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Sample records for globus pallidus gp

  1. Neurokinin-1 receptor activation in globus pallidus

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    Lei Chen

    2009-10-01

    Full Text Available The undecapeptide substance P has been demonstrated to modulate neuronal activity in a number of brain regions by acting on neurokinin-1 receptors. Anatomical studies revealed a moderate level of neurokinin-1 receptor in rat globus pallidus. To determine the electrophysiological effects of neurokinin-1 receptor activation in globus pallidus, whole-cell patch-clamp recordings were performed in the present study. Under current-clamp recordings, neurokinin-1 receptor agonist, [Sar9, Met(O211] substance P (SM-SP at 1 μM, depolarized globus pallidus neurons and increased their firing rate. Consistently, SM-SP induced an inward current under voltage-clamp recording. The depolarization evoked by SM-SP persisted in the presence of tetrodotoxin, glutamate and GABA receptor antagonists, indicating its direct postsynaptic effects. The neurokinin-1 receptor antagonist, SR140333B, could block SM-SP-induced depolarization. Further experiments showed that suppression of potassium conductance was the predominant ionic mechanism of SM-SP-induced depolarization. To determine if neurokinin-1 receptor activation exerts any effects on GABAergic and glutamatergic neurotransmission, the action of SM-SP on synaptic currents was studied. SM-SP significantly increased the frequency of spontaneous inhibitory postsynaptic currents, but only induced a transient increase in the frequency of miniature inhibitory postsynaptic currents. No change was observed in both spontaneous and miniature excitatory postsynaptic currents. Based on the direct excitatory effects of SM-SP on pallidal neurons, we hypothesize that neurokinin-1 receptor activation in globus pallidus may be involved in the beneficial effect of substance P in Parkinson’s disease.

  2. Major Cognitive Changes and Micrographia following Globus Pallidus Infarct

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    Sarah Nelson

    2014-01-01

    Full Text Available Importance. Globus pallidus (GP lesions are well known to cause motor deficits but are less commonly—and perhaps not conclusively—associated with cognitive problems. Observations. We present a 45-year-old male with no significant neurological or psychological problems who after suffering a GP infarct was subsequently found to have substantial cognitive problems and micrographia. Formal neuropsychological testing was not possible due to lack of patient follow-up. Conclusions and Relevance. Despite the conflicting literature on the association of GP lesions and cognitive deficits, our patient demonstrated significant neuropsychological changes following his stroke. In addition, evidence of micrographia likely adds to the literature on the localization of this finding. Our case thus suggests that neuropsychological testing may be beneficial after GP strokes.

  3. Motor function in a patient with bilateral lesions of the globus pallidus

    NARCIS (Netherlands)

    Haaxma, R; vanBoxtel, A; Brouwer, WH; Goeken, LNH; vanderGon, JJD; Colebatch, JG; Martin, A; Brooks, DJ; Noth, J; Marsden, CD

    1995-01-01

    This study describes the long-term motor deficits of a patient who, after a toxic encephalopathy, sustained extensive bilateral damage to both segments of the globus pallidus (GP) and the right substantia nigra (SN). There were no signs of lesions of the pyramidal tracts or of other motor

  4. Changes in globus pallidus with (pre)term kernicterus

    NARCIS (Netherlands)

    P. Govaert (Paul); R.M.C. Swarte (Renate); S.G.F. Robben (Simon); I.F.M. de Coo (René); N. Weisglas-Kuperus (Nynke); M. Sinaasappel (Maarten); J. Barkovich (James); Y.B. de Rijke (Yolanda); M.H. Lequin (Maarten)

    2003-01-01

    textabstractOBJECTIVE: We report serial magnetic resonance (MR) and sonographic behavior of globus pallidus in 5 preterm and 3 term infants with kernicterus and describe the clinical context in very low birth weight preterm infants. On the basis of this information, we suggest

  5. Simulating the Effects of Short-Term Synaptic Plasticity on Postsynaptic Dynamics in the Globus Pallidus

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    Moran eBrody

    2013-08-01

    Full Text Available The rat globus pallidus (GP is one of the nuclei of the basal ganglia and plays an important role in a variety of motor and cognitive processes. In vivo studies have shown that repetitive stimulation evokes complex modulations of GP activity. In vitro and computational studies have suggested that short-term synaptic plasticity (STP could be one of the underlying mechanisms. The current study used simplified single compartment modeling to explore the possible effect of STP on the activity of GP neurons during low and high frequency stimulation. To do this we constructed a model of a GP neuron connected to a small network of neurons from the three major input sources to GP neurons: striatum (Str, subthalamic nucleus (STN and GP collaterals. All synapses were implemented with a kinetic model of STP. The in vitro recordings of responses to low frequency repetitive stimulation were highly reconstructed, including rate changes and locking to the stimulus. Mainly involved were fast forms of plasticity which have been found at these synapses. . The simulations were qualitatively compared to a data set previously recorded in vitro in our lab. Reconstructions of experimental responses to high frequency stimulation required adding slower forms of plasticity to the STN and GP collateral synapses, as well as adding metabotropic receptors to the STN-GP synapses. These finding suggest the existence of as yet unreported slower short-term dynamics in the GP. The computational model made additional predictions about GP activity during low and high frequency stimulation that may further our understanding of the mechanisms underlying repetative stimulation of the GP.

  6. Clinical significance of the globus pallidus signal intensity ratio in patients with liver cirrhosis

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    Iwasa, Motoh; Kawamura, Noriko; Hiranuma, Kiyohiko [Kuwana Municipal Hospital, Mie (Japan)] [and others

    1996-11-01

    The object of this study was to evaluate the clinical value of the globus pallidus signal intensity ratio for the subclinical detection of hepatic encephalopathy. This study comprised 25 patients with liver cirrhosis without overt hepatic encephalopathy. There was a high frequency (56%) of patients exhibiting increased signal in the globus pallidus. The pallidal signal was related to the severity of the liver disease. The auditory brain stem reaction was not correlated with the pallidal intensity and laboratory parameters. During the follow-up study, 3 out of 5 patients presenting overt hepatic encephalopathy showed strong pallidal signals. The results of this investigation suggest that abnormal globus pallidus signal may constitute a useful method for the subclinical detection of hepatic encepalopathy. (author)

  7. Clinical significance of the globus pallidus signal intensity ratio in patients with liver cirrhosis

    International Nuclear Information System (INIS)

    Iwasa, Motoh; Kawamura, Noriko; Hiranuma, Kiyohiko

    1996-01-01

    The object of this study was to evaluate the clinical value of the globus pallidus signal intensity ratio for the subclinical detection of hepatic encephalopathy. This study comprised 25 patients with liver cirrhosis without overt hepatic encephalopathy. There was a high frequency (56%) of patients exhibiting increased signal in the globus pallidus. The pallidal signal was related to the severity of the liver disease. The auditory brain stem reaction was not correlated with the pallidal intensity and laboratory parameters. During the follow-up study, 3 out of 5 patients presenting overt hepatic encephalopathy showed strong pallidal signals. The results of this investigation suggest that abnormal globus pallidus signal may constitute a useful method for the subclinical detection of hepatic encepalopathy. (author)

  8. Bilateral haemorrhagic infarction of the globus pallidus after cocaine and alcohol intoxication.

    Science.gov (United States)

    Renard, Dimitri; Brunel, Hervé; Gaillard, Nicolas

    2009-06-01

    Cocaine is a risk factor for both ischemic and haemorrhagic stroke. We present the case of a 31-year-old man with bilateral ischemia of the globus pallidus after excessive alcohol and intranasal cocaine use. Drug-related globus pallidus infarctions are most often associated with heroin. Bilateral basal ganglia infarcts after the use of cocaine, without concurrent heroin use, have never been reported. In our patient, transient cardiac arrhythmia or respiratory dysfunction related to cocaine and/or ethanol use were the most likely causes of cerebral hypoperfusion.

  9. Are Subthalamicus Nucleus, Internal, Globus Pallidus and Thalamus Involved in Thinking?

    Czech Academy of Sciences Publication Activity Database

    Minks, E.; Jurák, Pavel; Chládek, Jan; Hummelová, Z.

    2015-01-01

    Roč. 86, e4 (2015), s. 46 ISSN 0022-3050. [Annual Meeting of the Association-of-British-Neurologists (ABN). 10.09.2015, London] Institutional support: RVO:68081731 Keywords : Subthalamicus Nucleus * Globus Pallidus * Involving Thinking Subject RIV: BH - Optics, Masers, Lasers

  10. Kernicterus with abnormal high-signal changes bilaterally in the globus pallidus: A case report.

    LENUS (Irish Health Repository)

    Culleton, S

    2018-04-01

    Kernicterus is a relatively rare consequence of hyperbilirubinemia. There is an important role for MRI imaging for this entity in the appropriate clinical context as there are distinct signal changes in the globus pallidus. A case report and image findings are presented

  11. Hyperintense globus pallidus on T1-weighted MR imaging in acute kernicterus: is it common or rare?

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    Coskun, Abdulhakim; Yikilmaz, Ali; Karahan, Okkes Ibrahim; Manav, Ali [Erciyes University Medical School, Department of Radiology, Kayseri (Turkey); Kumandas, Sefer [Erciyes University Medical School, Department of Neuropediatry, Kayseri (Turkey); Akcakus, Mustafa [Erciyes University Medical School, Department of Neonatalogy, Kayseri (Turkey)

    2005-06-01

    Globus pallidus involvement is a well-known magnetic resonance (MR) imaging finding of acute kernicterus. However, it is not clear how early the involvement of globus pallidus occurs and whether or not it is seen in every case. Therefore, we aimed to investigate the globus pallidus involvement in 13 neonates with acute kernicterus by MR imaging. Thirteen neonates who were admitted with jaundice, encephalopathy and indirect hyperbilirubinemia (mean, 37.0 mg/dl) were prospectively evaluated with cranial MR imaging. Pathological signal changes were noted concerning the globus pallidus. Eight of the 13 patients demonstrated bilateral, symmetric increased signal intensity in the globus pallidus on T1-weighted MR imaging. These lesions were not apparent on T2-weighted images. Multiple parenchymal punctuate T1 hyperintense lesions were detected in one patient without globus pallidus involvement. This appearance was consistent with hemorrhage. The MR imaging findings of the other four patients showed no evidence of abnormality. The symmetric involvement of globus pallidus seen as hyperintense on T1-weighted MR imaging is a common and characteristic finding of acute kernicterus. (orig.)

  12. Hyperintense globus pallidus on T1-weighted MR imaging in acute kernicterus: is it common or rare?

    International Nuclear Information System (INIS)

    Coskun, Abdulhakim; Yikilmaz, Ali; Karahan, Okkes Ibrahim; Manav, Ali; Kumandas, Sefer; Akcakus, Mustafa

    2005-01-01

    Globus pallidus involvement is a well-known magnetic resonance (MR) imaging finding of acute kernicterus. However, it is not clear how early the involvement of globus pallidus occurs and whether or not it is seen in every case. Therefore, we aimed to investigate the globus pallidus involvement in 13 neonates with acute kernicterus by MR imaging. Thirteen neonates who were admitted with jaundice, encephalopathy and indirect hyperbilirubinemia (mean, 37.0 mg/dl) were prospectively evaluated with cranial MR imaging. Pathological signal changes were noted concerning the globus pallidus. Eight of the 13 patients demonstrated bilateral, symmetric increased signal intensity in the globus pallidus on T1-weighted MR imaging. These lesions were not apparent on T2-weighted images. Multiple parenchymal punctuate T1 hyperintense lesions were detected in one patient without globus pallidus involvement. This appearance was consistent with hemorrhage. The MR imaging findings of the other four patients showed no evidence of abnormality. The symmetric involvement of globus pallidus seen as hyperintense on T1-weighted MR imaging is a common and characteristic finding of acute kernicterus. (orig.)

  13. Neurobehavioural Changes in a Patient with Bilateral Lesions of the Globus Pallidus

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    R. Haaxma

    1993-01-01

    Full Text Available This study has characterized the long-term neurobehavioural changes in a woman who, following the intake of an unidentified substance, sustained subtotal bilateral lesions of the globus pallidus and small lesions at selective sites adjacent to it. Associated with these lesions was a significantly reduced blood flow in multiple frontal cortical regions, most prominently in area 10, the anterior cingulate and the supplementary motor cortex. Her cognitive deficits were generally consistent with those found in patients with frontal lobe dysfunction but some deficits, i.e. in visual memory and learning, were more compatible with temporal lobe dysfunction. Incapacitating personality or obsessive compulsive changes as reported by others with similar lesions were absent and she could live independently. The cognitive changes are consistent with the view that the globus pallidus has important functions in mediating how internal representations of stimulus input are converted into various forms of action, for example, in planning solutions to problems and in working memory.

  14. Frontal lobe syndrome from bilateral globus pallidus lesions a complication of Wernicke's encephalopathy

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    Arruda, Walter Oleschko

    1991-01-01

    A 38 year-old man developed the classical clinical picture of Wernicke's encephalopathy as a consequence of prolonged total parenteral nutrition. As a late complication he developed a frontal lobe syndrome. Bilateral globus pallidus lesions were observed in the CT-scan examination. Some aspects related to the cortical syndromes caused by subcortical lesions are discussed. Relata-se um caso de encefalopatia de Wernicke que ocorreu em paciente masculino de 38 anos, como complicação de alimen...

  15. Globus Pallidus Interna Deep Brain Stimulation in a Patient with Medically Intractable Meige Syndrome

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    Dae-Woong Bae

    2014-10-01

    Full Text Available Medical therapies in patients with Meige syndrome, including botulinum toxin injection, have been limited because of incomplete response or adverse side effects. We evaluated a patient with Meige syndrome who was successfully treated with deep brain stimulation (DBS in the globus pallidus interna (GPi. This case report and other previous reports suggest that bilateral GPi DBS may be an effective treatment for medically refractory Meige syndrome, without significant adverse effects.

  16. The Impact of Stimulation Induced Short Term Synaptic Plasticity on Firing Patterns in the Globus Pallidus of the Rat

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    Jenia eBugaysen

    2011-03-01

    Full Text Available Electrical stimulation in the globus pallidus (GP leads to complex modulations of neuronal activity in the stimulated nucleus. Multiple in-vivo studies have demonstrated the modulation of both firing rates and patterns during and immediately following the GP stimulation. Previous in-vitro studies, together with computational studies, have suggested the involvement of short-term synaptic plasticity (STP during the stimulation. The aim of the current study was to explore in-vitro the effects of STP on neuronal activity of GP neurons during local repetitive stimulation. We recorded synaptic potentials and assessed the modulations of spontaneous firing in a postsynaptic neuron in acute brain slices via a whole-cell pipette. Low-frequency repetitive stimulation locked the firing of the neuron to the stimulus. However, high-frequency repetitive stimulation in the GP generated a biphasic modulation of the firing frequency consisting of inhibitory and excitatory phases. Using blockers of synaptic transmission, we show that GABAergic synapses mediated the inhibitory and glutamatergic synapses the excitatory part of the response. Furthermore, we report that at high stimulation frequencies both types of synapses undergo short-term depression leading to a time dependent modulation of the neuronal firing. These findings indicate that STP modulates the dynamic responses of pallidal activity during electrical stimulation, and may contribute to a better understanding of the mechanism underlying deep brain stimulation (DBS like protocols.

  17. T1 Shortening in the Globus Pallidus after Multiple Administrations of Gadobutrol: Assessment with a Multidynamic Multiecho Sequence.

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    Kang, Koung Mi; Choi, Seung Hong; Hwang, Moonjung; Yun, Tae Jin; Kim, Ji-Hoon; Sohn, Chul-Ho

    2018-04-01

    Purpose To determine the association between the administration of the macrocyclic contrast medium gadobutrol and T1 relaxation time in the brains of patients with normal renal function by using multidynamic multiecho (MDME) magnetic resonance (MR) imaging sequences. Materials and Methods The institutional review board approved this retrospective study, and the need to obtain written informed consent was waived. This study included 46 patients (revealed by an electronic medical record search) who had received one or more gadobutrol injections and a maximum of one MR imaging contrast medium injection other than gadobutrol before MDME sequence acquisition. One radiologist performed quantitative analyses of regions of interest on quantitative T1 maps twice to cover the normal-appearing globus pallidus (GP), frontal white matter, frontal cortex, and thalamus. The number of administrations and the cumulative dose of gadobutrol, age, intervals between administrations, sex, and treatment were investigated. Univariable and multivariable linear regression analyses of the T1 values in four brain regions and the GP-to-thalamus signal intensity (SI) ratio were performed. P values of less than the Bonferroni-corrected value of .01 were considered to indicate significant differences. Results Intraobserver reproducibility was good to excellent (intraclass correlation coefficients, 0.62-0.81). Because of high multicollinearity between the number of gadobutrol administrations and accumulated dose (r = 0.96, P .01). Conclusion Multiple exposures to gadobutrol are associated with T1 shortening in the GP. © RSNA, 2017 Online supplemental material is available for this article.

  18. High and low frequency stimulation of the subthalamic nucleus induce prolonged changes in subthalamic and globus pallidus neurons

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    Hagar eLavian

    2013-12-01

    Full Text Available High frequency stimulation (HFS of the subthalamic nucleus (STN is widely used to treat the symptoms of Parkinson’s disease but the mechanism of this therapy is unclear. Using a rat brain slice preparation maintaining the connectivity between the STN and one of its target nuclei, the globus pallidus (GP, we investigated the effects of high and low frequency stimulation (HFS 100 Hz, LFS 10 Hz on activity of single neurons in the STN and GP. Both HFS and LFS caused changes in firing frequency and pattern of subthalamic and pallidal neurons. These changes were of synaptic origin, as they were abolished by glutamate and GABA antagonists. Both HFS and LFS also induced a long-lasting reduction in firing frequency in STN neurons possibly contending a direct causal link between HFS and the outcome DBS. In the GP both HFS and LFS induced either a long-lasting depression, or less frequently, a long-lasting excitation. Thus, in addition to the intrinsic activation of the stimulated neurons, long-lasting stimulation of the STN may trigger prolonged biochemical processes.

  19. The emergence of two anti-phase oscillatory neural populations in a computational model of the Parkinsonian globus pallidus

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    Robert John Merrison-Hort

    2013-12-01

    Full Text Available Experiments in rodent models of Parkinson's Disease have demonstrated a prominent increase of oscillatory firing patterns in neurons within the Parkinsonian globus pallidus (GP which may underlie some of the motor symptoms of the disease. There are two main pathways from the cortex to GP: via the striatum and via the subthalamic nucleus (STN, but it is not known how these inputs sculpt the pathological pallidal firing patterns. To study this we developed a novel neural network model of conductance-based spiking pallidal neurons with cortex-modulated input from STN neurons. Our results support the hypothesis that entrainment occurs primarily via the subthalamic pathway. We find that as a result of the interplay between excitatory input from the STN and mutual inhibitory coupling between GP neurons, a homogeneous population of GP neurons demonstrates a self-organising dynamical behaviour where two groups of neurons emerge: one spiking in-phase with the cortical rhythm and the other in anti-phase. This finding mirrors what is seen in recordings from the GP of rodents that have had Parkinsonism induced via brain lesions. Our model also includes downregulation of Hyperpolarization-activated Cyclic Nucleotide-gated (HCN channels in response to burst firing of GP neurons, since this has been suggested as a possible mechanism for the emergence of Parkinsonian activity. We found that the downregulation of HCN channels provides even better correspondence with experimental data but that it is not essential in order for the two groups of oscillatory neurons to appear. We discuss how the influence of inhibitory striatal input will strengthen our results.

  20. Adenosine A2A Receptor Modulates the Activity of Globus Pallidus Neurons in Rats

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    Hui-Ling Diao

    2017-11-01

    Full Text Available The globus pallidus is a central nucleus in the basal ganglia motor control circuit. Morphological studies have revealed the expression of adenosine A2A receptors in the globus pallidus. To determine the modulation of adenosine A2A receptors on the activity of pallidal neurons in both normal and parkinsonian rats, in vivo electrophysiological and behavioral tests were performed in the present study. The extracellular single unit recordings showed that micro-pressure administration of adenosine A2A receptor agonist, CGS21680, regulated the pallidal firing activity. GABAergic neurotransmission was involved in CGS21680-induced modulation of pallidal neurons via a PKA pathway. Furthermore, application of two adenosine A2A receptor antagonists, KW6002 or SCH442416, mainly increased the spontaneous firing of pallidal neurons, suggesting that endogenous adenosine system modulates the activity of pallidal neurons through adenosine A2A receptors. Finally, elevated body swing test (EBST showed that intrapallidal microinjection of adenosine A2A receptor agonist/antagonist induced ipsilateral/contralateral-biased swing, respectively. In addition, the electrophysiological and behavioral findings also revealed that activation of dopamine D2 receptors by quinpirole strengthened KW6002/SCH442416-induced excitation of pallidal activity. Co-application of quinpirole with KW6002 or SCH442416 alleviated biased swing in hemi-parkinsonian rats. Based on the present findings, we concluded that pallidal adenosine A2A receptors may be potentially useful in the treatment of Parkinson's disease.

  1. Seizure-induced damage to substantia nigra and globus pallidus is accompanied by pronounced intra- and extracellular acidosis

    International Nuclear Information System (INIS)

    Inamura, K.; Smith, M.L.; Hansen, A.J.; Siesjoe, B.K.

    1989-01-01

    Status epilepticus of greater than 30-min duration in rats gives rise to a conspicuous lesion in the substantia nigra pars reticulata (SNPR) and globus pallidus (GP). The objective of the present study was to explore whether the lesion, which encompasses necrosis of both neurons and glial cells, is related to intra- and extracellular acidosis. Using the flurothyl model previously described to produce seizures, we assessed regional pH values with the autoradiographic 5,5-dimethyl[2-14C]oxazolidine-2,4-dione technique. Regional pH values were assessed in animals with continuous seizures for 20 and 60 min, as well as in those allowed to recover for 30 and 120 min after seizure periods of 20 or 60 min. In additional animals, changes in extracellular fluid pH (pHe) were measured with ion-selective microelectrodes, and extracellular fluid (ECF) volume was calculated from the diffusion profile for electrophoretically administered tetramethylammonium. In structures such as the neocortex and the hippocampus, which show intense metabolic activation during seizures, status epilepticus of 20- and 60-min duration was accompanied by a reduction of the composite tissue pH (pHt) of 0.2-0.3 unit. Recovery of pHt was observed upon termination of seizures. In SNPR and in GP, the acidosis was marked to excessive after 20 and 60 min of seizures (delta pHt approximately 0.6 after 60 min)

  2. Deep Brain Stimulation of the internal globus pallidus in refractory Tourette Syndrome.

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    Smeets, A Y J M; Duits, A A; Plantinga, B R; Leentjens, A F G; Oosterloo, M; Visser-Vandewalle, V; Temel, Y; Ackermans, L

    2016-03-01

    Deep Brain Stimulation in psychiatric disorders is becoming an increasingly performed surgery. At present, seven different targets have been stimulated in Tourette Syndrome, including the internal globus pallidus. We describe the effects on tics and comorbid behavioral disorders of Deep Brain Stimulation of the anterior internal globus pallidus in five patients with refractory Tourette Syndrome. This study was performed as an open label study with follow-up assessment between 12 and 38 months. Patients were evaluated twice, one month before surgery and at long-term follow-up. Primary outcome was tic severity, assessed by several scales. Secondary outcomes were comorbid behavioral disorders, mood and cognition. The final position of the active contacts of the implanted electrodes was investigated and side effects were reported. Three males and two females were included with a mean age of 41.6 years (SD 9.7). The total post-operative score on the Yale Global Tic Severity Scale was significantly lower than the pre-operative score (42.2±4.8 versus 12.8±3.8, P=0.043). There was also a significant reduction on the modified Rush Video-Based Tic Rating Scale (13.0±2.0 versus 7.0±1.6, P=0.041) and in the total number of video-rated tics (259.6±107.3 versus 49.6±24.8, P=0.043). No significant difference on the secondary outcomes was found, however, there was an improvement on an individual level for obsessive-compulsive behavior. The final position of the active contacts was variable in our sample and no relationship between position and stimulation effects could be established. Our study suggests that Deep Brain Stimulation of the anterior internal globus pallidus is effective in reducing tic severity, and possibly also obsessive-compulsive behavior, in refractory Tourette patients without serious adverse events or side-effects. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. The globus pallidus sends reward-related signals to the lateral habenula.

