative stress. However, the role of the TRPC channel in neurodegeneration is not known. Here, we report a mechanism of TRPC5 activation by oxidants and the effect of glutathionylated TRPC5 on striatal neurons in Huntington's disease. Intracellular oxidized glutathione leads to TRPC5 activation via TRPC5 S-glutathionylation at Cys176/Cys178 residues. The oxidized glutathione-activated TRPC5-like current results in a sustained increase in cytosolic Ca(2+), activated calmodulin-dependent protein kinase and the calpain-caspase pathway, ultimately inducing striatal neuronal cell death. We observed an abnormal glutathione pool indicative of an oxidized state in the striatum of Huntington's disease transgenic (YAC128) mice. Increased levels of endogenous TRPC5 S-glutathionylation were observed in the striatum in both transgenic mice and patients with Huntington's disease. Both knockdown and inhibition of TRPC5 significantly attenuated oxidation-induced striatal neuronal cell death. Moreover, a TRPC5 blocker improved rearing behaviour in Huntington's disease transgenic mice and motor behavioural symptoms in littermate control mice by increasing striatal neuron survival. Notably, low levels of TRPC1 increased the formation of TRPC5 homotetramer, a highly Ca(2+)-permeable channel, and stimulated Ca(2+)-dependent apoptosis in Huntington's disease cells (STHdh(Q111/111)). Taken together, these novel findings indicate that increased TRPC5 S-glutathionylation by oxidative stress and decreased TRPC1 expression contribute to neuronal damage in the striatum and may underlie neurodegeneration in Huntington's disease. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain

  9. Increased TRPC5 glutathionylation contributes to striatal neuron loss in Huntington’s disease

    Science.gov (United States)

    Hong, Chansik; Seo, Hyemyung; Kwak, Misun; Jeon, Jeha; Jang, Jihoon; Jeong, Eui Man; Myeong, Jongyun; Hwang, Yu Jin; Ha, Kotdaji; Kang, Min Jueng; Lee, Kyu Pil; Yi, Eugene C.; Kim, In-Gyu; Jeon, Ju-Hong

    2015-01-01

    Aberrant glutathione or Ca2+ homeostasis due to oxidative stress is associated with the pathogenesis of neurodegenerative disorders. The Ca2+-permeable transient receptor potential cation (TRPC) channel is predominantly expressed in the brain, which is sensitive to oxidative stress. However, the role of the TRPC channel in neurodegeneration is not known. Here, we report a mechanism of TRPC5 activation by oxidants and the effect of glutathionylated TRPC5 on striatal neurons in Huntington’s disease. Intracellular oxidized glutathione leads to TRPC5 activation via TRPC5 S-glutathionylation at Cys176/Cys178 residues. The oxidized glutathione-activated TRPC5-like current results in a sustained increase in cytosolic Ca2+, activated calmodulin-dependent protein kinase and the calpain-caspase pathway, ultimately inducing striatal neuronal cell death. We observed an abnormal glutathione pool indicative of an oxidized state in the striatum of Huntington’s disease transgenic (YAC128) mice. Increased levels of endogenous TRPC5 S-glutathionylation were observed in the striatum in both transgenic mice and patients with Huntington’s disease. Both knockdown and inhibition of TRPC5 significantly attenuated oxidation-induced striatal neuronal cell death. Moreover, a TRPC5 blocker improved rearing behaviour in Huntington’s disease transgenic mice and motor behavioural symptoms in littermate control mice by increasing striatal neuron survival. Notably, low levels of TRPC1 increased the formation of TRPC5 homotetramer, a highly Ca2+-permeable channel, and stimulated Ca2+-dependent apoptosis in Huntington’s disease cells (STHdhQ111/111). Taken together, these novel findings indicate that increased TRPC5 S-glutathionylation by oxidative stress and decreased TRPC1 expression contribute to neuronal damage in the striatum and may underlie neurodegeneration in Huntington’s disease. PMID:26133660

  10. Extrasynaptic neurotransmission in the modulation of brain function. Focus on the striatal neuronal-glial networks

    Directory of Open Access Journals (Sweden)

    Kjell eFuxe

    2012-06-01

    Full Text Available Extrasynaptic neurotransmission is an important short distance form of volume transmission (VT and describes the extracellular diffusion of transmitters and modulators after synaptic spillover or extrasynaptic release in the local circuit regions binding to and activating mainly extrasynaptic neuronal and glial receptors in the neuroglial networks of the brain. Receptor-receptor interactions in G protein-coupled receptor (GPCR heteromers play a major role, on dendritic spines and nerve terminals including glutamate synapses, in the integrative processes of the extrasynaptic signaling. Heteromeric complexes between GPCR and ion-channel receptors play a special role in the integration of the synaptic and extrasynaptic signals. Changes in extracellular concentrations of the classical synaptic neurotransmitters glutamate and GABA found with microdialysis is likely an expression of the activity of the neuron-astrocyte unit of the brain and can be used as an index of VT-mediated actions of these two neurotransmitters in the brain. Thus, the activity of neurons may be functionally linked to the activity of astrocytes, which may release glutamate and GABA to the extracellular space where extrasynaptic glutamate and GABA receptors do exist. Wiring transmission (WT and VT are fundamental properties of all neurons of the CNS but the balance between WT and VT varies from one nerve cell population to the other. The focus is on the striatal cellular networks, and the WT and VT and their integration via receptor heteromers are described in the GABA projection neurons, the glutamate, dopamine, 5-hydroxytryptamine (5-HT and histamine striatal afferents, the cholinergic interneurons and different types of GABA interneurons. In addition, the role in these networks of VT signaling of the energy-dependent modulator adenosine and of endocannabinoids mainly formed in the striatal projection neurons will be underlined to understand the communication in the striatal

  11. Concomitant Appearance of Pisa Syndrome and Striatal Hand in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Sanjay Pandey

    2011-10-01

    Full Text Available Pisa syndrome is (PS usually seen in patients receiving antipsychotic drugs and characterised by lateral flexion of trunk and axial dystonia. It is believed that antipsychotic drugs lead to dopamine blockage causing PS. We describe a Parkinson’s disease patient who was doing well with levodopa/carbidopa for 3 years and developed lateral flexion of trunk. His abnormal posture used to completely improve upon lying down position. He also had striatal hand deformity suggestive of focal dystonia.

  12. Dopamine D1-like receptors depress excitatory synaptic transmissions in striatal neurons after transient forebrain ischemia.

    Science.gov (United States)

    Zhang, Yuchun; Deng, Ping; Ruan, Yiwen; Xu, Zao C

    2008-08-01

    Spiny neurons in the neostriatum are highly vulnerable to ischemia. Despite an enormous body of research suggesting that dopamine is involved in ischemia-induced neuronal loss in the striatum, it remains unclear how dopamine interacts with the glutamatergic excitotoxicity that is widely accepted as a major cause of ischemic cell death. Our study was designed to investigate the effects of dopamine D1 receptor (D1R) activation on excitatory neurotransmission in postischemic striatal neurons. We used the 4-vessel occlusion ischemia model and brain slice preparations. Whole-cell voltage-clamp recording was performed on striatal neurons to measure excitatory postsynaptic currents (EPSCs). Systemic administration of a D1R agonist after ischemia and hematoxylin/eosin staining were performed to evaluate the effects of D1R activation on ischemia-induced neuronal degeneration in the striatum. D1R activation depressed EPSCs in postischemic striatal neurons. The depression was attributable to inhibition of presynaptic release. An activator of cAMP-dependent protein kinase A (PKA) mimicked the depressive effects of D1R activation. Bath application of a PKA inhibitor blocked the depression of EPSCs, whereas intracellular postsynaptic application of the PKA inhibitor had no effect. The D1R agonist failed to reduce EPSC amplitude in the presence of an adenosine A1 receptor antagonist. Systemic administration of a D1R agonist after ischemia significantly attenuated ischemia-induced cell death in the striatum. These results indicate that D1R activation presynaptically depresses excitatory synaptic transmission in striatal neurons after ischemia through activation of PKA and adenosine A1 receptors and thus demonstrate a novel mechanism of D1R-mediated protection against ischemia.

  13. High-throughput automated scoring of Ki67 in breast cancer tissue microarrays from the Breast Cancer Association Consortium (BCAC) : Large-scale scoring of Ki67 in breast cancer TMAs

    NARCIS (Netherlands)

    M. Abubakar (Mustapha); W.J. Howat (Will); F. Daley (Frances); L. Zabaglo (Lila); L.A. McDuffus (Leigh-Anne); F. Blows (Fiona); P. Coulson (Penny); H.A. Raza (Ali); J. Benitez (Javier); R.L. Milne (Roger); H. Brenner (Hermann); C. Stegmaier (Christa); A. Mannermaa (Arto); J. Chang-Claude (Jenny); A. Rudolph (Anja); P. Sinn (Peter); F.J. Couch (Fergus); P. Devilee (Peter); J.D. Figueroa (Jonine); M.E. Sherman (Mark); J. Lissowska (Jolanta); S.M. Hewitt (Stephen); D. Eccles (Diana); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); J.W.M. Martens (John); C.H.M. van Deurzen (Carolien); K. Investigators (Kconfab); M.K. Bolla (Manjeet); Q. Wang (Qin); M. Jones (Michael); M. Schoemaker (Minouk); A. Broeks (Annegien); F.E. van Leeuwen (Flora); L.J. van 't Veer (Laura); A.J. Swerdlow (Anthony ); N. Orr (Nick); M. Dowsett (Mitch); D.F. Easton (Douglas); M. Schmidt (Marjanka); P.D.P. Pharoah (Paul); M. García-Closas (Montserrat)

    2016-01-01

    textabstractAutomated methods are needed to facilitate high-throughput and reproducible scoring of Ki67 and other markers in breast cancer tissue microarrays (TMAs) in large-scale studies. To address this need, we developed an automated protocol for Ki67 scoring and evaluated its performance in

  14. Prognostic significance of Ki67 in Chinese women diagnosed with ER+/HER2-breast cancers by the 2015 St. Gallen consensus classification.

    Science.gov (United States)

    Hu, Yue; Gu, Ran; Zhao, Jinghua; Yang, Yaping; Liu, Fengtao; Jin, Liang; Chen, Kai; Jia, Haixia; Wang, Hongli; Liu, Qiang; Su, Fengxi; Jia, Weijuan

    2017-01-06

    This study evaluated the distribution pattern of the Ki67-labeling index (LI) among patients at a Chinese breast cancer center, and analyzed its prognostic significance in the 2015 St Gallen consensus breast cancer classification, estrogen receptor-positive and human epidermal growth factor receptor 2-negative(ER + /HER2 - )subtype. We classified 939 women with ER + /HER2 - breast cancer into three groups by Ki67-LI levels, and followed their clinicopathologic characteristics and prognoses. In the 939 eligible subjects, 342 had Ki67-LI ≤10% (Ki67 Low ), 281 had Ki67-LI between 10 and 30% (Ki67 Medium ), and 316 had Ki67-LI ≥30% (Ki67 High ). Although the Ki67 High group had less favorable clinicopathologic factors, the Ki67 Medium group's factors varied considerably. Kaplan-Meier estimates showed that disease-free survival(DFS) for the Ki67 Medium group was significantly shorter than the Ki67 Low group but longer than the Ki67 High group. Ki67-LI had independent prognostic significance in multivariate analysis. Other diagnostic factors, including tumor size >2 cm, positive lymph nodes, and grade III disease, were significantly associated with poorer disease-free survival only in the Ki67 Medium group. For patients with ER + /HER2 - breast cancer, we confirmed three distinct risk patterns by Ki67-LI levels according to the 2015 St Gallen consensus. For patients with clearly low or high Ki67-LI, straightforward clinical decisions could be offered, but for patients with intermediate Ki67-LI, other factors might provide valuable information.

  15. Contribution of fronto-striatal regions to emotional valence and repetition under cognitive conflict.

    Science.gov (United States)

    Chun, Ji-Won; Park, Hae-Jeong; Kim, Dai Jin; Kim, Eosu; Kim, Jae-Jin

    2017-07-01

    Conflict processing mediated by fronto-striatal regions may be influenced by emotional properties of stimuli. This study aimed to examine the effects of emotion repetition on cognitive control in a conflict-provoking situation. Twenty-one healthy subjects were scanned using functional magnetic resonance imaging while performing a sequential cognitive conflict task composed of emotional stimuli. The regional effects were analyzed according to the repetition or non-repetition of cognitive congruency and emotional valence between the preceding and current trials. Post-incongruence interference in error rate and reaction time was significantly smaller than post-congruence interference, particularly under repeated positive and non-repeated positive, respectively, and post-incongruence interference, compared to post-congruence interference, increased activity in the ACC, DLPFC, and striatum. ACC and DLPFC activities were significantly correlated with error rate or reaction time in some conditions, and fronto-striatal connections were related to the conflict processing heightened by negative emotion. These findings suggest that the repetition of emotional stimuli adaptively regulates cognitive control and the fronto-striatal circuit may engage in the conflict adaptation process induced by emotion repetition. Both repetition enhancement and repetition suppression of prefrontal activity may underlie the relationship between emotion and conflict adaptation. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Reduced amygdala and ventral striatal activity to happy faces in PTSD is associated with emotional numbing.

    Directory of Open Access Journals (Sweden)

    Kim L Felmingham

    Full Text Available There has been a growing recognition of the importance of reward processing in PTSD, yet little is known of the underlying neural networks. This study tested the predictions that (1 individuals with PTSD would display reduced responses to happy facial expressions in ventral striatal reward networks, and (2 that this reduction would be associated with emotional numbing symptoms. 23 treatment-seeking patients with Posttraumatic Stress Disorder were recruited from the treatment clinic at the Centre for Traumatic Stress Studies, Westmead Hospital, and 20 trauma-exposed controls were recruited from a community sample. We examined functional magnetic resonance imaging responses during the presentation of happy and neutral facial expressions in a passive viewing task. PTSD participants rated happy facial expression as less intense than trauma-exposed controls. Relative to controls, PTSD participants revealed lower activation to happy (-neutral faces in ventral striatum and and a trend for reduced activation in left amygdala. A significant negative correlation was found between emotional numbing symptoms in PTSD and right ventral striatal regions after controlling for depression, anxiety and PTSD severity. This study provides initial evidence that individuals with PTSD have lower reactivity to happy facial expressions, and that lower activation in ventral striatal-limbic reward networks may be associated with symptoms of emotional numbing.

  17. Reduced striatal dopamine D2/3 receptor availability in Body Dysmorphic Disorder.

    Science.gov (United States)

    Vulink, Nienke C; Planting, Robin S; Figee, Martijn; Booij, Jan; Denys, Damiaan

    2016-02-01

    Though the dopaminergic system is implicated in Obsessive Compulsive and Related Disorders (OCRD), the dopaminergic system has never been investigated in-vivo in Body Dysmorphic Disorder (BDD). In line with consistent findings of reduced striatal dopamine D2/3 receptor availability in Obsessive Compulsive Disorder (OCD), we hypothesized that the dopamine D2/3 receptor availability in the striatum will be lower in patients with BDD in comparison to healthy subjects. Striatal dopamine D2/3 receptor Binding Potential (BPND) was examined in 12 drug-free BDD patients and 12 control subjects pairwise matched by age, sex, and handedness using [(123)I]iodobenzamide Single Photon Emission Computed Tomography (SPECT; bolus/constant infusion technique). Regions of interest were the caudate nucleus and the putamen. BPND was calculated as the ratio of specific striatal to binding in the occipital cortex (representing nonspecific binding). Compared to controls, dopamine D2/3 receptor BPND was significantly lower in BDD, both in the putamen (p=0.017) and caudate nucleus (p=0.022). This study provides the first evidence of a disturbed dopaminergic system in BDD patients. Although previously BDD was classified as a separate disorder (somatoform disorder), our findings give pathophysiological support for the recent reclassification of BDD to the OCRD in DSM-5. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  18. Beyond Neuronal Activity Markers: Select Immediate Early Genes in Striatal Neuron Subtypes Functionally Mediate Psychostimulant Addiction

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    Ramesh Chandra

    2017-06-01

    Full Text Available Immediate early genes (IEGs were traditionally used as markers of neuronal activity in striatum in response to stimuli including drugs of abuse such as psychostimulants. Early studies using these neuronal activity markers led to important insights in striatal neuron subtype responsiveness to psychostimulants. Such studies have helped identify striatum as a critical brain center for motivational, reinforcement and habitual behaviors in psychostimulant addiction. While the use of IEGs as neuronal activity markers in response to psychostimulants and other stimuli persists today, the functional role and implications of these IEGs has often been neglected. Nonetheless, there is a subset of research that investigates the functional role of IEGs in molecular, cellular and behavioral alterations by psychostimulants through striatal medium spiny neuron (MSN subtypes, the two projection neuron subtypes in striatum. This review article will address and highlight the studies that provide a functional mechanism by which IEGs mediate psychostimulant molecular, cellular and behavioral plasticity through MSN subtypes. Insight into the functional role of IEGs in striatal MSN subtypes could provide improved understanding into addiction and neuropsychiatric diseases affecting striatum, such as affective disorders and compulsive disorders characterized by dysfunctional motivation and habitual behavior.

  19. Dermatoglyphic asymmetries and fronto-striatal dysfunction in young-adults reporting non-clinical psychosis

    Science.gov (United States)

    Mittal, Vijay A.; Dean, Derek J.; Pelletier, Andrea

    2012-01-01

    Objective Growing evidence indicates that non-clinical psychotic-like experiences occur in otherwise healthy individuals, suggesting that psychosis may occur on a continuum. However, little is know about how the diathesis for formal psychosis maps on to individuals at the non-clinical side of this continuum. Our current understanding of the pathophysiology of schizophrenia implicates certain key factors such as early developmental abnormalities and fronto-striatal dysfunction. To date, no studies have examined these core factors in the context of non-clinical psychosis. Method A total of 221 young adults were assessed for distressing attenuated positive symptoms (DAPS), dermatoglyphic asymmetries (a marker of early developmental insult), and procedural memory (a proxy for fronto-striatal function). Results Participants reporting DAPS (n=16; 7.2%) and no-DAPS (n=205; 92.7%) were split into two groups. The DAPS group showed significantly elevated depression, elevated dermatoglyphic asymmetries, and a pattern of procedural learning consistent with other studies with formally psychotic patients. Conclusion The results indicate that the non-clinical side of the psychosis continuum also shares key vulnerability factors implicated in schizophrenia, suggesting that both early developmental disruption and abnormalities in fronto-striatal function are core aspects underlying the disorder. PMID:22519833

  20. Dermatoglyphic asymmetries and fronto-striatal dysfunction in young adults reporting non-clinical psychosis.

    Science.gov (United States)

    Mittal, V A; Dean, D J; Pelletier, A

    2012-10-01

    Growing evidence indicates that non-clinical psychotic-like experiences occur in otherwise healthy individuals, suggesting that psychosis may occur on a continuum. However, little is known about how the diathesis for formal psychosis maps on to individuals at the non-clinical side of this continuum. Our current understanding of the pathophysiology of schizophrenia implicates certain key factors such as early developmental abnormalities and fronto-striatal dysfunction. To date, no studies have examined these core factors in the context of non-clinical psychosis. A total of 221 young adults were assessed for distressing attenuated positive symptoms (DAPS), dermatoglyphic asymmetries (a marker of early developmental insult), and procedural memory (a proxy for fronto-striatal function). Participants reporting DAPS (n = 16; 7.2%) and no-DAPS (n = 205; 92.7%) were split into two groups. The DAPS group showed significantly elevated depression, elevated dermatoglyphic asymmetries, and a pattern of procedural learning consistent with other studies with formally psychotic patients. The results indicate that the non-clinical side of the psychosis continuum also shares key vulnerability factors implicated in schizophrenia, suggesting that both early developmental disruption and abnormalities in fronto-striatal function are core aspects underlying the disorder. © 2012 John Wiley & Sons A/S.

  1. A negative relationship between ventral striatal loss anticipation response and impulsivity in borderline personality disorder.

    Science.gov (United States)

    Herbort, Maike C; Soch, Joram; Wüstenberg, Torsten; Krauel, Kerstin; Pujara, Maia; Koenigs, Michael; Gallinat, Jürgen; Walter, Henrik; Roepke, Stefan; Schott, Björn H

    2016-01-01

    Patients with borderline personality disorder (BPD) frequently exhibit impulsive behavior, and self-reported impulsivity is typically higher in BPD patients when compared to healthy controls. Previous functional neuroimaging studies have suggested a link between impulsivity, the ventral striatal response to reward anticipation, and prediction errors. Here we investigated the striatal neural response to monetary gain and loss anticipation and their relationship with impulsivity in 21 female BPD patients and 23 age-matched female healthy controls using functional magnetic resonance imaging (fMRI). Participants performed a delayed monetary incentive task in which three categories of objects predicted a potential gain, loss, or neutral outcome. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11). Compared to healthy controls, BPD patients exhibited significantly reduced fMRI responses of the ventral striatum/nucleus accumbens (VS/NAcc) to both reward-predicting and loss-predicting cues. BIS-11 scores showed a significant positive correlation with the VS/NAcc reward anticipation responses in healthy controls, and this correlation, while also nominally positive, failed to reach significance in BPD patients. BPD patients, on the other hand, exhibited a significantly negative correlation between ventral striatal loss anticipation responses and BIS-11 scores, whereas this correlation was significantly positive in healthy controls. Our results suggest that patients with BPD show attenuated anticipation responses in the VS/NAcc and, furthermore, that higher impulsivity in BPD patients might be related to impaired prediction of aversive outcomes.

  2. Disrupted functional connectivity of striatal sub-regions in Bell's palsy patients

    Directory of Open Access Journals (Sweden)

    Wenwen Song

    2017-01-01

    Full Text Available The striatum plays an important role in controlling motor function in humans, and its degeneration has the ability to cause severe motor disorders. More specifically, previous studies have demonstrated a disruption in the connectivity of the cortico-striatal loop in patients suffering from motor disorders caused by dopamine dysregulation, such as Parkinson's disease. However, little is known about striatal functional connectivity in patients with motor dysfunction not caused by dopamine dysregulation. In this study, we used early-state Bell's palsy (BP patients (within 14 days of onset to investigate how functional connectivity between the striatum and motor cortex is affected by peripheral nerve injury in which the dopamine system remains fully functional. We found a significant increase in the connectivity between the contralateral putamen, and the ipsilateral primary sensory (S1 and motor cortex (M1 in BP patients compared to healthy controls. We also found increased connectivity between the ventral striatum and supplementary motor area (SMA, and the dorsal caudate and medial prefrontal lobe in BP patients compared to healthy controls. Our results demonstrate that the entirety of the striatum is affected following acute peripheral nerve injury, and suggests that this disrupted striatal functional connectivity may reflect a compensatory mechanism for the sensory-motor mismatch caused by BP.

  3. Rapid eye movement sleep behaviour disorder and striatal dopamine depletion in patients with Parkinson's disease.

    Science.gov (United States)

    Chung, S J; Lee, Y; Lee, J J; Lee, P H; Sohn, Y H

    2017-10-01

    Rapid eye movement sleep behaviour disorder (RBD) is related to striatal dopamine depletion. This study was performed to confirm whether clinically probable RBD (cpRBD) in patients with Parkinson's disease (PD) is associated with a specific pattern of striatal dopamine depletion. A prospective survey was conducted using the RBD Screening Questionnaire (RBDSQ) in 122 patients with PD who had undergone dopamine transporter (DAT) positron emission tomography scan. Patients with cpRBD (RBDSQ ≥ 7) exhibited greater motor deficits, predominantly in the less-affected side and axial symptoms, and were prescribed higher levodopa-equivalent doses at follow-up than those without cpRBD (RBDSQ ≤ 4), despite their similar disease and treatment durations. Compared to patients without cpRBD, those with cpRBD showed lower DAT activities in the putamen, particularly in the less-affected side in all putaminal subregions, and a tendency to be lower in the ventral striatum. In addition, greater motor deficits in patients with cpRBD than in those without cpRBD remained significant after controlling for DAT binding in the putamen and other confounding variables. These results demonstrated that the presence of RBD in patients with PD is associated with different patterns of both motor deficit distribution and striatal DAT depletion, suggesting that the presence of RBD represents a distinct PD subtype with a malignant motor parkinsonism. © 2017 EAN.

  4. Tamoxifen counteracts estradiol induced effects on striatal and hypophyseal dopamine receptors

    International Nuclear Information System (INIS)

    Ferretti, C.; Blengio, M.; Ghi, P.; Racca, S.; Genazzani, E.; Portaleone, P.

    1988-01-01

    We investigated the ability of Tamoxifen (TAM), an antiestrogen drug, to counteract the modification induced by estrogens on dopamine (DA) receptors on striatum and on adenohypophysis of ovex female rats. Subacute treatment with 17β-estradiol (E 2 ) at both low (0.1 μg/kg) and high (20 μg/kg) doses confirmed its ability to increase the number of striatal 3 H-Spiperone ( 3 H-SPI) binding sites in a dose dependent manner. By contrast in the pituitary, only high doses of estrogen were effective in reducing the number of DA receptors. We treated ovex female rats for 15 days with TAM alone or associated with E 2 , to see if these estrogenic effects could be suppressed by an antiestrogenic drug. TAM did not affect the number of striatal DA receptors, but significantly increased the adenohypophy-seal DA binding sites, without varying their affinity. No changes were observed in pituitary and striatal DA receptor density, even when TAM was injected in association with estradiol. In conclusions: TAM is able to counteract the effects estrogens have on DA receptors. However there is some evidence that it could influence the pituitary DA systems independently of it antiestrogenic activity

  5. Tamoxifen counteracts estradiol induced effects on striatal and hypophyseal dopamine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Ferretti, C.; Blengio, M.; Ghi, P.; Racca, S.; Genazzani, E.; Portaleone, P.

    1988-01-01

    We investigated the ability of Tamoxifen (TAM), an antiestrogen drug, to counteract the modification induced by estrogens on dopamine (DA) receptors on striatum and on adenohypophysis of ovex female rats. Subacute treatment with 17..beta..-estradiol (E/sub 2/) at both low (0.1 ..mu..g/kg) and high (20 ..mu..g/kg) doses confirmed its ability to increase the number of striatal /sup 3/H-Spiperone (/sup 3/H-SPI) binding sites in a dose dependent manner. By contrast in the pituitary, only high doses of estrogen were effective in reducing the number of DA receptors. We treated ovex female rats for 15 days with TAM alone or associated with E/sub 2/, to see if these estrogenic effects could be suppressed by an antiestrogenic drug. TAM did not affect the number of striatal DA receptors, but significantly increased the adenohypophy-seal DA binding sites, without varying their affinity. No changes were observed in pituitary and striatal DA receptor density, even when TAM was injected in association with estradiol. In conclusions: TAM is able to counteract the effects estrogens have on DA receptors. However there is some evidence that it could influence the pituitary DA systems independently of it antiestrogenic activity.

  6. Postural & striatal deformities in Parkinson`s disease: Are these rare?

    Directory of Open Access Journals (Sweden)

    Sanjay Pandey

    2016-01-01

    Full Text Available Parkinson`s disease (PD is the most common neurodegenerative disease and is characterized by tremor, rigidity and akinesia. Diagnosis is clinical in the majority of the patients. Patients with PD may have stooped posture but some of them develop different types of postural and striatal deformities. Usually these deformities are more common in atypical parkinsonian disorders such as progressive supranuclear palsy and multisystem atrophy. But in many studies it has been highlighted that these may also be present in approximately one third of PD patients leading to severe disability. These include antecollis or dropped head, camptocormia, p0 isa syndrome, scoliosis, striatal hands and striatal toes. The pathogenesis of these deformities is a complex combination of central and peripheral influences such as rigidity, dystonia and degenerative skeletal changes. Duration of parkinsonism symptoms is an important risk factor and in majority of the patients these deformities are seen in advanced statge of the disease. The patients with such symptoms may initially respond to dopaminergic medications but if not intervened they may become fixed and difficult to treat. Pain and restriction of movement are most common clinical manifestations and these may mimick symptoms of musculoskeletal disorders like rheumatoid arthritis. Early diagnosis is important as the patients may respond to adjustment in dopaminergic medications. Recent advances such as deep brain stimulation (DBS and ultrasound guided botulinum toxin injection are helpful in management of these deformities in patients with PD.

  7. Striatal dopamine D2/3 receptor availability in treatment resistant depression.

    Directory of Open Access Journals (Sweden)

    Bart P de Kwaasteniet

    Full Text Available Several studies demonstrated improvement of depressive symptoms in treatment resistant depression (TRD after administering dopamine agonists which suggest abnormal dopaminergic neurotransmission in TRD. However, the role of dopaminergic signaling through measurement of striatal dopamine D(2/3 receptor (D2/3R binding has not been investigated in TRD subjects. We used [(123I]IBZM single photon emission computed tomography (SPECT to investigate striatal D2/3R binding in TRD. We included 6 severe TRD patients, 11 severe TRD patients on antipsychotics (TRD AP group and 15 matched healthy controls. Results showed no significant difference (p = 0.75 in striatal D2/3R availability was found between TRD patients and healthy controls. In the TRD AP group D2/3R availability was significantly decreased (reflecting occupancy of D2/3Rs by antipsychotics relative to TRD patients and healthy controls (p<0.001 but there were no differences in clinical symptoms between TRD AP and TRD patients. This preliminary study therefore does not provide evidence for large differences in D2/3 availability in severe TRD patients and suggests this TRD subgroup is not characterized by altered dopaminergic transmission. Atypical antipsychotics appear to have no clinical benefit in severe TRD patients who remain depressed, despite their strong occupancy of D2/3Rs.

  8. In Vitro Manganese Exposure Disrupts MAPK Signaling Pathways in Striatal and Hippocampal Slices from Immature Rats

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    Tanara Vieira Peres

    2013-01-01

    Full Text Available The molecular mechanisms mediating manganese (Mn-induced neurotoxicity, particularly in the immature central nervous system, have yet to be completely understood. In this study, we investigated whether mitogen-activated protein kinases (MAPKs and tyrosine hydroxylase (TH could represent potential targets of Mn in striatal and hippocampal slices obtained from immature rats (14 days old. The aim of this study was to evaluate if the MAPK pathways are modulated after subtoxic Mn exposure, which do not significantly affect cell viability. The concentrations of manganese chloride (MnCl2; 10–1,000 μM caused no change in cell viability in slices exposed for 3 or 6 hours. However, Mn exposure significantly increased extracellular signal-regulated kinase (ERK 1/2, as well as c-Jun N-terminal kinase (JNK 1/2/3 phosphorylation at both 3 and 6 hours incubations, in both brain structures. Furthermore, Mn exposure did not change the total content or phosphorylation of TH at the serine 40 site in striatal slices. Thus, Mn at concentrations that do not disrupt cell viability causes activation of MAPKs (ERK1/2 and JNK1/2/3 in immature hippocampal and striatal slices. These findings suggest that altered intracellular MAPKs signaling pathways may represent an early event concerning the effects of Mn in the immature brain.

  9. A negative relationship between ventral striatal loss anticipation response and impulsivity in borderline personality disorder

    Directory of Open Access Journals (Sweden)

    Maike C. Herbort

    2016-01-01

    Full Text Available Patients with borderline personality disorder (BPD frequently exhibit impulsive behavior, and self-reported impulsivity is typically higher in BPD patients when compared to healthy controls. Previous functional neuroimaging studies have suggested a link between impulsivity, the ventral striatal response to reward anticipation, and prediction errors. Here we investigated the striatal neural response to monetary gain and loss anticipation and their relationship with impulsivity in 21 female BPD patients and 23 age-matched female healthy controls using functional magnetic resonance imaging (fMRI. Participants performed a delayed monetary incentive task in which three categories of objects predicted a potential gain, loss, or neutral outcome. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11. Compared to healthy controls, BPD patients exhibited significantly reduced fMRI responses of the ventral striatum/nucleus accumbens (VS/NAcc to both reward-predicting and loss-predicting cues. BIS-11 scores showed a significant positive correlation with the VS/NAcc reward anticipation responses in healthy controls, and this correlation, while also nominally positive, failed to reach significance in BPD patients. BPD patients, on the other hand, exhibited a significantly negative correlation between ventral striatal loss anticipation responses and BIS-11 scores, whereas this correlation was significantly positive in healthy controls. Our results suggest that patients with BPD show attenuated anticipation responses in the VS/NAcc and, furthermore, that higher impulsivity in BPD patients might be related to impaired prediction of aversive outcomes.

  10. Phasic Dopamine Modifies Sensory-Driven Output of Striatal Neurons through Synaptic Plasticity.

    Science.gov (United States)

    Wieland, Sebastian; Schindler, Sebastian; Huber, Cathrin; Köhr, Georg; Oswald, Manfred J; Kelsch, Wolfgang

    2015-07-08

    Animals are facing a complex sensory world in which only few stimuli are relevant to guide behavior. Value has to be assigned to relevant stimuli such as odors to select them over concurring information. Phasic dopamine is involved in the value assignment to stimuli in the ventral striatum. The underlying cellular mechanisms are incompletely understood. In striatal projection neurons of the ventral striatum in adult mice, we therefore examined the features and dynamics of phasic dopamine-induced synaptic plasticity and how this plasticity may modify the striatal output. Phasic dopamine is predicted to tag inputs that occur in temporal proximity. Indeed, we observed D1 receptor-dependent synaptic potentiation only when odor-like bursts and optogenetically evoked phasic dopamine release were paired within a time window of synaptic potentiation persisted after the phasic dopamine signal had ceased, but gradually reversed when odor-like bursts continued to be presented. The synaptic plasticity depended on the sensory input rate and was input specific. Importantly, synaptic plasticity amplified the firing response to a given olfactory input as the dendritic integration and the firing threshold remained unchanged during synaptic potentiation. Thus, phasic dopamine-induced synaptic plasticity can change information transfer through dynamic increases of the output of striatal projection neurons to specific sensory inputs. This plasticity may provide a neural substrate for dynamic value assignment in the striatum. Copyright © 2015 the authors 0270-6474/15/359946-11$15.00/0.

  11. WU and KI polyomavirus prevalence in invasive respiratory samples from transplant recipients in Cantabria, Spain.

    Science.gov (United States)

    Gozalo-Margüello, M; Agüero-Balbín, J; Martínez-Martínez, L

    2015-01-01

    WU and KI polyomaviruses were discovered in 2007 in samples of respiratory secretions of children with acute respiratory symptoms. Seroepidemiologic studies have shown that these viruses are widely distributed throughout the world, but their incidence in Spain has not been determined. In transplant patients, early detection and treatment of viral infections may influence prognosis and survival, because they are associated with increased morbidity and mortality, including graft failure. We aimed to determine the prevalence and clinical characteristics of WU and KI polyomaviruses among patients undergoing hematologic or solid organ transplant in the Hospital Marqués de Valdecilla (Santander, Spain). An in-house polymerase chain reaction with the use of specific primers was carried out in invasive lower respiratory samples from hospitalized patients with suspected respiratory infection and/or graft dysfunction and compared with asymptomatic transplant patients. Overall, we obtained 5.5% KI-positive samples and 1.4% WU-positive samples, with a higher prevalence of WU and KI polyomaviruses in the symptomatic population compared with the control group. Although the data suggest that their detection in respiratory samples is sporadic and often associated with other microorganisms, we should pay special attention to their association with cases of graft failure. Studies are needed with a larger number of samples to explore the potential clinical impact of these emerging polyomaviruses in transplant recipients. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Analysis of the Ki-67 index in the vaginal epithelium of castrated rats treated with tamoxifen

    Directory of Open Access Journals (Sweden)

    Afif Rieth Nery-Aguiar

    2016-02-01

    Full Text Available OBJECTIVES: Vaginal atrophy and breast cancer are common conditions in postmenopausal women and tamoxifen is the standard endocrine treatment for hormone-sensitive tumors. The present study aimed to assess the effect of tamoxifen on Ki-67 protein expression in the vaginal epithelium of castrated rats. MATERIAL AND METHODS: Forty Wistar-Hannover adult, virgin, castrated rats were randomly divided into two groups, group I (control, n=20 and group II (tamoxifen, n=20, receiving 0.5 ml of propylene glycol and 250 µg of tamoxifen diluted in 0.5 ml of propylene glycol, respectively, daily by gavage for 30 days. On the 31st day, the rats were euthanized and their vaginas were removed and fixed in 10% buffered formalin for the immunohistochemical study of Ki-67 protein expression. Data were analyzed by the Levene and Student’s t tests (p<0.05. RESULTS: The mean index of Ki-67 expression in the rat vagina of groups I and II was 4.04±0.96 and 26.86±2.19, respectively (p<0.001. CONCLUSIONS: According to the results of the present study, tamoxifen, at the dose and treatment length used, induced a significant increase in the cell proliferation of the vaginal mucosa in castrated rats, as evaluated by Ki-67 protein expression.

  13. Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology

    DEFF Research Database (Denmark)

    Ikenberg, Hans; Bergeron, Christine; Schmidt, Dietmar

    2013-01-01

    Pap cytology is known to be more specific but less sensitive than testing for human papillomavirus (HPV) for the detection of high-grade cervical intraepithelial neoplasia (CIN2+). We assessed whether p16/Ki-67 dual-stained cytology, a biomarker combination indicative of transforming HPV infectio...

  14. Kriitikud hindavad Cannes'is seni enim Kaurismäki filmi / Jaan Ruus

    Index Scriptorium Estoniae

    Ruus, Jaan, 1938-2017

    2011-01-01

    64. Cannes'i filmifestivalil seni enim köitnud filmidest, pikemalt Aki Kaurismäki filmist "Sadam" ("Le Havre"). Lühidalt enim vaidlusi tekitanud ameerika režissööri Terrence Malicki filmist "Elupuu" ("The Tree of Life") ja taani režissööri Lars von Trieri filmist "Melanhoolia" ("Melancholia")

  15. Ion transport in Au doped/undoped KDP crystals with KI/NaI as ...

    Indian Academy of Sciences (India)

    Unknown

    as additives. R ANANDA KUMARI* and R CHANDRAMANI. Department of Physics, Bangalore University, Bangalore 560 056, India. MS received 25 June 2002; revised 6 November 2002. Abstract. Undoped KDP and KDP crystals containing KI/NaI with/without gold doping were grown by slow evaporation technique. All the ...

  16. A KiDS weak lensing analysis of assembly bias in GAMA galaxy groups

    NARCIS (Netherlands)

    Dvornik, Andrej; Cacciato, Marcello; Kuijken, Konrad; Viola, Massimo; Hoekstra, Henk; Nakajima, Reiko; van Uitert, Edo; Brouwer, Margot; Choi, Ami; Erben, Thomas; Fenech Conti, Ian; Farrow, Daniel J.; Herbonnet, Ricardo; Heymans, Catherine; Hildebrandt, Hendrik; Hopkins, Andrew. M.; McFarland, John; Norberg, Peder; Schneider, Peter; Sifón, Cristóbal; Valentijn, Edwin; Wang, Lingyu

    2017-01-01

    We investigate possible signatures of halo assembly bias for spectroscopically selected galaxy groups from the GAMA survey using weak lensing measurements from the spatially overlapping regions of the deeper, high-imaging-quality photometric KiDS survey. We use GAMA groups with an apparent richness

  17. Nemški Pavliha im Vergleich zu seiner Vorlage Tyll Eulenspiegels wunderbare und seltsame Historien

    Directory of Open Access Journals (Sweden)

    Marija Javor Briški

    2017-12-01

    Full Text Available Unter Berücksichtigung des soziohistorischen Hintergrundes der Zielleser befasst sich der Beitrag auf inhaltlicher, struktureller, medialer und phraseologischer Ebene mit dem Vergleich der slowenischen Übersetzung Nemški Pavliha und seiner wiederentdeckten Vorlage Tyll Eulenspiegels wunderbare und seltsame Historien.

  18. Differential effects of the KiVa anti-bullying program on popular and unpopular bullies

    NARCIS (Netherlands)

    Garandeau, Claire F.; Lee, Ihno A.; Salmivalli, Christina

    2014-01-01

    This study utilized data from the evaluation of the Finnish KiVa program in testing the prediction that school bullies' high perceived popularity would impede the success of anti-bullying interventions. Multiple-group structural equation modeling (SEM) analyses were conducted on a subsample of 911

  19. Vitamin D Receptor, Retinoid X Receptor, Ki-67, Survivin, and Ezrin Expression in Canine Osteosarcoma

    Directory of Open Access Journals (Sweden)

    John Davies

    2012-01-01

    Full Text Available Canine osteosarcoma (OS is an aggressive malignant bone tumor. Prognosis is primarily determined by clinical parameters. Vitamin D has been postulated as a novel therapeutic option for many malignancies. Upon activation, vitamin D receptors (VDRs combine with retinoid receptor (RXR forming a heterodimer initiating a cascade of events. Vitamin D's antineoplastic activity and its mechanism of action in OS remain to be clearly established. Expression of VDR, RXR, Ki-67, survivin, and ezrin was studied in 33 archived, canine OS specimens. VDR, RXR, survivin, and ezrin were expressed in the majority of cases. There was no statistically significant difference in VDR expression in relationship with tumor grade, type, or locations or animal breed, age, and/or sex. No significant association (p=0.316 between tumor grade and Ki-67 expression was found; in particular, no difference in Ki-67 expression between grades 2 and 3 OSs was found, while a negative correlation was noted between Ki-67 and VDR expression (ρ=−0.466, a positive correlation between survivin and RXR expression was found (p=0.374. A significant relationship exists between VDR and RXR expression in OSs and proliferative/apoptosis markers. These results establish a foundation for elucidating mechanisms by which vitamin D induces antineoplastic activity in OS.

  20. Tallink kaalub müüki pandud Silja Line'i ostu / Priit Rajalo

    Index Scriptorium Estoniae

    Rajalo, Priit, 1975-

    2005-01-01

    Soome Silja Oy AB omanikfirma Sea Containers otsustas 2. novembril Silja Line'i müüki panna, kuna laevafirma kasumlikkus on järsult vähenenud. Tallink Grupi finantsdirektori Janek Stalmeistri sõnul on Tallinki võimalikku ostuhuvi Silja Line'i vastu vara veel kommenteerida. Lisa: Silja laevad

  1. Study of Ki67 and CD10 expression as predictive factors of recurrence of ameloblastoma.

    Science.gov (United States)

    Ahlem, B; Wided, A; Amani, L; Nadia, Z; Amira, A; Faten, F

    2015-11-01

    Ameloblastoma is a rare, benign, purely epithelial odontogenic tumour, characterized by a high potential for local invasion and recurrence. To study the epidemiological and histological characteristics of ameloblastoma. To study Ki67 and CD10 immunostaining in ameloblastoma and to investigate a possible correlation between these two markers and recurrence of this tumour. An immunohistochemical study using Ki67 and CD10 monoclonal antibodies was performed on 37 paraffin blocks obtained from the Charles-Nicolle hospital pathology department in Tunis over a 9-year period (2004-2012). Statistical analysis was performed with Statistical Package for Social Sciences (SPSS) software version 15.1. This series of 37 cases comprised 21 males and 16 females (sex ratio: 1.3) with a mean age of 39 years (range: 7 to 70 years), corresponding to 36 cases of intraosseous ameloblastoma and one case of gingival ameloblastoma. Thirty-two cases were polycystic and 5 cases were unicystic. Eighteen cases of local recurrence were observed. No correlation was demonstrated between recurrence and the various clinical and histological parameters and treatment modalities. However, a significant correlation was demonstrated between recurrence and Ki67 and CD10 expression (P=0.000 and 0.002, respectively). The Ki67 proliferation index and stromal CD10 expression can be considered to be predictive factors of ameloblastoma recurrence. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  2. Analysis on the relation of pterygium with VEGF,SDF-1,Ki-67,PCNA and Survivin

    Directory of Open Access Journals (Sweden)

    Ying Song

    2015-12-01

    Full Text Available AIM:To analyze and study the relation of pterygium with vascular endothelial growth factor(VEGF,stroma cell-derived factor 1(SDF-1,tumor proliferating antigen(Ki-67,proliferating cell nuclear antigen(PCNAand survivin. METHODS:Seventy-nine patients(106 eyeswith pterygium from January 2013 to May 2015 in our hospital were selected as observation group. Seventy-nine persons with normal conjunctiva during the same period were selected as control group. Then the number of positive cells and staining intensity classification of the two groups for VEGF,SDF-1,Ki-67,PCNA and survivin were compared,and the detection results of patients with different gender,stages and types were compared too. Then the relation between pterygium and those indexes were analyzed by the Logistic analysis. RESULTS:The number of positive cells and staining intensity classification of observation group for VEGF,SDF-1,Ki-67,PCNA and survivin were all higher than those of control group,and the detection results of patients with different stages and types had certain differences too(all PP>0.05. All those indexes had close relation to pterygium by the Logistic analysis. CONCLUSION:The expression of VEGF,SDF-1,Ki-67,PCNA and survivin in tissue of patients with pterygium all show abnormal state,and those indexes all have close relation to pterygium.

  3. Association of tissue inhibitor of metalloproteinases-1 and Ki67 in estrogen receptor positive breast cancer

    DEFF Research Database (Denmark)

    Bjerre, Christina Annette; Knoop, Ann; Bjerre, Karsten

    2013-01-01

    The role of tissue inhibitor of metalloproteinases-1 (TIMP-1) in estrogen receptor (ER) positive breast cancer remains to be fully elucidated. We evaluated TIMP-1 as a prognostic marker in patients treated with adjuvant tamoxifen and investigated TIMP-1s association with Ki67 and ER/progesterone ....../progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) profiles....

  4. KI-Aikido for Handicapped Students at Leeward Community College: Theory and Practice.

    Science.gov (United States)

    MacGugan, Kirk

    In an effort to provide physical education instruction for handicapped students, Leeward Community College implemented, on a pilot basis, a non-credit course in KI-Aikido, an oriental martial art which combines theory and exercise toward the goal of controlling the body through the power of the mind. The course, offered to both handicapped and…

  5. Ki-67 acts as a biological surfactant to disperse mitotic chromosomes

    Science.gov (United States)

    Cuylen, Sara; Blaukopf, Claudia; Politi, Antonio Z.; Müller-Reichert, Thomas; Neumann, Beate; Poser, Ina; Ellenberg, Jan; Hyman, Anthony A.; Gerlich, Daniel W.

    2016-01-01

    Summary Eukaryotic genomes are partitioned into chromosomes, which during mitosis form compact and spatially well-separated mechanical bodies1–3.This enables chromosomes to move independently of each other for segregation of precisely one copy of the genome to each of the nascent daughter cells. Despite insights into the spatial organization of mitotic chromosomes4 and the discovery of proteins at the chromosome surface3,5,6, the molecular and biophysical basis of mitotic chromosome individuality have remained unclear. We report that Ki-67, a component of the mitotic chromosome periphery, prevents chromosomes from collapsing into a single chromatin mass after nuclear envelope disassembly, thus enabling independent chromosome motility and efficient interactions with the mitotic spindle. The chromosome separation function of Ki-67 is not confined within a specific protein domain but correlates with size and net charge of truncation mutants that apparently lack secondary structure. This suggests that Ki-67 forms a steric and electrical barrier, similar to surface-active agents (surfactants) that disperse particles or phase-separated liquid droplets in solvents. Fluorescence correlation spectroscopy showed a high surface density of Ki-67 and dual-color labeling of both protein termini revealed an extended molecular conformation, indicating brush-like arrangements that are characteristic for polymeric surfactants. Our study thus elucidates a biomechanical role of the mitotic chromosome periphery and suggests that natural proteins can function as surfactants in intracellular compartmentalization. PMID:27362226

  6. The National Heritage of Ki Hadjar Dewantara in Tamansiswa about Culture-Based Education and Learning

    Science.gov (United States)

    Towaf, Siti Malikhah

    2016-01-01

    Global interdependence is a reality; in the security, economics, politics, socio-culture, and especially in the education of a nation;. Relevant to the need for an international dialog on education, this study tries to explore: 1) the concepts of culture-based education and learning of Ki Hadjar Dewantara (KHD) in Tamansiswa, 2) the results of…

  7. Ion transport in Au doped/undoped KDP crystals with KI/NaI as ...

    Indian Academy of Sciences (India)

    Undoped KDP and KDP crystals containing KI/NaI with/without gold doping were grown by slow evaporation technique. All the grown crystals were -irradiated using 60Co source. Electrical conductivity measurements were carried out on all these crystals perpendicular to the unique direction before and after -irradiation.