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    Hong, Simon; Hikosaka, Okihide

    2008-11-26

    As a major output station of the basal ganglia, the globus pallidus internal segment (GPi) projects to the thalamus and brainstem nuclei thereby controlling motor behavior. A less well known fact is that the GPi also projects to the lateral habenula (LHb) which is often associated with the limbic system. Using the monkey performing a saccade task with positionally biased reward outcomes, we found that antidromically identified LHb-projecting neurons were distributed mainly in the dorsal and ventral borders of the GPi and that their activity was strongly modulated by expected reward outcomes. A majority of them were excited by the no-reward-predicting target and inhibited by the reward-predicting target. These reward-dependent modulations were similar to those in LHb neurons but started earlier than those in LHb neurons. These results suggest that GPi may initiate reward-related signals through its effects on the LHb, which then influences the dopaminergic and serotonergic systems.

  4. Left globus pallidus abnormality in never-medicated patients with schizophrenia

    International Nuclear Information System (INIS)

    Early, T.S.; Reiman, E.M.; Raichle, M.E.; Spitznagel, E.L.

    1987-01-01

    Schizophrenia is a severe psychiatric disorder characterized by onset in young adulthood, the occurrence of hallucinations and delusions, and the development of enduring psychosocial disability. The pathophysiology of this disorder remains unknown. Studies of cerebral blood flow and metabolism designed to identify brain abnormalities in schizophrenia have been limited by inadequate methods of anatomical localization and the possibility of persistent medication effects. The authors have now used positron emission tomography and a validated method of anatomical localization in an attempt to identify abnormalities of regional cerebral blood flow in newly diagnosed never-medicated patients with schizophrenia. An exploratory study of 5 patients and 10 normal control subjects identified abnormally high blood flow in the left globus pallidus of patients with schizophrenia. A replication study of 5 additional patients and 10 additional control subjects confirmed this finding. No other abnormalities were found

  5. Aberrant resting-state corticostriatal functional connectivity in cirrhotic patients with hyperintense globus pallidus on T1-weighted MR imaging.

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    Xi-Qi Zhu

    Full Text Available Neurobiological and neuroimaging studies have emphasized the structural and functional alterations in the striatum of cirrhotic patients, but alterations in the functional connections between the striatum and other brain regions have not yet been explored. Of note, manganese accumulation in the nervous system, frequently reflected by hyperintensity at the bilateral globus pallidus (GP on T1-weighted imaging, has been considered a factor affecting the striatal and cortical functions in hepatic decompensation. We employed resting-state functional magnetic resonance imaging to analyze the temporal correlation between the striatum and the remaining brain regions using seed-based correlation analyses. The two-sample t-test was conducted to detect the differences in corticostriatal connectivity between 44 cirrhotic patients with hyperintensity at the bilateral GP and 20 healthy controls. Decreased connectivity of the caudate was detected in the anterior/middle cingulate gyrus, and increased connectivity of the caudate was found in the left motor cortex. A reduction in functional connectivity was found between the putamen and several regions, including the anterior cingulate gyrus, right insular lobe, inferior frontal gyrus, left parahippocampal gyrus, and anterior lobe of the right cerebellum; increased connectivity was detected between the putamen and right middle temporal gyrus. There were significant correlations between the corticostriatal connectivity and neuropsychological performances in the patient group, but not between the striatal connectivity and GP signal intensity. These alterations in the corticostriatal functional connectivity suggested the abnormalities in the intrinsic brain functional organiztion among the cirrhotic patients with manganese deposition, and may be associated with development of metabolic encephalopathy. The manganese deposition in nervous system, however, can not be an independent factor predicting the resting

  6. Globus pallidus high-signal lesions: A predominant MRI finding in children with neurofibromatosis type 1

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    Arif Khan

    2013-01-01

    Full Text Available Introduction: Lesions of the brain, recognized as unidentified bright objects (UBOs, are commonly observed as areas of increased T2-weighted signal intensity on magnetic resonance imaging (MRI in children with neurofibromatosis type 1 (NF1. Identification of these lesions is not currently encompassed in the National Institute of Health (NIH diagnostic criteria for NF1. Objective: We aimed to determine the prevalence of UBOs in children with NF1 and identify areas of the brain that are commonly affected by these lesions, allowing us to evaluate whether UBOs should be included in the diagnostic criteria for the diagnosis of NF1. Materials and Methods: We reviewed the cranial MRI scans of 22 children who had been diagnosed with sporadic or familial NF1 in accordance with the criteria established by NIH. UBOs were present in 81% of the children with NF1. Results: These lesions have a predilection for specific areas of the brain, including the globus pallidus (72%, cerebellum (66%, brainstem (27% and cerebral hemispheres (16%. The prevalence of UBOs identified varied significantly with age and sex; they were infrequent in children less than 4 years of age but were common in those aged between 4 and 12 years of age. UBOs were more commonly seen in males (66.6% compared with females (33.3%. Repeat MRI scan on a subset of these patients with UBOs did not show any significant changes despite a worsening in clinical symptoms. Conclusion and Discussion: We have shown that UBOs are a common finding in children with NF1, and are most prevalent between the ages of 4 and 12 years. Many sites of the brain are affected by these lesions, most notably the globus pallidus and the cerebellum. Further research must be conducted to elucidate the significance of UBOs in patients with NF1 and whether these lesions have any utility in the clinical detection of NF1.

  7. Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus.

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    Hernández, Vivian M; Hegeman, Daniel J; Cui, Qiaoling; Kelver, Daniel A; Fiske, Michael P; Glajch, Kelly E; Pitt, Jason E; Huang, Tina Y; Justice, Nicholas J; Chan, C Savio

    2015-08-26

    Compelling evidence suggests that pathological activity of the external globus pallidus (GPe), a nucleus in the basal ganglia, contributes to the motor symptoms of a variety of movement disorders such as Parkinson's disease. Recent studies have challenged the idea that the GPe comprises a single, homogenous population of neurons that serves as a simple relay in the indirect pathway. However, we still lack a full understanding of the diversity of the neurons that make up the GPe. Specifically, a more precise classification scheme is needed to better describe the fundamental biology and function of different GPe neuron classes. To this end, we generated a novel multicistronic BAC (bacterial artificial chromosome) transgenic mouse line under the regulatory elements of the Npas1 gene. Using a combinatorial transgenic and immunohistochemical approach, we discovered that parvalbumin-expressing neurons and Npas1-expressing neurons in the GPe represent two nonoverlapping cell classes, amounting to 55% and 27% of the total GPe neuron population, respectively. These two genetically identified cell classes projected primarily to the subthalamic nucleus and to the striatum, respectively. Additionally, parvalbumin-expressing neurons and Npas1-expressing neurons were distinct in their autonomous and driven firing characteristics, their expression of intrinsic ion conductances, and their responsiveness to chronic 6-hydroxydopamine lesion. In summary, our data argue that parvalbumin-expressing neurons and Npas1-expressing neurons are two distinct functional classes of GPe neurons. This work revises our understanding of the GPe, and provides the foundation for future studies of its function and dysfunction. Until recently, the heterogeneity of the constituent neurons within the external globus pallidus (GPe) was not fully appreciated. We addressed this knowledge gap by discovering two principal GPe neuron classes, which were identified by their nonoverlapping expression of the

  8. Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus

    Science.gov (United States)

    Hernández, Vivian M.; Hegeman, Daniel J.; Cui, Qiaoling; Kelver, Daniel A.; Fiske, Michael P.; Glajch, Kelly E.; Pitt, Jason E.; Huang, Tina Y.; Justice, Nicholas J.

    2015-01-01

    Compelling evidence suggests that pathological activity of the external globus pallidus (GPe), a nucleus in the basal ganglia, contributes to the motor symptoms of a variety of movement disorders such as Parkinson's disease. Recent studies have challenged the idea that the GPe comprises a single, homogenous population of neurons that serves as a simple relay in the indirect pathway. However, we still lack a full understanding of the diversity of the neurons that make up the GPe. Specifically, a more precise classification scheme is needed to better describe the fundamental biology and function of different GPe neuron classes. To this end, we generated a novel multicistronic BAC (bacterial artificial chromosome) transgenic mouse line under the regulatory elements of the Npas1 gene. Using a combinatorial transgenic and immunohistochemical approach, we discovered that parvalbumin-expressing neurons and Npas1-expressing neurons in the GPe represent two nonoverlapping cell classes, amounting to 55% and 27% of the total GPe neuron population, respectively. These two genetically identified cell classes projected primarily to the subthalamic nucleus and to the striatum, respectively. Additionally, parvalbumin-expressing neurons and Npas1-expressing neurons were distinct in their autonomous and driven firing characteristics, their expression of intrinsic ion conductances, and their responsiveness to chronic 6-hydroxydopamine lesion. In summary, our data argue that parvalbumin-expressing neurons and Npas1-expressing neurons are two distinct functional classes of GPe neurons. This work revises our understanding of the GPe, and provides the foundation for future studies of its function and dysfunction. SIGNIFICANCE STATEMENT Until recently, the heterogeneity of the constituent neurons within the external globus pallidus (GPe) was not fully appreciated. We addressed this knowledge gap by discovering two principal GPe neuron classes, which were identified by their nonoverlapping

  9. New MRI findings in Creutzfeldt-Jakob disease: high signal in the globus pallidus on T 1-weighted images

    International Nuclear Information System (INIS)

    Priester, J.A. de; Wilmink, J.T.; Jansen, G.H.; Kruijk, J.R. de

    1999-01-01

    We report a 49-year-old woman with Creutzfeldt-Jakob disease (CJD). In addition to typical high-signal lesions on proton-density and T 2-weighted images there was high signal in the globus pallidus bilaterally on T 1-weighted images. The latter feature has not been described previously and probably due to deposition of prion protein, as found at autopsy. (orig.)

  10. New MRI findings in Creutzfeldt-Jakob disease: high signal in the globus pallidus on T 1-weighted images

    Energy Technology Data Exchange (ETDEWEB)

    Priester, J.A. de; Wilmink, J.T. [Dept. of Radiology, University Hospital Maastricht (Netherlands); Jansen, G.H. [Department of Neuropathology, University Hospital Utrecht (Netherlands); Kruijk, J.R. de [Department of Neurology, University Hospital Maastricht (Netherlands)

    1999-04-01

    We report a 49-year-old woman with Creutzfeldt-Jakob disease (CJD). In addition to typical high-signal lesions on proton-density and T 2-weighted images there was high signal in the globus pallidus bilaterally on T 1-weighted images. The latter feature has not been described previously and probably due to deposition of prion protein, as found at autopsy. (orig.) With 3 figs., 11 refs.

  11. Signal intensity change on unenhanced T1-weighted images in dentate nucleus and globus pallidus after multiple administrations of gadoxetate disodium: an intraindividual comparative study

    Energy Technology Data Exchange (ETDEWEB)

    Conte, Giorgio; Minotti, Marta; De Piano, Francesca [Universita degli Studi di Milano, Postgraduation School in Radiodiagnostics, Milan (Italy); Preda, Lorenzo [Universita degli Studi di Pavia, Department of Clinical-Surgical Diagnostic and Pediatric Sciences, Pavia (Italy); National Center of Oncological Hadrontherapy (CNAO Foundation), Division of Radiology, Pavia (Italy); Cocorocchio, Emilia; Ferrucci, Pier Francesco [European Institute of Oncology, Melanoma and Sarcoma Medical Oncology Division, Milan (Italy); Raimondi, Sara [European Institute of Oncology, Division of Epidemiology and Biostatistics, Milan (Italy); Giannitto, Caterina; Petralia, Giuseppe [European Institute of Oncology, Division of Radiology, Milan (Italy); Bellomi, Massimo [European Institute of Oncology, Division of Radiology, Milan (Italy); Universita degli Studi di Milano, Oncology and Haematology/Oncology Department, Milan (Italy)

    2017-10-15

    To investigate whether there is an increased signal intensity (SI) of dentate nucleus (DN) and globus pallidus (GP) on unenhanced T1-weighted magnetic resonance imaging (MRI), in patients who had undergone multiple administrations of gadoxetate disodium. We retrospectively included stage III melanoma patients, who had been previously enrolled in a trial of adjuvant therapy and who had undergone whole-body contrast-enhanced MRIs with gadoxetate disodium every three months for their follow-up. The SI ratios of DN-to-pons and GP-to-thalamus on unenhanced T1-weighted images were calculated. The difference in SI ratios between the first and the last MRI examinations was assessed and a linear mixed model was performed to detect how SI ratios varied with the number of administrations. Eighteen patients were included in our study. The number of gadoxetate disodium administrations ranged from 2 to 18. Paired t-test did not show any significant difference in DN-to-pons (p=0.21) and GP-to-thalamus (p=0.09) SI ratios by the end of the study. DN-to-pons SI ratio and GP-to-thalamus SI ratio did not significantly increase with increasing the number of administrations (p=0.14 and p=0.06, respectively). Multiple administrations of gadoxetate disodium are not associated with increased SI in DN and GP in the brain. (orig.)

  12. Systemic blockade of dopamine D2-like receptors increases high-voltage spindles in the globus pallidus and motor cortex of freely moving rats.

    Science.gov (United States)

    Yang, Chen; Ge, Shun-Nan; Zhang, Jia-Rui; Chen, Lei; Yan, Zhi-Qiang; Heng, Li-Jun; Zhao, Tian-Zhi; Li, Wei-Xin; Jia, Dong; Zhu, Jun-Ling; Gao, Guo-Dong

    2013-01-01

    High-voltage spindles (HVSs) have been reported to appear spontaneously and widely in the cortical-basal ganglia networks of rats. Our previous study showed that dopamine depletion can significantly increase the power and coherence of HVSs in the globus pallidus (GP) and motor cortex of freely moving rats. However, it is unclear whether dopamine regulates HVS activity by acting on dopamine D₁-like receptors or D₂-like receptors. We employed local-field potential and electrocorticogram methods to simultaneously record the oscillatory activities in the GP and primary motor cortex (M1) in freely moving rats following systemic administration of dopamine receptor antagonists or saline. The results showed that the dopamine D₂-like receptor antagonists, raclopride and haloperidol, significantly increased the number and duration of HVSs, and the relative power associated with HVS activity in the GP and M1 cortex. Coherence values for HVS activity between the GP and M1 cortex area were also significantly increased by dopamine D₂-like receptor antagonists. On the contrary, the selective dopamine D₁-like receptor antagonist, SCH23390, had no significant effect on the number, duration, or relative power of HVSs, or HVS-related coherence between M1 and GP. In conclusion, dopamine D₂-like receptors, but not D₁-like receptors, were involved in HVS regulation. This supports the important role of dopamine D₂-like receptors in the regulation of HVSs. An siRNA knock-down experiment on the striatum confirmed our conclusion.

  13. Globus pallidus MR signal abnormalities in children with chronic liver disease and/or porto-systemic shunting

    Energy Technology Data Exchange (ETDEWEB)

    Hanquinet, Sylviane; Anooshiravani, Mehrak; Merlini, Laura [University Hospital of Geneva, Department of Pediatric Radiology, Geneva (Switzerland); Morice, Claire; Cousin, Vladimir; McLin, Valerie A. [University Hospital of Geneva, Swiss Center for Liver Disease in Children, Geneva (Switzerland); Courvoisier, Delphine S. [University Hospital of Geneva, Division of Quality of Care, Geneva (Switzerland)

    2017-10-15

    Detection of subclinical hepatic encephalopathy in children is difficult. We aimed to assess the changes in imaging of the central nervous system in children with chronic liver disease using MR imaging, diffusion, and {sup 1}H -spectroscopy. Forty three children with chronic liver disease and/or porto-systemic shunting (111.4±56.9 months) and 24 controls (72.0±51.8 months) underwent brain MRI/spectroscopy on a 1.5T to examine T1, T2, ADC, Cho/Cr, ml/Cr, Glx/Cr ratio spectroscopy in the globus pallidus. Patients were divided into 3 groups according to the ratios of globus pallidus/putamen T1 signal: isointense (i), hyperintense (h), much more hyperintense (h+). The relationship with clinical and biological data was analyzed. T1 signal intensity and ml/Cr were significantly different between controls and group h+ (p=0.001). ADC did not differ significantly between groups. Age correlated strongly with the presence of a T1 signal ratio (p > 0.001). There was no correlation between imaging findings and biological parameters. In children with chronic liver disease and/or porto-systemic shunting, the presence of a hyperintense T1 signal in the globus pallidus correlated strongly with age. Biological and clinical parameters were not predictive of these changes. MRI may become a useful screening tool for hepatic encephalopathy in children. (orig.)

  14. Globus pallidus MR signal abnormalities in children with chronic liver disease and/or porto-systemic shunting

    International Nuclear Information System (INIS)

    Hanquinet, Sylviane; Anooshiravani, Mehrak; Merlini, Laura; Morice, Claire; Cousin, Vladimir; McLin, Valerie A.; Courvoisier, Delphine S.

    2017-01-01

    Detection of subclinical hepatic encephalopathy in children is difficult. We aimed to assess the changes in imaging of the central nervous system in children with chronic liver disease using MR imaging, diffusion, and "1H -spectroscopy. Forty three children with chronic liver disease and/or porto-systemic shunting (111.4±56.9 months) and 24 controls (72.0±51.8 months) underwent brain MRI/spectroscopy on a 1.5T to examine T1, T2, ADC, Cho/Cr, ml/Cr, Glx/Cr ratio spectroscopy in the globus pallidus. Patients were divided into 3 groups according to the ratios of globus pallidus/putamen T1 signal: isointense (i), hyperintense (h), much more hyperintense (h+). The relationship with clinical and biological data was analyzed. T1 signal intensity and ml/Cr were significantly different between controls and group h+ (p=0.001). ADC did not differ significantly between groups. Age correlated strongly with the presence of a T1 signal ratio (p > 0.001). There was no correlation between imaging findings and biological parameters. In children with chronic liver disease and/or porto-systemic shunting, the presence of a hyperintense T1 signal in the globus pallidus correlated strongly with age. Biological and clinical parameters were not predictive of these changes. MRI may become a useful screening tool for hepatic encephalopathy in children. (orig.)

  15. Modeling Laterality of the Globus Pallidus Internus in Patients With Parkinson's Disease.

    Science.gov (United States)

    Sharim, Justin; Yazdi, Daniel; Baohan, Amy; Behnke, Eric; Pouratian, Nader

    2017-04-01

    Neurosurgical interventions such as deep brain stimulation surgery of the globus pallidus internus (GPi) play an important role in the treatment of medically refractory Parkinson's disease (PD), and require high targeting accuracy. Variability in the laterality of the GPi across patients with PD has not been well characterized. The aim of this report is to identify factors that may contribute to differences in position of the motor region of GPi. The charts and operative reports of 101 PD patients following deep brain stimulation surgery (70 males, aged 11-78 years) representing 201 GPi were retrospectively reviewed. Data extracted for each subject include age, gender, anterior and posterior commissures (AC-PC) distance, and third ventricular width. Multiple linear regression, stepwise regression, and relative importance of regressors analysis were performed to assess the predictive ability of these variables on GPi laterality. Multiple linear regression for target vs. third ventricular width, gender, AC-PC distance, and age were significant for normalized linear regression coefficients of 0.333 (p laterality of 0.19 mm per mm of ventricular width, 0.11 mm per mm of AC-PC distance, 0.017 mm per year in age, and 0.54 mm increase for male gender. This variability highlights the limitations of indirect targeting alone, and argues for the continued use of MRI as well as intraoperative physiological testing to account for such factors that contribute to patient-specific variability in GPi localization. © 2016 International Neuromodulation Society.

  16. Childhood Laryngeal Dystonia Following Bilateral Globus Pallidus Abnormality: A Case Study and Review of Literature

    Directory of Open Access Journals (Sweden)

    Mohammad Javad Saeedi Borujeni

    2017-01-01

    Full Text Available Introduction:Dystonia is a disorder of movement caused by various etiologies. Laryngeal dystonia is caused by the spasm of laryngeal muscles. It is a disorder caused by vocal fold movement in which excessive adduction or abduction of the vocal folds occurs during speech. The pathophysiology of this type of dystonia is not fully known. Some researchers have suggested that basal ganglia structures and their connections with cortical areas have been involved in the pathogenesis of dystonia. Case Report:In this paper a 7.5-year-old boy suffering from laryngeal dystonia with bilateral lesions in Globus Pallidus is presented. The patient also suffered from swallowing problems, monotone voice, vocal tremor, hypersensitivity of gag reflex, and stuttering. Drug treatment failed to cure him; therefore, he was referred to rehabilitation therapy.  Conclusion:In conclusion, special attention should be brought upon laryngeal dystonia, especially in patients showing Extra-pyramidal symptoms and/or abnormalities of the basal ganglia. In children, laryngeal dystonia may be potentially fatal. Lack of consideration for this condition during rehabilitation therapy can lead to serious consequences for a child.

  17. Optimal MRI methods for direct stereotactic targeting of the subthalamic nucleus and globus pallidus

    International Nuclear Information System (INIS)

    O'Gorman, Ruth L.; Shmueli, Karin; Ashkan, Keyoumars; Selway, Richard P.; Samuel, Michael; Lythgoe, David J.; Shahidiani, Asal; Wastling, Stephen J.; Footman, Michelle; Jarosz, Jozef

    2011-01-01

    Reliable identification of the subthalamic nucleus (STN) and globus pallidus interna (GPi) is critical for deep brain stimulation (DBS) of these structures. The purpose of this study was to compare the visibility of the STN and GPi with various MRI techniques and to assess the suitability of each technique for direct stereotactic targeting. MR images were acquired from nine volunteers with T2- and proton density-weighted (PD-W) fast spin echo, susceptibility-weighted imaging (SWI), phase-sensitive inversion recovery and quantitative T1, T2 and T2 * mapping sequences. Contrast-to-noise ratios (CNR) for the STN and GPi were calculated for all sequences. Targeting errors on SWI were evaluated on magnetic susceptibility maps. The sequences demonstrating the best conspicuity of DBS target structures (SWI and T2*) were then applied to ten patients with movement disorders, and the CNRs for these techniques were assessed. SWI offers the highest CNR for the STN, but standard PD-W images provide the best CNR for the pallidum. Susceptibility maps indicated that the GPi margins may be shifted slightly on SWI, although no shifts were seen for the STN. SWI may improve the visibility of the STN on pre-operative MRI, potentially improving the accuracy of direct stereotactic targeting. (orig.)