  8. Immunohistochemical Ki67 after short-term hormone therapy identifies low-risk breast cancers as reliably as genomic markers.

    Science.gov (United States)

    Iwamoto, Takayuki; Katagiri, Toyomasa; Niikura, Naoki; Miyoshi, Yuichiro; Kochi, Mariko; Nogami, Tomohiro; Shien, Tadahiko; Motoki, Takayuki; Taira, Naruto; Omori, Masako; Tokuda, Yutaka; Fujiwara, Toshiyoshi; Doihara, Hiroyoshi; Gyorffy, Balazs; Matsuoka, Junji

    2017-04-18

    The purpose of this study was to test whether immunohistochemical (IHC) Ki67 levels after short-term preoperative hormone therapy (post-Ki67) predict similar numbers of patients with favorable prognoses as genomic markers. Thirty paired cases (60 samples) were enrolled in this study. Post-Ki67 levels were significantly lower than pre-treatment Ki67 levels (P Ki67 predicted more low-risk cases (83.3%, 25/30) than pre-genomic surrogate signature(GSS) (66.7%: 20/30), but the difference in predictive power was not significant (P = 0.233). Proliferation (MKI67, STK15, Survivin, CCNB1, and MYBL2) and estrogen (ER, PGR, BCL2, and SCUBE2) related signatures were significantly downregulated after therapy (P breast cancer were collected at Okayama University Hospital from hormone receptor-positive and human epidermal growth factor 2-negative patients that subsequently received two weeks of neoadjuvant hormone therapy. Paired post-treatment specimens from surgical samples were also collected. IHC Ki67 levels and GSS were compared between pre- and post-hormone treatment samples. Changes of gene expression pattern in short-term hormone therapy were also assessed. IHC based post-Ki67 levels may have distinct predictive power compared with the naïve IHC Ki67. Future studies with larger cohorts and longer follow-up periods may be needed to validate our results.

  9. Correlation between expression of LRP16, Ki67 and EGFR and breast cancer clinical pathologic factors and prognosis.

    Science.gov (United States)

    Yao, D-J; Qiao, S; Zhang, Y; Zhao, Y-T; Yuan, C-H

    2017-07-01

    To investigate the expression of leukemia-related protein 16 (LRP16), proliferating cell nuclear antigen K-67 (Ki67) and epidermal growth factor receptor-1 (EGFR-1) in breast cancer tissue and to explore the correlation between the expression of those proteins and breast cancer clinical pathologic factors and prognosis. The expressions of LRP16, Ki67 and EGFR in breast cancer tissues of 86 cases were detected by the immunohistochemical method and the correlations between the expression of LRP16, Ki67 and EGFR and clinical pathologic factors and prognosis were investigated. Positive expression rates of LRP16, Ki67 and EGFR in breast cancer tissue were 52.3%, 70.9% and 16.3%, respectively. There was no statistical difference in the expression of RP16, Ki67 and EGFR between different age groups (p>0.05). The expression of LRP16 was correlated with clinical stage, histological grade, tumor size and lymphatic metastasis (pKi67 was correlated with clinical stage, histological grade, tumor size and lymphatic metastasis (pKi67 positive group and negative group also showed statistically significant difference (pKi67 and EGFR in breast cancer tissue improves the understanding of biological behaviors of breast cancer, which in turn provide clinical guidance in diagnosis, treatment and prognosis assessment.

  10. A simple algorithm for subregional striatal uptake analysis with partial volume correction in dopaminergic PET imaging

    International Nuclear Information System (INIS)

    Lue Kunhan; Lin Hsinhon; Chuang Kehshih; Kao Chihhao, K.; Hsieh Hungjen; Liu Shuhsin

    2014-01-01

    In positron emission tomography (PET) of the dopaminergic system, quantitative measurements of nigrostriatal dopamine function are useful for differential diagnosis. A subregional analysis of striatal uptake enables the diagnostic performance to be more powerful. However, the partial volume effect (PVE) induces an underestimation of the true radioactivity concentration in small structures. This work proposes a simple algorithm for subregional analysis of striatal uptake with partial volume correction (PVC) in dopaminergic PET imaging. The PVC algorithm analyzes the separate striatal subregions and takes into account the PVE based on the recovery coefficient (RC). The RC is defined as the ratio of the PVE-uncorrected to PVE-corrected radioactivity concentration, and is derived from a combination of the traditional volume of interest (VOI) analysis and the large VOI technique. The clinical studies, comprising 11 patients with Parkinson's disease (PD) and 6 healthy subjects, were used to assess the impact of PVC on the quantitative measurements. Simulations on a numerical phantom that mimicked realistic healthy and neurodegenerative situations were used to evaluate the performance of the proposed PVC algorithm. In both the clinical and the simulation studies, the striatal-to-occipital ratio (SOR) values for the entire striatum and its subregions were calculated with and without PVC. In the clinical studies, the SOR values in each structure (caudate, anterior putamen, posterior putamen, putamen, and striatum) were significantly higher by using PVC in contrast to those without. Among the PD patients, the SOR values in each structure and quantitative disease severity ratings were shown to be significantly related only when PVC was used. For the simulation studies, the average absolute percentage error of the SOR estimates before and after PVC were 22.74% and 1.54% in the healthy situation, respectively; those in the neurodegenerative situation were 20.69% and 2

  11. Is there a relation between novelty seeking, striatal dopamine release and frontal cortical thickness?

    Directory of Open Access Journals (Sweden)

    Natalia Jaworska

    Full Text Available Novelty-seeking (NS and impulsive personality traits have been proposed to reflect an interplay between fronto-cortical and limbic systems, including the limbic striatum (LS. Although neuroimaging studies have provided some evidence for this, most are comprised of small samples and many report surprisingly large effects given the challenges of trying to relate a snapshot of brain function or structure to an entity as complex as personality. The current work tested a priori hypotheses about associations between striatal dopamine (DA release, cortical thickness (CT, and NS in a large sample of healthy adults.Fifty-two healthy adults (45M/7F; age: 23.8±4.93 underwent two positron emission tomography scans with [11C]raclopride (specific for striatal DA D2/3 receptors with or without amphetamine (0.3 mg/kg, p.o.. Structural magnetic resonance image scans were acquired, as were Tridimensional Personality Questionnaire data. Amphetamine-induced changes in [11C]raclopride binding potential values (ΔBPND were examined in the limbic, sensorimotor (SMS and associative (AST striatum. CT measures, adjusted for whole brain volume, were extracted from the dorsolateral sensorimotor and ventromedial/limbic cortices.BPND values were lower in the amphetamine vs. no-drug sessions, with the largest effect in the LS. When comparing low vs. high LS ΔBPND groups (median split, higher NS2 (impulsiveness scores were found in the high ΔBPND group. Partial correlations (age and gender as covariates yielded a negative relation between ASTS ΔBPND and sensorimotor CT; trends for inverse associations existed between ΔBPND values in other striatal regions and frontal CT. In other words, the greater the amphetamine-induced striatal DA response, the thinner the frontal cortex.These data expand upon previously reported associations between striatal DA release in the LS and both NS related impulsiveness and CT in the largest sample reported to date. The findings add to the

  12. Dopamine D(1) receptor-mediated control of striatal acetylcholine release by endogenous dopamine.

    Science.gov (United States)

    Acquas, E; Di Chiara, G

    1999-10-27

    The role of dopamine D(1) and D(2) receptors in the control of acetylcholine release in the dorsal striatum by endogenous dopamine was investigated by monitoring with microdialysis the effect of the separate or combined administration of the dopamine D(1) receptor antagonist, SCH 39166 ¿(-)-trans-6,7,7a,8,9, 13b-exahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]-nap hto-[2, 1b]-azepine hydrochloride¿ (50 microg/kg subcutaneous (s.c.)), of the dopamine D(2)/D(3) receptor agonist, quinpirole (trans-(-)-4aR, 4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo-(3,4-g)-quinoline hydrochloride) (5 and 10 microg/kg s.c.), and of the D(3) receptor selective agonist, PD 128,907 [S(+)-(4aR,10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin -9-ol hydrochloride] (50 microg/kg s.c.), on in vivo dopamine and acetylcholine release. Microdialysis was performed with a Ringer containing low concentrations (0.01 microM) of the acetylcholinesterase inhibitor, neostigmine. Quinpirole (10 microg/kg s.c.) decreased striatal dopamine and acetylcholine release. Administration of PD 128,907 (50 microg/kg) decreased dopamine but failed to affect acetylcholine release. SCH 39166 (50 microg/kg s.c.) stimulated dopamine release and reduced acetylcholine release. Pretreatment with quinpirole reduced (5 microg/kg s.c.) or completely prevented (10 microg/kg s.c.) the stimulation of dopamine release elicited by SCH 39166 (50 microg/kg s.c.); on the other hand, pretreatment with quinpirole (5 and 10 microg/kg) potentiated the reduction of striatal acetylcholine release induced by SCH 39166 (50 microg/kg s.c.). Similarly, pretreatment with PD 128,907 (50 microg/kg) which prevented the increase of dopamine release induced by SCH 39166 (50 microg/kg), potentiated the reduction of striatal acetylcholine transmission elicited by SCH 39166. Thus, pretreatment with low doses of quinpirole or PD 128,907 influences in opposite manner the effect of SCH 39166 on striatal dopamine and

  13. A Population of Indirect Pathway Striatal Projection Neurons Is Selectively Entrained to Parkinsonian Beta Oscillations.

    Science.gov (United States)

    Sharott, Andrew; Vinciati, Federica; Nakamura, Kouichi C; Magill, Peter J

    2017-10-11

    Classical schemes of basal ganglia organization posit that parkinsonian movement difficulties presenting after striatal dopamine depletion stem from the disproportionate firing rates of spiny projection neurons (SPNs) therein. There remains, however, a pressing need to elucidate striatal SPN firing in the context of the synchronized network oscillations that are abnormally exaggerated in cortical-basal ganglia circuits in parkinsonism. To address this, we recorded unit activities in the dorsal striatum of dopamine-intact and dopamine-depleted rats during two brain states, respectively defined by cortical slow-wave activity (SWA) and activation. Dopamine depletion escalated striatal net output but had contrasting effects on "direct pathway" SPNs (dSPNs) and "indirect pathway" SPNs (iSPNs); their firing rates became imbalanced, and they disparately engaged in network oscillations. Disturbed striatal activity dynamics relating to the slow (∼1 Hz) oscillations prevalent during SWA partly generalized to the exaggerated beta-frequency (15-30 Hz) oscillations arising during cortical activation. In both cases, SPNs exhibited higher incidences of phase-locked firing to ongoing cortical oscillations, and SPN ensembles showed higher levels of rhythmic correlated firing, after dopamine depletion. Importantly, in dopamine-depleted striatum, a widespread population of iSPNs, which often displayed excessive firing rates and aberrant phase-locked firing to cortical beta oscillations, preferentially and excessively synchronized their firing at beta frequencies. Conversely, dSPNs were neither hyperactive nor synchronized to a large extent during cortical activation. These data collectively demonstrate a cell type-selective entrainment of SPN firing to parkinsonian beta oscillations. We conclude that a population of overactive, excessively synchronized iSPNs could orchestrate these pathological rhythms in basal ganglia circuits. SIGNIFICANCE STATEMENT Chronic depletion of dopamine

  14. Striatal hypometabolism in premanifest and manifest Huntington's disease patients

    Energy Technology Data Exchange (ETDEWEB)

    Lopez-Mora, Diego Alfonso; Camacho, Valle; Fernandez, Alejandro; Montes, Alberto; Carrio, Ignasi [Autonomous University of Barcelona, Nuclear Medicine Department, Hospital Sant Pau, Barcelona (Spain); Perez-Perez, Jesus; Martinez-Horta, Sauel; Kulisevsky, Jaime [Autonomous University of Barcelona, Movement Disorders Unit, Neurology Department, Hospital Sant Pau, Barcelona (Spain); Sampedro, Frederic [University of Barcelona, Barcelona (Spain); Lozano-Martinez, Gloria Andrea; Gomez-Anson, Beatriz [Autonomous University of Barcelona, Neuroradiology, Radiology Department, Hospital Sant Pau, Barcelona (Spain)

    2016-11-15

    To assess metabolic changes in cerebral {sup 18}F-FDG PET/CT in premanifest and manifest Huntington's disease (HD) subjects compared to a control group and to correlate {sup 18}F-FDG uptake patterns with different disease stages. Thirty-three gene-expanded carriers (Eight males; mean age: 43 y/o; CAG > 39) were prospectively included. Based on the Unified Huntington's Disease Rating Scale Total Motor Score and the Total Functional Capacity, subjects were classified as premanifest (preHD = 15) and manifest (mHD = 18). Estimated time disease-onset was calculated using the Langbehn formula, which allowed classifying preHD as far-to (preHD-A) and close-to (PreHD-B) disease-onset. Eighteen properly matched participants were included as a control group (CG). All subjects underwent brain {sup 18}F-FDG PET/CT and MRI. {sup 18}F-FDG PET/CT were initially assessed by two nuclear medicine physicians identifying qualitative metabolic changes in the striatum. Quantitative analysis was performed using SPM8 with gray matter atrophy correction using the BPM toolbox. Visual analysis showed a marked striatal hypometabolism in mHD. A normal striatal distribution of {sup 18}F-FDG uptake was observed for most of the preHD subjects. Quantitative analysis showed a significant striatal hypometabolism in mHD subjects compared to CG (p < 0.001 uncorrected, k = 50 voxels). In both preHD groups we observed a significant striatal hypometabolism with respect to CG (p < 0.001 uncorrected, k = 50 voxels). In mHD subjects we observed a significant striatal hypometabolism with respect to both preHD groups (p < 0.001 uncorrected, k = 50 voxels). {sup 18}F-FDG PET/CT might be a helpful tool to identify patterns of glucose metabolism in the striatum across the stages of HD and might be relevant in assessing the clinical status of gene-expanded HD carriers due to the fact that dysfunctional glucose metabolism begins at early preHD stages of the disease. {sup 18}F-FDG PET/CT appears as a

  15. EGFR, CD10 and proliferation marker Ki67 expression in ameloblastoma: possible role in local recurrence

    Directory of Open Access Journals (Sweden)

    Abdel-Aziz Azza

    2012-02-01

    Full Text Available Abstract Background Ameloblastoma is an odontogenic neoplasm characterized by local invasiveness and tendency towards recurrence. Aims Studying the role played by EGFR, CD10 and Ki67 in the recurrence of ameloblastoma. Methods This study was carried out on 22 retrospective cases of mandibular ameloblastoma from the period from Jan 2002 to Jan 2008 with follow up period until Jan 2011 (3 to 8 years follow up peroid. Archival materials were obtained from pathology department, Mansoura university. Paraffin sections of tumor tissue from all cases were submitted for routine H&E stains and immunohistochemistry using EGFR, CD10 and Ki67 monoclonal antibodies. Statistical analysis using of clinical data for all patients, tumor type, EGFR, CD10 and Ki67 expression in relation to recurrence were evaluated. Results Among the 22 cases, 10 cases were males and 12 were females with sex ratio 1:1.2. Age ranged from 34 to 59 years old with a mean age 44.18 year. Five cases showed local recurrence within studied period and proved by biopsy. No statistically significant relation was found between local recurrence and patient age, tumor size, tumor type, EGFR expression. There was a significant relation between CD10 expression as well as Ki67 labelling index and recurrence (P value = 0.003, 0.000 respectively. Conclusion Evaluation of CD10 and Ki67 status together with conventional histological evaluation can help in providing more information about the biologic behavior of the tumor, while EGFR could be a target of an expanding class of anticancer therapies. Since ameloblastomas are EGFR-positive tumors, anti-EGFR agents could be considered to reduce the size of large tumors and to treat unresectable tumors that are in close proximity to vital structures. Virtual Slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1902106905645651

  16. Immunohistochemical expression of GLUT-1 and Ki-67 in chronic plaque psoriasis.

    Science.gov (United States)

    Abdou, Asmaa G; Maraee, Alaa H; Eltahmoudy, Mohamed; El-Aziz, Reem A

    2013-10-01

    Many inflammatory mediators and other biological markers are upregulated in psoriatic lesions; some of these alterations also persist in nonlesional skin. Glucose is the major source of energy for cells, and glucose transporter 1 is the most common glucose transporter in humans (GLUT-1). The present study aimed at evaluating the pattern of expression of GLUT-1 and Ki-67 in psoriatic skin (involved and uninvolved) and correlating their expression with the clinicopathological parameters in the studied patients. This study was carried out on 30 patients presented with chronic plaque psoriasis and 10 apparently healthy volunteers as a control group. GLUT-1 was not expressed in epidermis of normal skin, whereas it was expressed in 76.6% of uninvolved and 86.7% of involved skin of psoriatic patients, where both the latter differed significantly regarding the intensity (P = 0.001) and localization (P = 0.001) of GLUT-1 expression. The percentage of Ki-67 expression did not differ significantly between involved and uninvolved skin of psoriatic patients, but they were higher than that of normal skin of control group. Nucleolar pattern of Ki-67 expression was significantly associated with male sex (P = 0.05), marked parakeratosis (P = 0.01), and marked angiogenesis (P = 0.05). GLUT-1 expression was associated with degree of acanthosis and percentage of Ki-67 expression. From this study, GLUT-1 is upregulated in psoriatic epidermis and may be involved in facilitation of keratinocyte proliferation in psoriasis. Nucleolar pattern of Ki-67 is an indicator of progressive keratinocyte proliferation in psoriasis.

  17. KiDS-450: testing extensions to the standard cosmological model

    Science.gov (United States)

    Joudaki, Shahab; Mead, Alexander; Blake, Chris; Choi, Ami; de Jong, Jelte; Erben, Thomas; Fenech Conti, Ian; Herbonnet, Ricardo; Heymans, Catherine; Hildebrandt, Hendrik; Hoekstra, Henk; Joachimi, Benjamin; Klaes, Dominik; Köhlinger, Fabian; Kuijken, Konrad; McFarland, John; Miller, Lance; Schneider, Peter; Viola, Massimo

    2017-10-01

    We test extensions to the standard cosmological model with weak gravitational lensing tomography using 450 deg2 of imaging data from the Kilo Degree Survey (KiDS). In these extended cosmologies, which include massive neutrinos, non-zero curvature, evolving dark energy, modified gravity and running of the scalar spectral index, we also examine the discordance between KiDS and cosmic microwave background (CMB) measurements from Planck. The discordance between the two data sets is largely unaffected by a more conservative treatment of the lensing systematics and the removal of angular scales most sensitive to non-linear physics. The only extended cosmology that simultaneously alleviates the discordance with Planck and is at least moderately favoured by the data includes evolving dark energy with a time-dependent equation of state (in the form of the w0 - wa parametrization). In this model, the respective S_8=σ _8√{Ω m/0.3} constraints agree at the 1σ level, and there is 'substantial concordance' between the KiDS and Planck data sets when accounting for the full parameter space. Moreover, the Planck constraint on the Hubble constant is wider than in Λ cold dark matter (ΛCDM) and in agreement with the Riess et al. (2016) direct measurement of H0. The dark energy model is moderately favoured as compared to ΛCDM when combining the KiDS and Planck measurements, and marginalized constraints in the w0-wa plane are discrepant with a cosmological constant at the 3σ level. KiDS further constrains the sum of neutrino masses to 4.0 eV (95% CL), finds no preference for time or scale-dependent modifications to the metric potentials, and is consistent with flatness and no running of the spectral index.

  18. Inverse relationship between Ki67 and survival in early luminal breast cancer: confirmation in a multivariate analysis.

    Science.gov (United States)

    Gallardo, Alberto; Garcia-Valdecasas, Barbara; Murata, Paola; Teran, Rolando; Lopez, Laura; Barnadas, Agusti; Lerma, Enrique

    2018-01-01

    Ki67 is a prognostic marker in early breast cancer, but its real usefulness remains controversial. The standard cut-off values for Ki67 have not been universally accepted and different values may be used depending on the type of biopsy (fine needle biopsy versus surgical specimen biopsy). The objective of this study was to evaluate the prognostic significance of Ki67 and to determine the most accurate prognostic cut-off. 495 tissue samples from patients with luminal tumours who underwent breast surgery between 2005 and 2011 were collected from the Department of Pathology at Hospital de la Santa Creu i Sant Pau, Barcelona. Patients with stage IV, HER2-positive tumours or triple-negative breast carcinoma were excluded from the study. Pathology data including tumour grading and ki67 percentage were obtained retrospectively from clinical records. In all cases, the percentage of ki67 was evaluated in fine needle biopsies. In the multivariate analysis, Ki67 as a continuous variable was associated with poor overall survival (OS) and cancer-specific survival (CSS) (OS p = 0.0001, HR 1.037, CI 1.014-1.059; CSS p = 0.0001, HR 1.063, CI 1.031-1.096) (Cox regression model). CSS was poor when associated with a KI67 cut-off point >14% (p = 0.013, HR 14.85; CI 1.074-120.53) (Cox regression model). Disease-free survival (DFS) was not associated with Ki67 CONCLUSIONS: Prognosis of luminal breast carcinoma can be predicted using Ki67 as a continuous variable and a standard cut-off value of 14%. Information about the specimen type used to determine ki67 should be recorded in the pathological report.

  19. Prognostic value of Ki67 expression in HR-negative breast cancer before and after neoadjuvant chemotherapy.

    Science.gov (United States)

    Tan, Qi-Xing; Qin, Qing-Hong; Yang, Wei-Ping; Mo, Qin-Guo; Wei, Chang-Yuan

    2014-01-01

    Immunohistochemical (IHC) expression of Ki67 has been identified as a prognostic and predictive marker in hormone receptor (HR)-positive breast cancer, however, there is little evidence of the association of Ki67 with prognosis in HR-negative patients. We aimed to assess the benefit of Ki67 assessment in HR-negative breast cancers after neoadjuvant chemotherapy (NAC). In the present study, a total of 183 HR-negative breast cancer patients with Stage II to III that treated with anthracycline and/or taxane-based neoadjuvant chemotherapy between 2004 and 2011 were retrospectively analyzed. Endocrine therapy and trastuzumab was not administered to any patients in this study. Clinical and pathological features of the patients with breast cancer were retrieved from the hospital records. Predictive factors for NAC response and survival were analyzed. Of the 183 patients, 122 (66.6%) were HR- HER2+, and 61 (33.3%) were triple-negative. The clinical response rates were similar across breast cancer subtype. Patients whose tumors contained high Ki67 expression effectively responded to NAC. Ki67 labeling index was a predictive marker for pathologic complete response (pCR). Ki67 expression showed a positive correlation with HER2 status, tumor size, lymph node status, lymphovascular invasion and tumor grade. Furthermore, high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free survival (DFS), but no correlation of Ki-67 expression with overall survival (OS) was observed. Our results suggest that Ki67 expression in HR-negative breast cancer may improve the assessment of pathological response after NAC, and Ki67 score in residual tumor was an independent prognosticator for DFS in the HR-negative breast cancer patients.

  20. Prognostic value of programmed death ligand 1, p53, and Ki-67 in patients with advanced-stage colorectal cancer.

    Science.gov (United States)

    Wang, Lisha; Liu, Zebing; Fisher, Kurt W; Ren, Fei; Lv, Jiaojie; Davidson, Darrell D; Baldridge, Lee A; Du, Xiang; Cheng, Liang

    2018-01-01

    Current prognostic indicators are ineffective for identifying advanced-stage colorectal cancer (CRC) patients with high risk of recurrence after surgical resection. We investigated the prognostic value of p53, Ki-67, and programmed death ligand 1 (PD-L1) in 254 patients with stage II and III CRC. The expression of p53 was positive in 63% of cases. Up-regulation of p53 was associated with smaller tumor size (P=.001) and higher Ki-67 labeling index (LI) (P=.031). The tumor Ki-67 LI was high (≥20%) in 197 (78%) of the patients. High Ki-67 LI was associated with higher TNM stage (P=.031), positive p53 expression (P=.031), and negative PD-L1 expression (P=.003). The 5-year relapse-free survivals (RFS) were 53% and 89%, respectively, for the p53-positive and Ki-67 LI-high patients and the p53-negative and Ki-67 LI-low patients (P<.001). In univariate analysis, negative p53 (P=.001), low Ki-67 LI (P=.006), low PD-L1 expression (P=.044), low TNM stage (P<.001), rectosigmoid location (P=.026), and small size (P=.013) were significantly related to RFS. In multivariate Cox regression analysis, positive p53 expression (hazard ratio [HR]: 2.48; 95% confidence interval: 1.34-4.59, P=.004), high Ki-67 LI (HR, 2.62; 95% CI, 1.12-6.14, P=.027) and high TNM stage (HR, 2.598; 95% CI, 1.55-4.37, P<.001,) were independent predictors of unfavorable prognosis. In summary, PD-L1, Ki-67, and p53 staining individually had significant prognostic value for patients with stage II and III CRC. Moreover, combining p53 H-score ≥35 and Ki-67 LI ≥20% identifies patients with poor clinical outcome. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Further human evidence for striatal dopamine release induced by administration of ∆9-tetrahydrocannabinol (THC): selectivity to limbic striatum.

    Science.gov (United States)

    Bossong, Matthijs G; Mehta, Mitul A; van Berckel, Bart N M; Howes, Oliver D; Kahn, René S; Stokes, Paul R A

    2015-08-01

    Elevated dopamine function is thought to play a key role in both the rewarding effects of addictive drugs and the pathophysiology of schizophrenia. Accumulating epidemiological evidence indicates that cannabis use is a risk factor for the development of schizophrenia. However, human neurochemical imaging studies that examined the impact of ∆9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, on striatal dopamine release have provided inconsistent results. The objective of this study is to assess the effect of a THC challenge on human striatal dopamine release in a large sample of healthy participants. We combined human neurochemical imaging data from two previous studies that used [(11)C]raclopride positron emission tomography (PET) (n = 7 and n = 13, respectively) to examine the effect of THC on striatal dopamine neurotransmission in humans. PET images were re-analysed to overcome differences in PET data analysis. THC administration induced a significant reduction in [(11)C]raclopride binding in the limbic striatum (-3.65 %, from 2.39 ± 0.26 to 2.30 ± 0.23, p = 0.023). This is consistent with increased dopamine levels in this region. No significant differences between THC and placebo were found in other striatal subdivisions. In the largest data set of healthy participants so far, we provide evidence for a modest increase in human striatal dopamine transmission after administration of THC compared to other drugs of abuse. This finding suggests limited involvement of the endocannabinoid system in regulating human striatal dopamine release and thereby challenges the hypothesis that an increase in striatal dopamine levels after cannabis use is the primary biological mechanism underlying the associated higher risk of schizophrenia.

  2. GDNF control of the glutamatergic cortico-striatal pathway requires tonic activation of adenosine A2A Receptors

    Science.gov (United States)

    Gomes, Catarina A.R.V.; Simões, Patrícia F.; Canas, Paula M.; Quiroz, César; Sebastião, Ana M.; Ferré, Sergi; Cunha, Rodrigo A.; Ribeiro, Joaquim A.

    2009-01-01

    Glial cell line-derived neurotrophic factor (GDNF) affords neuroprotection in Parkinson’s disease in accordance with its ability to bolster nigrostriatal innervation. We previously found that GDNF facilitates dopamine release in a manner dependent on adenosine A2A receptor activation. Since motor dysfunction also involves modifications of striatal glutamatergic innervation, we now tested if GDNF and its receptor system, Ret (rearranged during transfection) and GFRα1 (GDNF family receptor alpha 1) controlled the cortico-striatal glutamatergic pathway in an A2A receptor-dependent manner. GDNF (10 ng/ml) enhanced (by ≈13%) glutamate release from rat striatal nerve endings, an effect potentiated (up to ≈ 30%) by the A2A receptor agonist CGS 21680 (10 nM) and prevented by the A2A receptor antagonist, SCH 58261 (50 nM). Triple immunocytochemical studies revealed that Ret and GFRα1 were located in 50% of rat striatal glutamatergic terminals (immunopositive for vesicular glutamate transporters-1/2), where they were found to be co-located with A2A receptors. Activation of the glutamatergic system upon in vivo electrical stimulation of the rat cortico-striatal input induced striatal Ret phosphoprylation that was prevented by pre-treatment with the A2A receptor antagonist, MSX-3 (3 mg/kg). The results provide the first functional and morphological evidence that GDNF controls cortico-striatal glutamatergic pathways in a manner largely dependent on the co-activation of adenosine A2A receptors. PMID:19141075

  3. Growth hormone (GH) is a survival rather than a proliferative factor for embryonic striatal neural precursor cells.

    Science.gov (United States)

    Regalado-Santiago, Citlalli; López-Meraz, María Leonor; Santiago-García, Juan; Fernández-Pomares, Cynthia; Juárez-Aguilar, Enrique

    2013-10-01

    A possible role of GH during central nervous system (CNS) development has been suggested by the presence of this hormone and its receptor in brain areas before its production by the pituitary gland. Although several effects have been reported for GH, the specific role of this hormone during CNS development remains unclear. Here, we examined the effect of GH on proliferation, survival and neurosphere formation in primary cultures of striatal tissue from 14-day-old (E14) mouse embryos. GH receptor gene expression was confirmed by RT-PCR. Primary cultures of embryonic striatal cells were treated with different doses of GH in serum free media, then the number of neurospheres was determined. To examine the GH effect on proliferation and survival of the striatal primary cultures, bromodeoxyuridine (BrdU) and TUNEL immunoreactivity was conducted. In the presence of the epidermal growth factor (EGF), GH increased the formation of neurospheres, with a maximal response at 10 ng/ml, higher doses were inhibitory. In absence of EGF, GH failed to stimulate neurosphere formation. Proliferation rate in the primary striatal cultures was inhibited by 24 or 48 h incubation with GH. However, in the absence of EGF, GH increased BrdU incorporation. GH treatment decreases the rate of apoptosis of nestin and GFAP positive cells in the primary striatal cultures, enhancing neurosphere formation. Our in vitro data demonstrate that GH plays a survival role on the original population of embryonic striatal cells, improving Neural Precursor Cells (NPCs) expansion. We suggest that this GH action could be predominant during striatal neurodevelopment. © 2013.

  4. Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment.

    Science.gov (United States)

    Robertson, Chelsea L; Ishibashi, Kenji; Chudzynski, Joy; Mooney, Larissa J; Rawson, Richard A; Dolezal, Brett A; Cooper, Christopher B; Brown, Amira K; Mandelkern, Mark A; London, Edythe D

    2016-05-01

    Methamphetamine use disorder is associated with striatal dopaminergic deficits that have been linked to poor treatment outcomes, identifying these deficits as an important therapeutic target. Exercise attenuates methamphetamine-induced neurochemical damage in the rat brain, and a preliminary observation suggests that exercise increases striatal D2/D3 receptor availability (measured as nondisplaceable binding potential (BPND)) in patients with Parkinson's disease. The goal of this study was to evaluate whether adding an exercise training program to an inpatient behavioral intervention for methamphetamine use disorder reverses deficits in striatal D2/D3 receptors. Participants were adult men and women who met DSM-IV criteria for methamphetamine dependence and were enrolled in a residential facility, where they maintained abstinence from illicit drugs of abuse and received behavioral therapy for their addiction. They were randomized to a group that received 1 h supervised exercise training (n=10) or one that received equal-time health education training (n=9), 3 days/week for 8 weeks. They came to an academic research center for positron emission tomography (PET) using [(18)F]fallypride to determine the effects of the 8-week interventions on striatal D2/D3 receptor BPND. At baseline, striatal D2/D3 BPND did not differ between groups. However, after 8 weeks, participants in the exercise group displayed a significant increase in striatal D2/D3 BPND, whereas those in the education group did not. There were no changes in D2/D3 BPND in extrastriatal regions in either group. These findings suggest that structured exercise training can ameliorate striatal D2/D3 receptor deficits in methamphetamine users, and warrants further evaluation as an adjunctive treatment for stimulant dependence.

  5. [Prevalence of common allergies in children and adolescents in Germany: results of the KiGGS study: first follow-up (KiGGS Wave 1)].

    Science.gov (United States)

    Schmitz, R; Thamm, M; Ellert, U; Kalcklösch, M; Schlaud, M

    2014-07-01

    The first follow-up of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS Wave 1) was conducted from 2009 to 2012 as a combined cross-sectional and longitudinal study and provides, among other things, data on allergic diseases. Data collection was carried out by telephone interviews. In total, 6,093 girls and 6,275 boys were included, among them 4,455 newly recruited 0- to 6-year-olds (response 38.8%) and 7,913 KiGGS follow-up participants aged 7-17 years (response 72.9%). Based on parent reports, 15.6% (95% confidence interval 14.7-16.5) of children and adolescents aged 0-17 years were currently affected by at least one atopic disease. The 12-month prevalence rates of hay fever, atopic dermatitis, and asthma were 9.1% (8.4-9.8), 6.0% (5.4-6.6), and 4.1% (3.6-4.6), respectively. In all, 2.2% (1.9-2.6) of the children and adolescents were currently suffering from contact dermatitis. Compared with the baseline KiGGS survey from 2003 to 2006, a higher percentage of participants reported the occurrence of asthma within the past 12 months in the recent KiGGS Wave 1 (4.1 vs. 3.2%; p = 0.0034). The total increase is mainly due to higher prevalence rates among 0- to 6-year-olds, especially in girls. Higher 12-month prevalence rates can be also observed for hay fever among 0- to 6-year-olds, especially in girls, although the total increase is not statistically significant (9.1 vs. 8.3%; p = 0.08). There was a declining trend for atopic dermatitis: 6.8% (2003-2006) vs. 5.4% (2009-2012); p = 0.0015.

  6. A Comparison of Visual Assessment and Automated Digital Image Analysis of Ki67 Labeling Index in Breast Cancer.

    Science.gov (United States)

    Zhong, Fangfang; Bi, Rui; Yu, Baohua; Yang, Fei; Yang, Wentao; Shui, Ruohong

    2016-01-01

    Ki67 labeling index (LI) is critical for treatment options and prognosis evaluation in breast cancer. Visual assessment (VA) is widely used to assess Ki67 LI, but has some limitations. In this study, we compared the consistency between VA and automated digital image analysis (DIA) of Ki67 LI in breast cancer, and to evaluate the application value of DIA in Ki67 LI assessment. Ki67 immunostained slides of 155 cases of primary invasive breast cancer were eyeballing assessed by five breast pathologists and automated digital image analyzed by one breast pathologist respectively. Two score methods, hot-spot score and average score, were used to choose score areas. The intra-class correlation coefficient (ICC) was used to analyze the consistency between VA and DIA, and Wilcoxon signed-rank test was used to compare the median of paired-difference between VA and DIA values. (1) A perfect agreement was demonstrated between VA and DIA of Ki67 LI by ICC analysis (PKi67 LI was also showed in G2-G3, ER positive/HER2 negative cases. Average score and hot-spot score methods both demonstrated a perfect concordance between VA and DIA of Ki67 LI. (2) All cases were classified into three groups by VA values (≤10%, 11%-30% and >30% Ki67 LI). The concordance was relatively lower in intermediate Ki67 LI group (11%-30%) compared with high (>30%) Ki67 LI groups according to both methods. (3) All cases were classified into three groups by paired-difference (d) between VA values of hot-spot score and average score (dKi67 staining distribution (heterogeneous or homogenous) and reproducibility of assessment. A perfect agreement was all demonstrated in three groups, and a slightly better Ki67 LI agreement between VA and DIA was indicated in homogenous staining slides than in heterogeneous staining ones. (4) VA values were relatively smaller than DIA values (average score: median of paired-difference -3.72; hot-spot score: median of paired-difference -9.12). An excellent agreement between VA

  7. Longitudinal study of striatal activation to reward and loss anticipation from mid-adolescence into late adolescence/early adulthood.

    Science.gov (United States)

    Lamm, C; Benson, B E; Guyer, A E; Perez-Edgar, K; Fox, N A; Pine, D S; Ernst, M

    2014-08-01

    Adolescent risk-taking behavior has been associated with age-related changes in striatal activation to incentives. Previous cross-sectional studies have shown both increased and decreased striatal activation to incentives for adolescents compared to adults. The monetary incentive delay (MID) task, designed to assess functional brain activation in anticipation of reward, has been used extensively to examine striatal activation in both adult and adolescent populations. The current study used this task with a longitudinal approach across mid-adolescence and late adolescence/early adulthood. Twenty-two participants (13 male) were studied using the MID task at two time-points, once in mid-adolescence (mean age=16.11; SD=1.44) and a second time in late adolescence/early adulthood (mean age=20.14; SD=.67). Results revealed greater striatal activation with increased age in high- compared to low-incentive contexts (incentive magnitude), for gain as well as for loss trials (incentive valence). Results extend cross-sectional findings and show reduced striatal engagement in adolescence compared to adulthood during preparation for action in an incentive context. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Automated characterization and counting of Ki-67 protein for breast cancer prognosis: A quantitative immunohistochemistry approach.

    Science.gov (United States)

    Mungle, Tushar; Tewary, Suman; Arun, Indu; Basak, Bijan; Agarwal, Sanjit; Ahmed, Rosina; Chatterjee, Sanjoy; Maity, Asok Kumar; Chakraborty, Chandan

    2017-02-01

    Ki-67 protein expression plays an important role in predicting the proliferative status of tumour cells and deciding the future course of therapy in breast cancer. Immunohistochemical (IHC) determination of Ki-67 score or labelling index, by estimating the fraction of Ki67 positively stained tumour cells, is the most widely practiced method to assess tumour proliferation (Dowsett et al. 2011). Accurate manual counting of these cells (specifically nuclei) due to complex and dense distribution of cells, therefore, becomes critical and presents a major challenge to pathologists. In this paper, we suggest a hybrid clustering algorithm to quantify the proliferative index of breast cancer cells based on automated counting of Ki-67 nuclei. The proposed methodology initially pre-processes the IHC images of Ki-67 stained slides of breast cancer. The RGB images are converted to grey, L*a*b*, HSI, YCbCr, YIQ and XYZ colour space. All the stained cells are then characterized by two stage segmentation process. Fuzzy C-means quantifies all the stained cells as one cluster. The blue channel of the first stage output is given as input to k-means algorithm, which provides separate cluster for Ki-67 positive and negative cells. The count of positive and negative nuclei is used to calculate the F-measure for each colour space. A comparative study of our work with the expert opinion is studied to evaluate the error rate. The positive and negative nuclei detection results for all colour spaces are compared with the ground truth for validation and F-measure is calculated. The F-measure for L*a*b* colour space (0.8847) provides the best statistical result as compared to grey, HSI, YCbCr, YIQ and XYZ colour space. Further, a study is carried out to count nuclei manually and automatically from the proposed algorithm with an average error rate of 6.84% which is significant. The study provides an automated count of positive and negative nuclei using L*a*b*colour space and hybrid

  9. Effect of doping of OH- and CN- on the liberation of I2 molecules in KI by gamma-irradiation, impurity concentration effect

    International Nuclear Information System (INIS)

    Shirke, A.K.; Pode, R.B.; Deshmukh, B.T.

    1996-01-01

    Photodecomposition of pure and doped KI powder (KI:KOH; KI:KCN; Impurity concentration, 100, 300, 500, 700 and 1000 ppm) to produce free I 2 molecules during gamma irradiation is studied with the help of absorption and IR measurements. Large number of I 2 molecules are formed in pure KI as compared to the doped samples. Hydroxide impurity increases the rate of liberation of I 2 molecules whereas the cyanide impurity decreases the rate of liberation of I 2 molecules. (Author)

  10. Distribution pattern of the Ki67 labelling index in breast cancer and its implications for choosing cut-off values.

    Science.gov (United States)

    Cserni, Gábor; Vörös, András; Liepniece-Karele, Inta; Bianchi, Simonetta; Vezzosi, Vania; Grabau, Dorthe; Sapino, Anna; Castellano, Isabella; Regitnig, Peter; Foschini, Maria Pia; Zolota, Vassiliki; Varga, Zsuzsanna; Figueiredo, Paulo; Decker, Thomas; Focke, Cornelia; Kulka, Janina; Kaya, Handan; Reiner-Concin, Angelika; Amendoeira, Isabel; Callagy, Grace; Caffrey, Emer; Wesseling, Jelle; Wells, Clive

    2014-06-01

    The Ki67 labelling index (LI - proportion of staining cells) is widely used to reflect proliferation in breast carcinomas. Several cut-off values have been suggested to distinguish between tumours with low and high proliferative activity. The aim of the current study was to evaluate the distribution of Ki67 LIs in breast carcinomas diagnosed at different institutions by different pathologists using the method reflecting their daily practice. Pathologists using Ki67 were asked to provide data (including the LI, type of the specimen, receptor status, grade) on 100 consecutively stained cases, as well as details of their evaluation. A full dataset of 1709 carcinomas was collected from 19 departments. The median Ki67 LI was 17% for all tumours and 14% for oestrogen receptor-positive and HER2-negative carcinomas. Tumours with higher mitotic counts were associated with higher Ki67 LIs. Ki67 LIs tended to cluster around values ending with 5 or 0 both in cases where the values were obtained by counting the proportion of stained tumour cell nuclei and those where the values were obtained by estimation. On the basis of the distribution pattern described, some currently used Ki67 LI cut off values are not realistic, and it is proposed to select more realistic values ending with 0 or 5. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Effects of Herbal-Acupuncture with Rosae Laevigatae Fructus Extract at KI10(Umgok on Osteoporosis in Ovariectomized Mice

    Directory of Open Access Journals (Sweden)

    Kim Dong-soo

    2009-12-01

    Full Text Available Objective & Methods : The purpose of this study was to observe the effects of herbal-acupuncture with Rosae Laevigatae Fructus extact(RLF-HA at KI10(Umgok on osteoporosis in ovariectomized(OVX ddy mice. We carried out several experimental items to analyze the changes in body weight, uterine weight, uterus index, tibial length, the ash bone weight, tibial BMD, serum ALP, serum osteocalcin, serum Ca, and the levels of Ca, P, Ca/P ratio in tibia, and we performed histological and histomorphological analysis as well. Results : 1. Herbal-acupuncture with Rosae Laevigatae Fructus at KI10(Umgok and saline injection at KI10(Umgok significantly inhibited the reduction of tibial calcium level in ovariectomized mice. 2. Herbal-acupuncture with Rosae Laevigatae Fructus at KI10(Umgok significantly inhibited the increase of tibial osteoclast cells in ovariectomized mice. 3. Herbal-acupuncture with Rosae Laevigatae Fructus at KI10(Umgok significantly inhibited the reduction of tibial trabecular bone thickness(TBT in ovariectomized mice. 4. Herbal-acupuncture with Rosae Laevigatae Fructus at KI10(Umgok significantly inhibited the overgrowth of tibial growth plate length(GPL in ovariectomized mice. Conclusion : These results suggested that herbal-acupuncture with Rosae Laevigatae Fructus at KI10(Umgok has a therapeutic effect on osteoporosis, and to be put to practical use in the future osteoporosis clinic.

  12. Targeted light-inactivation of the Ki-67 protein using theranostic liposomes leads to death of proliferating cells

    Science.gov (United States)

    Rahmanzadeh, Ramtin; Rai, Prakash; Gerdes, Johannes; Hasan, Tayyaba

    2010-02-01

    Nanomedicine is beginning to impact the treatment of several diseases and current research efforts include development of integrated nano-constructs (theranostics) which serve as probes for imaging and therapy in addition to delivering macromolecules intracellularly. In cancer, there is a vital unmet need for effective alternative treatments with high specificity and low systemic toxicity. This can be achieved by targeting key molecular markers associated with cancer cells with reduced effective drug doses. Here, we show an innovative proof-of-principle approach for efficient killing of proliferating ovarian cancer cells by inactivating a protein associated with cell proliferation namely, the nuclear Ki-67 protein (pKi-67), using nanotechnology-based photodynamic therapy (PDT). Antibodies against pKi-67 are widely used as prognostic tools for tumor diagnosis. In this work, anti pKi-67 antibodies were first conjugated to fluorescein isothiocyanate (FITC) and then encapsulated inside liposomes. After incubation of OVCAR-5 ovarian cancer cells with these liposomes, confocal microscopy confirmed the localization of the antibodies to the nucleoli of the cells. Irradiation with a 488 nm laser led to a significant loss of cell viability. The specificity of this approach for pKi-67 positive cells was demonstrated in confluent human lung fibroblasts (MRC-5) where only a small population of cells stain positive for pKi-67 and only minimal cell death was observed. Taken together, our findings suggest that pKi-67 targeted with nano-platform is an attractive therapeutic target in cancer therapy.

  13. Ki-ras gene mutations are invariably present in low-grade mucinous tumors of the vermiform appendix.

    Science.gov (United States)

    Zauber, Peter; Berman, Errol; Marotta, Stephen; Sabbath-Solitare, Marlene; Bishop, Timothy

    2011-07-01

    Low-grade mucinous tumors of the appendix appear to have a simple histological structure. Paradoxically, reports have suggested a greater frequency of Ki-ras gene mutation in these lesions than in more complex lesions such as benign colonic adenomas and carcinomas. We assessed several molecular genetic changes, including Ki-ras gene mutations, in a large series of low-grade mucinous tumors of the appendix. We retrospectively ascertained low-grade mucinous tumors of the appendix from computerized pathology records. Extracted DNA was analyzed for APC and DCC gene loss of heterozygosity, microsatellite instability and for the presence of Ki-ras gene mutation using standard molecular techniques. Controls consisted of normal appendices, other appendiceal neoplasms, and ovarian mucinous cystadenomas. A total of 31 low-grade appendiceal mucinous tumors were identified. All were microsatellite stable and none demonstrated loss of heterozygosity for the APC or DCC genes. By contrast, all 31 lesions contained a Ki-ras gene mutation. The presence of a Ki-ras gene mutation in all lesions, with no other molecular changes identified, strongly suggests a possible etiological role of the Ki-ras mutation in the development of this particular lesion of the appendix. Based on other work regarding intestinal bacteria, we hypothesize a relationship between chronic inflammation of the appendix from bacterial overgrowth and Ki-ras gene mutation.

  14. Prognostic value of the proliferation marker Ki-67 in laryngeal carcinoma : Results of the Accelerated Radiotherapy with Carbogen Breathing and Nicotinamide phase III randomized trial

    NARCIS (Netherlands)

    Rademakers, Saskia E.; Hoogsteen, Ilse J.; Rijken, Paul F.; Terhaard, Chris H.; Doornaert, Patricia A.; Langendijk, Johannes A.; van den Ende, Piet; van der Kogel, Albert J.; Bussink, Johan; Kaanders, Johannes H.