  18. Properties of Neurons in External Globus Pallidus Can Support Optimal Action Selection

    Science.gov (United States)

    Bogacz, Rafal; Martin Moraud, Eduardo; Abdi, Azzedine; Magill, Peter J.; Baufreton, Jérôme

    2016-01-01

    The external globus pallidus (GPe) is a key nucleus within basal ganglia circuits that are thought to be involved in action selection. A class of computational models assumes that, during action selection, the basal ganglia compute for all actions available in a given context the probabilities that they should be selected. These models suggest that a network of GPe and subthalamic nucleus (STN) neurons computes the normalization term in Bayes’ equation. In order to perform such computation, the GPe needs to send feedback to the STN equal to a particular function of the activity of STN neurons. However, the complex form of this function makes it unlikely that individual GPe neurons, or even a single GPe cell type, could compute it. Here, we demonstrate how this function could be computed within a network containing two types of GABAergic GPe projection neuron, so-called ‘prototypic’ and ‘arkypallidal’ neurons, that have different response properties in vivo and distinct connections. We compare our model predictions with the experimentally-reported connectivity and input-output functions (f-I curves) of the two populations of GPe neurons. We show that, together, these dichotomous cell types fulfil the requirements necessary to compute the function needed for optimal action selection. We conclude that, by virtue of their distinct response properties and connectivities, a network of arkypallidal and prototypic GPe neurons comprises a neural substrate capable of supporting the computation of the posterior probabilities of actions. PMID:27389780

  19. Long-Term Clinical Outcome of Internal Globus Pallidus Deep Brain Stimulation for Dystonia.

    Directory of Open Access Journals (Sweden)

    Hye Ran Park

    Full Text Available GPi (Internal globus pallidus DBS (deep brain stimulation is recognized as a safe, reliable, reversible and adjustable treatment in patients with medically refractory dystonia.This report describes the long-term clinical outcome of 36 patients implanted with GPi DBS at the Neurosurgery Department of Seoul National University Hospital.Nine patients with a known genetic cause, 12 patients with acquired dystonia, and 15 patients with isolated dystonia without a known genetic cause were included. When categorized by phenomenology, 29 patients had generalized, 5 patients had segmental, and 2 patients had multifocal dystonia. Patients were assessed preoperatively and at defined follow-up examinations postoperatively, using the Burke-Fahn-Marsden dystonia rating scale (BFMDRS for movement and functional disability assessment. The mean follow-up duration was 47 months (range, 12-84.The mean movement scores significantly decreased from 44.88 points preoperatively to 26.45 points at 60-month follow up (N = 19, P = 0.006. The mean disability score was also decreased over time, from 11.54 points preoperatively to 8.26 points at 60-month follow up, despite no statistical significance (N = 19, P = 0.073. When analyzed the movement and disability improvement rates at 12-month follow up point, no significant difference was noted according to etiology, disease duration, age at surgery, age of onset, and phenomenology. However, the patients with DYT-1 dystonia and isolated dystonia without a known genetic cause showed marked improvement.GPi DBS is a safe and efficient therapeutic method for treatment of dystonia patients to improve both movement and disability. However, this study has some limitations caused by the retrospective design with small sample size in a single-center.

  20. Deep brain stimulation of the antero-medial globus pallidus interna for Tourette syndrome.

    Directory of Open Access Journals (Sweden)

    Perminder S Sachdev

    Full Text Available BACKGROUND: We have previously reported the results of Deep Brain Stimulation (DBS of the antero-medial globus pallidus interna (GPi for severe Tourette Syndrome (TS in 11 patients. We extend this case series to 17 patients and a longer follow-up to a maximum of 46 months. METHODS: 17 patients (14 male; mean age 29.1 years, range 17-51 years with severe and medically intractable TS were implanted with Medtronic quadripolar electrodes bilaterally in the antero-medial GPi. The primary outcome measure was the Yale Global Tic Severity Scale (YGTSS. Secondary outcome measures included the Yale-Brown Obsessive Compulsive Scale, Hamilton Depression Rating Scale, Gilles de la Tourette Quality of Life Scale and Global Assessment of Functioning. Follow up was at one month, three months and finally at a mean 24.1 months (range 8-46 months following surgery. RESULTS: Overall, there was a 48.3% reduction in motor tics and a 41.3% reduction in phonic tics at one month, and this improvement was maintained at final follow-up. 12 out of 17 (70.6% patients had a>50% reduction in YGTSS score at final follow up. Only 8 patients required ongoing pharmacotherapy for tics post-surgery. Patients improved significantly on all secondary measures. Adverse consequences included lead breakage in 4 patients, infection (1, transient anxiety (2, dizziness (1, poor balance (1 and worsening of stuttering (1. CONCLUSIONS: This case series provides further support that antero-medial GPi DBS is an effective and well tolerated treatment for a subgroup of severe TS, with benefits sustained up to 4 years.

  1. Prototypic and Arkypallidal Neurons in the Dopamine-Intact External Globus Pallidus

    Science.gov (United States)

    Abdi, Azzedine; Mallet, Nicolas; Mohamed, Foad Y.; Sharott, Andrew; Dodson, Paul D.; Nakamura, Kouichi C.; Suri, Sana; Avery, Sophie V.; Larvin, Joseph T.; Garas, Farid N.; Garas, Shady N.; Vinciati, Federica; Morin, Stéphanie; Bezard, Erwan

    2015-01-01

    Studies in dopamine-depleted rats indicate that the external globus pallidus (GPe) contains two main types of GABAergic projection cell; so-called “prototypic” and “arkypallidal” neurons. Here, we used correlative anatomical and electrophysiological approaches in rats to determine whether and how this dichotomous organization applies to the dopamine-intact GPe. Prototypic neurons coexpressed the transcription factors Nkx2-1 and Lhx6, comprised approximately two-thirds of all GPe neurons, and were the major GPe cell type innervating the subthalamic nucleus (STN). In contrast, arkypallidal neurons expressed the transcription factor FoxP2, constituted just over one-fourth of GPe neurons, and innervated the striatum but not STN. In anesthetized dopamine-intact rats, molecularly identified prototypic neurons fired at relatively high rates and with high regularity, regardless of brain state (slow-wave activity or spontaneous activation). On average, arkypallidal neurons fired at lower rates and regularities than prototypic neurons, and the two cell types could be further distinguished by the temporal coupling of their firing to ongoing cortical oscillations. Complementing the activity differences observed in vivo, the autonomous firing of identified arkypallidal neurons in vitro was slower and more variable than that of prototypic neurons, which tallied with arkypallidal neurons displaying lower amplitudes of a “persistent” sodium current important for such pacemaking. Arkypallidal neurons also exhibited weaker driven and rebound firing compared with prototypic neurons. In conclusion, our data support the concept that a dichotomous functional organization, as actioned by arkypallidal and prototypic neurons with specialized molecular, structural, and physiological properties, is fundamental to the operations of the dopamine-intact GPe. PMID:25926446

  2. Altered neuronal activity in the primary motor cortex and globus pallidus after dopamine depletion in rats.

    Science.gov (United States)

    Wang, Min; Li, Min; Geng, Xiwen; Song, Zhimin; Albers, H Elliott; Yang, Maoquan; Zhang, Xiao; Xie, Jinlu; Qu, Qingyang; He, Tingting

    2015-01-15

    The involvement of dopamine (DA) neuron loss in the etiology of Parkinson's disease has been well documented. The neural mechanisms underlying the effects of DA loss and the resultant motor dysfunction remain unknown. To gain insights into how loss of DA disrupts the electrical processes in the cortico-subcortical network, the present study explores the effects of DA neuron depletion on electrical activity in the primary motor cortex (M1), on the external and the internal segment of the globus pallidus (GPe and GPi respectively), and on their temporal relationships. Comparison of local field potentials (LFPs) in these brain regions from unilateral hemispheric DA neuron depleted rats and neurologically intact rats revealed that the spectrum power of LFPs in 12-70Hz (for M1, and GPe) and in 25-40Hz (for GPi) was significantly greater in the DA depleted rats than that in the control group. These changes were associated with a shortening of latency in LFP activities between M1 and GPe, from several hundred milliseconds in the intact animals to close to zero in the DA depleted animals. LFP oscillations in M1 were significantly more synchronized with those in GPe in the DA depleted rats compared with those in the control rats. By contrast, the synchronization of oscillation in LFP activities between M1 and GPi did not differ between the DA depleted and intact rats. Not surprisingly, rats that had DA neuron depletion spent more time along the ladder compared with the control rats. These data suggest that enhanced oscillatory activity and increased synchronization of LFPs may contribute to movement impairment in the rat model of Parkinson's disease. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Mean diffusivity of globus pallidus associated with verbal creativity measured by divergent thinking and creativity‐related temperaments in young healthy adults

    Science.gov (United States)

    Taki, Yasuyuki; Sekiguchi, Atsushi; Hashizume, Hiroshi; Nouchi, Rui; Sassa, Yuko; Kotozaki, Yuka; Miyauchi, Carlos Makoto; Yokoyama, Ryoichi; Iizuka, Kunio; Nakagawa, Seishu; Nagase, Tomomi; Kunitoki, Keiko; Kawashima, Ryuta

    2015-01-01

    Abstract Recent investigations revealed mean diffusivity (MD) in gray matter and white matter areas is correlated with individual cognitive differences in healthy subjects and show unique properties and sensitivity that other neuroimaging tools donot have. In this study, we tested the hypothesis that the MD in the dopaminergic system is associated with individual differences in verbal creativity measured by divergent thinking (VCDT) and novelty seeking based on prior studies suggesting associations between these and dopaminergic functions. We examined this issue in a large sample of right‐handed healthy young adults. We used analyses of MD and a psychological measure of VCDT, as well as personality measures of the Temperament and Character Inventory (TCI). Our results revealed associations between higher VCDT and lower MD in the bilateral globus pallidus. Furthermore, not only higher novelty seeking, but also lower harm avoidance, higher self‐directedness, and higher self‐transcendence were robustly associated with lower MD in the right globus pallidus, whereas higher persistence was associated with lower MD in the left globus pallidus. These personality variables were also associated with VCDT. The globus pallidus receives the dopaminergic input from the substantia nigra and plays a key role in motivation which is critically linked to dopamine. These results suggested the MD in the globus pallidus, underlie the association between VCDT and multiple personalities in TCI including novelty seeking. Hum Brain Mapp 36:1808–1827, 2015. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID:25627674

  4. Dopamine depletion increases the power and coherence of high-voltage spindles in the globus pallidus and motor cortex of freely moving rats.

    Science.gov (United States)

    Ge, Shunnan; Yang, Chen; Li, Min; Li, Jiang; Chang, Xiaozan; Fu, Jian; Chen, Lei; Chang, Chongwang; Wang, Xuelian; Zhu, Junling; Gao, Guodong

    2012-07-17

    Studies on patients with Parkinson's disease and in animal models have observed enhanced synchronization of oscillations in several frequency bands within and between the cortical-basal ganglia (BG) structures. Recent research has also shown that synchronization of high-voltage spindles (HVSs) in the cortex, striatum and substantia nigra pars reticulate is increased by dopamine depletion. However, more evidence is needed to determine whether HVS activity in the whole cortex-BG network represents homologous alteration following dopamine depletion. As the globus pallidus (GP) is in a central position to propagate and synchronize oscillations in the cortical-BG circuits, we employed local-field potentials and electrocorticogram to simultaneously record oscillations in the GP and primary (M1) and secondary (M2) motor cortices on freely moving 6-hydroxydopamine (6-OHDA) lesioned and control rats. Results showed that HVS episodes recorded from GP, and M2 and M1 cortex areas were more numerous and longer in 6-OHDA lesioned rats compared to controls. Relative power associated with HVS activity in the GP, and M2 and M1 cortices of 6-OHDA lesioned rats was significantly greater than that for control rats. Coherence values for HVS activity between the GP, and M2 and M1 cortex areas were significantly increased by dopamine depletion. Time lag between the M1 cortex HVS and GP HVS was significantly shorter for dopamine depleted than normal rats. Findings indicate a crucial rule for dopamine in the regulation of HVS activity in the whole cortical-BG circuit, and suggest a close relationship between abnormally synchronized HVS oscillations in the cortex-BG network and Parkinson's disease. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Neuronal firing in the globus pallidus internus and the ventrolateral thalamus related to parkinsonian motor symptoms

    Institute of Scientific and Technical Information of China (English)

    CHEN Hai; ZHUANG Ping; ZHANG Yu-qing; LI Jian-yu; LI Yong-jie

    2009-01-01

    Background It has been proposed that parkinsonian motor signs result from hyperactivity in the output nucleus of the basal ganglia, which suppress the motor thalamus and cortical areas. This study aimed to explore the neuronal activity in the globus pallidus internus (GPi) and the ventrolateral thalamic nuclear group (ventral oral posterior/ventral intermediate, Vop/Vim) in patients with Parkinson's disease (PD).Methods Twenty patients with PD who underwent neurosurgery were studied. Microelectrode recording was performed in the GPi (n=10) and the Vop/Vim (n=10) intraoperatively. Electromyography (EMG) contralateral to the surgery was simultaneously performed. Single unit analysis was carried out. The interspike intervals (ISI) and coefficient of variation (CV) of ISI were calculated. Histograms of ISI were constructed. A unified Parkinson's disease rating scale (UPDRS) was used to assess the clinical outcome of surgery.Results Three hundred and sixty-three neurons were obtained from 20 trajectories. Of 175 GPi neurons, there were 15.4% with tremor frequency, 69.2% with tonic firing, and 15.4% with irregular discharge. Of 188 thalamic neurons, there were 46.8% with tremor frequency, 22.9% with tonic firing, and 30.3% with irregular discharge. The numbers of three patterns of neuron in GPi and Vop/Vim were significantly different (P <0.001). ISI analysis revealed that mean firing rate of the three patterns of GPi neurons was (80.9±63.9) Hz (n=78), which was higher than similar neurons with 62.9 Hz in a normal primate. For the Vop/Vim group, ISI revealed that mean firing rate of the three patterns of neurons (n=95) was (23.2±17.1) Hz which was lower than similar neurons with 30 Hz in the motor thalamus of normal primates. UPDRS indicated that the clinical outcome of pallidotomy was (64.3±9.5)%, (83.4±19.1)% and (63.4±36.3)%, and clinical outcome of thalamotomy was (92.2±12.9)%, (68.0±25.2)% and (44.3±27.2)% for tremor, rigidity and bradykinesia, respectively

  6. Systemic blockade of dopamine D2-like receptors increases high-voltage spindles in the globus pallidus and motor cortex of freely moving rats.

    Directory of Open Access Journals (Sweden)

    Chen Yang

    Full Text Available High-voltage spindles (HVSs have been reported to appear spontaneously and widely in the cortical-basal ganglia networks of rats. Our previous study showed that dopamine depletion can significantly increase the power and coherence of HVSs in the globus pallidus (GP and motor cortex of freely moving rats. However, it is unclear whether dopamine regulates HVS activity by acting on dopamine D₁-like receptors or D₂-like receptors. We employed local-field potential and electrocorticogram methods to simultaneously record the oscillatory activities in the GP and primary motor cortex (M1 in freely moving rats following systemic administration of dopamine receptor antagonists or saline. The results showed that the dopamine D₂-like receptor antagonists, raclopride and haloperidol, significantly increased the number and duration of HVSs, and the relative power associated with HVS activity in the GP and M1 cortex. Coherence values for HVS activity between the GP and M1 cortex area were also significantly increased by dopamine D₂-like receptor antagonists. On the contrary, the selective dopamine D₁-like receptor antagonist, SCH23390, had no significant effect on the number, duration, or relative power of HVSs, or HVS-related coherence between M1 and GP. In conclusion, dopamine D₂-like receptors, but not D₁-like receptors, were involved in HVS regulation. This supports the important role of dopamine D₂-like receptors in the regulation of HVSs. An siRNA knock-down experiment on the striatum confirmed our conclusion.

  7. Reversibility of hyperintense globus pallidus on T 1-weighted MRI following surgery for a portosystemic shunt in an 8-year-old girl

    International Nuclear Information System (INIS)

    Ikeda, Shinji; Sera, Yoshihisa; Yoshida, Mituhiro; Ohshiro, Hajime; Uchino, Shinichiro; Seguchi, Sasa; Endo, Fumio

    1999-01-01

    An 8-year-old Japanese girl with a portosystemic shunt had shown hyperammonaemia since she was 3 years of age. MRI of her brain showed bilateral hyperintense globus pallidus. A portosystemic shunt was evident on US and angiography. She underwent surgical banding of the shunt, after which the lesion and clinical symptoms disappeared. (orig.)

  8. High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted MR Images: Comparison between Gadobutrol and Linear Gadolinium-Based Contrast Agents.

    Science.gov (United States)

    Moser, F G; Watterson, C T; Weiss, S; Austin, M; Mirocha, J; Prasad, R; Wang, J

    2018-02-01

    In view of the recent observations that gadolinium deposits in brain tissue after intravenous injection, our aim of this study was to compare signal changes in the globus pallidus and dentate nucleus on unenhanced T1-weighted MR images in patients receiving serial doses of gadobutrol, a macrocyclic gadolinium-based contrast agent, with those seen in patients receiving linear gadolinium-based contrast agents. This was a retrospective analysis of on-site patients with brain tumors. Fifty-nine patients received only gadobutrol, and 60 patients received only linear gadolinium-based contrast agents. Linear gadolinium-based contrast agents included gadoversetamide, gadobenate dimeglumine, and gadodiamide. T1 signal intensity in the globus pallidus, dentate nucleus, and pons was measured on the precontrast portions of patients' first and seventh brain MRIs. Ratios of signal intensity comparing the globus pallidus with the pons (globus pallidus/pons) and dentate nucleus with the pons (dentate nucleus/pons) were calculated. Changes in the above signal intensity ratios were compared within the gadobutrol and linear agent groups, as well as between groups. The dentate nucleus/pons signal ratio increased in the linear gadolinium-based contrast agent group ( t = 4.215, P linear gadolinium-based contrast agent group ( t = 2.931, P linear gadolinium-based contrast agents. © 2018 by American Journal of Neuroradiology.

  9. Distinct Developmental Origins Manifest in the Specialized Encoding of Movement by Adult Neurons of the External Globus Pallidus

    Science.gov (United States)

    Dodson, Paul D.; Larvin, Joseph T.; Duffell, James M.; Garas, Farid N.; Doig, Natalie M.; Kessaris, Nicoletta; Duguid, Ian C.; Bogacz, Rafal; Butt, Simon J.B.; Magill, Peter J.

    2015-01-01

    Summary Transcriptional codes initiated during brain development are ultimately realized in adulthood as distinct cell types performing specialized roles in behavior. Focusing on the mouse external globus pallidus (GPe), we demonstrate that the potential contributions of two GABAergic GPe cell types to voluntary action are fated from early life to be distinct. Prototypic GPe neurons derive from the medial ganglionic eminence of the embryonic subpallium and express the transcription factor Nkx2-1. These neurons fire at high rates during alert rest, and encode movements through heterogeneous firing rate changes, with many neurons decreasing their activity. In contrast, arkypallidal GPe neurons originate from lateral/caudal ganglionic eminences, express the transcription factor FoxP2, fire at low rates during rest, and encode movements with robust increases in firing. We conclude that developmental diversity positions prototypic and arkypallidal neurons to fulfil distinct roles in behavior via their disparate regulation of GABA release onto different basal ganglia targets. PMID:25843402

  10. Supersensitivity of GABAergic systems induced within rat substantia nigra and globus pallidus by haloperidol

    International Nuclear Information System (INIS)

    Frey, J.J.M.

    1986-01-01

    The supersensitivity was demonstrated by an increase in the responsiveness of individual neurons within these brain regions to microiontophoretically-applied GABA and by an up regulation of GABA binding sites. Rates received haloperidol for 30 days in their feed and were then withdrawn from treatment for 48 hrs. 3 H-GABA binding was found to be significantly elevated with the SN R (55%) and GP (42%). Scatchard analysis of 3 H-muscimol binding isotherms indicated that the number (B max ) of high affinity binding sites within the GP was significantly increased (32%); within the SN R , significant increases were detected in the B max of both high (23%) and low (58%) affinity 3 H-muscimol binding sites. After CHAL treatment, signs of dopaminergic supersensitivity within the basal ganglia were also observed. Spontaneous locomotor activity and apomorphine-induced stereotyped behavior were increased and specific 3 H-spiroperidol binding was elevated within the striatum (60%) and GP (236%)

  11. Effect of subthalamic nucleus or globus pallidus interna stimulation on oculomotor function in patients with Parkinson's disease.

    Science.gov (United States)

    Fridley, Jared; Adams, Gareth; Sun, Ping; York, Michelle; Atassi, Farah; Lai, Eugene; Simpson, Richard; Viswanathan, Ashwin; Yoshor, Daniel

    2013-01-01

    Deep brain stimulation (DBS) of either the globus pallidus interna (GPi) or subthalamic nucleus (STN) is similarly effective for treating somatomotor manifestations of Parkinson's disease (PD), but differences in how stimulation of each target affects oculomotor function are poorly understood. We sought to determine if stimulation of the STN, but not the GPi, affects oculomotor function in PD patients. Nineteen PD patients with DBS implants (8 bilateral GPi, 9 bilateral STN and 2 unilateral STN) were studied. Testing was performed with stimulation on, then off. Somatomotor function was tested using the Unified Parkinson's Disease Rating Scale (UPDRS) motor exam. For oculomotor testing, patients performed pro- and antisaccade tasks while monitored with an infrared eye tracker. Saccadic latency, saccadic intrusions, and square-wave jerks (SWJs) were measured for each trial. As expected, UPDRS motor scores improved with both GPi and STN stimulation. With GPi stimulation, there was no significant difference in oculomotor function with stimulation on or off. However, with STN stimulation on, there was a significant increase in the mean number of SWJs/s, as well as a significant decrease in latency for both pro- and antisaccade tasks. Stimulation of either GPi or STN had similar effects on somatomotor function, but only STN stimulation significantly altered oculomotor function. Copyright © 2013 S. Karger AG, Basel.

  12. Gadolinium deposition within the dentate nucleus and globus pallidus after repeated administrations of gadolinium-based contrast agents - current status

    Energy Technology Data Exchange (ETDEWEB)

    Stojanov, Dragan [University of Nis, Faculty of Medicine, Nis (Serbia); Center for Radiology, Nis (Serbia); Aracki-Trenkic, Aleksandra [Center for Radiology, Nis (Serbia); Benedeto-Stojanov, Daniela [University of Nis, Faculty of Medicine, Nis (Serbia)

    2016-05-15

    Gadolinium-based contrast agents (GBCAs) have been used clinically since 1988 for contrast-enhanced magnetic resonance imaging (CE-MRI). Generally, GBCAs are considered to have an excellent safety profile. However, GBCA administration has been associated with increased occurrence of nephrogenic systemic fibrosis (NSF) in patients with severely compromised renal function, and several studies have shown evidence of gadolinium deposition in specific brain structures, the globus pallidus and dentate nucleus, in patients with normal renal function. Gadolinium deposition in the brain following repeated CE-MRI scans has been demonstrated in patients using T1-weighted unenhanced MRI and inductively coupled plasma mass spectroscopy. Additionally, rodent studies with controlled GBCA administration also resulted in neural gadolinium deposits. Repeated GBCA use is associated with gadolinium deposition in the brain. This is especially true with the use of less-stable, linear GBCAs. In spite of increasing evidence of gadolinium deposits in the brains of patients after multiple GBCA administrations, the clinical significance of these deposits continues to be unclear. Here, we discuss the current state of scientific evidence surrounding gadolinium deposition in the brain following GBCA use, and the potential clinical significance of gadolinium deposition. There is considerable need for further research, both to understand the mechanism by which gadolinium deposition in the brain occurs and how it affects the patients in which it occurs. (orig.)