    BackgroundThe prognostic and predictive value of the proliferation marker Ki-67 was investigated in a randomized trial comparing accelerated radiotherapy with carbogen breathing and nicotinamide (ARCON) to accelerated radiotherapy in laryngeal carcinoma. MethodsLabeling index of Ki-67 (Li Ki-67) in

  15. Prognostic value of the proliferation marker Ki-67 in laryngeal carcinoma : Results of the Accelerated Radiotherapy with Carbogen Breathing and Nicotinamide phase III randomized trial

    NARCIS (Netherlands)

    Rademakers, Saskia E.; Hoogsteen, Ilse J.; Rijken, Paul F.; Terhaard, Chris H.; Doornaert, Patricia A.; Langendijk, Johannes A.; Van Den Ende, Piet; Van Der Kogel, Albert J.; Bussink, Johan; Kaanders, Johannes H.

    2015-01-01

    Background The prognostic and predictive value of the proliferation marker Ki-67 was investigated in a randomized trial comparing accelerated radiotherapy with carbogen breathing and nicotinamide (ARCON) to accelerated radiotherapy in laryngeal carcinoma. Methods Labeling index of Ki-67 (Li Ki-67)

  16. Immunohistochemical detection of Ki67 in breast cancer correlates with transcriptional regulation of genes related to apoptosis and cell death.

    Science.gov (United States)

    Tan, Puay-Hoon; Bay, Boon-Huat; Yip, George; Selvarajan, Sathiyamoorthy; Tan, Patrick; Wu, Jeanie; Lee, Chee-How; Li, Kuo-Bin

    2005-03-01

    Ki67 is a nuclear protein that is tightly linked to the cell cycle. It is a marker of cell proliferation and has been used to stratify good and poor prognostic categories in invasive breast cancer. Its correlation with gene expression patterns has not been fully elucidated. In this study, Ki67 immunohistochemistry using the MIB-1 antibody was performed on sections cut from 21 formalin-fixed, paraffin-embedded invasive breast cancers. Scoring was determined as nil (no immunostaining), low (10% or less immunopositivity) or high (>10% immunoreactive cells) respectively. The relationship of Ki67 immunohistochemical detection with clinicopathologic parameters was evaluated. Using Affymetrix U133A GeneChips, expression profiles for these tumors were generated and correlated with Ki67 immunohistochemical findings. Analysis of variance was used to define genes that were differentially regulated between the groups. Real-time polymerase chain reaction (PCR) was used to confirm the presence of a downregulated gene. Our results showed high, low and nil Ki67 immunostaining in nine (43%), six (28.5%) and six (28.5%) invasive breast cancers respectively, with increased Ki67 protein expression correlating with high histologic grade (P=0.02), mitotic score (P=0.001) and estrogen receptor immunonegativity (P=0.002). Expression profiling trends of the Ki67 gene mirrored the observed proportions of immunostained cells when the Ki67 immunoscore was >10%. Genes related to apoptosis and cell death (bcl2, MAP2K4, TNF10) were noted to be downregulated in tumors that disclosed >40% Ki67 immunostaining (Pbreast cancers.

  17. The Nishino Breathing Method and Ki-energy (Life-energy: A Challenge to Traditional Scientific Thinking

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    Tsuyoshi Ohnishi

    2006-01-01

    Full Text Available The breathing method, which was developed and is being taught by Kozo Nishino, a Japanese Ki-expert, is for raising the levels of Ki-energy (life-energy or the vitality of an individual. It is neither a therapy nor a healing technique. However, many of his students have experienced an improvement in their health, and in some cases, they were able to overcome health problems by themselves. Since this is an interesting subject from the standpoint of complementary and alternative medicine (CAM, we have been collaborating with Nishino to conduct a scientific investigation of his Ki-energy. We found that Nishino's Ki-energy can inhibit cell division of cancer cells, protect isolated mitochondria from heat deterioration and reduce lipid peroxidation in heat-treated mitochondria. Although Ki-energy may consist of several different energy forms, we found that at least one of them is near-infrared radiation between the wavelength range of 0.8 and 2.7 µm. Another interesting observation at his school is the Taiki-practice (paired Ki-practice. During this practice, Nishino can ‘move’ his students without any physical contact. Many of them run, jump or roll on the floor when they receive his Ki-energy. We studied this and propose that ‘information’ is conveyed through the air between two individuals by Ki-energy. This may be called a five sense-independent, life-to-life communication by Ki. All of our results suggest that we should re-evaluate the Cartesian dualism (separation of mind and body which has been a fundamental principle of modern science for the past three centuries.

  18. Prenatal stress induces increased striatal dopamine transporter binding in adult nonhuman primates.

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    Converse, Alexander K; Moore, Colleen F; Moirano, Jeffrey M; Ahlers, Elizabeth O; Larson, Julie A; Engle, Jonathan W; Barnhart, Todd E; Murali, Dhanabalan; Christian, Bradley T; DeJesus, Onofre T; Holden, James E; Nickles, Robert J; Schneider, Mary L

    2013-10-01

    To determine the effects in adult offspring of maternal exposure to stress and alcohol during pregnancy, we imaged striatal and midbrain dopamine transporter (DAT) binding by positron emission tomography in rhesus monkeys (Macaca mulatta). We also evaluated the relationship between DAT binding and behavioral responses previously found to relate to dopamine D2 receptor density (responsivity to tactile stimuli, performance on a learning task, and behavior during a learning task). Subjects were adult offspring derived from a 2 × 2 experiment in which pregnant monkeys were randomly assigned to control, daily mild stress exposure (acoustic startle), voluntary consumption of moderate-level alcohol, or both daily stress and alcohol. Adult offspring (n = 38) were imaged by positron emission tomography with the DAT ligand [(18)F]2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane ([(18)F]FECNT). Results showed that prenatal stress yielded an overall increase of 15% in [(18)F]FECNT binding in the striatum (p = .016), 17% greater binding in the putamen (p = .012), and 13% greater binding in the head of the caudate (p = .028) relative to animals not exposed to prenatal stress. Striatal [(18)F]FECNT binding correlated negatively with habituation to repeated tactile stimulation and positively with tactile responsivity. There were no significant effects of prenatal alcohol exposure on [(18)F]FECNT binding. Maternal exposure to mild daily stress during pregnancy yielded increases in striatal DAT availability that were apparent in adult offspring and were associated with behavioral characteristics reflecting tactile hyperresponsivity, a condition associated with problem behaviors in children. © 2013 Society of Biological Psychiatry.

  19. Striatal fast-spiking interneurons: from firing patterns to postsynaptic impact

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    Andreas eKlaus

    2011-07-01

    Full Text Available In the striatal microcircuit, fast-spiking (FS interneurons have an important role in mediating inhibition onto neighboring medium spiny (MS projection neurons. In this study, we combined computational modeling with in vitro and in vivo electrophysiological measurements to investigate FS cells in terms of their discharge properties and their synaptic efficacies onto MS neurons. In vivo firing of striatal FS interneurons is characterized by a high firing variability. It is not known, however, if this variability results from the input that FS cells receive, or if it is promoted by the stuttering spike behavior of these neurons. Both our model and measurements in vitro show that FS neurons that exhibit random stuttering discharge in response to steady depolarization, do not show the typical stuttering behavior when they receive fluctuating input. Importantly, our model predicts that electrically coupled FS cells show substantial spike synchronization only when they are in the stuttering regime. Therefore, together with the lack of synchronized firing of striatal FS interneurons that has been reported in vivo, these results suggest that neighboring FS neurons are not in the stuttering regime simultaneously and that in vivo FS firing variability is more likely determined by the input fluctuations. Furthermore, the variability in FS firing is translated to variability in the postsynaptic amplitudes in MS neurons due to the strong synaptic depression of the FS-to-MS synapse. Our results support the idea that these synapses operate over a wide range from strongly depressed to almost fully recovered. The strong inhibitory effects that FS cells can impose on their postsynaptic targets, and the fact that the FS-to-MS synapse model showed substantial depression over extended periods of time might indicate the importance of cooperative effects of multiple presynaptic FS interneurons and the precise orchestration of their activity.

  20. Striatal dysfunction in X-linked dystonia-parkinsonism is associated with disease progression.

    Science.gov (United States)

    Brüggemann, N; Rosales, R L; Waugh, J L; Blood, A J; Domingo, A; Heldmann, M; Jamora, R D; Münchau, A; Münte, T F; Lee, L V; Buchmann, I; Klein, C

    2017-05-01

    X-linked dystonia-parkinsonism (XDP) is an inherited neurodegenerative adult-onset movement disorder associated with striatal atrophy. As the dopaminergic system has not yet been systemically studied in this basal ganglia model disease, it is unclear whether nigrostriatal dysfunction contributes to parkinsonism in XDP. Pre- and post-synaptic dopaminergic function was assessed in XDP. A total of 10 123 jod-benzamide (IBZM) single-photon emission computed tomography (SPECT) images were obtained for nine patients aged 42.3 ± 9.5 years (SD; range 30-52) and one asymptomatic mutation carrier (38 years), and four ioflupane (FP-CIT) SPECT images were obtained for four patients, aged 41.5 ± 11.6 years (range 30-52 years). Structural magnetic resonance imaging was also performed for all mutation carriers and 10 matched healthy controls. All patients were men who suffered from severe, disabling segmental or generalized dystonia and had varying degrees of parkinsonism. IBZM SPECT images were pathological in 8/9 symptomatic patients with distinct reduced post-synaptic tracer uptake in the caudate nucleus and putamen, and unremarkable in the asymptomatic mutation carrier. Longer disease duration was correlated with lower IBZM binding ratios. All subjects exhibited slightly reduced FP-CIT uptake values compared to controls for each analyzed region (-37% to -41%) which may be linked to basal ganglia volume loss. Visual inspection revealed physiological FP-CIT uptake in 1/4 patients. This nuclear imaging study provides evidence that the functional decline of post-synaptic dopaminergic neurotransmission is related to disease duration and ongoing neurodegeneration. Given the severe striatal cell loss which could be verified with post-synaptic nuclear imaging, both parkinsonism and dystonia in XDP are probably mainly due to striatal dysfunction. © 2017 EAN.

  1. Lower levels of uric acid and striatal dopamine in non-tremor dominant Parkinson's disease subtype.

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    Ismael Huertas

    Full Text Available Parkinson's disease (PD patients who present with tremor and maintain a predominance of tremor have a better prognosis. Similarly, PD patients with high levels of uric acid (UA, a natural neuroprotectant, have also a better disease course. Our aim was to investigate whether PD motor subtypes differ in their levels of UA, and if these differences correlate with the degree of dopamine transporter (DAT availability. We included 75 PD patients from whom we collected information about their motor symptoms, DAT imaging and UA concentration levels. Based on the predominance of their motor symptoms, patients were classified into postural instability and gait disorder (PIGD, n = 36, intermediate (I, n = 22, and tremor-dominant (TD, n = 17 subtypes. The levels of UA and striatal DAT were compared across subtypes and the correlation between these two measures was also explored. We found that PIGD patients had lower levels of UA (3.7 vs 4.5 vs 5.3 mg/dL; P<0.001 and striatal DAT than patients with an intermediate or TD phenotype. Furthermore, UA levels significantly correlated with the levels of striatal DAT. We also observed that some PIGD (25% and I (45% patients had a predominance of tremor at disease onset. We speculate that UA might be involved in the maintenance of the less damaging TD phenotype and thus also in the conversion from TD to PIGD. Low levels of this natural antioxidant could lead to a major neuronal damage and therefore influence the conversion to a more severe motor phenotype.

  2. TRPC1 Deletion Causes Striatal Neuronal Cell Apoptosis and Proteomic Alterations in Mice

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    Dian Wang

    2018-03-01

    Full Text Available Transient receptor potential channel 1 (TRPC1 is widely expressed throughout the nervous system, while its biological role remains unclear. In this study, we showed that TRPC1 deletion caused striatal neuronal loss and significantly increased TUNEL-positive and 8-hydroxy-2′-deoxyguanosine (8-OHdG staining in the striatum. Proteomic analysis by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE coupled with mass spectrometry (MS revealed a total of 51 differentially expressed proteins (26 increased and 25 decreased in the stratum of TRPC1 knockout (TRPC1−/− mice compared to that of wild type (WT mice. Bioinformatics analysis showed these dysregulated proteins included: oxidative stress-related proteins, synaptic proteins, endoplasmic reticulum (ER stress-related proteins and apoptosis-related proteins. STRING analysis showed these differential proteins have a well-established interaction network. Based on the proteomic data, we revealed by Western-blot analysis that TRPC1 deletion caused ER stress as evidenced by the dysregulation of GRP78 and PERK activation-related signaling pathway, and elevated oxidative stress as suggested by increased 8-OHdG staining, increased NADH dehydrogenase (ubiquinone flavoprotein 2 (NDUV2 and decreased protein deglycase (DJ-1, two oxidative stress-related proteins. In addition, we also demonstrated that TRPC1 deletion led to significantly increased apoptosis in striatum with concurrent decrease in both 14–3–3Z and dynamin-1 (D2 dopamine (DA receptor binding, two apoptosis-related proteins. Taken together, we concluded that TRPC1 deletion might cause striatal neuronal apoptosis by disturbing multiple biological processes (i.e., ER stress, oxidative stress and apoptosis-related signaling. These data suggest that TRPC1 may be a key player in the regulation of striatal cellular survival and death.

  3. Abnormal striatal dopaminergic neurotransmission during rest and task production in spasmodic dysphonia.

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    Simonyan, Kristina; Berman, Brian D; Herscovitch, Peter; Hallett, Mark

    2013-09-11

    Spasmodic dysphonia is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. The pathophysiology of spasmodic dysphonia is thought to involve structural and functional abnormalities in the basal ganglia-thalamo-cortical circuitry; however, neurochemical correlates underpinning these abnormalities as well as their relations to spasmodic dysphonia symptoms remain unknown. We used positron emission tomography with the radioligand [(11)C]raclopride (RAC) to study striatal dopaminergic neurotransmission at the resting state and during production of symptomatic sentences and asymptomatic finger tapping in spasmodic dysphonia patients. We found that patients, compared to healthy controls, had bilaterally decreased RAC binding potential (BP) to striatal dopamine D2/D3 receptors on average by 29.2%, which was associated with decreased RAC displacement (RAC ΔBP) in the left striatum during symptomatic speaking (group average difference 10.2%), but increased RAC ΔBP in the bilateral striatum during asymptomatic tapping (group average difference 10.1%). Patients with more severe voice symptoms and subclinically longer reaction time to initiate the tapping sequence had greater RAC ΔBP measures, while longer duration of spasmodic dysphonia was associated with a decrease in task-induced RAC ΔBP. Decreased dopaminergic transmission during symptomatic speech production may represent a disorder-specific pathophysiological trait involved in symptom generation, whereas increased dopaminergic function during unaffected task performance may be explained by a compensatory adaptation of the nigrostriatal dopaminergic system possibly due to decreased striatal D2/D3 receptor availability. These changes can be linked to the clinical and subclinical features of spasmodic dysphonia and may represent the neurochemical basis of basal ganglia alterations in this disorder.

  4. Striatal Volume Increases in Active Methamphetamine-Dependent Individuals and Correlation with Cognitive Performance

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    Rob R. Kydd

    2012-10-01

    Full Text Available The effect of methamphetamine (MA dependence on the structure of the human brain has not been extensively studied, especially in active users. Previous studies reported cortical deficits and striatal gains in grey matter (GM volume of abstinent MA abusers compared with control participants. This study aimed to investigate structural GM changes in the brains of 17 active MA-dependent participants compared with 20 control participants aged 18–46 years using voxel-based morphometry and region of interest volumetric analysis of structural magnetic resonance imaging data, and whether these changes might be associated with cognitive performance. Significant volume increases were observed in the right and left putamen and left nucleus accumbens of MA-dependent compared to control participants. The volumetric gain in the right putamen remained significant after Bonferroni correction, and was inversely correlated with the number of errors (standardised z-scores on the Go/No-go task. MA-dependent participants exhibited cortical GM deficits in the left superior frontal and precentral gyri in comparison to control participants, although these findings did not survive correction for multiple comparisons. In conclusion, consistent with findings from previous studies of abstinent users, active chronic MA-dependent participants showed significant striatal enlargement which was associated with improved performance on the Go/No-go, a cognitive task of response inhibition and impulsivity. Striatal enlargement may reflect the involvement of neurotrophic effects, inflammation or microgliosis. However, since it was associated with improved cognitive function, it is likely to reflect a compensatory response to MA-induced neurotoxicity in the striatum, in order to maintain cognitive function. Follow-up studies are recommended to ascertain whether this effect continues to be present following abstinence. Several factors may have contributed to the lack of more

  5. Fronto-striatal glutamate in children with Tourette's disorder and attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Naaijen, Jilly; Forde, Natalie J; Lythgoe, David J; Akkermans, Sophie E A; Openneer, Thaira J C; Dietrich, Andrea; Zwiers, Marcel P; Hoekstra, Pieter J; Buitelaar, Jan K

    2017-01-01

    Both Tourette's disorder (TD) and attention-deficit/hyperactivity disorder (ADHD) have been related to abnormalities in glutamatergic neurochemistry in the fronto-striatal circuitry. TD and ADHD often co-occur and the neural underpinnings of this co-occurrence have been insufficiently investigated in prior studies. We used proton magnetic resonance spectroscopy (1H-MRS) in children between 8 and 12 years of age (TD n  = 15, ADHD n  = 39, TD + ADHD n  = 29, and healthy controls n  = 53) as an in vivo method of evaluating glutamate concentrations in the fronto-striatal circuit. Spectra were collected on a 3 Tesla Siemens scanner from two voxels in each participant: the anterior cingulate cortex (ACC) and the left dorsal striatum. LC-model was used to process spectra and generate glutamate concentrations in institutional units. A one-way analysis of variance was performed to determine significant effects of diagnostic group on glutamate concentrations. We did not find any group differences in glutamate concentrations in either the ACC (F (3132)  = 0.97, p  = 0.41) or striatum (F (3121)  = 0.59, p  = 0.62). Furthermore, variation in glutamate concentration in these regions was unrelated to age, sex, medication use, IQ, tic, or ADHD severity. Obsessive-compulsive (OC) symptoms were positively correlated with ACC glutamate concentration within the participants with TD (rho = 0.35, p uncorrected  = 0.02). We found no evidence for glutamatergic neuropathology in TD or ADHD within the fronto-striatal circuits. However, the correlation of OC-symptoms with ACC glutamate concentrations suggests that altered glutamatergic transmission is involved in OC-symptoms within TD, but this needs further investigation.

  6. De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions.

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    Mencacci, Niccolò E; Kamsteeg, Erik-Jan; Nakashima, Kosuke; R'Bibo, Lea; Lynch, David S; Balint, Bettina; Willemsen, Michèl A A P; Adams, Matthew E; Wiethoff, Sarah; Suzuki, Kazunori; Davies, Ceri H; Ng, Joanne; Meyer, Esther; Veneziano, Liana; Giunti, Paola; Hughes, Deborah; Raymond, F Lucy; Carecchio, Miryam; Zorzi, Giovanna; Nardocci, Nardo; Barzaghi, Chiara; Garavaglia, Barbara; Salpietro, Vincenzo; Hardy, John; Pittman, Alan M; Houlden, Henry; Kurian, Manju A; Kimura, Haruhide; Vissers, Lisenka E L M; Wood, Nicholas W; Bhatia, Kailash P

    2016-04-07

    Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Morphine Reward Promotes Cue-Sensitive Learning: Implication of Dorsal Striatal CREB Activity

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    Mathieu Baudonnat

    2017-05-01

    Full Text Available Different parallel neural circuits interact and may even compete to process and store information: whereas stimulus–response (S–R learning critically depends on the dorsal striatum (DS, spatial memory relies on the hippocampus (HPC. Strikingly, despite its potential importance for our understanding of addictive behaviors, the impact of drug rewards on memory systems dynamics has not been extensively studied. Here, we assessed long-term effects of drug- vs food reinforcement on the subsequent use of S–R vs spatial learning strategies and their neural substrates. Mice were trained in a Y-maze cue-guided task, during which either food or morphine injections into the ventral tegmental area (VTA were used as rewards. Although drug- and food-reinforced mice learned the Y-maze task equally well, drug-reinforced mice exhibited a preferential use of an S–R learning strategy when tested in a water-maze competition task designed to dissociate cue-based and spatial learning. This cognitive bias was associated with a persistent increase in the phosphorylated form of cAMP response element-binding protein phosphorylation (pCREB within the DS, and a decrease of pCREB expression in the HPC. Pharmacological inhibition of striatal PKA pathway in drug-rewarded mice limited the morphine-induced increase in levels of pCREB in DS and restored a balanced use of spatial vs cue-based learning. Our findings suggest that drug (opiate reward biases the engagement of separate memory systems toward a predominant use of the cue-dependent system via an increase in learning-related striatal pCREB activity. Persistent functional imbalance between striatal and hippocampal activity could contribute to the persistence of addictive behaviors, or counteract the efficiency of pharmacological or psychotherapeutic treatments.

  8. Striatal Activity and Reward Relativity: Neural Signals Encoding Dynamic Outcome Valuation.

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    Webber, Emily S; Mankin, David E; Cromwell, Howard C

    2016-01-01

    The striatum is a key brain region involved in reward processing. Striatal activity has been linked to encoding reward magnitude and integrating diverse reward outcome information. Recent work has supported the involvement of striatum in the valuation of outcomes. The present work extends this idea by examining striatal activity during dynamic shifts in value that include different levels and directions of magnitude disparity. A novel task was used to produce diverse relative reward effects on a chain of instrumental action. Rats ( Rattus norvegicus ) were trained to respond to cues associated with specific outcomes varying by food pellet magnitude. Animals were exposed to single-outcome sessions followed by mixed-outcome sessions, and neural activity was compared among identical outcome trials from the different behavioral contexts. Results recording striatal activity show that neural responses to different task elements reflect incentive contrast as well as other relative effects that involve generalization between outcomes or possible influences of outcome variety. The activity that was most prevalent was linked to food consumption and post-food consumption periods. Relative encoding was sensitive to magnitude disparity. A within-session analysis showed strong contrast effects that were dependent upon the outcome received in the immediately preceding trial. Significantly higher numbers of responses were found in ventral striatum linked to relative outcome effects. Our results support the idea that relative value can incorporate diverse relationships, including comparisons from specific individual outcomes to general behavioral contexts. The striatum contains these diverse relative processes, possibly enabling both a higher information yield concerning value shifts and a greater behavioral flexibility.

  9. Chemical anatomy of striatal interneurons in normal individuals and in patients with Huntington's disease.

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    Cicchetti, F; Prensa, L; Wu, Y; Parent, A

    2000-11-01

    This paper reviews the major anatomical and chemical features of the various types of interneurons in the human striatum, as detected by immunostaining procedures applied to postmortem tissue from normal individuals and patients with Huntington's disease (HD). The human striatum harbors a highly pleomorphic population of aspiny interneurons that stain for either a calcium-binding protein (calretinin, parvalbumin or calbindin D-28k), choline acetyltransferase (ChAT) or NADPH-diaphorase, or various combinations thereof. Neurons that express calretinin (CR), including multitudinous medium and a smaller number of large neurons, are by far the most abundant interneurons in the human striatum. The medium CR+ neurons do not colocalize with any of the known chemical markers of striatal neurons, except perhaps GABA, and are selectively spared in HD. Most large CR+ interneurons display ChAT immunoreactivity and also express substance P receptors. The medium and large CR+ neurons are enriched with glutamate receptor subunit GluR2 and GluR4, respectively. This difference in AMPA GluR subunit expression may account for the relative resistance of medium CR+ neurons to glutamate-mediated excitotoxicity that may be involved in HD. The various striatal chemical markers display a highly heterogeneous distribution pattern in human. In addition to the classic striosomes/matrix compartmentalization, the striosomal compartment itself is composed of a core and a peripheral region, each subdivided by distinct subsets of striatal interneurons. A proper knowledge of all these features that appear unique to humans should greatly help our understanding of the organization of the human striatum in both health and disease states.

  10. Lower levels of uric acid and striatal dopamine in non-tremor dominant Parkinson's disease subtype.

    Science.gov (United States)

    Huertas, Ismael; Jesús, Silvia; Lojo, José Antonio; García-Gómez, Francisco Javier; Cáceres-Redondo, María Teresa; Oropesa-Ruiz, Juan Manuel; Carrillo, Fátima; Vargas-Gonzalez, Laura; Martín Rodríguez, Juan Francisco; Gómez-Garre, Pilar; García-Solís, David; Mir, Pablo

    2017-01-01

    Parkinson's disease (PD) patients who present with tremor and maintain a predominance of tremor have a better prognosis. Similarly, PD patients with high levels of uric acid (UA), a natural neuroprotectant, have also a better disease course. Our aim was to investigate whether PD motor subtypes differ in their levels of UA, and if these differences correlate with the degree of dopamine transporter (DAT) availability. We included 75 PD patients from whom we collected information about their motor symptoms, DAT imaging and UA concentration levels. Based on the predominance of their motor symptoms, patients were classified into postural instability and gait disorder (PIGD, n = 36), intermediate (I, n = 22), and tremor-dominant (TD, n = 17) subtypes. The levels of UA and striatal DAT were compared across subtypes and the correlation between these two measures was also explored. We found that PIGD patients had lower levels of UA (3.7 vs 4.5 vs 5.3 mg/dL; P<0.001) and striatal DAT than patients with an intermediate or TD phenotype. Furthermore, UA levels significantly correlated with the levels of striatal DAT. We also observed that some PIGD (25%) and I (45%) patients had a predominance of tremor at disease onset. We speculate that UA might be involved in the maintenance of the less damaging TD phenotype and thus also in the conversion from TD to PIGD. Low levels of this natural antioxidant could lead to a major neuronal damage and therefore influence the conversion to a more severe motor phenotype.

  11. Convergence of dopamine and glutamate signalling onto striatal ERK activation in response to drugs of abuse.

    Directory of Open Access Journals (Sweden)

    Emma eCahill

    2014-01-01

    Full Text Available Despite their distinct targets, all addictive drugs commonly abused by humans evoke increases in dopamine (DA concentration within the striatum. The main DA G-Protein Coupled Receptors (GPCRs expressed by medium-sized spiny neurons (MSNs of the striatum are the D1R and D2R, which are positively and negatively coupled to cAMP/protein kinase A (PKA signalling, respectively. These two DA GPCRs are largely segregated into distinct neuronal populations, where they are co-expressed with glutamate receptors in dendritic spines. Direct and indirect interactions between DA GPCRs and glutamate receptors are the molecular basis by which DA modulates glutamate transmission and controls striatal plasticity and behaviour induced by drugs of abuse. A major downstream target of striatal D1R is the Extracellular signal-Regulated Kinase (ERK kinase pathway. ERK activation by drugs of abuse behaves as a key integrator of D1R and glutamate NMDAR signalling. Once activated, ERK can trigger chromatin remodelling and induce gene expression that permits long-term cellular alterations and drug-induced morphological and behavioural changes. Besides the classical cAMP/PKA pathway, downstream of D1R, recent evidence implicates a cAMP-independent crosstalk mechanism by which the D1R potentiates NMDAR-mediated calcium influx and ERK activation. The mounting evidence of reciprocal modulation of DA and glutamate receptors adds further intricacy to striatal synaptic signalling and is liable to prove relevant for addictive drug-induced signalling, plasticity and behaviour. Herein, we review the evidence that built our understanding of the consequences of this synergistic signalling for the actions of drugs of abuse.

  12. The Genomic Grade Assay Compared With Ki67 to Determine Risk of Distant Breast Cancer Recurrence

    DEFF Research Database (Denmark)

    Ignatiadis, Michail; Azim, Hatem A; Desmedt, Christine

    2016-01-01

    (formerly HER2 or HER2/neu). The likelihood ratio statistic was used to assess the added prognostic value. Interventions: Central evaluation and comparison, blinded for clinical information, of the GG assay, breast cancer histological grade, and Ki67. Main Outcomes and Measures: Distant recurrence...... to the clinicopathological prognostic factors. In patients with early node-negative breast cancer who were endocrine-only treated, 38% were GG1 with a 10-year DRFI of 99% (95% CI, 97%-100%), and 18% were histological grade 1 with a 10-year DRFI of 100% (95% CI, 100%-100%). For GG equivocal patients, the 10-year DRFI was 94......% (95% CI, 90%-98%), and for GG3 patients, the 10-year DRFI was 87% (95% CI, 80%-94%). Conclusions and Relevance: Either the GG assay or centrally reviewed Ki67 significantly improves clinicopathological models to determine distant recurrence of breast cancer. Compared with the histological grade...

  13. On the r>h Shift in Kiên Giang Khmer

    Directory of Open Access Journals (Sweden)

    James Kirby

    2017-12-01

    Full Text Available This paper presents an acoustic and perceptual study of the r>h shift in the variety of Khmer spoken in Giồng Riềng district, Kiên Giang province, Vietnam. In Phnom Penh Khmer, /r/ is realized as [h] in syllable onsets and onset clusters, and accompanied by lowered pitch, breathiness, and in some cases a change in the quality of the following vowel. In Kiên Giang Khmer, the r>h shift is accompanied by pitch lowering, but without changes in aspiration or vowel quality, and spectral measures did not indicate substantial differences in voice quality. Consistent with their productions, users of this dialect appear to rely solely on differences pitch to identify these lexical items. We discuss the implications of our findings for Khmer dialectology, mechanisms of sound change, and variation in the realization of rhotics more generally.

  14. Obtaining and characterization catalyst Ki/Al2O3 by physical dispersion process via wet

    International Nuclear Information System (INIS)

    Silva, M.C. da; Dantas, J.; Costa, A.C.F.M.; Costa, N.C.O.; Freitas, N.L. de

    2014-01-01

    The aim of this study is the Obtention and characterization of catalysts being supported alumina impregnated with KI by physical dispersion in wet via attritor mill in periods of 30 and 60 minutes. Before and after impregnation the catalysts were characterized by XRD, X ray fluorescence, particle size distribution, textural analysis (BET). The results show the presence of the stable crystalline phase Al 2 O 3 in all samples after impregnation and the second phase formed from KI and K 2 O. There was a decrease in the agglomerates incorporated with the potassium due to the milling process. It was observed that the highest specific surface area was obtained by the impregnated sample into a 60 min. (author)

  15. Prognostic impact of discrepant Ki67 and mitotic index on hormone receptor-positive, HER2-negative breast carcinoma

    Science.gov (United States)

    Rossi, L; Laas, E; Mallon, P; Vincent-Salomon, A; Guinebretiere, J-M; Lerebours, F; Rouzier, R; Pierga, J-Y; Reyal, F

    2015-01-01

    Background: Inconsistencies between mitotic index (MI) and Ki67 measures have been identified in many breast tumour samples. The aim of this study was to describe the prognosis of hormone receptor-positive (HR+) HER2− tumours having discrepant MI and Ki67. Methods: We included a cohort of breast cancer patients initially treated by surgery between 2001 and 2005 in the Institut Curie. Breast cancer-specific survival (BCSS) and disease-free survival (DFS) were analysed according to three proliferation groups: high MI/high Ki67 (MI=3, Ki67>20%), low MI/low Ki67 (MIKi67⩽20%) and discrepant (high MI/low Ki67 or low MI/high Ki67). Results: Among the 1430 patients, 19.6% had discrepant Ki67 and MI, 11.6% had high markers and 68.8% had low markers. The 5-year BCSS was 95.8%, 95% CI (0.93–0.98) in the discrepant group, 99.3%, 95% CI (0.993–0.999) in the low-proliferation group and 91.8%, 95% CI (0.88–0.96) in the high-proliferation group. In multivariate analysis, the survival of the discrepant group was lower than that of the low-proliferation group: BCSS hazard ratio (HR)=3.01 (1.32–6.84; P=0.008) and DFS HR=2.07, 95% CI (1.31–3.26; P=0.002). Among grade 2 tumours in multivariate analysis, DFS of the discrepant group was lower than that of the low MI/low Ki67 group: HR=1.98, 95% CI (1.14–3.46), P=0.02. Regarding BCSS, the obtained results were similar. Conclusion: The prognosis of patients with discrepant MI and Ki67 appears intermediate between that of low MI/low Ki67 and high MI/high Ki67 groups. These markers should be jointly analysed to clarify prognosis. PMID:26379080

  16. Prognostic value of automated KI67 scoring in breast cancer: a centralised evaluation of 8088 patients from 10 study groups.

    Science.gov (United States)

    Abubakar, Mustapha; Orr, Nick; Daley, Frances; Coulson, Penny; Ali, H Raza; Blows, Fiona; Benitez, Javier; Milne, Roger; Brenner, Herman; Stegmaier, Christa; Mannermaa, Arto; Chang-Claude, Jenny; Rudolph, Anja; Sinn, Peter; Couch, Fergus J; Devilee, Peter; Tollenaar, Rob A E M; Seynaeve, Caroline; Figueroa, Jonine; Sherman, Mark E; Lissowska, Jolanta; Hewitt, Stephen; Eccles, Diana; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W M; van Deurzen, Carolien H M; Investigators, kConFab; Bolla, Manjeet K; Wang, Qin; Jones, Michael; Schoemaker, Minouk; Wesseling, Jelle; van Leeuwen, Flora E; Van 't Veer, Laura; Easton, Douglas; Swerdlow, Anthony J; Dowsett, Mitch; Pharoah, Paul D; Schmidt, Marjanka K; Garcia-Closas, Montserrat

    2016-10-18

    The value of KI67 in breast cancer prognostication has been questioned due to concerns on the analytical validity of visual KI67 assessment and methodological limitations of published studies. Here, we investigate the prognostic value of automated KI67 scoring in a large, multicentre study, and compare this with pathologists' visual scores available in a subset of patients. We utilised 143 tissue microarrays containing 15,313 tumour tissue cores from 8088 breast cancer patients in 10 collaborating studies. A total of 1401 deaths occurred during a median follow-up of 7.5 years. Centralised KI67 assessment was performed using an automated scoring protocol. The relationship of KI67 levels with 10-year breast cancer specific survival (BCSS) was investigated using Kaplan-Meier survival curves and Cox proportional hazard regression models adjusted for known prognostic factors. Patients in the highest quartile of KI67 (>12 % positive KI67 cells) had a worse 10-year BCSS than patients in the lower three quartiles. This association was statistically significant for ER-positive patients (hazard ratio (HR) (95 % CI) at baseline = 1.96 (1.31-2.93); P = 0.001) but not for ER-negative patients (1.23 (0.86-1.77); P = 0.248) (P-heterogeneity = 0.064). In spite of differences in characteristics of the study populations, the estimates of HR were consistent across all studies (P-heterogeneity = 0.941 for ER-positive and P-heterogeneity = 0.866 for ER-negative). Among ER-positive cancers, KI67 was associated with worse prognosis in both node-negative (2.47 (1.16-5.27)) and node-positive (1.74 (1.05-2.86)) tumours (P-heterogeneity = 0.671). Further classification according to ER, PR and HER2 showed statistically significant associations with prognosis among hormone receptor-positive patients regardless of HER2 status (P-heterogeneity = 0.270) and among triple-negative patients (1.70 (1.02-2.84)). Model fit parameters were similar for visual and

  17. Predictive Role of p53 Protein as a Single Marker or Associated to Ki67 Antigen in Oral Carcinogenesis

    OpenAIRE

    Montebugnoli, L.; Felicetti, L.; Gissi, D.B.; Cervellati, F.; Servidio, D.; Marchetti, C.; Prati, C.; Flamminio, F.; Foschini, M.P.

    2008-01-01

    p53 over-expression has been proposed as a reliable marker associated to oral carcinogenesis, although only about 50% of oral carcinomas (OSCC) are associated with p53 over-expression and even p53-negative lesions can progress to OSCC. The aim of the study was to determine whether the combination of p53 over-expression and p53 low-expression associated with Ki67 over-expression (high Ki67/p53 ratio) could lead to a more sensitive parameter. Immunohistochemical expression of Ki67 and p53 was m...

  18. Dopaminergic differentiation of human neural stem cells mediated by co-cultured rat striatal brain slices

    DEFF Research Database (Denmark)

    Anwar, Mohammad Raffaqat; Andreasen, Christian Maaløv; Lippert, Solvej Kølvraa

    2008-01-01

    differentiation, we co-cultured cells from a human neural forebrain-derived stem cell line (hNS1) with rat striatal brain slices. In brief, coronal slices of neonatal rat striatum were cultured on semiporous membrane inserts placed in six-well trays overlying monolayers of hNS1 cells. After 12 days of co......Properly committed neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. To establish a setting for identification of secreted neural compounds promoting dopaminergic...

  19. Sensory Entrainment Mechanisms in Auditory Perception: Neural Synchronization Cortico-Striatal Activation

    Science.gov (United States)

    Sameiro-Barbosa, Catia M.; Geiser, Eveline

    2016-01-01

    The auditory system displays modulations in sensitivity that can align with the temporal structure of the acoustic environment. This sensory entrainment can facilitate sensory perception and is particularly relevant for audition. Systems neuroscience is slowly uncovering the neural mechanisms underlying the behaviorally observed sensory entrainment effects in the human sensory system. The present article summarizes the prominent behavioral effects of sensory entrainment and reviews our current understanding of the neural basis of sensory entrainment, such as synchronized neural oscillations, and potentially, neural activation in the cortico-striatal system. PMID:27559306

  20. Key modulatory role of presynaptic adenosine A2A receptors in cortical neurotransmission to the striatal direct pathway.

    Science.gov (United States)

    Quiroz, César; Luján, Rafael; Uchigashima, Motokazu; Simoes, Ana Patrícia; Lerner, Talia N; Borycz, Janusz; Kachroo, Anil; Canas, Paula M; Orru, Marco; Schwarzschild, Michael A; Rosin, Diane L; Kreitzer, Anatol C; Cunha, Rodrigo A; Watanabe, Masahiko; Ferré, Sergi

    2009-11-18

    Basal ganglia processing results from a balanced activation of direct and indirect striatal efferent pathways, which are controlled by dopamine D1 and D2 receptors, respectively. Adenosine A2A receptors are considered novel antiparkinsonian targets, based on their selective postsynaptic localization in the indirect pathway, where they modulate D2 receptor function. The present study provides evidence for the existence of an additional, functionally significant, segregation of A2A receptors at the presynaptic level. Using integrated anatomical, electrophysiological, and biochemical approaches, we demonstrate that presynaptic A2A receptors are preferentially localized in cortical glutamatergic terminals that contact striatal neurons of the direct pathway, where they exert a selective modulation of corticostriatal neurotransmission. Presynaptic striatal A2A receptors could provide a new target for the treatment of neuropsychiatric disorders.

  1. Key Modulatory Role of Presynaptic Adenosine A2A Receptors in Cortical Neurotransmission to the Striatal Direct Pathway

    Directory of Open Access Journals (Sweden)

    César Quiroz

    2009-01-01

    Full Text Available Basal ganglia processing results from a balanced activation of direct and indirect striatal efferent pathways, which are controlled by dopamine D1 and D2 receptors, respectively. Adenosine A2A receptors are considered novel antiparkinsonian targets, based on their selective postsynaptic localization in the indirect pathway, where they modulate D2 receptor function. The present study provides evidence for the existence of an additional, functionally significant, segregation of A2A receptors at the presynaptic level. Using integrated anatomical, electrophysiological, and biochemical approaches, we demonstrate that presynaptic A2A receptors are preferentially localized in cortical glutamatergic terminals that contact striatal neurons of the direct pathway, where they exert a selective modulation of corticostriatal neurotransmission. Presynaptic striatal A2A receptors could provide a new target for the treatment of neuropsychiatric disorders.

  2. Euro tulekust lahutab 1,5 miljardit ülejääki / Raimo Poom

    Index Scriptorium Estoniae

    Poom, Raimo

    2010-01-01

    2009. aasta III kvartali lõpus oli Eesti eelarvedefitsiit 4,9% SKT-st, eelarve ülejääk oli III kvartalis 1,4 mld. Rahandusministeeriumi nõunik Sven Kirsipuu on arvamusel, et ka IV kvartal peaks olema ülejäägiga. Euroalaga liitumiseks on vaja vähemalt 1,5-miljardilist ülejääki. Graafikud

  3. Effectiveness of the KiVa Antibullying Program: Grades 1-3 and 7-9

    Science.gov (United States)

    Karna, Antti; Voeten, Marinus; Little, Todd D.; Alanen, Erkki; Poskiparta, Elisa; Salmivalli, Christina

    2013-01-01

    This study investigated the effectiveness of the KiVa Antibullying Program in two samples of students, one from Grades 1-3 (7-9 years old, N = 6,927) and the other from Grades 7-9 (13-15 years old, N = 16, 503). The Grades 1-3 students were located in 74 schools and Grades 7-9 students in 73 schools that were randomly assigned to intervention and…

  4. Strong lens search in the ESO public Survey KiDS

    NARCIS (Netherlands)

    Napolitano, N. R.; Covone, G.; Roy, N.; Tortora, C.; Barbera, F. La; Radovich, M.; Getman, F.; Capaccioli, M.; Colonna, A.; Paolillo, M.; Kleijn, G. A. Verdoes; Koopmans, L. V. E.; Valentijn, E; Napolitano, Nicola R.; Longo, Giuseppe; Marconi, Marcella; Paolillo, Maurizio; Lodice, Enrichetta

    2015-01-01

    We have started a systematic search for strong lens candidates in the ESO public survey KiDS based on the visual inspection of massive galaxies in the redshift range 0. 1 < z < 0. 5. As a pilot program we have inspected 100 deg2, which overlap with SDSS and where there are known lenses to use as a

  5. Expression of Ki-67 (MIB-1) and GLUT-1 proteins in non-advanced prostatic cancer.

    Science.gov (United States)

    Luczynska, Elzbieta; Gasinska, Anna; Wilk, Waclaw

    2012-12-01

    The expression of Ki-67 (MIB-1) and glucose transporter-1 (GLUT-1) were evaluated in patients with clinically localized prostate cancer (PC) who had undergone radical prostatectomy with curative intent. 140 low advanced PC specimens were studied. Protein expression was assessed immunohistochemically on tumour sections and expressed as a labelling index, i.e. the percentage of positively stained cells. In the case of Ki-67 nuclear staining and in the case of GLUT-1 membrane and cytoplasmic staining was considered as positive. The patients' mean age was 62.9 ±6.2 years. There were 13 (9.3%) at pTNM stage 1, 78 (55.7%) at stage 2, 40 (28.6%) at stage 3 and 9 (6.4%) at stage 4, respectively. 75 (53.6%) tumours were well differentiated (Gleason score ≤6), 52 (37.1%) moderately differentiated (Gleason score of 7) and 13 (9.3%) poorly differentiated (Gleason score 8-10). The mean pre-operative serum PSA was 9.9 ± SE 0.5 ng/ml, and the mean LI was equal to 8.1 ±0.6% and 29.7 ±2.0%, for MIB-1 and GLUT-1, respectively. Increase of pathological tumor volume and tumor grade was associated with statistically significant growth of PSA (p GLUT-1 LI the relation was not significant. Ki-67 expression was correlated with PSA levels (p = 0.013) and GLUT-1 scores (p = 0.04). In PC, an increase in the proliferation rate (higher MIB-1LI) in higher pTNM stages and tumour grades may point to Ki-67 as a good marker of biological aggressiveness useful in selecting patients for more aggressive treatment. A correlation between proliferation and GLUT-1 score may be the evidence of active glycolytic metabolism in hypoxic regions.

  6. Ki67, PCNA, and MCM proteins: Markers of proliferation in the diagnosis of breast cancer.

    Science.gov (United States)

    Juríková, Miroslava; Danihel, Ľudovít; Polák, Štefan; Varga, Ivan

    2016-06-01

    The proliferative activity of tumour cells represents an important prognostic marker in the diagnosis of cancer. One of the methods for assessing the proliferative activity of cells is the immunohistochemical detection of cell cycle-specific antigens. For example, Ki67, proliferating cell nuclear antigen (PCNA), and minichromosome maintenance (MCM) proteins are standard markers of proliferation that are commonly used to assess the growth fraction of a cell population. The function of Ki67, the widely used marker of proliferation, still remains unclear. In contrast, PCNA and MCM proteins have been identified as important participants of DNA replication. All three proteins only manifest their expression during the cell division of normal and neoplastic cells. Since the expression of these proliferative markers was confirmed in several malignant tumours, their prognostic and predictive values have been evaluated to determine their significance in the diagnosis of cancer. This review offers insight into the discovery of the abovementioned proteins, as well as their current molecular and biological importance. In addition, the functions and properties of all three proteins and their use as markers of proliferation in the diagnosis of breast cancer are described. This work also reveals new findings about the role of Ki67 during the mitotic phase of the cell cycle. Finally, information is provided about the advantages and disadvantages of using all three antigens in the diagnosis of cancer. Copyright © 2016 Elsevier GmbH. All rights reserved.

  7. WACANA SOSIAL MITOS KERIS KI BARU GAJAH DALAM TRADISI NGREBEG DI KECAMATAN KEDIRI, TABANAN

    Directory of Open Access Journals (Sweden)

    Anak Agung Ayu Meitridwiastiti

    2017-12-01

    Full Text Available Penelitian wacana sosial atas mitos keris Ki Baru Gajah dalam tradisi Ngrebeg di Kecamatan Kediri, Tabanan dilakukan untuk menganalisis struktur mitos yang bersifat tekstual, menjelaskan implementasi dan fungsi mitos keris Ki Baru Gajah dalam Purana Pura Luhur Pakendungan pada Tradisi Ngrebeg. Penelitian ini juga mengungkapkan wacana sosial yang ada dan berkembang di masyarakat Kecamatan Kediri, Tabanan yang bersifat kontekstual.Teori yang digunakan dalam penelitian ini adalah teori fungsi dan semiotika (Charles Sander Pierce. Pengumpulan data dikumpulkan melalui studi pustaka, wawancara, dan perekaman. Analisis data yang digunakan adalah hermeneutika dan deskriptif analitik.Penyajian hasil analisis data yang digunakan adalah metode informal. Implementasi mitos keris Ki Baru Gajah meliputi tradisi Ngrebeg, sedangkan fungsinya meliputi fungsi pelengkap upacara Dewa Yadnya, sebagai media pendidikan masyarakat, mempererat hubungan sosial masyarakat, dan pengusir wabah penyakit. Wacana sosial meliputi makna dari mitos tersebut, yaitu makna simbolik, loyalitas, dan kesuburan. Diharapkan dengan tradisi yang berasal dari sebuah mitos dapat memberikan keharmonisan dan kesejahteraan kehidupan dalam masyarakat Kecamatan Kediri, Tabanan.

  8. Solvent Controlled Structural Transition of KI4K Self-Assemblies: from Nanotubes to Nanofibrils.

    Science.gov (United States)

    Zhao, Yurong; Deng, Li; Wang, Jiqian; Xu, Hai; Lu, Jian R

    2015-12-01

    The structural modulation of peptide and protein assemblies under well-controlled conditions is of both fundamental and practical significance. In spite of extensive studies, it remains hugely challenging to tune the self-assembled nanostructures in a controllable manner because the self-assembly processes are dictated by various noncovalent interactions and their interplay. We report here how to manipulate the self-assembly of a designed, symmetric amphiphilic peptide (KI4K) via the solvent-controlled structural transition. Structural transition processes were carefully followed by the combination of transmission electronic microscopy (TEM), atomic force microscopy (AFM), circular dichroism (CD), Fourier transform infrared spectroscopy (FTIR), and small angle neutron scattering (SANS). The results show that the introduction of acetonitrile into water significantly affected the hydrophobic interactions among hydrophobic side chains while imposing little impact on the β-sheet hydrogen bonding between peptide backbones. A structural transition occurred from nanotubes to helical/twisted ribbons and then to thin fibrils with the addition of acetonitrile due to the reduced hydrophobic interactions and the consequent weakening of the lateral stacking between KI4K β-sheets. The increased intermolecular electrostatic repulsions among lysine side chain amino groups had little effect on the lateral stacking of KI4K β-sheets due to the molecular symmetry. Complementary molecular dynamic (MD) simulations also indicated the solvation of acetonitrile molecules into the hydrophobic domains weakening the coherence between the neighboring sheets.