  13. Serial 1H-MRS of thalamus during deep brain stimulation of bilateral globus pallidus internus for primary generalized dystonia

    International Nuclear Information System (INIS)

    Chernov, Mikhail F.; Iseki, Hiroshi; Takakura, Kintomo; Ochiai, Taku; Taira, Takaomi; Hori, Tomokatsu; Ono, Yuko; Nakamura, Ryoichi; Muragaki, Yoshihiro

    2008-01-01

    The physiological mechanisms of deep brain stimulation (DBS) are not completely clear. Our understanding of them may be facilitated with the use of proton magnetic resonance spectroscopy ( 1 H-MRS). Serial 1 H-MRS of both thalami was performed during the course of DBS of bilateral globus pallidus internus in a patient with primary generalized dystonia. Two days after microelectrode implantation, a pulse frequency of 185 Hz was applied for stimulation. It resulted in relief of symptoms and a decrease of Burke-Fahn-Marsden dystonia rating scale (BFMDRS) scores, and was accompanied by a prominent increase of N-acetylaspartate (NAA)/choline-containing compounds (Cho) ratio, a mild increase of NAA/creatine (Cr) ratio, and a moderate decrease of Cho/Cr ratio. Two weeks later, for a search of the optimal stimulation mode, the pulse frequency was switched to 60 Hz, which resulted in clinical deterioration and significant increase of BFMDRS scores. At that time, all investigated 1 H-MRS-detected metabolic parameters had nearly returned to the pretreatment levels. Use of serial 1 H-MRS investigations of various brain structures during DBS in cases of movement disorders permits detailed evaluation of the treatment response, has a potential for its possible prediction, and may facilitate understanding of the physiological mechanisms of stimulation. (orig.)

  14. Comparison of Globus Pallidus Interna and Subthalamic Nucleus in Deep Brain Stimulation for Parkinson Disease: An Institutional Experience and Review

    Directory of Open Access Journals (Sweden)

    Shazia Mirza

    2017-01-01

    Full Text Available Deep Brain Stimulation (DBS has revolutionized the lives of patients of Parkinson disease, offering therapeutic options to those not benefiting entirely from medications alone. With its proven track record of outperforming the best medical management, the goal is to unlock the full potential of this therapy. Currently, the Globus Pallidus Interna (GPi and Subthalamic Nucleus (STN are both viable targets for DBS, and the choice of site should focus on the constellation of symptoms, both motor and nonmotor, which are key determinants to quality of life. Our article sheds light on the specific advantages and drawbacks of the two sites, highlighting the need for matching the inherent properties of a target with specific desired effects in patients. UT Southwestern Medical Center has a robust and constantly evolving DBS program and the narrative from our center provides invaluable insight into the practical realities of DBS. The ultimate decision in selecting a DBS target is complex, ideally made by a multidisciplinary team, tailored towards each patient’s profile and their expectations, by drawing upon scientific evidence coupled with experience. Ongoing research is expanding our knowledge base, which should be dynamically incorporated into an institute’s DBS paradigm to ensure that patients receive the optimal therapy.

  15. Transgenic Mouse Lines Subdivide External Segment of the Globus Pallidus (GPe) Neurons and Reveal Distinct GPe Output Pathways

    Science.gov (United States)

    Mastro, Kevin J.; Bouchard, Rachel S.; Holt, Hiromi A. K.

    2014-01-01

    Cell-type diversity in the brain enables the assembly of complex neural circuits, whose organization and patterns of activity give rise to brain function. However, the identification of distinct neuronal populations within a given brain region is often complicated by a lack of objective criteria to distinguish one neuronal population from another. In the external segment of the globus pallidus (GPe), neuronal populations have been defined using molecular, anatomical, and electrophysiological criteria, but these classification schemes are often not generalizable across preparations and lack consistency even within the same preparation. Here, we present a novel use of existing transgenic mouse lines, Lim homeobox 6 (Lhx6)–Cre and parvalbumin (PV)–Cre, to define genetically distinct cell populations in the GPe that differ molecularly, anatomically, and electrophysiologically. Lhx6–GPe neurons, which do not express PV, are concentrated in the medial portion of the GPe. They have lower spontaneous firing rates, narrower dynamic ranges, and make stronger projections to the striatum and substantia nigra pars compacta compared with PV–GPe neurons. In contrast, PV–GPe neurons are more concentrated in the lateral portions of the GPe. They have narrower action potentials, deeper afterhyperpolarizations, and make stronger projections to the subthalamic nucleus and parafascicular nucleus of the thalamus. These electrophysiological and anatomical differences suggest that Lhx6–GPe and PV–GPe neurons participate in different circuits with the potential to contribute to different aspects of motor function and dysfunction in disease. PMID:24501350

  16. Tonic and phasic changes in anteromedial globus pallidus activity in Tourette syndrome.

    Science.gov (United States)

    Israelashvili, Michal; Smeets, Anouk Y J M; Bronfeld, Maya; Zeef, Dagmar H; Leentjens, Albert F G; van Kranen-Mastenbroek, Vivianne; Janssen, Marcus L F; Temel, Yasin; Ackermans, Linda; Bar-Gad, Izhar

    2017-07-01

    Tourette syndrome is a hyperkinetic neurodevelopmental disorder characterized by tics. Assess the neuronal changes in the associative/limbic GP associated with Tourette syndrome. Neurophysiological recordings were performed from the anterior (associative/limbic) GPe and GPi of 8 awake patients during DBS electrode implantation surgeries. The baseline firing rate of the neurons was low in a state-dependent manner in both segments of the GP. Tic-dependent transient rate changes were found in the activity of individual neurons of both segments around the time of the tic. Neither oscillatory activity of individual neurons nor correlations in their interactions were observed. The results demonstrate the involvement of the associative/limbic pathway in the underlying pathophysiology of Tourette syndrome and point to tonic and phasic modulations of basal ganglia output as a key mechanisms underlying the abnormal state of the disorder and the expression of individual tics, respectively. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  17. High-frequency stimulation of the globus pallidus interna nucleus modulates GFRα1 gene expression in the basal ganglia.

    Science.gov (United States)

    Ho, Duncun Xun Kiat; Tan, Yong Chee; Tan, Jiayi; Too, Heng Phon; Ng, Wai Hoe

    2014-04-01

    Deep brain stimulation (DBS) is an established therapy for movement disorders such as Parkinson's disease (PD). Although the efficacy of DBS is clear, its precise molecular mechanism remains unknown. The glial cell line derived factor (GDNF) family of ligands has been shown to confer neuroprotective effects on dopaminergic neurons, and putaminal infusion of GDNF have been investigated in PD patients with promising results. Despite the potential therapeutic role of GDNF in alleviating motor symptoms, there is no data on the effects of electrical stimulation on GDNF-family receptor (GFR) expression in the basal ganglia structures. Here, we report the effects of electrical stimulation on GFRα1 isoforms, particularly GFRα1a and GFRα1b. Wistar rats underwent 2 hours of high frequency stimulation (HFS) at the globus pallidus interna nucleus. A control group was subjected to a similar procedure but without stimulation. The HFS group, sacrificed 24 hours after treatment, had a threefold decrease in mRNA expression level of GFRα1b (p=0.037), but the expression level reverted to normal 72 hours after stimulation. Our preliminary data reveal the acute effects of HFS on splice isoforms of GFRα1, and suggest that HFS may modulate the splice isoforms of GFRα1a and GFRα1b to varying degrees. Going forward, elucidating the interactions between HFS and GFR may shed new insights into the complexity of GDNF signaling in the nervous system and lead to better design of clinical trials using these signaling pathways to halt disease progression in PD and other neurodegenerative diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Efficient digital implementation of a conductance-based globus pallidus neuron and the dynamics analysis

    Science.gov (United States)

    Yang, Shuangming; Wei, Xile; Deng, Bin; Liu, Chen; Li, Huiyan; Wang, Jiang

    2018-03-01

    Balance between biological plausibility of dynamical activities and computational efficiency is one of challenging problems in computational neuroscience and neural system engineering. This paper proposes a set of efficient methods for the hardware realization of the conductance-based neuron model with relevant dynamics, targeting reproducing the biological behaviors with low-cost implementation on digital programmable platform, which can be applied in wide range of conductance-based neuron models. Modified GP neuron models for efficient hardware implementation are presented to reproduce reliable pallidal dynamics, which decode the information of basal ganglia and regulate the movement disorder related voluntary activities. Implementation results on a field-programmable gate array (FPGA) demonstrate that the proposed techniques and models can reduce the resource cost significantly and reproduce the biological dynamics accurately. Besides, the biological behaviors with weak network coupling are explored on the proposed platform, and theoretical analysis is also made for the investigation of biological characteristics of the structured pallidal oscillator and network. The implementation techniques provide an essential step towards the large-scale neural network to explore the dynamical mechanisms in real time. Furthermore, the proposed methodology enables the FPGA-based system a powerful platform for the investigation on neurodegenerative diseases and real-time control of bio-inspired neuro-robotics.

  19. Meta-analysis comparing deep brain stimulation of the globus pallidus and subthalamic nucleus to treat advanced Parkinson disease.

    Science.gov (United States)

    Liu, Yi; Li, Weina; Tan, Changhong; Liu, Xi; Wang, Xin; Gui, Yuejiang; Qin, Lu; Deng, Fen; Hu, Changlin; Chen, Lifen

    2014-09-01

    Deep brain stimulation (DBS) is the surgical procedure of choice for patients with advanced Parkinson disease (PD). The globus pallidus internus (GPi) and the subthalamic nucleus (STN) are commonly targeted by this procedure. The purpose of this meta-analysis was to compare the efficacy of DBS in each region. MEDLINE/PubMed, EMBASE, Web of Knowledge, and the Cochrane Library were searched for English-language studies published before April 2013. of studies investigating the efficacy and clinical outcomes of DBS of the GPi and STN for PD were analyzed. Six eligible trials containing a total of 563 patients were included in the analysis. Deep brain stimulation of the GPi or STN equally improved motor function, measured by the Unified Parkinson's Disease Rating Scale Section III (UPDRSIII) (motor section, for patients in on- and off-medication phases), within 1 year postsurgery. The change score for the on-medication phase was 0.68 (95% CI - 2.12 to 3.47, p > 0.05; 5 studies, 518 patients) and for the off-medication phase was 1.83 (95% CI - 3.12 to 6.77, p > 0.05; 5 studies, 518 patients). The UPDRS Section II (activities of daily living) scores for patients on medication improved equally in both DBS groups (p = 0.97). STN DBS allowed medication dosages to be reduced more than GPi DBS (95% CI 129.27-316.64, p < 0.00001; 5 studies, 540 patients). Psychiatric symptoms, measured by Beck Depression Inventory, 2nd edition scores, showed greater improvement from baseline after GPi DBS than after STN DBS (standardized mean difference -2.28, 95% CI -3.73 to -0.84, p = 0.002; 3 studies, 382 patients). GPi and STN DBS improve motor function and activities of daily living for PD patients. Differences in therapeutic efficacy for PD were not observed between the 2 procedures. STN DBS allowed greater reduction in medication for patients, whereas GPi DBS provided greater relief from psychiatric symptoms. An understanding of other symptomatic aspects of targeting each region and long

  20. Increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W magnetic resonance images in patients with relapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium-based contrast agent, gadobutrol

    Energy Technology Data Exchange (ETDEWEB)

    Stojanov, Dragan A. [University of Nis, Faculty of Medicine, Nis (Serbia); Clinical Center Nis, Center for Radiology, Nis (Serbia); Aracki-Trenkic, Aleksandra [Clinical Center Nis, Center for Radiology, Nis (Serbia); Vojinovic, Slobodan; Ljubisavljevic, Srdjan [University of Nis, Faculty of Medicine, Nis (Serbia); Clinical Center Nis, Clinic for Neurology, Nis (Serbia); Benedeto-Stojanov, Daniela [University of Nis, Faculty of Medicine, Nis (Serbia)

    2016-03-15

    To evaluate correlation between cumulative dose of gadobutrol and signal intensity (SI) within dentate nucleus and globus pallidus on unenhanced T1-weighted images in patients with relapsing-remitting multiple sclerosis (RRMS). Dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios, and renal and liver functions, were evaluated after multiple intravenous administrations of 0.1 mmol/kg gadobutrol at 27, 96-98, and 168 weeks. We compared SI ratios based on the number of administrations, total amount of gadobutrol administered, and time between injections. Globus pallidus-to-thalamus (p = 0.025) and dentate nucleus-to-pons (p < 0.001) SI ratios increased after multiple gadobutrol administrations, correlated with the number of administrations (ρ = 0.263, p = 0.046, respectively) and depended on the length of administration (p = 0.017, p = 0.037, respectively). Patients receiving gadobutrol at 27 weeks showed the greatest increase in both SI ratios (p = 0.006; p = 0.014, respectively, versus 96-98 weeks). GGT increased at the end of the study (p = 0.004). In patients with RRMS, SI within the dentate nucleus and globus pallidus increased on unenhanced T1-weighted images after multiple gadobutrol injections. Administration of the same total amount of gadobutrol over a shorter period caused greater SI increase. (orig.)

  1. Immediate recovery of neurological function in response to deep brain stimulation of the globus pallidus internus in a patient with idiopathic camptocormia

    Directory of Open Access Journals (Sweden)

    I. Madrazo

    2016-04-01

    Full Text Available Camptocormia is a major disabling abnormality characterized by severe forward flexion of the thoracolumbar spine. We report here on the effectiveness of deep brain stimulation (DBS for the management of a case of untreatable idiopathic camptocormia. The patient, a 51-year-old male, with an 11-year-long history of radicular pain. Camptocormia symptomatology initiated 4 years ago. Preoperative muscle electrodiagnostic testing was within normal limits. Myopathy was ruled out. In the standing position myokymic discharges were recorded. Under local anesthesia and stereotactic control, electrodes for DBS were placed bilaterally in the globus pallidus internus. Patient's symptoms disappeared immediately following DBS. This response cannot be attributed to the surgical procedure itself. When stimulators were turned “off” accidentally, the patient returned immediately to his pre-surgery condition. Erect posture and walking were restored when stimulators were back “on”.

  2. Increased signal intensities in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evidence in children undergoing multiple gadolinium MRI exams

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Houchun H.; Pokorney, Amber; Towbin, Richard B.; Miller, Jeffrey H. [Phoenix Children' s Hospital, Department of Medical Imaging and Radiology, Phoenix, AZ (United States)

    2016-10-15

    Recent reports have suggested residual gadolinium deposition in the brain in subjects undergoing multiple contrast-enhanced MRI exams. These findings have raised some concerns regarding gadolinium-based contrast agent (GBCA) usage and retention in brain tissues. To summarize findings of hyperintense brain structures on precontrast T1-weighted images in 21 children undergoing multiple GBCA MRI exams. This retrospective study involved 21 patients, each of whom received multiple MRI examinations (range: 5-37 exams) with GBCA over the course of their medical treatment (duration from first to most recent exam: 1.2-12.9 years). The patients were between 0.9 and 14.4 years of age at the time of their first GBCA exam. Regions of interest were drawn in the dentate nucleus and the globus pallidus on 2-D fast spin echo images acquired at 1.5 T. The signal intensities of these two structures were normalized by that of the corpus callosum genu. Signal intensity ratios from these patients were compared to control patients of similar ages who have never received GBCA. Signal intensity ratios increased between the first and the most recent MRI exam in all 21 patients receiving GBCA, with an increase of 18.6%±12.7% (range: 0.5% to 47.5%) for the dentate nucleus and 12.4%±7.4% (range: -1.2% to 33.7%) for the globus pallidus (P<0.0001). Signal intensity ratios were also higher in GBCA patients than in controls (P<0.01). The degree of signal intensity enhancement did not correlate with statistical significance to the cumulative number or volume of GBCA administrations each patient received, the patient's age or the elapsed time between the first and most recent GBCA MRI exams. These results in children are consistent with recent findings in adults, suggesting possible gadolinium deposition in the brain. (orig.)

  3. Signal intensity at unenhanced T1-weighted magnetic resonance in the globus pallidus and dentate nucleus after serial administrations of a macrocyclic gadolinium-based contrast agent in children

    Energy Technology Data Exchange (ETDEWEB)

    Rossi Espagnet, Maria Camilla; Bernardi, Bruno; Figa-Talamanca, Lorenzo [Ospedale Pediatrico Bambino Gesu, IRCCS, Neuroradiology Unit, Imaging Department, Rome (Italy); Pasquini, Luca [Ospedale Pediatrico Bambino Gesu, IRCCS, Neuroradiology Unit, Imaging Department, Rome (Italy); University Sapienza, Neuroradiology Unit, Azienda Ospedaliera Sant' Andrea, Rome (Italy); Toma, Paolo [Ospedale Pediatrico Bambino Gesu, IRCCS, Department of Imaging, Rome (Italy); Napolitano, Antonio [Ospedale Pediatrico Bambino Gesu, IRCCS, Enterprise Risk Management, Medical Physics Department, Rome (Italy)

    2017-09-15

    Few studies have been conducted on the relations between T1-weighted signal intensity changes in the pediatric brain following gadolinium-based contrast agent (GBCA) exposure. The purpose of this study is to investigate the effect of multiple administrations of a macrocyclic GBCA on signal intensity in the globus pallidus and dentate nucleus of the pediatric brain on unenhanced T1-weighted MR images. This retrospective study included 50 patients, mean age: 8 years (standard deviation: 4.8 years), with normal renal function exposed to ≥6 administrations of the same macrocyclic GBCA (gadoterate meglumine) and a control group of 59 age-matched GBCA-naive patients. The globus pallidus-to-thalamus signal intensity ratio and dentate nucleus-to-pons signal intensity ratio were calculated from unenhanced T1-weighted images for both patients and controls. A mixed linear model was used to evaluate the effects on signal intensity ratios of the number of GBCA administrations, the time interval between administrations, age, radiotherapy and chemotherapy. T-test analyses were performed to compare signal intensity ratio differences between successive administrations and baseline MR signal intensity ratios in patients compared to controls. P-values were considered significant if <0.05. A significant effect of the number of GBCA administrations on relative signal intensities globus pallidus-to-thalamus (F[8]=3.09; P=0.002) and dentate nucleus-to-pons (F[8]=2.36; P=0.021) was found. The relative signal intensities were higher at last MR examination than at baseline (P<0.001). Quantitative analysis evaluation of globus pallidus:thalamus and dentate nucleus:pons of the pediatric brain demonstrated an increase after serial administrations of macrocyclic GBCA. Further research is necessary to fully understand GBCA pharmacokinetic in children. (orig.)

  4. Holmes’ Tremor with Shoulder Pain Treated by Deep Brain Stimulation of Unilateral Ventral Intermediate Thalamic Nucleus and Globus Pallidus Internus

    Directory of Open Access Journals (Sweden)

    Sabri Aydın

    2017-05-01

    Full Text Available A 21-year-old male was admitted with severe right arm and hand tremors after a thalamic hemorrhage caused by a traffic accident. He was also suffering from agonizing pain in his right shoulder that manifested after the tremor. Neurologic examination revealed a disabling, severe, and irregular kinetic and postural tremor in the right arm during target-directed movements. There was also an irregular ipsilateral rest tremor and dystonic movements in the distal part of the right arm. The amplitude was moderate at rest and extremely high during kinetic and intentional movements. The patient underwent left globus pallidum internus and ventral intermediate thalamic nucleus deep brain stimulation. The patient improved by more than 80% as rated by the Fahn-Tolosa-Marin Tremor Rating Scale and Visual Analog Scale six months after surgery.

  5. Cognition and Depression Following Deep Brain Stimulation of the Subthalamic Nucleus and Globus Pallidus Pars Internus in Parkinson's Disease: A Meta-Analysis.

    Science.gov (United States)

    Combs, Hannah L; Folley, Bradley S; Berry, David T R; Segerstrom, Suzanne C; Han, Dong Y; Anderson-Mooney, Amelia J; Walls, Brittany D; van Horne, Craig

    2015-12-01

    Parkinson's disease (PD) is a common, degenerative disorder of the central nervous system. Individuals experience predominantly extrapyramidal symptoms including resting tremor, rigidity, bradykinesia, gait abnormalities, cognitive impairment, depression, and neurobehavioral concerns. Cognitive impairments associated with PD are diverse, including difficulty with attention, processing speed, executive functioning, memory recall, visuospatial functions, word-retrieval, and naming. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) is FDA approved and has been shown to be effective in reducing motor symptoms of PD. Studies have found that stimulating STN and GPi are equally effective at improving motor symptoms and dyskinesias; however, there has been discrepancy as to whether the cognitive, behavioral, and mood symptoms are affected differently between the two targets. The present study used random-effects meta-analytic models along with a novel p-curve analytic procedure to compare the potential cognitive and emotional impairments associated with STN-DBS in the current literature to those associated with GPi-DBS. Forty-one articles were reviewed with an aggregated sample size of 1622 patients. Following STN-DBS, small declines were found in psychomotor speed, memory, attention, executive functions, and overall cognition; and moderate declines were found in both semantic and phonemic fluency. However, GPi-DBS resulted in fewer neurocognitive declines than STN-DBS (small declines in attention and small-moderate declines in verbal fluency). With regards to its effect on depression symptomatology, both GPi-DBS and STN-DBS resulted in lower levels of depressive symptoms post-surgery. From a neurocognitive standpoint, both GPi-DBS and STN-DBS produce subtle cognitive declines but appears to be relatively well tolerated.

  6. Deep Brain Stimulation of the Internal Globus Pallidus Improves Response Initiation and Proactive Inhibition in Patients With Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Yixin Pan

    2018-04-01

    Full Text Available Background: Impulse control disorder is not uncommon in patients with Parkinson’s disease (PD who are treated with dopamine replacement therapy and subthalamic deep brain stimulation (DBS. Internal globus pallidus (GPi-DBS is increasingly used, but its role in inhibitory control has rarely been explored. In this study, we evaluated the effect of GPi-DBS on inhibitory control in PD patients.Methods: A stop-signal paradigm was used to test response initiation, proactive inhibition, and reactive inhibition. The subjects enrolled in the experiment were 27 patients with PD, of whom 13 had received only drug treatment and 14 had received bilateral GPi-DBS in addition to conventional medical treatment and 15 healthy individuals.Results: Our results revealed that with GPi-DBS on, patients with PD showed significantly faster responses than the other groups in trials where it was certain that no stop signal would be presented. Proactive inhibition was significantly different in the surgical patients with GPi-DBS on versus when GPi-DBS was off, in surgical patients with GPi-DBS on versus drug-treated patients, and in healthy controls versus drug-treated patients. Correlation analyses revealed that when GPi-DBS was on, there was a statistically significant moderate positive relationship between proactive inhibition and dopaminergic medication.Conclusion: GPi-DBS may lead to an increase in response initiation speed and improve the dysfunctional proactive inhibitory control observed in PD patients. Our results may help us to understand the role of the GPi in cortical-basal ganglia circuits.