  9. FEASIBILITY STUDY FOR POTASSIUM IODIDE (KI) DISTRIBUTION IN NEW YORK CITY.

    Energy Technology Data Exchange (ETDEWEB)

    MOSS, STEVEN

    2005-04-29

    The New York City Department of Health and Mental Hygiene (DOHMH), Bureau of Environmental Science and Engineering, Office of Radiological Health (ORH) [as the primary local technical consultant in the event of a radiological or nuclear incident within the boundaries of New York City] requested the assistance of Brookhaven National Laboratory (BNL) with the development of a Feasibility Study for Potassium Iodide (KI) distribution in the unlikely event of a significant release of radioactive iodine in or near New York City. Brookhaven National Laboratory had previously provided support for New York City with the development of the radiological/nuclear portions of its All Hazards Emergency Response Plans. The work is funded by Medical and Health Research Association (MHRA) of New York City, Inc., under a work grant by the Federal Centers for Disease Control (CDC) for Public Health Preparedness and Response for Bioterrorism. This report is part of the result of that effort. The conclusions of this report are that: (1) There is no credible radiological scenario that would prompt the need for large segments of the general population of New York City to take KI as a result of a projected plume exposure to radioiodine reaching even the lowest threshold of 5 rem to the thyroid; and (2) KI should be stockpiled in amounts and locations sufficient for use by first responders/emergency responders in response to any localized release of radioiodine.

  10. STEREOLOGIC ESTIMATION OF KI-67, CASPASE 3 AND GSTP1 POSITIVE CELLS IN PROSTATE LESIONS

    Directory of Open Access Journals (Sweden)

    Luis Santamaría

    2011-05-01

    Full Text Available Cell proliferation, caspase 3 and pi-form of glutathione S transferase (GSTP1 were evaluated in prostate carcinoma (PCA, proliferative inflammatory atrophy (PIA and prostate intraepithelial neoplasia (PIN. Forty biopsies were classified as: without morphological lesions (controls: CTR, PIA, PIN and PCA. Ki67, caspase3 and GSTP1 were immunostained. The following estimates were performed: Numerical densities of Ki67+ cells (NVEPKi67, of all epithelial cells (NVEPtotal and of GSTP1+ cells (NVEPGSTP1; labelling index for Ki67 (LIKi67; volume fraction to caspase 3 positive tissue (VVcaspase 3 and of GSTP1 positive tissue (VVGSTP1. ANOVA was performed to compare the groups. NVEPtotal and NVEPKi67 were increased in PIA. LIKi67 was only increased in PCA. VVcaspase 3 was decreased in PIN and PCA. VVEGSTP1 was decreased in PCA. In our results PIA lacks the characteristics of a premalignant lesion. The result may be explained by the use of unbiased quantitative methods, the inadequate definition of PIA and the scarce inflammation observed in the samples with PIA included in this study.

  11. KiDS-450: tomographic cross-correlation of galaxy shear with Planck lensing

    Science.gov (United States)

    Harnois-Déraps, Joachim; Tröster, Tilman; Chisari, Nora Elisa; Heymans, Catherine; van Waerbeke, Ludovic; Asgari, Marika; Bilicki, Maciej; Choi, Ami; Erben, Thomas; Hildebrandt, Hendrik; Hoekstra, Henk; Joudaki, Shahab; Kuijken, Konrad; Merten, Julian; Miller, Lance; Robertson, Naomi; Schneider, Peter; Viola, Massimo

    2017-10-01

    We present the tomographic cross-correlation between galaxy lensing measured in the Kilo Degree Survey (KiDS-450) with overlapping lensing measurements of the cosmic microwave background (CMB), as detected by Planck 2015. We compare our joint probe measurement to the theoretical expectation for a flat Λ cold dark matter cosmology, assuming the best-fitting cosmological parameters from the KiDS-450 cosmic shear and Planck CMB analyses. We find that our results are consistent within 1σ with the KiDS-450 cosmology, with an amplitude re-scaling parameter AKiDS = 0.86 ± 0.19. Adopting a Planck cosmology, we find our results are consistent within 2σ, with APlanck = 0.68 ± 0.15. We show that the agreement is improved in both cases when the contamination to the signal by intrinsic galaxy alignments is accounted for, increasing A by ∼0.1. This is the first tomographic analysis of the galaxy lensing - CMB lensing cross-correlation signal, and is based on five photometric redshift bins. We use this measurement as an independent validation of the multiplicative shear calibration and of the calibrated source redshift distribution at high redshifts. We find that constraints on these two quantities are strongly correlated when obtained from this technique, which should therefore not be considered as a stand-alone competitive calibration tool.

  12. Don Kişot ve Daniş Çelebi Don Kişot And Daniş Çelebi

    Directory of Open Access Journals (Sweden)

    Canan OLPAK KOÇ

    2013-07-01

    Full Text Available Although novel is mostly depend on fiction, it is one of the writtensources and withnesses for people who are trying history of human andgoods. It is submit itself to people in a different ways in the past. But wewant to talk abount modern novel here. For modern it is admit that donQuixote is the inception of novel. In this sense it is definitely anticipatedto be something from Don Quixote in every heros of novels. Also thiseffect in Turkish literature begins to seen as a species. The are which istalking about the effect of Don Quixote is seen at piece of Ahmet mithatEfendi who is undertake social tasks as written machine.Cervantes and Ahmet Mithat Efendi are the two importantnovelists in the world literature. Because both authors used their pensfor art and community servise. In this study these two authors will becompared with the character Don Quixote that meets them in common.In this comparison the novel of Cervante's Don Quixote and the novel ofAhmet Mithat efendi's Don Quixote in İstanbul will be summarized andthe main charactors of each one will be compared exactly witheachother. In this comparison our aim is not only using same types butalso how the writers avaluate their social lives. Before giving it, firstly itwill be montioned the process of known of the novel in Turkishliterature. Roman, çoğunlukla her ne kadar kurguya dayanıyor olsa da eşyanın ve insanın tarihini yazmaya kalkışanlar için önemli yazılı kaynaklardan, tanıklardan biridir. Geçmişte farklı şekiller içinde okura kendini takdim etmiştir. Ancak biz burada modern romandan bahsetmek istiyoruz. Modern anlamda romanın başlangıcı Don Kişot olarak kabul edilir. Bu anlamda sonraki devirlerin her romanında Cervantes’ten, her roman kahramanında da Don Kişot’tan mutlaka bir şeylerin olması beklenir. Türk edebiyatında da bu etki romanın bir tür olarak girmesi ile görülmeye başlar. Bahsedilen dönemde bu Don Kişot etkisi bir yazı makinesi

  13. Neonatal astrocyte damage is sufficient to trigger progressive striatal degeneration in a rat model of glutaric acidemia-I.

    Directory of Open Access Journals (Sweden)

    Silvia Olivera-Bravo

    Full Text Available BACKGROUND: We have investigated whether an acute metabolic damage to astrocytes during the neonatal period may critically disrupt subsequent brain development, leading to neurodevelopmental disorders. Astrocytes are vulnerable to glutaric acid (GA, a dicarboxylic acid that accumulates in millimolar concentrations in Glutaric Acidemia I (GA-I, an inherited neurometabolic childhood disease characterized by degeneration of striatal neurons. While GA induces astrocyte mitochondrial dysfunction, oxidative stress and subsequent increased proliferation, it is presently unknown whether such astrocytic dysfunction is sufficient to trigger striatal neuronal loss. METHODOLOGY/PRINCIPAL FINDINGS: A single intracerebroventricular dose of GA was administered to rat pups at postnatal day 0 (P0 to induce an acute, transient rise of GA levels in the central nervous system (CNS. GA administration potently elicited proliferation of astrocytes expressing S100β followed by GFAP astrocytosis and nitrotyrosine staining lasting until P45. Remarkably, GA did not induce acute neuronal loss assessed by FluoroJade C and NeuN cell count. Instead, neuronal death appeared several days after GA treatment and progressively increased until P45, suggesting a delayed onset of striatal degeneration. The axonal bundles perforating the striatum were disorganized following GA administration. In cell cultures, GA did not affect survival of either striatal astrocytes or neurons, even at high concentrations. However, astrocytes activated by a short exposure to GA caused neuronal death through the production of soluble factors. Iron porphyrin antioxidants prevented GA-induced astrocyte proliferation and striatal degeneration in vivo, as well as astrocyte-mediated neuronal loss in vitro. CONCLUSIONS/SIGNIFICANCE: Taken together, these results indicate that a transient metabolic insult with GA induces long lasting phenotypic changes in astrocytes that cause them to promote striatal

  14. Ventral striatal activity correlates with memory confidence for old- and new-responses in a difficult recognition test.

    Directory of Open Access Journals (Sweden)

    Ulrike Schwarze

    Full Text Available Activity in the ventral striatum has frequently been associated with retrieval success, i.e., it is higher for hits than correct rejections. Based on the prominent role of the ventral striatum in the reward circuit, its activity has been interpreted to reflect the higher subjective value of hits compared to correct rejections in standard recognition tests. This hypothesis was supported by a recent study showing that ventral striatal activity is higher for correct rejections than hits when the value of rejections is increased by external incentives. These findings imply that the striatal response during recognition is context-sensitive and modulated by the adaptive significance of "oldness" or "newness" to the current goals. The present study is based on the idea that not only external incentives, but also other deviations from standard recognition tests which affect the subjective value of specific response types should modulate striatal activity. Therefore, we explored ventral striatal activity in an unusually difficult recognition test that was characterized by low levels of confidence and accuracy. Based on the human uncertainty aversion, in such a recognition context, the subjective value of all high confident decisions is expected to be higher than usual, i.e., also rejecting items with high certainty is deemed rewarding. In an accompanying behavioural experiment, participants rated the pleasantness of each recognition response. As hypothesized, ventral striatal activity correlated in the current unusually difficult recognition test not only with retrieval success, but also with confidence. Moreover, participants indicated that they were more satisfied by higher confidence in addition to perceived oldness of an item. Taken together, the results are in line with the hypothesis that ventral striatal activity during recognition codes the subjective value of different response types that is modulated by the context of the recognition test.

  15. OPREMLJENOST ŠOL Z DIDAKTIČNIMI PRIPOMOČKI ZA PODROČJE ARITMETIKE IN ALGEBRE V PRVEM TRILETJU IN NJIHOVA RACIONALNA UPORABA

    OpenAIRE

    Sraka, Petra

    2011-01-01

    V diplomskem delu so predstavljeni didaktični pripomočki na splošno, sledi pregled terminov, ki so se zanje uporabljali skozi zgodovino vse do danes, klasifikacija ter lastnosti temeljnih didaktičnih pripomočkov. Podane so osnovne smernice kritične izbire ter racionalne uporabe pripomočkov pri pouku matematike. Bolj podrobno so predstavljeni didaktični pripomočki pri pouku matematike v sklopu aritmetike in algebre v prvem triletju osnovne šole oziroma tisti pripomočki, ki jih predpisuje učni ...

  16. Impact of tissue sampling on accuracy of Ki67 immunohistochemistry evaluation in breast cancer.

    Science.gov (United States)

    Besusparis, Justinas; Plancoulaine, Benoit; Rasmusson, Allan; Augulis, Renaldas; Green, Andrew R; Ellis, Ian O; Laurinaviciene, Aida; Herlin, Paulette; Laurinavicius, Arvydas

    2016-08-30

    Gene expression studies have identified molecular subtypes of breast cancer with implications to chemotherapy recommendations. For distinction of these types, a combination of immunohistochemistry (IHC) markers, including proliferative activity of tumor cells, estimated by Ki67 labeling index is used. Clinical studies are frequently based on IHC performed on tissue microarrays (TMA) with variable tissue sampling. This raises the need for evidence-based sampling criteria for individual IHC biomarker studies. We present a novel tissue sampling simulation model and demonstrate its application on Ki67 assessment in breast cancer tissue taking intratumoral heterogeneity into account. Whole slide images (WSI) of 297 breast cancer sections, immunohistochemically stained for Ki67, were subjected to digital image analysis (DIA). Percentage of tumor cells stained for Ki67 was computed for hexagonal tiles super-imposed on the WSI. From this, intratumoral Ki67 heterogeneity indicators (Haralick's entropy values) were extracted and used to dichotomize the tumors into homogeneous and heterogeneous subsets. Simulations with random selection of hexagons, equivalent to 0.75 mm circular diameter TMA cores, were performed. The tissue sampling requirements were investigated in relation to tumor heterogeneity using linear regression and extended error analysis. The sampling requirements were dependent on the heterogeneity of the biomarker expression. To achieve a coefficient error of 10 %, 5-6 cores were needed for homogeneous cases, 11-12 cores for heterogeneous cases; in mixed tumor population 8 TMA cores were required. Similarly, to achieve the same accuracy, approximately 4,000 nuclei must be counted when the intratumor heterogeneity is mixed/unknown. Tumors of low proliferative activity would require larger sampling (10-12 TMA cores, or 6,250 nuclei) to achieve the same error measurement results as for highly proliferative tumors. Our data show that optimal tissue sampling for

  17. KiVa Antibullying Program: Overview of Evaluation Studies Based on a Randomized Controlled Trial and National Rollout in Finland

    Directory of Open Access Journals (Sweden)

    Christina Salmivalli

    2012-12-01

    Full Text Available The effects of a Finnish national school-based antibullying program (KiVa were evaluated in a randomized controlled trial (2007–2009 and during nationwide implementation (since 2009. The KiVa program is been found to reduce bullying and victimization and increase empathy towards victimized peers and self-efficacy to support and defend them. KiVa increases school liking and motivation and contributes to significant reductions in anxiety, depression, and negative peer perceptions. Somewhat larger reductions in bullying and victimization were found in the randomized controlled trial than in the broad rollout, and the largest effects were obtained in primary school (grades 1–6. The uptake of the KiVa program is remarkable, with 90 percent of Finnish comprehensive schools currently registered as program users.

  18. Kaurismäki ja Almodovar võtavad Cannes'is mõõtu / Andres Laasik

    Index Scriptorium Estoniae

    Laasik, Andres, 1960-2016

    2006-01-01

    Filmidest, mis osalevad 17. mail algava Cannes'i filmifestivali võistlusprogrammis : Aki Kaurismäki "Äärelinna tuled" ("Laitakaupungin valot"), Pedro Almodovari "Tagasipöördumine" ("Volver"), Sofia Coppola "Marie-Antoinette" jt

  19. Ki67 expression in invasive breast cancer: the use of tissue microarrays compared with whole tissue sections.

    Science.gov (United States)

    Muftah, Abir A; Aleskandarany, Mohammed A; Al-Kaabi, Methaq M; Sonbul, Sultan N; Diez-Rodriguez, Maria; Nolan, Chris C; Caldas, Carlos; Ellis, Ian O; Rakha, Emad A; Green, Andrew R

    2017-07-01

    Although the prognostic value of Ki67 in breast cancer is well documented, using optimal cut-points for patient stratification, reproducibility of the scoring and interpretation of the results remains a matter of debate particularly when using tissue microarrays (TMAs). This study aims to assess Ki67 expression assessed on TMAs and their matched whole tissue sections (WTS). Moreover, whether the cut-off used for WTS is reproducible on TMA in BC molecular classes and the association between Ki67 expression cut-off, assessed on TMAs and WTS, and clinicopathological parameters and patient outcome were tested. A large series (n = 707) of primary invasive breast tumours were immunostained for Ki67 using both TMA and WTS and assessed as percentage staining and correlated with each other, clinicopathological parameters and patient outcome. In addition, MKI67 mRNA expression was correlated with Ki67 protein levels on WTS and TMAs in a subset of cases included in the METABRIC study. There was moderate concordance in Ki67 expression between WTS and TMA when analysed as a continuous variable (Intraclass correlation coefficient = 0.61) and low concordance when dichotomised (kappa value = 0.3). TMA showed low levels of Ki67 with mean percentage of expression of 35 and 22% on WTS and TMA, respectively. MKI67 mRNA expression was significantly correlated with protein expression determined on WTS (Spearman Correlation, r = 0.52) and to a lesser extent on TMA (r = 0.34) (p Ki67 at 10, 15, 20, 25 or 30% in TMA. Using TMA, ≥20% Ki67 provided the best prognostic cut-off particularly in triple-negative and HER2-positive classes. Ki67 expression in breast cancer can be evaluated using TMA although different cut-points are required to emulate results from WTS. A cut-off of ≥20% for Ki67 expression in BC provides the best prognostic correlations when TMAs are used.

  20. Modulation of acetylcholine release from rat striatal slices by the GABA/benzodiazepine receptor complex

    Energy Technology Data Exchange (ETDEWEB)

    Supavilai, P.; Karobath, M.

    1985-02-04

    GABA, THIP and muscimol enhance spontaneous and inhibit electrically induced release of tritium labelled compounds from rat striatal slices which have been pre-labelled with /sup 3/H-choline. Baclofen is inactive in this model. Muscimol can inhibit electrically induced release of tritiated material by approximately 75% with half maximal effects at 2 ..mu..M. The response to muscimol can be blocked by the GABA antagonists bicuculline methobromide, picrotoxin, anisatin, R 5135 and CPTBO (cyclopentylbicyclophosphate). Drugs which act on the benzodiazepine receptor (BR) require the presence of muscimol to be effective and they modulate the effects of muscimol in a bidirectional manner. Thus BR agonists enhance and inverse BR agonists attenuate the inhibitory effects of muscimol on electrically induced release. Ro15-1788, a BR antagonist, does not modulate the inhibitory effects of muscimol but antagonizes the actions of clonazepam, a BR agonist, and of DMCM, an inverse BR agonist. These results demonstrate that a GABA/benzodiazepine receptor complex can modulate acetylcholine release from rat striatal slices in vitro. 24 references, 3 figures, 5 table.

  1. Decreased striatal D2 receptor density associated with severe behavioral abnormality in Alzheimer's disease

    International Nuclear Information System (INIS)

    Tanaka, Yasuhiro; Meguro, Kenichi; Yamaguchi, Satoshi

    2003-01-01

    Since patients manifesting behavioral and psychological symptoms of dementia (BPSD) are a burden for their families and caregivers, the underlying neurobiological mechanism of this condition should be clarified. Using positron emission tomography (PET), we previously reported that wandering behavior in dementia was associated with a disturbed dopaminergic neuron system. We herein investigated the relationship between the severity of BPSD and the striatal D 2 receptor density in Alzheimer's disease (AD). Ten patients with probable AD as per the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the AD and Related Disorders Association (ADRDA) criteria and five normal subjects were examined with PET. The tracer used was [ 11 C]raclopride (D 2 antagonist). The uptake of [ 11 C]raclopride was calculated as the estimation of binding potential (BP) of the striatum to the cerebellum. The AD patients were institutionalized in multiple nursing homes, and their BPSD were evaluated by the Behavioral Pathology in AD Frequency Weighted Severity Scale (BEHAVE-AD-FW) scale (Reisberg). There was a significant inverse Spearman's correlation between BEHAVE-AD-FW score and the BP, especially between the score of the behavioral domain and the BP values. The BP was found to be lower in severer BPSD patients. Patients with AD who manifest severe BPSD may have some dysfunction of striatal dopamine metabolism compared with those without BPSD. (author)

  2. Effects of caffeine on striatal neurotransmission: focus on cannabinoid CB1 receptors.

    Science.gov (United States)

    Rossi, Silvia; De Chiara, Valentina; Musella, Alessandra; Mataluni, Giorgia; Sacchetti, Lucia; Siracusano, Alberto; Bernardi, Giorgio; Usiello, Alessandro; Centonze, Diego

    2010-04-01

    Caffeine is the most commonly self-administered psychoactive substance worldwide. At usual doses, the effects of caffeine on vigilance, attention, mood and arousal largely depend on the modulation of central adenosine receptors. The present review article describes the action of caffeine within the striatum, to provide a possible molecular mechanism at the basis of the psychomotor and reinforcing properties of this pharmacological agent. The striatum is in fact a subcortical area involved in sensorimotor, cognitive, and emotional processes, and recent experimental findings showed that chronic caffeine consumption enhances the sensitivity of striatal GABAergic synapses to the stimulation of cannabinoid CB1 receptors. The endocannabinoid system is involved in the psychoactive effects of many compounds, and adenosine A2A receptors (the main receptor target of caffeine) elicit a permissive effect towards CB1 receptors, thus suggesting that A2A-CB1 receptor interaction plays a major role in the generation and maintenance of caffeine reinforcing behavior. Aim of this review is to describe the effects of caffeine on striatal neurotransmission with special reference to the modulation of the endocannabinoid system.

  3. Levodopa administration modulates striatal processing of punishment-associated items in healthy participants.

    Science.gov (United States)

    Wittmann, Bianca C; D'Esposito, Mark

    2015-01-01

    Appetitive and aversive processes share a number of features such as their relevance for action and learning. On a neural level, reward and its predictors are associated with increased firing of dopaminergic neurons, whereas punishment processing has been linked to the serotonergic system and to decreases in dopamine transmission. Recent data indicate, however, that the dopaminergic system also responds to aversive stimuli and associated actions. In this pharmacological functional magnetic resonance imaging study, we investigated the contribution of the dopaminergic system to reward and punishment processing in humans. Two groups of participants received either placebo or the dopamine precursor levodopa and were scanned during alternating reward and punishment anticipation blocks. Levodopa administration increased striatal activations for cues presented in punishment blocks. In an interaction with individual personality scores, levodopa also enhanced striatal activation for punishment-predictive compared with neutral cues in participants scoring higher on the novelty-seeking dimension. These data support recent indications that dopamine contributes to punishment processing and suggest that the novelty-seeking trait is a measure of susceptibility to drug effects on motivation. These findings are also consistent with the possibility of an inverted U-shaped response function of dopamine in the striatum, suggesting an optimal level of dopamine release for motivational processing.

  4. KV7 Channels Regulate Firing during Synaptic Integration in GABAergic Striatal Neurons

    Directory of Open Access Journals (Sweden)

    M. Belén Pérez-Ramírez

    2015-01-01

    Full Text Available Striatal projection neurons (SPNs process motor and cognitive information. Their activity is affected by Parkinson’s disease, in which dopamine concentration is decreased and acetylcholine concentration is increased. Acetylcholine activates muscarinic receptors in SPNs. Its main source is the cholinergic interneuron that responds with a briefer latency than SPNs during a cortical command. Therefore, an important question is whether muscarinic G-protein coupled receptors and their signaling cascades are fast enough to intervene during synaptic responses to regulate synaptic integration and firing. One of the most known voltage dependent channels regulated by muscarinic receptors is the KV7/KCNQ channel. It is not known whether these channels regulate the integration of suprathreshold corticostriatal responses. Here, we study the impact of cholinergic muscarinic modulation on the synaptic response of SPNs by regulating KV7 channels. We found that KV7 channels regulate corticostriatal synaptic integration and that this modulation occurs in the dendritic/spines compartment. In contrast, it is negligible in the somatic compartment. This modulation occurs on sub- and suprathreshold responses and lasts during the whole duration of the responses, hundreds of milliseconds, greatly altering SPNs firing properties. This modulation affected the behavior of the striatal microcircuit.