  7. Visualization of the internal globus pallidus: sequence and orientation for deep brain stimulation using a standard installation protocol at 3.0 Tesla.

    Science.gov (United States)

    Nölte, Ingo S; Gerigk, Lars; Al-Zghloul, Mansour; Groden, Christoph; Kerl, Hans U

    2012-03-01

    Deep-brain stimulation (DBS) of the internal globus pallidus (GPi) has shown remarkable therapeutic benefits for treatment-resistant neurological disorders including dystonia and Parkinson's disease (PD). The success of the DBS is critically dependent on the reliable visualization of the GPi. The aim of the study was to evaluate promising 3.0 Tesla magnetic resonance imaging (MRI) methods for pre-stereotactic visualization of the GPi using a standard installation protocol. MRI at 3.0 T of nine healthy individuals and of one patient with PD was acquired (FLAIR, T1-MPRAGE, T2-SPACE, T2*-FLASH2D, susceptibility-weighted imaging mapping (SWI)). Image quality and visualization of the GPi for each sequence were assessed by two neuroradiologists independently using a 6-point scale. Axial, coronal, and sagittal planes of the T2*-FLASH2D images were compared. Inter-rater reliability, contrast-to-noise ratios (CNR) and signal-to-noise ratios (SNR) for the GPi were determined. For illustration, axial T2*-FLASH2D images were fused with a section schema of the Schaltenbrand-Wahren stereotactic atlas. The GPi was best and reliably visualized in axial and to a lesser degree on coronal T2*-FLASH2D images. No major artifacts in the GPi were observed in any of the sequences. SWI offered a significantly higher CNR for the GPi compared to standard T2-weighted imaging using the standard parameters. The fusion of the axial T2*-FLASH2D images and the atlas projected the GPi clearly in the boundaries of the section schema. Using a standard installation protocol at 3.0 T T2*-FLASH2D imaging (particularly axial view) provides optimal and reliable delineation of the GPi.

  8. Deep Brain Stimulation of the Globus Pallidus Internus in Patients with Intractable Tourette Syndrome: A 1-year Follow-up Study

    Institute of Scientific and Technical Information of China (English)

    Xiao-Hua Zhang; Jian-Yu Li; Yu-Qing Zhang; Yong-Jie Li

    2016-01-01

    Background:Deep brain stimulation (DBS) has been a promising treatment for patients with refractory Tourette syndrome (TS) for more than a decade.Despite successful DBS treatment of TS in more than 100 patients worldwide,studies with a large patient sample and long-term follow-up assessments are still scarce.Accordingly,we investigated the clinical efficacy and safety of globus pallidus internus (GPi) DBS in the treatment of intractable TS in 24 patients with a l-year follow-up assessment.Methods:Bilateral/unilateral GPi-DBS was performed in 24 patients with TS.We evaluated symptoms of tics and obsessive-compulsive disorder (OCD) through the Yale Global Tic Severity Scale (YGTSS) and Yale-Brown Obsessive-compulsive Scale (Y-BOCS).We used the Wechsler Adult Intelligence Scale-Revised in China (WAIS-RC) to evaluate the safety of the treatment.We conducted follow-up assessments of all patients for at least 12 months (12-99 months).Results:Symptoms of tics and OCD were significantly relieved at a 12-month follow-up assessment.The mean YGTSS score was 74.04 ± 11.52,49.83 ± 10.91,32.58 ± 7.97,and 31.21 ± 8.87 at baseline,3,6,and 12 months,respectively.The mean YGTSS scores obtained at the follow-up assessments were significantly different from the baseline (P < 0.05).The improvement in motor tics was superior to that in phonic tics.The mean Y-BOCS scores were 21.61 ± 4.97,18 ± 4.58,14.39 ± 3.99,and 13.78 ± 4.56 at baseline,3,6,and 12 months,respectively (P < 0.05).We observed a remarkable improvement in psychiatric comorbidities,such as OCD and attention-deficit hyperactivity disorder,after the procedure.WAIS-RC scores were comparable before and after the operation.There were no severe postoperative complications.Conclusion:GPi-DBS appears to comprehensively alleviate tic symptoms and psychiatric comorbidities in patients with TS,thus significantly improving patients' quality of life.

  9. Gadolinium Accumulation in the Deep Cerebellar Nuclei and Globus Pallidus After Exposure to Linear but Not Macrocyclic Gadolinium-Based Contrast Agents in a Retrospective Pig Study With High Similarity to Clinical Conditions.

    Science.gov (United States)

    Boyken, Janina; Frenzel, Thomas; Lohrke, Jessica; Jost, Gregor; Pietsch, Hubertus

    2018-05-01

    The aim of this retrospective study was to determine the gadolinium (Gd) concentration in different brain areas in a pig cohort that received repeated administration of Gd-based contrast agents (GBCAs) at standard doses over several years, comparable with a clinical setting. Brain tissue was collected from 13 Göttingen mini pigs that had received repeated intravenous injections of gadopentetate dimeglumine (Gd-DTPA; Magnevist) and/or gadobutrol (Gadovist). The animals have been included in several preclinical imaging studies since 2008 and received cumulative Gd doses ranging from 7 to 129 mmol per animal over an extended period. Two animals with no history of administration of GBCA were included as controls. Brain autopsies were performed not earlier than 8 and not later than 38 months after the last GBCA application. Tissues from multiple brain areas including cerebellar and cerebral deep nuclei, cerebellar and cerebral cortex, and pons were analyzed for Gd using inductively coupled plasma mass spectrometry. Of the 13 animals, 8 received up to 48 injections of gadobutrol and Gd-DTPA and 5 received up to 29 injections of gadobutrol only. In animals that had received both Gd-DTPA and gadobutrol, a median (interquartile range) Gd concentration of 1.0 nmol/g tissue (0.44-1.42) was measured in the cerebellar nuclei and 0.53 nmol/g (0.29-0.62) in the globus pallidus. The Gd concentration in these areas in gadobutrol-only animals was 50-fold lower with median concentrations of 0.02 nmol/g (0.01-0.02) for cerebellar nuclei and 0.01 nmol/g (0.01-0.01) for globus pallidus and was comparable with control animals with no GBCA history. Accordingly, in animals that received both GBCAs, the amount of residual Gd correlated with the administered dose of Gd-DTPA (P ≤ 0.002) but not with the total Gd dose, consisting of Gd-DTPA and gadobutrol. The Gd concentration in cortical tissue and in the pons was very low (≤0.07 nmol/g tissue) in all animals analyzed. Multiple exposure

  10. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on Subthalamic Nucleus and Globus Pallidus Internus Deep Brain Stimulation for the Treatment of Patients With Parkinson's Disease: Executive Summary.

    Science.gov (United States)

    Rughani, Anand; Schwalb, Jason M; Sidiropoulos, Christos; Pilitsis, Julie; Ramirez-Zamora, Adolfo; Sweet, Jennifer A; Mittal, Sandeep; Espay, Alberto J; Martinez, Jorge Gonzalez; Abosch, Aviva; Eskandar, Emad; Gross, Robert; Alterman, Ron; Hamani, Clement

    2018-06-01

    Is bilateral subthalamic nucleus deep brain stimulation (STN DBS) more, less, or as effective as bilateral globus pallidus internus deep brain stimulation (GPi DBS) in treating motor symptoms of Parkinson's disease, as measured by improvements in Unified Parkinson's Disease Rating Scale, part III (UPDRS-III) scores? Given that bilateral STN DBS is at least as effective as bilateral GPi DBS in treating motor symptoms of Parkinson's disease (as measured by improvements in UPDRS-III scores), consideration can be given to the selection of either target in patients undergoing surgery to treat motor symptoms. (Level I). Is bilateral STN DBS more, less, or as effective as bilateral GPi DBS in allowing reduction of dopaminergic medication in Parkinson's disease? When the main goal of surgery is reduction of dopaminergic medications in a patient with Parkinson's disease, then bilateral STN DBS should be performed instead of GPi DBS. (Level I). Is bilateral STN DBS more, less, or as effective as bilateral GPi DBS in treating dyskinesias associated with Parkinson's disease? There is insufficient evidence to make a generalizable recommendation regarding the target selection for reduction of dyskinesias. However, when the reduction of medication is not anticipated and there is a goal to reduce the severity of "on" medication dyskinesias, the GPi should be targeted. (Level I). Is bilateral STN DBS more, less, or as effective as bilateral GPi DBS in improving quality of life measures in Parkinson's disease? When considering improvements in quality of life in a patient undergoing DBS for Parkinson's disease, there is no basis to recommend bilateral DBS in 1 target over the other. (Level I). Is bilateral STN DBS associated with greater, lesser, or a similar impact on neurocognitive function than bilateral GPi DBS in Parkinson disease? If there is significant concern about cognitive decline, particularly in regards to processing speed and working memory in a patient undergoing DBS

  11. Management of Globus Pharyngeus

    Directory of Open Access Journals (Sweden)

    S. Kortequee

    2013-01-01

    Full Text Available Globus pharyngeus is a common ENT condition. This paper reviews the current evidence on globus and gives a rational guide to the management of patients with globus. The aetiology of globus is still unclear though most ENT surgeons believe that reflux whether acidic or not plays a significant role. Though proton pump inhibitors are used extensively in practice, there is little evidence to support their efficacy. Most patients with globus can be discharged after simple office investigations. The role of pepsin-induced laryngeal injury is an exciting concept that needs further study. Given the benign nature of globus pharyngeus, in most cases, reassurance rather than treatment or extensive investigation with rigid oesophagoscopy or contrast swallows is all that is needed. We need more research into the aetiology of globus.

  12. Correlation between Relaxometry and Diffusion Tensor Imaging in the Globus Pallidus of Huntington's Disease Patients

    Czech Academy of Sciences Publication Activity Database

    Syka, Michael; Keller, J.; Klempíř, J.; Rulseh, A. M.; Roth, J.; Jech, R.; Voříšek, Ivan; Vymazal, J.

    2015-01-01

    Roč. 10, č. 3 (2015), e0118907 E-ISSN 1932-6203 R&D Projects: GA ČR(CZ) GAP303/11/2378 Institutional support: RVO:68378041 Keywords : basal ganglia * gray-matter * human brain Subject RIV: FH - Neurology Impact factor: 3.057, year: 2015

  13. Involvement of the subthalamic nucleus and globus pallidus internus in attention

    Czech Academy of Sciences Publication Activity Database

    Bocková, M.; Chládek, Jan; Jurák, Pavel; Halámek, Josef; Baláž, M.; Rektor, I.

    2011-01-01

    Roč. 118, č. 8 (2011), s. 1235-1245 ISSN 0300-9564 R&D Projects: GA AV ČR IAA200650801; GA MŠk ED0017/01/01 Institutional research plan: CEZ:AV0Z20650511 Keywords : basal ganglia * ERP * ERD/S * attention * DBS Subject RIV: FH - Neurology Impact factor: 2.730, year: 2011

  14. Mossbauer and SQUID Characterization of Iron in Human Tissue: Case of Globus Pallidus

    Czech Academy of Sciences Publication Activity Database

    Miglierini, M.; Boca, R.; Kopáni, M.; Lančok, Adriana

    2014-01-01

    Roč. 126, č. 1 (2014), s. 240-241 ISSN 0587-4246 R&D Projects: GA ČR GAP204/10/0035 Institutional support: RVO:61388980 Keywords : FERRITIN Subject RIV: CF - Physical ; The oretical Chemistry Impact factor: 0.530, year: 2014

  15. Malignant Neuroleptic Syndrome following Deep Brain Stimulation Surgery of Globus Pallidus Pars Internus in Cerebral Palsy

    Directory of Open Access Journals (Sweden)

    Jae Meen Lee

    2016-02-01

    Full Text Available Neuroleptic malignant syndrome (NMS is a rare but potentially lethal outcome caused by sudden discontinuation or dose reduction of dopaminergic agents. We report an extremely rare case of NMS after deep brain stimulation (DBS surgery in a cerebral palsy (CP patient without the withdrawal of dopaminergic agents. A 19-year-old girl with CP was admitted for DBS due to medically refractory dystonia and rigidity. Dopaminergic agents were not stopped preoperatively. DBS was performed uneventfully under monitored anesthesia. Dopaminergic medication was continued during the postoperative period. She manifested spasticity and muscle rigidity, and was high fever resistant to anti-pyretic drugs at 2 h postoperative. At postoperative 20 h, she suffered cardiac arrest and expired, despite vigorous cardiopulmonary resuscitation. NMS should be considered for hyperthermia and severe spasticity in CP patients after DBS surgery, irrespective of continued dopaminergic medication.

  16. Gastropharyngeal and gastroesophageal reflux in globus and hoarseness

    NARCIS (Netherlands)

    Smit, C. F.; van Leeuwen, J. A.; Mathus-Vliegen, L. M.; Devriese, P. P.; Semin, A.; Tan, J.; Schouwenburg, P. F.

    2000-01-01

    The role of gastropharyngeal reflux in patients with globus pharyngeus and hoarseness remains unclear. To evaluate patients with complaints of globus, hoarseness, or globus and hoarseness combined for the presence of gastropharyngeal and gastroesophageal reflux. Prospective clinical cohort study of

  17. Globus

    Science.gov (United States)

    ... Publications Library En Español Digestive Health Matters Medical Definitions Links Books of Interest Video Corner Clinical Corner Survey Corner News Medical and Treatment News Events Press Releases Commentary For Media Research Research Awards Research Grants Funding Research Clinical Trials & ...

  18. Globus File Transfer Services | High-Performance Computing | NREL

    Science.gov (United States)

    installed on the systems at both ends of the data transfer. The NREL endpoint is nrel#globus. Click Login on the Globus web site. On the login page select "Globus ID" as the login method and click Login to the Globus website. From the Manage Data drop down menu, select Transfer Files. Then click Get

  19. Application experiences with the Globus toolkit.

    Energy Technology Data Exchange (ETDEWEB)

    Brunett, S.

    1998-06-09

    The Globus grid toolkit is a collection of software components designed to support the development of applications for high-performance distributed computing environments, or ''computational grids'' [14]. The Globus toolkit is an implementation of a ''bag of services'' architecture, which provides application and tool developers not with a monolithic system but rather with a set of stand-alone services. Each Globus component provides a basic service, such as authentication, resource allocation, information, communication, fault detection, and remote data access. Different applications and tools can combine these services in different ways to construct ''grid-enabled'' systems. The Globus toolkit has been used to construct the Globus Ubiquitous Supercomputing Testbed, or GUSTO: a large-scale testbed spanning 20 sites and included over 4000 compute nodes for a total compute power of over 2 TFLOPS. Over the past six months, we and others have used this testbed to conduct a variety of application experiments, including multi-user collaborative environments (tele-immersion), computational steering, distributed supercomputing, and high throughput computing. The goal of this paper is to review what has been learned from these experiments regarding the effectiveness of the toolkit approach. To this end, we describe two of the application experiments in detail, noting what worked well and what worked less well. The two applications are a distributed supercomputing application, SF-Express, in which multiple supercomputers are harnessed to perform large distributed interactive simulations; and a tele-immersion application, CAVERNsoft, in which the focus is on connecting multiple people to a distributed simulated world.

  20. OGSA Globus Toolkits evaluation activity at CERN

    CERN Document Server

    Chen, D; Foster, D; Kalyaev, V; Kryukov, A; Lamanna, M; Pose, V; Rocha, R; Wang, C

    2004-01-01

    An Open Grid Service Architecture (OGSA) Globus Toolkit 3 (GT3) evaluation group is active at CERN since GT3 was available in early beta version (Spring 2003). This activity focuses on the evaluation of the technology as promised by the OGSA/OGSI paradigm and on GT3 in particular. The goal is to study this new technology and its implications with the goal to provide useful input for the large grid initiatives active in the LHC Computing Grid (LCG) project. A particular effort has been devoted to investigate performance and deployment issues, having in mind the LCG requirements, in particular scalability and robustness.

  1. Radiologic evaluation of the globus symptom using videotape recorder

    International Nuclear Information System (INIS)

    Kim, Myeong Jin; Chung, Tae Sub; Lee, Jong Tae; Yoo, Hyung Sik; Suh, Jung Ho; Chang, Tae Young; Park, In Yong

    1988-01-01

    The authors examined barium swallow in 213 patients with globus symptom and 79 patients with vague gastric problems without globus symptom. Abnormal findings were more frequently detected on videorecording than on conventional esophagogram. Radiologic findings were transient cricopharyngeal indentation (CPI), residual barium collection and delayed clearing from hypopharynx (RB), laryngeal penetration of barium, barium retention in vallecula and or pyriform sinuses. Among them residual barium in hypopharynx was more frequently detected in patients with globus symptom than in patients without globus symptom. Globus symptom was more frequent in adult women, but age and sex difference did not affect the incidence of the abnormal radiologic findings. Cricopharyngeal indentation was most frequently seen at the level of C5-6 interspace and had a tendency of moving upward gradually during the indentation in about half of the cases. Most of the CPI was seen in early phase of swallowing and was visible within 1 sec. Residual barium collection was mostly seen in C6 or C6-7 level. RB had no cause and effect relationship with CPI, and it was not secondary result of obstructive effect of CPI. The authors think that videotape recording can be a useful method for evaluation of globus symptom. The residual barium collection in hypopharynx can be a significant finding in globus symptom

  2. Epiglottic cyst as an etiological factor of globus sensation.

    Science.gov (United States)

    Polat, Bahtiyar; Karahatay, Serdar; Gerek, Mustafa

    2015-09-01

    Globus is a subjective complaint that describes a sensation of a lump or a foreign body in the throat. Despite being a well-known and common clinical condition, the etiological factors have not been definitely elucidated yet. The study was set up to ascertain the relationship between epiglottic cysts and globus sensation. All patients undergoing investigation and treatments for globus sensation were included in the study. Patients with epiglottic cysts but no other possible causes of globus sensation were constituted the series of patients. Patients were asked to assess the levels of complaint before and after the carbon dioxide (CO2) laser excisions of the cysts. Epiglottic cysts were found in 10 (5.4%) of the 182 patients. Three of these 10 patients who had concomitant diseases or conditions that may cause globus sensation and one patient who refused the surgery were excluded from the study. All the remaining six patients reported relief of the globus sensation after the CO2 laser excisions of the cysts. Our results, obtained from this limited series, indicated that epiglottic cysts may be considered as one of the etiological factors of globus sensation.

  3. Reclassification of Geobacillus pallidus (Scholz et al. 1988) Banat et al. 2004 as Aeribacillus pallidus gen. nov., comb. nov.

    Science.gov (United States)

    Miñana-Galbis, David; Pinzón, Dora L; Lorén, J Gaspar; Manresa, Angels; Oliart-Ros, Rosa M

    2010-07-01

    Although Anoxybacillus and Geobacillus, two genera of thermophilic bacteria close to the genus Bacillus, have only been described recently, the number of species in these genera has increased rapidly. Four thermophilic, lipolytic strains (DR01, DR02, DR03 and DR04) isolated from a hot spring in Veracruz (Mexico), which could not be identified phenotypically, were subjected to 16S rRNA gene sequence analysis. Three strains were identified as belonging to the genus Anoxybacillus, but strain DR03 was identified as Geobacillus pallidus. This result led us to perform a phylogenetic analysis of the genera Anoxybacillus and Geobacillus based on 16S rRNA gene sequences from all the type strains of these genera. Phylogenetic trees showed three major clusters, Anoxybacillus-Geobacillus tepidamans, Geobacillus sensu stricto and Geobacillus pallidus, while the 16S rRNA gene sequences of G. pallidus (DR03 and the type strain) showed low similarity to sequences of Anoxybacillus (92.5-95.1 %) and Geobacillus (92.8-94.5 %) species, as well as to Bacillus subtilis (92.2-92.4 %). In addition, G. pallidus could be differentiated from Anoxybacillus and Geobacillus on the basis of DNA G+C content and fatty acid and polar lipid profiles. From these results, it is proposed that Geobacillus pallidus should be classified in a novel genus, for which we propose the name Aeribacillus, as Aeribacillus pallidus gen. nov., comb. nov. The type strain of Aeribacillus pallidus is H12(T) (=ATCC 51176(T) =DSM 3670(T) =LMG 19006(T)).

  4. A GridFTP transport driver for Globus XIO

    International Nuclear Information System (INIS)

    Kettimuthu, R.; Wantao, L.; Link, J.; Bresnahan, J.

    2008-01-01

    GridFTP is a high-performance, reliable data transfer protocol optimized for high-bandwidth wide-area networks. Based on the Internet FTP protocol, it defines extensions for high-performance operation and security. The Globus implementation of GridFTP provides a modular and extensible data transfer system architecture suitable for wide area and high-performance environments. GridFTP is the de facto standard in projects requiring secure, robust, high-speed bulk data transport. For example, the high energy physics community is basing its entire tiered data movement infrastructure for the Large Hadron Collider computing Grid on GridFTP; the Laser Interferometer Gravitational Wave Observatory routinely uses GridFTP to move 1 TB a day during production runs; and GridFTP is the recommended data transfer mechanism to maximize data transfer rates on the TeraGrid. Commonly used GridFTP clients include globus-url-copy, uberftp, and the Globus Reliable File Transfer service. In this paper, we present a Globus XIO based client to GridFTP that provides a simple Open/Close/Read/Write (OCRW) interface to the users. Such a client greatly eases the addition of GridFTP support to third-party programs, such as SRB and MPICH-G2. Further, this client provides an easier and familiar interface for applications to efficiently access remote files. We compare the performance of this client with that of globus-url-copy on multiple endpoints in the TeraGrid infrastructure. We perform both memory-to-memory and disk-to-disk transfers and show that the performance of this OCRW client is comparable to that of globus-url-copy. We also show that our GridFTP client significantly outperforms the GPFS WAN on the TeraGrid.

  5. Globus Platform-as-a-Service for Collaborative Science Applications.

    Science.gov (United States)

    Ananthakrishnan, Rachana; Chard, Kyle; Foster, Ian; Tuecke, Steven

    2015-02-01

    Globus, developed as Software-as-a-Service (SaaS) for research data management, also provides APIs that constitute a flexible and powerful Platform-as-a-Service (PaaS) to which developers can outsource data management activities such as transfer and sharing, as well as identity, profile and group management. By providing these frequently important but always challenging capabilities as a service, accessible over the network, Globus PaaS streamlines web application development and makes it easy for individuals, teams, and institutions to create collaborative applications such as science gateways for science communities. We introduce the capabilities of this platform and review representative applications.

  6. stableGP

    Data.gov (United States)

    National Aeronautics and Space Administration — The code in the stableGP package implements Gaussian process calculations using efficient and numerically stable algorithms. Description of the algorithms is in the...

  7. Globus Identity, Access, and Data Management: Platform Services for Collaborative Science

    Science.gov (United States)

    Ananthakrishnan, R.; Foster, I.; Wagner, R.

    2016-12-01

    Globus is software-as-a-service for research data management, developed at, and operated by, the University of Chicago. Globus, accessible at www.globus.org, provides high speed, secure file transfer; file sharing directly from existing storage systems; and data publication to institutional repositories. 40,000 registered users have used Globus to transfer tens of billions of files totaling hundreds of petabytes between more than 10,000 storage systems within campuses and national laboratories in the US and internationally. Web, command line, and REST interfaces support both interactive use and integration into applications and infrastructures. An important component of the Globus system is its foundational identity and access management (IAM) platform service, Globus Auth. Both Globus research data management and other applications use Globus Auth for brokering authentication and authorization interactions between end-users, identity providers, resource servers (services), and a range of clients, including web, mobile, and desktop applications, and other services. Compliant with important standards such as OAuth, OpenID, and SAML, Globus Auth provides mechanisms required for an extensible, integrated ecosystem of services and clients for the research and education community. It underpins projects such as the US National Science Foundation's XSEDE system, NCAR's Research Data Archive, and the DOE Systems Biology Knowledge Base. Current work is extending Globus services to be compliant with FEDRAMP standards for security assessment, authorization, and monitoring for cloud services. We will present Globus IAM solutions and give examples of Globus use in various projects for federated access to resources. We will also describe how Globus Auth and Globus research data management capabilities enable rapid development and low-cost operations of secure data sharing platforms that leverage Globus services and integrate them with local policy and security.

  8. Deploying HEP applications using Xen and Globus Virtual Workspaces

    International Nuclear Information System (INIS)

    Agarwal, A; Desmarais, R; Gable, I; Grundy, D; P-Brown, D; Seuster, R; Vanderster, D C; Sobie, R; Charbonneau, A; Enge, R

    2008-01-01

    The deployment of HEP applications in heterogeneous grid environments can be challenging because many of the applications are dependent on specific OS versions and have a large number of complex software dependencies. Virtual machine monitors such as Xen could be used to package HEP applications, complete with their execution environments, to run on resources that do not meet their operating system requirements. Our previous work has shown HEP applications running within Xen suffer little or no performance penalty as a result of virtualization. However, a practical strategy is required for remotely deploying, booting, and controlling virtual machines on a remote cluster. One tool that promises to overcome the deployment hurdles using standard grid technology is the Globus Virtual Workspaces project. We describe strategies for the deployment of Xen virtual machines using Globus Virtual Workspace middleware that simplify the deployment of HEP applications

  9. Monitoring the grid with the Globus Toolkit MDS4

    International Nuclear Information System (INIS)

    Schopf, Jennifer M; Pearlman, Laura; Miller, Neill; Kesselman, Carl; Foster, Ian; D'Arcy, Mike; Chervenak, Ann

    2006-01-01

    The Globus Toolkit Monitoring and Discovery System (MDS4) defines and implements mechanisms for service and resource discovery and monitoring in distributed environments. MDS4 is distinguished from previous similar systems by its extensive use of interfaces and behaviors defined in the WS-Resource Framework and WS-Notification specifications, and by its deep integration into essentially every component of the Globus Toolkit. We describe the MDS4 architecture and the Web service interfaces and behaviors that allow users to discover resources and services, monitor resource and service states, receive updates on current status, and visualize monitoring results. We present two current deployments to provide insights into the functionality that can be achieved via the use of these mechanisms

  10. New results from Globus-M spherical tokamak

    International Nuclear Information System (INIS)

    Gusev, V.K.

    2002-01-01

    New results from Globus-M spherical tokamak (ST) are presented. Reported are the achievements of high plasma current of 0.36 MA and high toroidal magnetic field of 0.55 T. Plasma column stability in Globus-M is conserved at low edge safety factors and high plasma densities. Achieved lowest safety factor was q(cyl) 19 m -3 . New methods of density increase are discussed. Low-density boarder of operational space is investigated. Runaway electrons properties and conditions of their generation are investigated. Results look promising for STs. Plasma-wall interaction study was performed. Silicon probes were installed into vacuum vessel. They were exposed to boronization, first, and then deposited film interacted with plasma. Discussed are film properties. Briefly described are new diagnostic tools installed on tokamak. Status and preliminary results obtained with auxiliary heating systems are shown. (author)

  11. [Use of high frequency cinematography in diagnosis of globus sensation].

    Science.gov (United States)

    Alberty, J; Oelerich, M

    1996-09-01

    Globus pharyngis is a frequent symptom in patients who consult an otolaryngologist. In many cases, routine diagnostic work-up including history, clinical examination, and barium swallow fail to revealing the underlying pathogenesis. In a retrospective study, we present 51 selected patients suffering from globus pharyngis of unknown origin who were investigated by high-speed cineradiography in a standardized manner. Twenty-four of the patients enrolled in the study (47.1%) showed functional and/or structural swallowing disorders. In 13 cases (25.5%) dyskinesias of the superior esophagus sphincter muscle were found. Five of these patients (9.8%) also had an inconstant hypopharyngeal diverticulum. Six cases (11.8%) showed laryngeal penetration or tracheal aspiration. In four cases (7.8%) functional disorders of pharyngeal, and in three cases (5.9%) functional disorders of oral bolus transport were found. Furthermore one hypopharyngeal web (1.9%) and two benign tumors (3.9%) were detected. In many cases, varying combinations of these findings occurred. Using high-speed cineradiography for evaluation of globus pharyngis results in an increased incidence of pathologic findings, and thus is an important method for interdisciplinary diagnostic work up of patients suffering from this symptom.

  12. Globus Online: Climate Data Management for Small Teams

    Science.gov (United States)

    Ananthakrishnan, R.; Foster, I.

    2013-12-01

    Large and highly distributed climate data demands new approaches to data organization and lifecycle management. We need, in particular, catalogs that can allow researchers to track the location and properties of large numbers of data files, and management tools that can allow researchers to update data properties and organization during their research, move data among different locations, and invoke analysis computations on data--all as easily as if they were working with small numbers of files on their desktop computer. Both catalogs and management tools often need to be able to scale to extremely large quantities of data. When developing solutions to these problems, it is important to distinguish between the needs of (a) large communities, for whom the ability to organize published data is crucial (e.g., by implementing formal data publication processes, assigning DOIs, recording definitive metadata, providing for versioning), and (b) individual researchers and small teams, who are more frequently concerned with tracking the diverse data and computations involved in what highly dynamic and iterative research processes. Key requirements in the latter case include automated data registration and metadata extraction, ease of update, close-to-zero management overheads (e.g., no local software install); and flexible, user-managed sharing support, allowing read and write privileges within small groups. We describe here how new capabilities provided by the Globus Online system address the needs of the latter group of climate scientists, providing for the rapid creation and establishment of lightweight individual- or team-specific catalogs; the definition of logical groupings of data elements, called datasets; the evolution of catalogs, dataset definitions, and associated metadata over time, to track changes in data properties and organization as a result of research processes; and the manipulation of data referenced by catalog entries (e.g., replication of a dataset to

  13. Microsoft Dynamics GP 2013 implementation

    CERN Document Server

    Yudin, Victoria

    2013-01-01

    A step-by-step guide for planning and carrying out your Microsoft Dynamics GP 2013 implementation. Detailed descriptions and illustrations of setup screens and practical examples and advice are included for the Dynamics GP system and core modules.If you are a new or existing Microsoft Dynamics GP consultant or an end user who wants to implement, install, and set up core modules of Dynamics GP 2013, then this book is for you. A basic understanding of business management systems and either Dynamics GP or a similar application is recommended.

  14. Characterization of Thermophilic Halotolerant Aeribacillus pallidus TD1 from Tao Dam Hot Spring, Thailand

    Directory of Open Access Journals (Sweden)

    Somchai Santiwatanakul

    2011-08-01

    Full Text Available The bacterial strain TD1 was isolated from Tao Dam hot spring in Thailand. Strain TD1 was Gram positive, rod-shaped, aerobic, motile, and endospore forming. The cell was 2.0–40 mm in length and about 0.4 mm in diameter. The optimum growth occurred at 55–60 °C and at pH 7–8. Strain TD1 was able to grow on medium containing up to 10% NaCl. The DNA G+C content was 38.9 mol%. The cellular fatty acid content was mainly C16:0, which comprised 25.04% of the total amount of cellular fatty acid. 16S rDNA showed 99% identity to Aeribacillus pallidus DSM 3670T. Bayesian tree analysis strongly supported the idea that strain TD1 is affiliated with genus Aeribacillus, as Aeribacillus pallidus strain TD1. Although the 16S rDNA of A. pallidus strain TD1 is similar to that of A. pallidus DSM 3670T, some physiological properties and the cellular fatty acid profiles differ significantly. A. pallidus strain TD1 can produce extracellular pectate lyase, which has not been reported elsewhere for other bacterial strains in the genus Aeribacillus. A. pallidus strain TD1 may be a good candidate as a pectate lyase producer, which may have useful industrial applications.

  15. Characterization of thermophilic halotolerant Aeribacillus pallidus TD1 from Tao Dam Hot Spring, Thailand.

    Science.gov (United States)

    Yasawong, Montri; Areekit, Supatra; Pakpitchareon, Arda; Santiwatanakul, Somchai; Chansiri, Kosum

    2011-01-01

    The bacterial strain TD1 was isolated from Tao Dam hot spring in Thailand. Strain TD1 was Gram positive, rod-shaped, aerobic, motile, and endospore forming. The cell was 2.0-40 μm in length and about 0.4 μm in diameter. The optimum growth occurred at 55-60 °C and at pH 7-8. Strain TD1 was able to grow on medium containing up to 10% NaCl. The DNA G+C content was 38.9 mol%. The cellular fatty acid content was mainly C(16:0), which comprised 25.04% of the total amount of cellular fatty acid. 16S rDNA showed 99% identity to Aeribacillus pallidus DSM 3670(T). Bayesian tree analysis strongly supported the idea that strain TD1 is affiliated with genus Aeribacillus, as Aeribacillus pallidus strain TD1. Although the 16S rDNA of A. pallidus strain TD1 is similar to that of A. pallidus DSM 3670(T), some physiological properties and the cellular fatty acid profiles differ significantly. A. pallidus strain TD1 can produce extracellular pectate lyase, which has not been reported elsewhere for other bacterial strains in the genus Aeribacillus. A. pallidus strain TD1 may be a good candidate as a pectate lyase producer, which may have useful industrial applications.

  16. New results from the Globus-M spherical tokamak

    International Nuclear Information System (INIS)

    Gusev, V.K.; Ananiev, A.S.; Amoskov, V.M.

    2003-01-01

    New results from the Globus-M spherical tokamak are presented. High plasma current of 0.36 MA, high toroidal magnetic field of 0.55 T and other important plasma characteristics were achieved. Described are the operational space and plasma stability limits in the OH regime. The factors limiting operational space (MHD instabilities, runaway electrons, etc.) are discussed. New experiments on plasma fuelling are described. First results of experiments with a coaxial plasma gun injector are presented. Initial results of a plasma - wall interaction study are outlined. First results obtained with new diagnostic tools installed on the tokamak are presented. An auxiliary heating system test was performed. Preliminary results of simulations and experiments are given. (author)

  17. The increased risk of globus pharyngeus in patients with chronic thyroiditis: a case control study.

    Science.gov (United States)

    Karahatay, S; Ayan, A; Aydin, U; Ince, S; Emer, O; Alagoz, E

    2015-12-01

    A correlation between globus pharyngeus and thyroid gland inflammation has been mentioned in previous studies. However, the potential risk of globus pharyngeus in chronic thyroiditis patients has not been shown so far. The aim of this study is to investigate a possible association between chronic thyroiditis and globus pharyngeus. The study was performed in an ultrasound (US) center of a tertiary health care institution. Ninety-two patients who were under examination for suspected thyroid pathologies or undergoing follow-up for a previously diagnosed thyroid disease were enrolled in the study. The patients were divided into two groups according to the existence of globus symptoms. Subsequently, all patients underwent high-resolution thyroid ultrasounds. The patients whose ultrasound findings were suggestive of chronic thyroiditis constituted the second subgroup. The demographic data of the patients and other ultrasound findings including the volume of the thyroid glands and nodules, if any, were noted as well. Sixty-seven female (73%) and 25 male (27%) patients were enrolled in the study. Thirty-two (35%) of the 92 patients constituted the globus pharyngeus group according to their responses to the questionnaire and the US findings were concordant with chronic thyroiditis in 36 (39%) patients. The correlation between chronic thyroiditis and globus sensation was significant (p = 0.004), and the odds ratio was calculated as 3.7 (95% CI = 1.5-9.11). Other parameters including age, sex, thyroid volume and nodule status were not significantly related to globus pharyngeus in this particular patient series. In the presented study, the risk of globus pharyngeus occurrence was calculated as 3.7-fold higher in patients with chronic thyroiditis. Being a preliminary report, it is necessary to confirm this finding and understand the pathophysiological mechanism via further investigations with a larger patient series.

  18. Psychosocial factors in GP work: the effects of taking a GP position or leaving GP work.

    Science.gov (United States)

    Heponiemi, Tarja; Kouvonen, Anne; Aalto, Anna-Mari; Elovainio, Marko

    2013-06-01

    We examined the effects of leaving public sector general practitioner (GP) work and of taking a GP position on changes in work-related psychosocial factors, such as time pressure, patient-related stress, distress and work interference with family. In addition, we examined whether changes in time pressure and patient-related stress mediated the association of employment change with changes of distress and work interference with family. Participants were 1705 Finnish physicians (60% women) who responded to surveys in 2006 and 2010. Analyses of covariance were conducted to examine the effect of employment change to outcome changes adjusted for gender, age and response format. Mediational effects were tested following the procedures outlined by Baron and Kenny. Employment change was significantly associated with all the outcomes. Leaving public sector GP work was associated with substantially decreased time pressure, patient-related stress, distress and work interference with family. In contrast, taking a position as a public sector GP was associated with an increase in these factors. Mediation tests suggested that the associations of employment change with distress change and work interference with family change were partially explained by the changes in time pressure and patient-related stress. Our results showed that leaving public sector GP work is associated with favourable outcomes, whereas taking a GP position in the public sector is associated with adverse effects. Primary health-care organizations should pay more attention to the working conditions of their GPs, in particular, to time pressure and patient-related stress.

  19. Structural and biochemical characterization of a nitrilase from the thermophilic bacterium, Geobacillus pallidus RAPc8

    CSIR Research Space (South Africa)

    Williamson, DS

    2010-09-01

    Full Text Available . In common with the plant nitrilases, the recombinant G. pallidus RAPc8 enzyme produced both acid and amide products from nitrile substrates. Electron microscopy and image classification showed complexes having crescentlike, “c-shaped”, circular and “figure...

  20. Esophageal Sensorimotor Function and Psychological Factors Each Contribute to Symptom Severity in Globus Patients.

    Science.gov (United States)

    Rommel, Nathalie; Van Oudenhove, Lukas; Arts, Joris; Caenepeel, Philip; Tack, Jan; Pauwels, Ans

    2016-10-01

    Altered upper esophageal sphincter (UES) and esophageal body (EB) sensorimotor function and psychosocial factors may both be involved in symptom generation in globus, but their common impact is not yet assessed. The aim of the study is (1) to compare UES and EB sensitivity and compliance of globus patients with healthy controls (HC); (2) to study the association of globus symptom severity (GSS) with UES and EB sensitivity and compliance, UES motor function and psychosocial factors. In 58 globus patients, GSS, somatization, and anxiety disorders were determined using validated questionnaires. In 26 HC and 42/58 patients, UES and EB sensitivity and compliance were assessed twice using barostat measurements. UES function of 27 globus patients was evaluated using high-resolution manometry. Bivariate correlations and a general linear model tested the association of these factors with GSS. UES and EB compliance did not differ between globus patients and HC. Upon repeated distension, UES habituation was seen in both groups, whereas EB sensitization (23.3±1.3 vs. 19.5±1.5 mm Hg, Pdisorder (t=3.04, P=0.004), and post-traumatic stress severity (ρ=0.40, P=0.005) were associated with GSS. UES compliance and somatization were independently associated with GSS. A trend (P=0.061) was found for the association of GSS with change in EB compliance. UES compliance, change in EB compliance, and somatization explain 40% of the variance in GSS. This indicates that globus is a complex disorder of the brain-gut axis rather than a "psychosomatic" disorder or a peripheral esophageal disorder.

  1. GeoDataspaces: Simplifying Data Management Tasks with Globus

    Science.gov (United States)

    Malik, T.; Chard, K.; Tchoua, R. B.; Foster, I.

    2014-12-01

    Data and its management are central to modern scientific enterprise. Typically, geoscientists rely on observations and model output data from several disparate sources (file systems, RDBMS, spreadsheets, remote data sources). Integrated data management solutions that provide intuitive semantics and uniform interfaces, irrespective of the kind of data source are, however, lacking. Consequently, geoscientists are left to conduct low-level and time-consuming data management tasks, individually, and repeatedly for discovering each data source, often resulting in errors in handling. In this talk we will describe how the EarthCube GeoDataspace project is improving this situation for seismologists, hydrologists, and space scientists by simplifying some of the existing data management tasks that arise when developing computational models. We will demonstrate a GeoDataspace, bootstrapped with "geounits", which are self-contained metadata packages that provide complete description of all data elements associated with a model run, including input/output and parameter files, model executable and any associated libraries. Geounits link raw and derived data as well as associating provenance information describing how data was derived. We will discuss challenges in establishing geounits and describe machine learning and human annotation approaches that can be used for extracting and associating ad hoc and unstructured scientific metadata hidden in binary formats with data resources and models. We will show how geounits can improve search and discoverability of data associated with model runs. To support this model, we will describe efforts related towards creating a scalable metadata catalog that helps to maintain, search and discover geounits within the Globus network of accessible endpoints. This talk will focus on the issue of creating comprehensive personal inventories of data assets for computational geoscientists, and describe a publishing mechanism, which can be used to

  2. Association between swallow perception and esophageal bolus clearance in patients with globus sensation.

    Science.gov (United States)

    Chen, Chien-Lin; Yi, Chih-Hsun; Liu, Tso-Tsai

    2013-04-01

    Globus sensation is common, but its pathogenesis is not yet clear. Our purpose was to investigate subjective perception of swallowing and esophageal motility by combined multichannel intraluminal impedance and manometry (MII-EM) for patients with globus sensation. Combined MII-EM was performed for 25 globus patients and 15 healthy controls. Swallows were abnormal if hypocontractivity or simultaneous contractions occurred. Esophageal bolus transit was incomplete if bolus exit was not found at one or more of all measurement sites. Perception of each swallow was assessed by use of a standardized scoring system, and was enhanced if the score was >1. Few globus patients reported enhanced perception during viscous or solid swallows. Incomplete bolus transit and enhanced perception occurred similarly between viscous and solid boluses. Agreement between enhanced perception and proximal bolus clearance was greater during solid swallows (κ = 0.45, 95 % CI: 0.32-0.58) than during viscous swallows (κ = 0.13, 95 % CI: 0-0.25) (P perception and total bolus clearance was greater during solid swallows (κ = 0.46, 95 % CI: 0.34-0.58) than during viscous swallows (κ = 0.11, 95 % CI: 0-0.22) (P perception is uncommon in patients with globus sensation, although there is a significant association between enhanced esophageal perception and solid bolus clearance. Application of a solid bolus may help better delineation of the interrelationship between the subjective perception of bolus passage and the objective measurement of bolus clearance.

  3. Globus Nexus: A Platform-as-a-Service Provider of Research Identity, Profile, and Group Management.

    Science.gov (United States)

    Chard, Kyle; Lidman, Mattias; McCollam, Brendan; Bryan, Josh; Ananthakrishnan, Rachana; Tuecke, Steven; Foster, Ian

    2016-03-01

    Globus Nexus is a professionally hosted Platform-as-a-Service that provides identity, profile and group management functionality for the research community. Many collaborative e-Science applications need to manage large numbers of user identities, profiles, and groups. However, developing and maintaining such capabilities is often challenging given the complexity of modern security protocols and requirements for scalable, robust, and highly available implementations. By outsourcing this functionality to Globus Nexus, developers can leverage best-practice implementations without incurring development and operations overhead. Users benefit from enhanced capabilities such as identity federation, flexible profile management, and user-oriented group management. In this paper we present Globus Nexus, describe its capabilities and architecture, summarize how several e-Science applications leverage these capabilities, and present results that characterize its scalability, reliability, and availability.

  4. The role of transnasal oesophagoscopy in the management of globus pharyngeus and non-progressive dysphagia.

    Science.gov (United States)

    Sanyaolu, L N; Jemah, A; Stew, B; Ingrams, D R

    2016-01-01

    Introduction Transnasal oesophagoscopy is a relatively new method of examining the upper aerodigestive tract via the nasal passage as an outpatient procedure without the need for sedation. It has been shown to be a well tolerated, safe and accurate technique, that can therefore be used in the investigation of patients thought to have globus pharyngeus and other non sinister causes of dysphagia. Methods A total of 150 consecutive patients undergoing transnasal oesophagoscopy were analysed retrospectively. Results The main indications for this procedure were non-progressive dysphagia (n=68, 45%) and globus pharyngeus (n=60, 40%). Transnasal oesophagoscopy was normal in 65% of patients and 42% of patients were discharged from clinic at the same appointment with no further investigation. The most common positive findings were laryngeal erythema (13%) and oesophagitis (10%). Conclusions Transnasal oesophagoscopy is a useful adjunct to the management of patients with the symptoms of globus pharyngeus and non-progressive dysphagia.

  5. Globus Nexus: A Platform-as-a-Service provider of research identity, profile, and group management

    Energy Technology Data Exchange (ETDEWEB)

    Chard, Kyle; Lidman, Mattias; McCollam, Brendan; Bryan, Josh; Ananthakrishnan, Rachana; Tuecke, Steven; Foster, Ian

    2016-03-01

    Globus Nexus is a professionally hosted Platform-as-a-Service that provides identity, profile and group management functionality for the research community. Many collaborative e-Science applications need to manage large numbers of user identities, profiles, and groups. However, developing and maintaining such capabilities is often challenging given the complexity of modern security protocols and requirements for scalable, robust, and highly available implementations. By outsourcing this functionality to Globus Nexus, developers can leverage best-practice implementations without incurring development and operations overhead. Users benefit from enhanced capabilities such as identity federation, flexible profile management, and user-oriented group management. In this paper we present Globus Nexus, describe its capabilities and architecture, summarize how several e-Science applications leverage these capabilities, and present results that characterize its scalability, reliability, and availability.

  6. Structures of Ebola virus GP and sGP in complex with therapeutic antibodies.

    Science.gov (United States)

    Pallesen, Jesper; Murin, Charles D; de Val, Natalia; Cottrell, Christopher A; Hastie, Kathryn M; Turner, Hannah L; Fusco, Marnie L; Flyak, Andrew I; Zeitlin, Larry; Crowe, James E; Andersen, Kristian G; Saphire, Erica Ollmann; Ward, Andrew B

    2016-08-08

    The Ebola virus (EBOV) GP gene encodes two glycoproteins. The major product is a soluble, dimeric glycoprotein (sGP) that is secreted abundantly. Despite the abundance of sGP during infection, little is known regarding its structure or functional role. A minor product, resulting from transcriptional editing, is the transmembrane-anchored, trimeric viral surface glycoprotein (GP). GP mediates attachment to and entry into host cells, and is the intended target of antibody therapeutics. Because large portions of sequence are shared between GP and sGP, it has been hypothesized that sGP may potentially subvert the immune response or may contribute to pathogenicity. In this study, we present cryo-electron microscopy structures of GP and sGP in complex with GP-specific and GP/sGP cross-reactive antibodies undergoing human clinical trials. The structure of the sGP dimer presented here, in complex with both an sGP-specific antibody and a GP/sGP cross-reactive antibody, permits us to unambiguously assign the oligomeric arrangement of sGP and compare its structure and epitope presentation to those of GP. We also provide biophysical evaluation of naturally occurring GP/sGP mutations that fall within the footprints identified by our high-resolution structures. Taken together, our data provide a detailed and more complete picture of the accessible Ebolavirus glycoprotein landscape and a structural basis to evaluate patient and vaccine antibody responses towards differently structured products of the GP gene.