  5. Cortico-striatal oxidative status, dopamine turnover and relation with stereotypy in the deer mouse.

    Science.gov (United States)

    Güldenpfennig, Marianne; Wolmarans, De Wet; du Preez, Jan L; Stein, Dan J; Harvey, Brian H

    2011-06-01

    The deer mouse presents with spontaneous stereotypic movements that resemble the repetitive behaviours of obsessive-compulsive disorder (OCD), and demonstrates a selective response to serotonin reuptake inhibitors. OCD has been linked to altered redox status and since increased dopamine signalling can promote stereotypies as well as oxidative stress, we investigated whether the severity of deer mouse stereotypy may be associated with altered dopamine turnover and cortico-striatal redox status. Deer mice were separated into high (HSB), low (LSB) and non-stereotypy (NS) groups. Frontal cortical and striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), as well as superoxide dismutase (SOD) activity, reduced (GSH) and oxidised (GSSG) glutathione and glutathione redox index, were analysed as markers for regional dopamine turnover and oxidative stress, respectively. Dopamine and its metabolites and SOD activity did not differ across the stereotypy groups. Significantly reduced GSH and GSSG and increased glutathione redox index were only observed in the frontal cortex of HSB animals. Frontal cortical GSH and GSSG were inversely correlated while glutathione redox index was positively correlated with stereotypy. Deer mouse stereotypy is thus characterised by a deficient glutathione system in the frontal cortex but not striatum, and provides a therapeutic rationale for using glutathione-active antioxidants in OCD. The evidence for a primary frontal lesion has importance for future OCD research. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Phasic dopamine release drives rapid activation of striatal D2-receptors

    Science.gov (United States)

    Marcott, Pamela F; Mamaligas, Aphroditi A; Ford, Christopher P

    2014-01-01

    Summary Striatal dopamine transmission underlies numerous goal-directed behaviors. Medium spiny neurons (MSNs) are a major target of dopamine in the striatum. However, as dopamine does not directly evoke a synaptic event in MSNs, the time course of dopamine signaling in these cells remains unclear. To examine how dopamine release activates D2-receptors on MSNs, G-protein activated inwardly rectifying potassium (GIRK2; Kir 3.2) channels were virally overexpressed in the striatum and the resulting outward currents were used as a sensor of D2-receptor activation. Electrical and optogenetic stimulation of dopamine terminals evoked robust D2-receptor inhibitory post-synaptic currents (IPSCs) in GIRK2-expressing MSNs that occurred in under a second. Evoked D2-IPSCs could be driven by repetitive stimulation and were not occluded by background dopamine tone. Together, the results indicate that D2-receptors on MSNs exhibit functional low affinity and suggest that striatal D2-receptors can encode both tonic and phasic dopamine signals. PMID:25242218

  7. Somatostatin regulates dopamine release in rat striatal slices and cat caudate nuclei

    International Nuclear Information System (INIS)

    Chesselet, M.F.; Reisine, T.D.

    1983-01-01

    The effects of somatostatin on the release of tritiated dopamine (DA) formed continuously from tritiated tyrosine were studied in vitro in superfused striatal slices and in vivo in both caudate nuclei and both substantiae nigrae of halothane-anesthetized cats using a push-pull cannula technique. Somatostatin (3 X 10(-10) to 3 X 10(-7) M) increased the spontaneous tritiated dopamine release from rat striatal slices. This effect was dose dependent and was completely prevented by tetrodotoxin (5 X 10(-7) M). When applied for 30 min in one cat caudate nucleus, somatostatin (10(-7) M) immediately increased the local release of tritiated DA, while a gradual inhibition of the tritiated amine's efflux was observed in the contralateral caudate nucleus. No changes in tritiated dopamine were seen in either substantia nigra during or after the peptide's application in the caudate nucleus. These results suggest that somatostatin in the striatum may play a role in the local and the distal control of dopamine release from the terminals of dopaminergic nigrostriatal neurons

  8. FACS identifies unique cocaine-induced gene regulation in selectively activated adult striatal neurons.

    Science.gov (United States)

    Guez-Barber, Danielle; Fanous, Sanya; Golden, Sam A; Schrama, Regina; Koya, Eisuke; Stern, Anna L; Bossert, Jennifer M; Harvey, Brandon K; Picciotto, Marina R; Hope, Bruce T

    2011-03-16

    Numerous studies with the neural activity marker Fos indicate that cocaine activates only a small proportion of sparsely distributed striatal neurons. Until now, efficient methods were not available to assess neuroadaptations induced specifically within these activated neurons. We used fluorescence-activated cell sorting (FACS) to purify striatal neurons activated during cocaine-induced locomotion in naive and cocaine-sensitized cfos-lacZ transgenic rats. Activated neurons were labeled with an antibody against β-galactosidase, the protein product of the lacZ gene. Cocaine induced a unique gene expression profile selectively in the small proportion of activated neurons that was not observed in the nonactivated majority of neurons. These genes included altered levels of the immediate early genes arc, fosB, and nr4a3, as well as genes involved in p38 MAPK signaling and cell-type specificity. We propose that this FACS method can be used to study molecular neuroadaptations in specific neurons encoding the behavioral effects of abused drugs and other learned behaviors.

  9. DRD4 and striatal modulation of the link between childhood behavioral inhibition and adolescent anxiety

    Science.gov (United States)

    Hardee, Jillian E.; Guyer, Amanda E.; Benson, Brenda E.; Nelson, Eric E.; Gorodetsky, Elena; Goldman, David; Fox, Nathan A.; Pine, Daniel S.; Ernst, Monique

    2014-01-01

    Behavioral inhibition (BI), a temperament characterized by vigilance to novelty, sensitivity to approach–withdrawal cues and social reticence in childhood, is associated with risk for anxiety in adolescence. Independent studies link reward hyper-responsivity to BI, adolescent anxiety and dopamine gene variants. This exploratory study extends these observations by examining the impact of DRD4 genotype and reward hyper-responsivity on the BI–anxiety link. Adolescents (N = 78) completed a monetary incentive delay task in the fMRI environment. Participants were characterized based on a continuous score of BI and the 7-repeat allele (7R+) of the DRD4 functional polymorphism. Parent-report and self-report measures of anxiety were also collected. Across the entire sample, striatal activation increased systematically with increases in the magnitude of anticipated monetary gains and losses. DRD4 status moderated the relation between BI and activation in the caudate nucleus. Childhood BI was associated with parent report of adolescent anxiety among 7R+ participants with elevated levels of striatal response to incentive cues. DRD4 genotype influenced the relations among neural response to incentives, early childhood BI and anxiety. The findings help refine our understanding of the role reward-related brain systems play in the emergence of anxiety in temperamentally at-risk individuals, building a foundation for future larger scale studies. PMID:23314010

  10. Regulation of GABA and benzodiazepine receptors following neurotoxin-induced striatal and medial forebrain bundle lesions

    International Nuclear Information System (INIS)

    Pan, H.S.I.

    1985-01-01

    GABA, a major inhibitory transmitter, is used by many projection neurons of the striatum. To investigate the role of GABA in striatal function, the GABA receptor complex was studied after lesions of the striatum or the nigrostriatal neurons. Quantitative receptor autoradiography using thaw-mounted tissue slices was developed for the study of GABA and benzodiazepine (BDZ) receptors. With the technique established, binding to GABA and BDZ receptors after unilateral striatal kainate lesions was examined. Subsequently, changes in GABA and BDZ receptors were studied following the destruction of dopaminergic nigrostriatal cells by unilateral 6-hydroxydopamine lesion of the medial forebrain bundle. In summary, quantitative receptor autoradiography allowed the detection of GABA and BDZ receptor changes in multiple small areas in each lesioned brain. This technique made it feasible to carry out kinetic saturation, and competition studies using less than 1 mg of tissue. The data suggest that dopamine is functionally inhibitory on striatopallidal neurons but is functionally excitatory on striatoentopeduncular and striatonigral cells which in turn inhibit the thalamus. This quantitative autoradiographic technique can be generalized to study other transmitter receptors and can be combined with 2-deoxyglucose uptake studies

  11. Effects of isomers of apomorphines on dopamine receptors in striatal and limbic tissue of rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Kula, N.S.; Baldessarini, R.J.; Bromley, S.; Neumeyer, J.L.

    1985-09-16

    The optical isomers of apomorphine (APO) and N-propylnorapomorphine (NPA) were interacted with three biochemical indices of dopamine (Da) receptors in extrapyramidal and limbic preparations of rat brain tissues. There were consistent isomeric preferences for the R(-) configuration of both DA analogs in stimulation adenylate cyclase (D-1 sites) and in competing for high affinity binding of /sup 3/H-spiroperidol (D-2 sites) and of /sup 3/H-ADTN (DA agonist binding sites) in striatal tissue, with lesser isomeric differences in the limbic tissue. The S(+) apomorphines did not inhibit stimulation of adenylate cyclase by DA. The tendency for greater activity of higher apparent affinity of R(-) apomorphines in striatum may reflect the evidently greater abundance of receptor sites in that region. There were only small regional differences in interactions of the apomorphine isomers with all three receptor sites, except for a strong preference of (-)NPA for striatal D-2 sites. These results do not parallel our recent observations indicating potent and selective antidopaminergic actions of S(+) apomorphines in the rat limbic system. They suggest caution in assuming close parallels between current biochemical functional, especially behavioral, methods of evaluating dopamine receptors of mammalian brain.

  12. Compromised fronto-striatal functioning in HIV: an fMRI investigation of semantic event sequencing.

    Science.gov (United States)

    Melrose, Rebecca J; Tinaz, Sule; Castelo, J Mimi Boer; Courtney, Maureen G; Stern, Chantal E

    2008-04-09

    The human immunodeficiency virus (HIV) damages fronto-striatal regions, and is associated with deficits in executive functioning. We recently developed a semantic event sequencing task based on the Picture Arrangement subtest of the Wechsler Adult Intelligence Scale-III for use with functional magnetic resonance imaging (fMRI) and found recruitment of dorsolateral prefrontal cortex and basal ganglia in healthy participants. To assess the impact of HIV on the functioning of the basal ganglia and prefrontal cortex, we administered this task to 11 HIV+ and 11 Control participants matched for age and education. Neuropsychological evaluation demonstrated that the HIV+ group had mild impairment in memory retrieval and motor functioning, but was not demented. Morphometric measurements suggested no atrophy in basal ganglia regions. The results of the fMRI analysis revealed hypoactivation of the left caudate, left dorsolateral prefrontal cortex, and bilateral ventral prefrontal cortex in the HIV+ group. Functional connectivity analysis demonstrated less functional connectivity between the caudate and prefrontal cortex and basal ganglia regions in the HIV+ group. In contrast, the HIV+ group demonstrated increased activation of right postcentral/supramarginal gyrus, and greater connectivity between the caudate and this same anterior parietal region. The results of this study extend previous investigations by demonstrating compromised function of the caudate and connected prefrontal regions in HIV during cognition. This disruption of fronto-striatal circuitry likely precedes the development of cognitive impairment in HIV.

  13. Optogenetic approaches to evaluate striatal function in animal models of Parkinson disease.

    Science.gov (United States)

    Parker, Krystal L; Kim, Youngcho; Alberico, Stephanie L; Emmons, Eric B; Narayanan, Nandakumar S

    2016-03-01

    Optogenetics refers to the ability to control cells that have been genetically modified to express light-sensitive ion channels. The introduction of optogenetic approaches has facilitated the dissection of neural circuits. Optogenetics allows for the precise stimulation and inhibition of specific sets of neurons and their projections with fine temporal specificity. These techniques are ideally suited to investigating neural circuitry underlying motor and cognitive dysfunction in animal models of human disease. Here, we focus on how optogenetics has been used over the last decade to probe striatal circuits that are involved in Parkinson disease, a neurodegenerative condition involving motor and cognitive abnormalities resulting from degeneration of midbrain dopaminergic neurons. The precise mechanisms underlying the striatal contribution to both cognitive and motor dysfunction in Parkinson disease are unknown. Although optogenetic approaches are somewhat removed from clinical use, insight from these studies can help identify novel therapeutic targets and may inspire new treatments for Parkinson disease. Elucidating how neuronal and behavioral functions are influenced and potentially rescued by optogenetic manipulation in animal models could prove to be translatable to humans. These insights can be used to guide future brain-stimulation approaches for motor and cognitive abnormalities in Parkinson disease and other neuropsychiatric diseases.

  14. Episodic Memory Encoding Interferes with Reward Learning and Decreases Striatal Prediction Errors

    Science.gov (United States)

    Braun, Erin Kendall; Daw, Nathaniel D.

    2014-01-01

    Learning is essential for adaptive decision making. The striatum and its dopaminergic inputs are known to support incremental reward-based learning, while the hippocampus is known to support encoding of single events (episodic memory). Although traditionally studied separately, in even simple experiences, these two types of learning are likely to co-occur and may interact. Here we sought to understand the nature of this interaction by examining how incremental reward learning is related to concurrent episodic memory encoding. During the experiment, human participants made choices between two options (colored squares), each associated with a drifting probability of reward, with the goal of earning as much money as possible. Incidental, trial-unique object pictures, unrelated to the choice, were overlaid on each option. The next day, participants were given a surprise memory test for these pictures. We found that better episodic memory was related to a decreased influence of recent reward experience on choice, both within and across participants. fMRI analyses further revealed that during learning the canonical striatal reward prediction error signal was significantly weaker when episodic memory was stronger. This decrease in reward prediction error signals in the striatum was associated with enhanced functional connectivity between the hippocampus and striatum at the time of choice. Our results suggest a mechanism by which memory encoding may compete for striatal processing and provide insight into how interactions between different forms of learning guide reward-based decision making. PMID:25378157

  15. Low striatal glutamate levels underlie cognitive decline in the elderly: evidence from in vivo molecular spectroscopy.

    Science.gov (United States)

    Zahr, Natalie M; Mayer, Dirk; Pfefferbaum, Adolf; Sullivan, Edith V

    2008-10-01

    Glutamate (Glu), the principal excitatory neurotransmitter of prefrontal cortical efferents, potentially mediates higher order cognitive processes, and its altered availability may underlie mechanisms of age-related decline in frontally based functions. Although animal studies support a role for Glu in age-related cognitive deterioration, human studies, which require magnetic resonance spectroscopy for in vivo measurement of this neurotransmitter, have been impeded because of the similarity of Glu's spectroscopic signature to those of neighboring spectral brain metabolites. Here, we used a spectroscopic protocol, optimized for Glu detection, to examine the effect of age in 3 brain regions targeted by cortical efferents--the striatum, cerebellum, and pons--and to test whether performance on frontally based cognitive tests would be predicted by regional Glu levels. Healthy elderly men and women had lower Glu in the striatum but not pons or cerebellum than young adults. In the combined age groups, levels of striatal Glu (but no other proton metabolite also measured) correlated selectively with performance on cognitive tests showing age-related decline. The selective relations between performance and striatal Glu provide initial and novel, human in vivo support for age-related modification of Glu levels as contributing to cognitive decline in normal aging.

  16. Clinical report on and CT findings in two siblings with bilateral striatal necrosis

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    Maya, Kiyomi; Imai, Terukuni; Hashimoto, Shuji; Yamasaki, Masahiro (Kitano Hospital, Osaka (Japan)); Kajiura, Ichiro

    1983-12-01

    Two siblings, a 13-year-old girl and a 9-year-old boy, presented a similar progressive extrapyramidal disorder. The onsets were at the age of 4 years and at that of 2 1/2 years respectively, and a certain febrile illness had preceded it for two or three months in both cases. The major clinical features were progressive gait disturbance, dysarthria, and dystonia; they were associated with secondary skeletal deformities in the sister and with abnormal ocular movements in the brother. The CT findings, essentially similar in both cases, were characterized by symmetrical hypodensity lesions and an atrophy of the corpora striata, namely, the putamen and the caudate nucleus. Based on the clinical features and the CT findings, and on a comparison with the previous clinico-pathological reports in the literature, the present cases were diagnosed as bilateral striatal necrosis. The disorder termed ''bilateral striatal necrosis'' has not been widely known; this report stresses the great usefulness of CT examination in the clinical diagnosis of this rare disorder.

  17. Emotion-induced loss aversion and striatal-amygdala coupling in low-anxious individuals.

    Science.gov (United States)

    Charpentier, Caroline J; De Martino, Benedetto; Sim, Alena L; Sharot, Tali; Roiser, Jonathan P

    2016-04-01

    Adapting behavior to changes in the environment is a crucial ability for survival but such adaptation varies widely across individuals. Here, we asked how humans alter their economic decision-making in response to emotional cues, and whether this is related to trait anxiety. Developing an emotional decision-making task for functional magnetic resonance imaging, in which gambling decisions were preceded by emotional and non-emotional primes, we assessed emotional influences on loss aversion, the tendency to overweigh potential monetary losses relative to gains. Our behavioral results revealed that only low-anxious individuals exhibited increased loss aversion under emotional conditions. This emotional modulation of decision-making was accompanied by a corresponding emotion-elicited increase in amygdala-striatal functional connectivity, which correlated with the behavioral effect across participants. Consistent with prior reports of 'neural loss aversion', both amygdala and ventral striatum tracked losses more strongly than gains, and amygdala loss aversion signals were exaggerated by emotion, suggesting a potential role for this structure in integrating value and emotion cues. Increased loss aversion and striatal-amygdala coupling induced by emotional cues may reflect the engagement of adaptive harm-avoidance mechanisms in low-anxious individuals, possibly promoting resilience to psychopathology. © The Author (2015). Published by Oxford University Press.

  18. Perineuronal nets play a role in regulating striatal function in the mouse.

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    Hyunchul Lee

    Full Text Available The striatum is the primary input nucleus of the basal ganglia, a collection of nuclei that play important roles in motor control and associative learning. We have previously reported that perineuronal nets (PNNs, aggregations of chondroitin-sulfate proteoglycans (CSPGs, form in the matrix compartment of the mouse striatum during the second postnatal week. This period overlaps with important developmental changes, including the attainment of an adult-like gait. Here, we investigate the identity of the cells encapsulated by PNNs, characterize their topographical distribution and determine their function by assessing the impact of enzymatic digestion of PNNs on two striatum-dependent behaviors: ambulation and goal-directed spatial learning. We show PNNs are more numerous caudally, and that a substantial fraction (41% of these structures surrounds parvalbumin positive (PV+ interneurons, while approximately 51% of PV+ cells are ensheathed by PNNs. The colocalization of these structures is greatest in dorsal, lateral and caudal regions of the striatum. Bilateral digestion of striatal PNNs led to an increase in both the width and variability of hind limb gait. Intriguingly, this also resulted in an improvement in the acquisition rate of the Morris water maze. Together, these data show that PNNs are associated with specific elements of striatal circuits and play a key role in regulating the function of this important structure in the mouse.

  19. Perineuronal nets play a role in regulating striatal function in the mouse.

    Science.gov (United States)

    Lee, Hyunchul; Leamey, Catherine A; Sawatari, Atomu

    2012-01-01

    The striatum is the primary input nucleus of the basal ganglia, a collection of nuclei that play important roles in motor control and associative learning. We have previously reported that perineuronal nets (PNNs), aggregations of chondroitin-sulfate proteoglycans (CSPGs), form in the matrix compartment of the mouse striatum during the second postnatal week. This period overlaps with important developmental changes, including the attainment of an adult-like gait. Here, we investigate the identity of the cells encapsulated by PNNs, characterize their topographical distribution and determine their function by assessing the impact of enzymatic digestion of PNNs on two striatum-dependent behaviors: ambulation and goal-directed spatial learning. We show PNNs are more numerous caudally, and that a substantial fraction (41%) of these structures surrounds parvalbumin positive (PV+) interneurons, while approximately 51% of PV+ cells are ensheathed by PNNs. The colocalization of these structures is greatest in dorsal, lateral and caudal regions of the striatum. Bilateral digestion of striatal PNNs led to an increase in both the width and variability of hind limb gait. Intriguingly, this also resulted in an improvement in the acquisition rate of the Morris water maze. Together, these data show that PNNs are associated with specific elements of striatal circuits and play a key role in regulating the function of this important structure in the mouse.

  20. Episodic memory encoding interferes with reward learning and decreases striatal prediction errors.

    Science.gov (United States)

    Wimmer, G Elliott; Braun, Erin Kendall; Daw, Nathaniel D; Shohamy, Daphna

    2014-11-05

    Learning is essential for adaptive decision making. The striatum and its dopaminergic inputs are known to support incremental reward-based learning, while the hippocampus is known to support encoding of single events (episodic memory). Although traditionally studied separately, in even simple experiences, these two types of learning are likely to co-occur and may interact. Here we sought to understand the nature of this interaction by examining how incremental reward learning is related to concurrent episodic memory encoding. During the experiment, human participants made choices between two options (colored squares), each associated with a drifting probability of reward, with the goal of earning as much money as possible. Incidental, trial-unique object pictures, unrelated to the choice, were overlaid on each option. The next day, participants were given a surprise memory test for these pictures. We found that better episodic memory was related to a decreased influence of recent reward experience on choice, both within and across participants. fMRI analyses further revealed that during learning the canonical striatal reward prediction error signal was significantly weaker when episodic memory was stronger. This decrease in reward prediction error signals in the striatum was associated with enhanced functional connectivity between the hippocampus and striatum at the time of choice. Our results suggest a mechanism by which memory encoding may compete for striatal processing and provide insight into how interactions between different forms of learning guide reward-based decision making. Copyright © 2014 the authors 0270-6474/14/3414901-12$15.00/0.

  1. The Value of Ki67 in Very Young Women with Hormone Receptor-Positive Breast Cancer: Retrospective Analysis of 9,321 Korean Women.

    Science.gov (United States)

    Kim, Jisun; Han, Wonshik; Jung, So-Youn; Park, Yeon Hee; Moon, Hyeong-Gon; Ahn, Soo Kyung; Lee, Jun Woo; Kim, Min Kyoon; Kim, Jong Jin; Lee, Eun Shin; You, Tae Kyung; Kang, Han-Sung; Lee, Eun Sook; Ro, Jungsil; Lee, Jeong Eon; Nam, Seok Jin; Yim, Young-Hyuck; Park, In Ae; Noh, Dong-Young

    2015-10-01

    Young breast cancer patients have a poorer prognosis, especially when their tumors are hormone receptor positive. We analyzed the association between Ki67 and age and the impact of these factors on outcomes in hormone receptor-positive breast cancer. The records of 9,321 hormone receptor-positive invasive breast cancer patients from three large centers were retrospectively reviewed. Each institution separately assayed Ki67 level immunohistochemically. Univariate and multivariate analysis for recurrence-free survival (RFS) was performed on 4,738 patients from a single center. Ki67 level was inversely proportional to age in all three data sets and was significantly higher for younger patients (p Ki67 level (≥10 %) were independent prognostic factors. Although young age was a worse prognostic indicator regardless of HER2 status, Ki67 index was associated with worse prognosis only in HER2-negative patients. When patients were stratified into those with low and high Ki67, young age remained a significant factor for RFS, with hazard ratios in these two Ki67 groups of 2.15 and 2.57, respectively (p Ki67 group had significantly poorer RFS than the older age/high Ki67 group (p Ki67 level was higher in younger patients. However, very young patients had a poorer prognosis regardless of Ki67 level. Unknown biologic factors other than high cell proliferation might play a role in the aggressiveness of hormone receptor-positive breast cancer in very young patients.

  2. Correlation Between GATA-3, Ki67 and p53 Expressions to Histopathology Grading of Breast Cancer in Makassar, Indonesia

    OpenAIRE

    Rosdiana Natzir, Rosdiana Natzir

    2016-01-01

    - Abstract: Background: During the last two decades, research about GATA-3, Ki-67, p53 expressions have been done, but it is still a debate on their use in predicting breast cancer patients1 prognosis and survival rate. Expressions of GATA-3 decreased with increasing of histopathology grading of breast cancer and increase with decrease of histopathology grading of breast cancer. The level expression of Ki-67 has a positive relation with breast cancer histopathology grading. p53 has no corr...

  3. An analysis of potassium iodide (