  7. Studies on the clinical significance of pallidal high intensity of T1-weighted MR imaging in patients with liver cirrhosis

    International Nuclear Information System (INIS)

    Morino, Koutaro

    1997-01-01

    We investigated the clinical significances of signals in cirrhotic patients with special relation to subclinical hepatic encephalopathy. MRI was carried out in 30 patients with liver cirrhosis in the abscence of hepatic encephalopathy greater than grade II, and in 20 healthy subjects. Signal intensity of the globus pallidus was standardized to GP index. GP index=100 x (signal intensity of the globus pallidus - signal intensity of the putamen)/(signal intensity of the globus pallidus + signal intensity of the putamen). Normal value of GP index obtained in healthy subjects was -0.66∼4.70. Twenty seven of 30 cirrhotic patients showed GP index higher than the normal range. GP index correlated significantly with the blood manganese concentration. This observation suggested that the pallidal high intensity signals were brought about by the deposition of Mn in the globus pallidus. GP index correlated significantly with the central conduction time (CCT) measured by somatosensory evoked potentials. GP index and CCT may reflect the similar pathophysiological changes of the brain in patients with liver cirrhosis. Multivariate analysis revealed that GP index was explained well by the presence of portal systemic shunts and by preceding histories of hepatic encephalopathy but not by the present grade of the liver parenchymal damage. For the earlier diagnosis of subclinical hepatic encephalopathy, GP index showed an excellent parameter similar to those of somatosensory evoked potentials and psychometric tests. GP index is favorable than electrophysiological methods in terms of its non-invasiveness to the patients and simplicity of the examination technique. (K.H.)

  8. Studies on the clinical significance of pallidal high intensity of T{sub 1}-weighted MR imaging in patients with liver cirrhosis

    Energy Technology Data Exchange (ETDEWEB)

    Morino, Koutaro [Gifu Univ. (Japan). School of Medicine

    1997-03-01

    We investigated the clinical significances of signals in cirrhotic patients with special relation to subclinical hepatic encephalopathy. MRI was carried out in 30 patients with liver cirrhosis in the abscence of hepatic encephalopathy greater than grade II, and in 20 healthy subjects. Signal intensity of the globus pallidus was standardized to GP index. GP index=100 x (signal intensity of the globus pallidus - signal intensity of the putamen)/(signal intensity of the globus pallidus + signal intensity of the putamen). Normal value of GP index obtained in healthy subjects was -0.66{approx}4.70. Twenty seven of 30 cirrhotic patients showed GP index higher than the normal range. GP index correlated significantly with the blood manganese concentration. This observation suggested that the pallidal high intensity signals were brought about by the deposition of Mn in the globus pallidus. GP index correlated significantly with the central conduction time (CCT) measured by somatosensory evoked potentials. GP index and CCT may reflect the similar pathophysiological changes of the brain in patients with liver cirrhosis. Multivariate analysis revealed that GP index was explained well by the presence of portal systemic shunts and by preceding histories of hepatic encephalopathy but not by the present grade of the liver parenchymal damage. For the earlier diagnosis of subclinical hepatic encephalopathy, GP index showed an excellent parameter similar to those of somatosensory evoked potentials and psychometric tests. GP index is favorable than electrophysiological methods in terms of its non-invasiveness to the patients and simplicity of the examination technique. (K.H.)

  9. Production and characterization of a new antibacterial peptide obtained from Aeribacillus pallidus SAT4

    OpenAIRE

    Muhammad, Syed Aun; Ahmed, Safia

    2015-01-01

    A novel thermophilic bacterial strain of the genus Aeribacillus was isolated from Thar Dessert Pakistan. This strain showed significant antibacterial activity against Micrococcus luteus, Staphylococcus aureus, and Pseudomonas aeruginosa. The strain coded as ‘SAT4’ resembled with Aeribacillus pallidus in the morphological, biochemical and molecular tests. The production of antibacterial metabolites by SAT4 was optimized. These active metabolites were precipitated by 50% ammonium sulphate and p...

  10. Characterization and emulsifying property of a novel bioemulsifier by Aeribacillus pallidus YM-1.

    Science.gov (United States)

    Zheng, C; Li, Z; Su, J; Zhang, R; Liu, C; Zhao, M

    2012-07-01

      Biosurfactants and bioemulsifiers commonly have the advantages of biodegradability, low toxicity, selectivity and biocompatibility over chemically synthesized surfactants. The goal of the study is to present a novel bioemulsifier with great application potential.   Aeribacillus pallidus YM-1, isolated from crude oil contaminated soil, was found to produce a novel high molecular bioemulsifier with an emulsification index of 60 ± 1% without remarkable surface tension reduction (45·7 ± 0·1 mN m(-1) ). The number-average molecular weight was determined as 526 369 Da by gel permeation chromatography analysis. Bioemulsifier was subjected to FT-IR and a complex of carbohydrates (41·1%), lipids (47·6%) and proteins (11·3%) was determined.   The bioemulsifier of A. pallidus YM-1 was isolated from the glucose-based culture medium and characterized with the help of chemical analytical techniques. The bioemulsifier exhibited a promising emulsifying property for biotechnology application potential in bioremediation and microbial enhanced oil recovery.   This is the first report of the bioemulsifier production by A. pallidus. The potential emulsifying activity of the bioemulsifier in the present study may be explored in various biotechnological and industrial applications. © 2012 The Authors. Journal of Applied Microbiology © 2012 The Society for Applied Microbiology.

  11. Biofilm characteristics and evaluation of the sanitation procedures of thermophilic Aeribacillus pallidus E334 biofilms.

    Science.gov (United States)

    Kilic, Tugba; Karaca, Basar; Ozel, Beste Piril; Ozcan, Birgul; Cokmus, Cumhur; Coleri Cihan, Arzu

    2017-04-01

    The ability of Aeribacillus pallidus E334 to produce pellicle and form a biofilm was studied. Optimal biofilm formation occurred at 60 °C, pH 7.5 and 1.5% NaCl. Extra polymeric substances (EPS) were composed of proteins and eDNA (21.4 kb). E334 formed biofilm on many surfaces, but mostly preferred polypropylene and glass. Using CLSM analysis, the network-like structure of the EPS was observed. The A. pallidus biofilm had a novel eDNA content. DNaseI susceptibility (86.8% removal) of eDNA revealed its importance in mature biofilms, but the purified eDNA was resistant to DNaseI, probably due to its extended folding outside the matrix. Among 15 cleaning agents, biofilms could be removed with alkaline protease and sodium dodecyl sulphate (SDS). The removal of cells from polypropylene and biomass on glass was achieved with combined SDS/alkaline protease treatment. Strong A. pallidus biofilms could cause risks for industrial processes and abiotic surfaces must be taken into consideration in terms of sanitation procedures.

  12. More than Just Fun and Games: BSG and Glo-Bus as Strategic Education Instruments

    Science.gov (United States)

    Karriker, Joy H.; Aaron, Joshua R.

    2014-01-01

    Simulations like the BSG and Glo-Bus allow students the opportunity to practice their integrated, strategic management skills in a relatively risk-free environment or "live case." We review these games and address their strengths, along with the challenges associated with their classroom application. Because of their sound designs and…

  13. Pathophysiology and treatment of patients with globus sensation ―from the viewpoint of esophageal motility dysfunction―

    Science.gov (United States)

    Manabe, Noriaki; Tsutsui, Hideaki; Kusunoki, Hiroaki; Hata, Jiro; Haruma, Ken

    2014-01-01

    "Globus sensation" is often described as the sensation of a lump in the throat associated with dry swallowing or the need for dry swallowing, which disappears completely during eating or drinking and for which no organic cause can be established. Due to the uncertain etiology of "globus sensation", it remains difficult to establish standard treatment strategies for affected patients. Lately most attention has been focused on gastroesophageal reflux disease and several reports have indicated that there is a close relationship between esophageal acid reflux and globus sensation. Nowadays, empirical therapy with a high dose of a proton pump inhibitor (PPI) is considered to be indicated for patients with globus sensation, after excluding organic diseases such as pharyngeal cancer, Zenker's diverticulum, or thyroid enlargement. If patients are nonresponsive to PPI therapy, evaluation of esophageal motility should be done. In our recent study, 47.9% had abnormal esophageal motility, with the most common esophageal motility abnormality being an ineffective esophageal motility in PPI-resistant patients with globus sensation. This suggests that prokinetics alone or adding prokinetics to PPI should be the treatment to be considered, although few studies have investigated the efficacy of prokinetics in the treatment of patients with globus sensation. If patients without any esophageal motility dysfunctions are nonresponsive to PPI therapy, either cognitive-behavioral therapy, anti-depressants, or gabapentin could be helpful, although further well-designed, randomized controlled large-scale studies will be necessary to determine the effectiveness of each treatment strategy on patients with globus sensation. PMID:26081369

  14. Microsoft Dynamics GP 2013 financial management

    CERN Document Server

    Grieve, Ian

    2013-01-01

    A standard tutorial-based approach covering Microsoft Dynamics GP 2013 and its six financial modules. The book is intended to allow users to improve their system use and workflow by introducing new modules to assist in financial management.This book is for you if you're a Dynamics GP partner, or Dynamics GP user, primarily focused on delivering application optimizations. This book assumes that you have a working knowledge of Microsoft Dynamics GP and have an understanding of the requirements of financial management.

  15. A prospective cohort-study of 122 adult patients presenting to an otolaryngologist's office with globus pharyngeus

    DEFF Research Database (Denmark)

    Rasmussen, Eva Rye; Schnack, Didde Traerup; Ravn, Andreas Tomaas

    2018-01-01

    OBJECTIVES: To investigate the epidemiology of globus pharyngeus in adult patients presenting to the otolaryngologist's office. Also the predictors of persisting symptoms, prevalence of anxiety and the effect of clinical assessment were analyzed. DESIGN: This was a prospective cohort study. Follow......-up was done using a postal questionnaire. SETTING: One otolaryngologists' office comprising three medical doctors. PARTICIPANTS: 122 consecutive globus patients presenting to one otolaryngology office in a one-year period. MAIN OUTCOME MEASURES: Globus incidence, gender- and age-distribution, predictors...... of persisting symptoms and the patient's health related concerns. RESULTS: 3.8% of first-time visits were regarding globus. The mean age was 48 years [range 20-88 y] and a female predominance was found (ratio 1.49). 84% experienced anxiety, mainly due to fear of cancer. The most common pathological findings...

  16. Plasma heating and fuelling in the Globus-M spherical tokamak

    International Nuclear Information System (INIS)

    Gusev, V.K.; Barsukov, A.G.; Belyakov, V.A.

    2005-01-01

    The results of the last two years of plasma investigations at Globus-M are presented. Described are improvements helping to achieve high performance OH plasmas, which are used as the target for auxiliary heating and fuelling experiments. Increased energy content, high beta poloidal and good confinement are reported. Experiments on NBI plasma heating with a wide range of plasma parameters were performed. Some results are presented and analyzed. Experiments on RF plasma heating in the frequency range of fundamental ion cyclotron harmonics are described. In some experiments which were performed for the first time in spherical tokamaks, promising results were achieved. Noticeable ion heating was recorded at low launched power and a high concentration of hydrogen minority in deuterium plasmas. Simulations of RF wave absorption are briefly discussed. Described also are modification of the plasma gun and test-stand experiments. Fuelling experiments performed at Globus-M are discussed. (author)

  17. Videofluoroscopy of the pharynx and esophagus in patients with globus pharyngis. Comparison with static radiography

    International Nuclear Information System (INIS)

    Schober, E.; Schima, W.; Pokieser, P.

    1995-01-01

    The symptom is associated with a multitude of pharyngoesophageal abnormalities. Our study compares the diagnostic yield of videofluoroscopy to that of static radiography in patients suffering from globus pharnygis. A total of 150 consecutive patients complaining of a lump in the throat, but without evidence of dysphagia, were studied in a standardized fashion with both methods. Videofluoroscopy combined with static radiography revealed morphological or functional abnormalities in 75% of our patients. The combination of the two methods yielded significantly more abnormalities in the pharynx and esophagus than videofluoroscopy or static radiography alone. Esophageal motor disorders, pharyngoesophageal sphincter dysfunction and pharyngeal residue of contrast material proved to be the most common abnormalities. In conclusion, videofluoroscopy combined with static radiography is mandatory in the radiological assessment of patients suffering from the globus sensation. (orig.) [de

  18. Using Globus GridFTP to Transfer and Share Big Data | Poster

    Science.gov (United States)

    By Ashley DeVine, Staff Writer, and Mark Wance, Guest Writer; photo by Richard Frederickson, Staff Photographer Transferring big data, such as the genomics data delivered to customers from the Center for Cancer Research Sequencing Facility (CCR SF), has been difficult in the past because the transfer systems have not kept pace with the size of the data. However, the situation is changing as a result of the Globus GridFTP project.

  19. Integration of Globus Online with the ATLAS PanDA Workload Management System

    CERN Document Server

    Contreras, C; The ATLAS collaboration; Maeno, T; Nilsson, P; Potekhin, M

    2012-01-01

    The PanDA Workload Management System is the basis for distributed production and analysis for the ATLAS experiment at the LHC. In this role, it relies on sophisticated dynamic data movement facilities developed in ATLAS. In certain scenarios, such as small research teams in ATLAS Tier-3 sites and non-ATLAS Virtual Organizations, the overhead of installation and operation of these components makes their use not very cost effective. Globus Online is an emerging new tool from the Globus Alliance, which already proved popular within the research community. It provides the users with fast and robust file transfer capabilities that can also be managed from a Web interface, and in addition to grid sites, can have individual workstations and laptops serving as data transmission endpoints. We will describe the integration of the Globus Online functionality into the PanDA suite of software, in order to give more flexibility in choosing the method of data transfer to ATLAS Tier-3 and OSG users.

  20. Integration of Globus Online with the ATLAS PanDA Workload Management System

    International Nuclear Information System (INIS)

    Contreras, C; Deng, W; Maeno, T; Potekhin, M; Nilsson, P

    2012-01-01

    The PanDA Workload Management System is the basis for distributed production and analysis for the ATLAS experiment at the LHC. In this role, it relies on sophisticated dynamic data movement facilities developed in ATLAS. In certain scenarios, such as small research teams in ATLAS Tier-3 sites and non-ATLAS Virtual Organizations, the overhead of installation and operation of these components makes their use not very cost effective. Globus Online is an emerging new tool from the Globus Alliance, which already proved popular within the research community. It provides the users with fast and robust file transfer capabilities that can also be managed from a Web interface, and in addition to grid sites, can have individual workstations and laptops serving as data transmission endpoints. We will describe the integration of the Globus Online functionality into the PanDA suite of software, in order to give more flexibility in choosing the method of data transfer to ATLAS Tier-3 and Open Science Grid (OSG) users.

  1. Plasma jet source parameter optimisation and experiments on injection into Globus-M spherical tokamak

    International Nuclear Information System (INIS)

    Gusev, V.K.; Petrov, Yu.V.; Sakharov, N.V.; Semenov, A.A.; Voronin, A.V.

    2005-01-01

    Results of theoretical and experimental research on the plasma sources and injection of plasma and gas jet produced by the modified source into tokamak Globus-M are presented. An experimental test stand was developed for investigation of intense plasma jet generation. Optimisation of pulsed coaxial accelerator parameters by means of analytical calculations is performed with the aim of achieving the highest flow velocity at limited coaxial electrode length and discharge current. The optimal parameters of power supply to generate a plasma jet with minimal impurity contamination and maximum flow velocity were determined. A comparison of experimental and calculation results is made. Plasma jet parameters are measured, such as: impurity species content, pressure distribution across the jet, flow velocity, plasma density, etc. Experiments on the interaction of a higher kinetic energy plasma jet with the magnetic field and plasma of the Globus-M tokamak were performed. Experimental results on plasma and gas jet injection into different Globus-M discharge phases are presented and discussed. Results are presented on the investigation of plasma jet injection as the source for discharge breakdown, plasma current startup and initial density rise. (author)

  2. Role of transnasal flexible laryngo-oesophagoscopy (TNFLO) in investigating patients with globus symptoms.

    Science.gov (United States)

    Mohammed, H; Coates, M; Masterson, L; Chan, W Y; Hassan, Y; Nassif, R

    2017-12-01

    To explore the rationale for investigating patients presenting with globus symptoms. In this regard, we also assess the efficacy and safety of transnasal flexible laryngo-oesophagoscopy (TNFLO). A prospective study in a head and neck cancer centre of patients with persistent globus symptoms with normal flexible nasoendoscopy/indirect mirror laryngoscopy and failure of first-line medical treatment. The role of TNFLO in investigating these patients was assessed. A total of 218 patients were recruited in this study. Positive findings included upper aerodigestive cancers in two patients, other pathologies included reflux (four patients), cricopharyngeus-related pathologies (19 patients), candida (five patients). There were only five re-referrals of patients who were discharged following normal examination with TNFLO. In nine patients, TNFLO could not be completed and they went on to have other diagnostic procedures CONCLUSION: This article is the largest to date in the UK to assess the role of TNFLO in investigating patients with globus symptoms. TNFLO is equal to rigid endoscopy as a diagnostic tool. However, it is superior in terms of image clarity, ability to record video images and safety. © 2017 John Wiley & Sons Ltd.

  3. Production and properties of two novel exopolysaccharides synthesized by a thermophilic bacterium Aeribacillus pallidus 418.

    Science.gov (United States)

    Radchenkova, Nadja; Vassilev, Spasen; Panchev, Ivan; Anzelmo, Gianluca; Tomova, Iva; Nicolaus, Barbara; Kuncheva, Margarita; Petrov, Kaloyan; Kambourova, Margarita

    2013-09-01

    Synthesis of innovative exocellular polysaccharides (EPSs) was reported for few thermophilic microorganisms as one of the mechanisms for surviving at high temperature. Thermophilic aerobic spore-forming bacteria able to produce exopolysaccharides were isolated from hydrothermal springs in Bulgaria. They were referred to four species, such as Aeribacillus pallidus, Geobacillus toebii, Brevibacillus thermoruber, and Anoxybacillus kestanbolensis. The highest production was established for the strain 418, whose phylogenetic and phenotypic properties referred it to the species A. pallidus. Maltose and NH4Cl were observed to be correspondingly the best carbon and nitrogen sources and production yield was increased more than twofold in the process of culture condition optimization. After purification of the polymer fraction, a presence of two different EPSs, electroneutral EPS 1 and negatively charged EPS 2, in a relative weight ratio 3:2.2 was established. They were heteropolysaccharides consisting of unusual high variety of sugars (six for EPS 1 and seven for EPS 2). Six of the sugars were common for both EPSs. The main sugar in EPS 1 was mannose (69.3 %); smaller quantities of glucose (11.2 %), galactosamine (6.3 %), glucosamine (5.4 %), galactose (4.7 %), and ribose (2.9 %) were also identified. The main sugar in EPS 2 was also mannose (33.9 %), followed by galactose (17.9 %), glucose (15.5 %), galactosamine (11.7 %), glucosamine (8.1 %), ribose (5.3 %), and arabinose (4.9 %). Both polymers showed high molecular weight and high thermostability.

  4. On πgp-continuous functions in topological spaces

    International Nuclear Information System (INIS)

    Park, Jin Han; Park, Jin Keun

    2004-01-01

    The concept of πgp-closed sets was introduced by Park [On πgp-closed sets in topological spaces, Indian J. Pure Appl. Math., in press]. The aim of this paper is to consider and characterize πgp-irresolute and πgp-continuous functions via the concept of πgp-closed sets and to relate these concepts to the classes of πGPO-compact spaces and πGP-connected spaces

  5. DNA-binding properties of the Bacillus subtilis and Aeribacillus pallidus AC6 σ(D) proteins.

    Science.gov (United States)

    Sevim, Elif; Gaballa, Ahmed; Beldüz, A Osman; Helmann, John D

    2011-01-01

    σ(D) proteins from Aeribacillus pallidus AC6 and Bacillus subtilis bound specifically, albeit weakly, to promoter DNA even in the absence of core RNA polymerase. Binding required a conserved CG motif within the -10 element, and this motif is known to be recognized by σ region 2.4 and critical for promoter activity.

  6. DNA-Binding Properties of the Bacillus subtilis and Aeribacillus pallidus AC6 σD Proteins▿

    Science.gov (United States)

    Sevim, Elif; Gaballa, Ahmed; Beldüz, A. Osman; Helmann, John D.

    2011-01-01

    σD proteins from Aeribacillus pallidus AC6 and Bacillus subtilis bound specifically, albeit weakly, to promoter DNA even in the absence of core RNA polymerase. Binding required a conserved CG motif within the −10 element, and this motif is known to be recognized by σ region 2.4 and critical for promoter activity. PMID:21097624

  7. Genome Sequence of Aeribacillus pallidus Strain GS3372, an Endospore-Forming Bacterium Isolated in a Deep Geothermal Reservoir

    OpenAIRE

    Sevasti Filippidou; Marion Jaussi; Thomas Junier; Tina Wunderlin; Nicole Jeanneret; Simona Regenspurg; Po-E Li; Chien-Chi Lo; Shannon Johnson; Kim McMurry; Cheryl D. Gleasner; Momchilo Vuyisich; Patrick S. Chain; Pilar Junier

    2015-01-01

    The genome of strain GS3372 is the first publicly available strain of Aeribacillus pallidus. This endospore-forming thermophilic strain was isolated from a deep geothermal reservoir. The availability of this genome can contribute to the clarification of the taxonomy of the closely related Anoxybacillus, Geobacillus, and Aeribacillus genera.

  8. DNA-Binding Properties of the Bacillus subtilis and Aeribacillus pallidus AC6 σD Proteins▿

    OpenAIRE

    Sevim, Elif; Gaballa, Ahmed; Beldüz, A. Osman; Helmann, John D.

    2010-01-01

    σD proteins from Aeribacillus pallidus AC6 and Bacillus subtilis bound specifically, albeit weakly, to promoter DNA even in the absence of core RNA polymerase. Binding required a conserved CG motif within the −10 element, and this motif is known to be recognized by σ region 2.4 and critical for promoter activity.

  9. Genome Sequence of Aeribacillus pallidus Strain GS3372, an Endospore-Forming Bacterium Isolated in a Deep Geothermal Reservoir.

    Science.gov (United States)

    Filippidou, Sevasti; Jaussi, Marion; Junier, Thomas; Wunderlin, Tina; Jeanneret, Nicole; Regenspurg, Simona; Li, Po-E; Lo, Chien-Chi; Johnson, Shannon; McMurry, Kim; Gleasner, Cheryl D; Vuyisich, Momchilo; Chain, Patrick S; Junier, Pilar

    2015-08-27

    The genome of strain GS3372 is the first publicly available strain of Aeribacillus pallidus. This endospore-forming thermophilic strain was isolated from a deep geothermal reservoir. The availability of this genome can contribute to the clarification of the taxonomy of the closely related Anoxybacillus, Geobacillus, and Aeribacillus genera. Copyright © 2015 Filippidou et al.

  10. Diet, digestion, and food preferences of Galapagos land iguanas. [Conolophus pallidus

    Energy Technology Data Exchange (ETDEWEB)

    Christian, K.A.; Tracy, C.R.; Porter, W.P.

    1984-01-01

    The choice of food types and the length of time food passed through the gastrointestinal tract were determined in free-ranging Conolophus pallidus on Isla Santa Fe, Galapogos throughout the year. Natural foods were analyzed for energy, percent cellulose, percent nitrogen, and calcium as indices of the quality of food. Foods of highest quality were found to be among the preferred foods, but not all preferred foods were of high quality with respect to the nutrients measured. Passage time of food through the gastrointestinal tract, digestive efficiency, and digestion of cellulose were determined on captive Conolophus subcristatus. Ability to digest cellulose and digestive efficiency varied among five caged iguanas. Intra- and interspecific variabilities in digestive capacities result from variability in ecological factors, and interspecific variability among iguanines probably reflects differences in colic anatomy and the ability to absorb nutrients from the hindgut. 23 references, 4 tables.

  11. [Detection of a higher incidence of pathologic somatic findings in globus sensation by use of high frequency cinematography].

    Science.gov (United States)

    Hannig, C; Wuttge-Hannig, A; Bockmeyer, M

    1987-07-01

    Since December 1984 303 patients have undergone examination in our Multidisciplinary Consultation Service for Swallowing Disorders; 117 of them were suffering from typical globus symptoms. We were able to increase the yield of detection of organic lesions by use of the technique of 35 mm film cineradiography with a rate of 50 frames/s. Frame-by-frame analysis and computer-assisted evaluation showed that 80% of the patients with globus symptoms suffered from one or more underlying organic diseases, which could often be treated later with success. We found an increased incidence of early hypopharyngeal diverticula, webs, and motility disorders of the upper esophageal sphincter often associated with gastro-esophageal reflux or weakness of the pharyngeal wall. Cineradiography proved to be a very important tool in the analysis of the pharyngeal swallow in globus pharyngis.

  12. High kinetic energy plasma jet generation and its injection into the Globus-M spherical tokamak

    International Nuclear Information System (INIS)

    Voronin, A.V.; Gusev, V.K.; Petrov, Yu.V.; Sakharov, N.V.; Abramova, K.B.; Sklyarova, E.M.; Tolstyakov, S.Yu.

    2005-01-01

    Progress in the theoretical and experimental development of the plasma jet source and injection of hydrogen plasma and neutral gas jets into the Globus-M spherical tokamak is discussed. An experimental test bed is described for investigation of intense plasma jets that are generated by a double-stage plasma gun consisting of an intense source for neutral gas production and a conventional pulsed coaxial accelerator. A procedure for optimizing the accelerator parameters so as to achieve the maximum possible flow velocity with a limited discharge current and a reasonable length of the coaxial electrodes is presented. The calculations are compared with experiment. Plasma jet parameters, among them pressure distribution across the jet, flow velocity, plasma density, etc, were measured. Plasma jets with densities of up to 10 22 m -3 , total numbers of accelerated particles (1-5) x 10 19 , and flow velocities of 50-100 km s -1 were successfully injected into the plasma column of the Globus-M tokamak. Interferometric and Thomson scattering measurements confirmed deep jet penetration and a fast density rise ( 19 to 1 x 10 19 ) did not result in plasma degradation

  13. Rikkunshito improves globus sensation in patients with proton-pump inhibitor-refractory laryngopharyngeal reflux.

    Science.gov (United States)

    Tokashiki, Ryoji; Okamoto, Isaku; Funato, Nobutoshi; Suzuki, Mamoru

    2013-08-21

    To investigate the effect of rikkunshito on laryngopharyngeal reflux (LPR) symptoms and gastric emptying in patients with proton-pump inhibitor (PPI)-refractory LPR. In total, 22 patients with LPR were enrolled. Following a 2-wk treatment with PPI monotherapy, PPI-refractory LPR patients were randomly divided into two treatment groups (rikkunshito alone or rikkunshito plus the PPI, lansoprazole). LPR symptoms were assessed using a visual analog scale (VAS) score, gastrointestinal symptoms were assessed using the gastrointestinal symptom rating scale (GSRS), and gastric emptying was assessed using the radio-opaque marker method prior to and 4 wk following treatments. The 4-wk treatment with rikkunshito alone and with rikkunshito plus the PPI significantly decreased the globus sensation VAS scores. The VAS score for sore throat was significantly decreased following treatment with rikkunshito plus PPI but not by rikkunshito alone. Neither treatment significantly changed the GSRS scores. Rikkunshito improved delayed gastric emptying. We found a significant positive correlation between improvements in globus sensation and in gastric emptying (r² = 0.4582, P sensation in patients with PPI-refractory LPR, in part, because of stimulation of gastric emptying. Thus, rikkunshito is an effective treatment for PPI-refractory LPR.

  14. Envenomation by neotropical Opisthoglyphous colubrid Thamnodynastes cf. pallidus Linné, 1758 (Serpentes:Colubridae in Venezuela Envenenamiento por la colubrida opistoglifa Thamnodynastes cf. pallidus Linné, 1758 (Serpentes:Colubridae en Venezuela

    Directory of Open Access Journals (Sweden)

    Fresnel Diaz

    2004-10-01

    Full Text Available This is a case report of a "non-venomous" snake bite in a herpetologist observed at the Sciences Faculty of the Universidad de los Andes (Mérida, Venezuela. The patient was bitten on the middle finger of the left hand, and shows signs of pronounced local manifestations of envenomation such as bleeding from the tooth imprint, swelling and warmth. He was treated with local care, analgesics, and steroids. He was dismissed from the hospital and observed at home during five days with marked improvement of envenomation. The snake was brought to the medical consult and identified as a Thamnodynastes cf. pallidus specimen. This report represents the first T. pallidus accident described in a human.Se reporta un caso de una mordedura de serpiente "no venenosa", en un herpetólogo observado en la Facultad de Ciencias de la Universidad de los Andes (Mérida, Venezuela. El paciente fue mordido en el dedo medio de la mano izquierda, mostrando pronunciados signos locales de sangramiento por la impronta ocasionada por los dientes de la serpiente, edema y calor local. El paciente fue tratado con cuidados locales, analgésicos y esteroides. Fue dado de alta del hospital y observado en el hogar durante 5 días, con marcada mejoría del envenenamiento. La serpiente fue traída a la consulta médica e identificada como un espécimen de Thamnodynastes cf. pallidus. Este es el primer caso humano descrito, ocasionado por un T. pallidus.

  15. A multilevel approach to examining cephalopod growth using Octopus pallidus as a model.

    Science.gov (United States)

    Semmens, Jayson; Doubleday, Zoë; Hoyle, Kate; Pecl, Gretta

    2011-08-15

    Many aspects of octopus growth dynamics are poorly understood, particularly in relation to sub-adult or adult growth, muscle fibre dynamics and repro-somatic investment. The growth of 5 month old Octopus pallidus cultured in the laboratory was investigated under three temperature regimes over a 12 week period: seasonally increasing temperatures (14-18°C); seasonally decreasing temperatures (18-14°C); and a constant temperature mid-way between seasonal peaks (16°C). Differences in somatic growth at the whole-animal level, muscle tissue structure and rate of gonad development were investigated. Continuous exponential growth was observed, both at a group and at an individual level, and there was no detectable effect of temperature on whole-animal growth rate. Juvenile growth rate (from 1 to 156 days) was also monitored prior to the controlled experiment; exponential growth was observed, but at a significantly faster rate than in the older experimental animals, suggesting that O. pallidus exhibit a double-exponential two-phase growth pattern. There was considerable variability in size-at-age even between individuals growing under identical thermal regimes. Animals exposed to seasonally decreasing temperatures exhibited a higher rate of gonad development compared with animals exposed to increasing temperatures; however, this did not coincide with a detectable decline in somatic growth rate or mantle condition. The ongoing production of new mitochondria-poor and mitochondria-rich muscle fibres (hyperplasia) was observed, indicated by a decreased or stable mean muscle fibre diameter concurrent with an increase in whole-body size. Animals from both seasonal temperature regimes demonstrated higher rates of new mitochondria-rich fibre generation relative to those from the constant temperature regime, but this difference was not reflected in a difference in growth rate at the whole-body level. This is the first study to record ongoing hyperplasia in the muscle tissue of an

  16. Gp96 Peptide Antagonist gp96-II Confers Therapeutic Effects in Murine Intestinal Inflammation

    Directory of Open Access Journals (Sweden)

    Claudia A. Nold-Petry

    2017-12-01

    Full Text Available BackgroundThe expression of heat shock protein gp96 is strongly correlated with the degree of tissue inflammation in ulcerative colitis and Crohn’s disease, thereby leading us to the hypothesis that inhibition of expression via gp96-II peptide prevents intestinal inflammation.MethodsWe employed daily injections of gp96-II peptide in two murine models of intestinal inflammation, the first resulting from five daily injections of IL-12/IL-18, the second via a single intrarectal application of TNBS (2,4,6-trinitrobenzenesulfonic acid. We also assessed the effectiveness of gp96-II peptide in murine and human primary cell culture.ResultsIn the IL-12/IL-18 model, all gp96-II peptide-treated animals survived until day 5, whereas 80% of placebo-injected animals died. gp96-II peptide reduced IL-12/IL-18-induced plasma IFNγ by 89%, IL-1β by 63%, IL-6 by 43% and tumor necrosis factor (TNF by 70% compared to controls. The clinical assessment Disease Activity Index of intestinal inflammation severity was found to be significantly lower in the gp96-II-treated animals when compared to vehicle-injected mice. gp96-II peptide treatment in the TNBS model limited weight loss to 5% on day 7 compared with prednisolone treatment, whereas placebo-treated animals suffered a 20% weight loss. Histological disease severity was reduced equally by prednisolone (by 40% and gp96-II peptide (35%. Mice treated with either gp96-II peptide or prednisolone exhibited improved endoscopic scores compared with vehicle-treated control mice: vascularity, fibrin, granularity, and translucency scores were reduced by up to 49% by prednisolone and by up to 30% by gp96-II peptide. In vitro, gp96-II peptide reduced TLR2-, TLR4- and IL-12/IL-18-induced cytokine expression in murine splenocytes, with declines in constitutive IL-6 (54%, lipopolysaccharide-induced TNF (48%, IL-6 (81% and in Staphylococcus epidermidis-induced TNF (67% and IL-6 (81%, as well as IL-12/IL-18-induced IFNγ (75%. gp

  17. Suitability of the alkalistable carbonic anhydrase from a polyextremophilic bacterium Aeribacillus pallidus TSHB1 in biomimetic carbon sequestration.

    Science.gov (United States)

    Bose, Himadri; Satyanarayana, T

    2016-10-01

    Carbonic anhydrase (CA) was produced from the polyextremophilic (halotolerant, moderately thermophilic and alkaliphilic) bacterium Aeribacillus pallidus TSHB1 isolated from water and sediment samples of Choti Anhoni hot spring of Pipariya, Madhya Pradesh (India), is being reported to be suitable for carbon sequestration. Growth and CA production were inhibited at higher CO2 concentration (5-10 %). Under optimized culture variables (tryptone 0.8 %, yeast extract 0.08 %, glucose 1 %, micronutrient solution 1 %, inoculums size 1.10 %, agitation 200 at pH 8, and temperature 55 °C), 3.7-fold higher CA production was attained than that under unoptimized conditions. The zymogram analysis of the partially purified CA revealed an activity band corresponding to 32 kDa. The enzyme is stable in the pH range between 8.0 and 11.0 with T 1/2 of 40, 15, and 8 min at 60, 70, and 80 °C, respectively. The CA of A. pallidus displayed a marked enhancement in the rate of CaCO3 precipitation from aqueous CO2. The CA-aided formation of CaCO3 was 42.5 mg mg(-1) protein. Scanning electron microscopy revealed the formation of rhomboid calcite crystals. This is the first report on the production and applicability of CA from the polyextremophilic A. pallidus in carbon sequestration.

  18. Production and characterization of a new antibacterial peptide obtained from Aeribacillus pallidus SAT4

    Directory of Open Access Journals (Sweden)

    Syed Aun Muhammad

    2015-12-01

    Full Text Available A novel thermophilic bacterial strain of the genus Aeribacillus was isolated from Thar Dessert Pakistan. This strain showed significant antibacterial activity against Micrococcus luteus, Staphylococcus aureus, and Pseudomonas aeruginosa. The strain coded as ‘SAT4’ resembled with Aeribacillus pallidus in the morphological, biochemical and molecular tests. The production of antibacterial metabolites by SAT4 was optimized. These active metabolites were precipitated by 50% ammonium sulphate and purified through sephadex G-75 gel permeation chromatography and reverse phase HPLC. The molecular weight of 37 kDa was examined by SDS-PAGE. The structural elucidation of the purified product was studied by FTIR, 1H and 13C NMR. The X-ray diffractions study showed that the crystals belonged to the primitive orthorhombic lattice (a = 12.137, b = 13.421, c = 14.097 Å and 3D structure (proposed name: Aeritracin was determined. This new peptide antibacterial molecule can get a position in pharmaceutical and biotechnological industrial research.

  19. Physiological and ecological consequences of sleeping-site selection by the Galapagos land iguana (Conolophus pallidus)

    Energy Technology Data Exchange (ETDEWEB)

    Christian, K.A.; Tracy, C.R.

    1984-01-01

    Field observations and biophysical models were combined to analyze sleeping-site selection by Galapagos land iguanas (Conolophus pallidus). Iguanas slept in different kinds of sleeping sites during different seasons. In the coolest season (garua), adult land iguanas were found in sleeping sites that were warmer than the coolest sites available. This may be because the garua season (cool, overcast, and foggy) is a time when environmental conditions mitigate against rapid warm-up in the mornings, so lizards may regulate nighttime body temperatures so that it is easier to warm up to preferred daytime body temperatures. In the warmest season, adult iguanas were found in the coolest sleeping sites available. This observation is consistent with hypotheses of voluntary hypothermia, which can be advantageous in energy conservation and in avoiding detrimental effects associated with maintenance of constant body temperatures throughout the day and night. Juvenile iguanas were found sleeping in rock crevices regardless of the ambient thermal environments. Such sites are likely to be important as refugia for this life stage, which, unlike the adult stage, is vulnerable to predation. It was concluded that selection of sleeping sites is a process that may help in avoidance of predation, optimization of body temperature at the end of the sleeping period, and reduction of metabolic costs during sleeping. The importance of some of these factors may change with the thermal milieu (e.g., season).

  20. Role of urea in the postprandial urine concentration cycle of the insectivorous bat Antrozous pallidus.

    Science.gov (United States)

    Bassett, John E

    2004-02-01

    Insectivorous bats, which feed once daily, produce maximally concentrated urine only after feeding. The role of urea as an osmolyte in this process was investigated in pallid bats (Antrozous pallidus) in the laboratory. Following a 24-h fast, plasma and urine were sampled before and 2 h after feeding in postprandial (PP) animals and before and 2 h after similar treatment without feeding in nonfed (NF) animals. Food consumption by PP animals and handling of NF animals had no effect on blood water content as measured by hematocrit and plasma oncotic pressure. Food consumption increased both plasma osmolality (P(osm)) and plasma urea (P(urea)) by as much as 15%. Food consumption also increased urine osmolality (U(osm)) and urine urea (U(urea)) by 50-100%. Feeding increased U(osm) regardless of changes in P(osm), and elevation of U(osm) resulted primarily from increased U(urea). In NF bats, P(osm) and P(urea) were unchanged, while U(osm) and U(urea) increased by as much as 25%. Again, increased U(osm) resulted primarily from increased U(urea). The PP urine concentration cycle of pallid bats resulted from increased urea excretion in response to apparent rapid urea synthesis. Bats rapidly metabolized protein and excreted urea following feeding when body water was most plentiful.

  1. Production and characterization of a new antibacterial peptide obtained from Aeribacillus pallidus SAT4.

    Science.gov (United States)

    Muhammad, Syed Aun; Ahmed, Safia

    2015-12-01

    A novel thermophilic bacterial strain of the genus Aeribacillus was isolated from Thar Dessert Pakistan. This strain showed significant antibacterial activity against Micrococcus luteus , Staphylococcus aureus , and Pseudomonas aerugin osa. The strain coded as 'SAT4' resembled with Aeribacillus pallidus in the morphological, biochemical and molecular tests. The production of antibacterial metabolites by SAT4 was optimized. These active metabolites were precipitated by 50% ammonium sulphate and purified through sephadex G-75 gel permeation chromatography and reverse phase HPLC. The molecular weight of 37 kDa was examined by SDS-PAGE. The structural elucidation of the purified product was studied by FTIR, 1 H and 13 C NMR. The X-ray diffractions study showed that the crystals belonged to the primitive orthorhombic lattice ( a  = 12.137, b  = 13.421, c  = 14.097 Å) and 3D structure (proposed name: Aeritracin) was determined. This new peptide antibacterial molecule can get a position in pharmaceutical and biotechnological industrial research.

  2. Characterization of a novel protease from Aeribacillus pallidus strain VP3 with potential biotechnological interest.

    Science.gov (United States)

    Mechri, Sondes; Ben Elhoul Berrouina, Mouna; Omrane Benmrad, Maroua; Zaraî Jaouadi, Nadia; Rekik, Hatem; Moujehed, Emna; Chebbi, Alif; Sayadi, Sami; Chamkha, Mohamed; Bejar, Samir; Jaouadi, Bassem

    2017-01-01

    The present study investigates the purification and physico-chemical characterization of an extracellular protease from the Aeribacillus pallidus strain VP3 previously isolated from a geothermal oil-field (Sfax, Tunisia). The maximum protease activity recorded after 22h of incubation at 45°C was 3000U/ml. Pure enzyme, designated as SPVP, was obtained after ammonium sulfate fractionation (40-60%)-dialysis followed by heat-treatment (70°C for 30min) and UNO Q-6 FPLC anion-exchange chromatography. The purified enzyme is a monomer of molecular mass about 29kDa. The sequence of the 25 NH 2 -terminal residues of SPVP showed a high homology with those of Bacillus proteases. The almost complete inhibition by PMSF and DIFP confirmed that SPVP is a member of serine protease family. Its optima of pH and temperature were pH 10 and 60°C, respectively. Its half-life times at 70 and 80°C were 8 and 4h, respectively. Its catalytic efficiency was higher than those of SAPCG, Alcalase Ultra 2.5L, and Thermolysin type X. SPVP exhibited excellent stability to detergents and wash performance analysis revealed that it could remove blood-stains effectively and high resistance against organic solvents. These properties make SPVP a potential candidate for applications in detergent formulations and non-aqueous peptide biocatalysis. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Seasonal shifts in body temperature and use of microhabitats by Galapagos land iguanas (Conolophus pallidus)

    Energy Technology Data Exchange (ETDEWEB)

    Christian, K.; Tracy, C.R.; Porter, W.P.

    1983-06-01

    Seasonal differences in the body temperatures (T/sub b/) of free-ranging Galapagos land iguanas (Conolophus pallidus) were detected by temperature sensitive telemetry transmitters. Midday T/sub b/'s of iguanas average 4.4/sup 0/C lower in the Garua (cool) season than in the Hot season. Measured T/sub b/'s and those predicted from biophysical models permitted the following conclusions: (1) lower T/sub b/'s during the Garua season represent an active shift in thermoregulation by the iguanas rather than a passive result of a cooler season; (2) the average midday T/sub b/ selected by the iguanas in either season is the T/sub b/ that allows maintenance of a constant T/sub b/ for the longest possible portion of the day; (3) by exploiting the warmer microclimate created by a cliff face, the iguanas are able to maintain a constant T/sub b/ for a full hour longer than they could elsewhere in their home range. Census data demonstrated that the iguanas exploited the warmer microclimate created by the cliff extensively during the Garua season, and the cliff face was visited by the iguanas relatively infrequently during the Hot season. Thus, the exploitation of the microclimate created by the cliff results in seasonal differences in the pattern of space utilization within the home ranges of the iguanas. Within the Garua season the iguanas moved away from the cliff more often on sunny days than during cloudy days. It is concluded that the physical environment is an important determinant of patterns of space utilization both within and between seasons.

  4. Recrystallized graphite utilization as the first wall material in Globus-M spherical tokamak

    International Nuclear Information System (INIS)

    Gusev, V.; Novokhatsky, A.N.; Petrov, Y.V.; Sakharov, N.V.; Terukov, E.I.; Trapeznikova, I.N.; Denisov, E.A.; Kurdumov, A.A.; Kompaniec, T.N.; Lebedev, V.M.; Litunovstkii, N.V.; Mazul, I.

    2007-01-01

    Full text of publication follows: Globus-M spherical tokamak, built at A.F. Ioffe Physico-Technical Institute in 1999 is the first Russian spherical tokamak and has the broad area of research in controlled fusion [1]. Besides small aspect ratio (A=1.5) the distinguishing feature of the tokamak is the powerful energy supply system and auxiliary heating, which give opportunity to reach high specific power deposition up to few W/cm 3 . The utmost plasma current density and B/R ratio among spherical tokamaks allow operation in the range of high plasma densities ∼ 10 20 m -3 . This feature results in big power density loads to the first wall due to small plasma-wall spacing. The area of the first wall amour was gradually increased during few years since 2003, and nowadays reaches almost 90% of the inner vessel surface faced to plasma. Plasma facing protecting tiles are manufactured from recrystallized graphite doped by different elements (Ti, Si, B). Additionally the plasma facing surface was protected by films deposited during boronization. The tendency of short time and long time scale plasma parameters variation are discussed including the plasma performance improvement with increase of protected area. Technology of tiles preparation before installation into the tokamak vessel is briefly described, as well as technology of plasma facing armor preparation before the plasma experiments. Few protecting tiles doped by different elements which were exposed to plasma fluxes of dissimilar power densities for a long time were extracted from the vacuum vessel. The analysis of tiles material (RGT-91) to hold (accumulate) deuterium was made. The distribution of absorbed deuterium concentration along poloidal coordinate was measured. The elementary composition of the films deposited on the tiles was studied by Rutherford back scattering technique and by nuclear resonance reaction method. Other modern methods of surface and structural analysis of material exposed to prolonged

  5. Recrystallized graphite utilization as the first wall material in Globus-M spherical tokamak

    Energy Technology Data Exchange (ETDEWEB)

    Gusev, V.; Novokhatsky, A.N.; Petrov, Y.V.; Sakharov, N.V.; Terukov, E.I.; Trapeznikova, I.N. [A.F. IOFFE Physico-technical Institute, Russian Academy of Sciences, St Petersburg (Russian Federation); Denisov, E.A.; Kurdumov, A.A.; Kompaniec, T.N. [St. Petersburg State Univ., Research Institute of Physics (Russian Federation); Lebedev, V.M. [B.P. Konstantinov Nuclear Physics Institute, Russian Academy of Science, Gatchina (Russian Federation); Litunovstkii, N.V. [D.V. Efremov Institute of Electrophysical Apparatus, St.Petersburg (Russian Federation); Mazul, I. [Development of Plasma Facing Materials and Components Laboratory, EFREMOV INSTITUTE, St Petersbourg (Russian Federation)

    2007-07-01

    Full text of publication follows: Globus-M spherical tokamak, built at A.F. Ioffe Physico-Technical Institute in 1999 is the first Russian spherical tokamak and has the broad area of research in controlled fusion [1]. Besides small aspect ratio (A=1.5) the distinguishing feature of the tokamak is the powerful energy supply system and auxiliary heating, which give opportunity to reach high specific power deposition up to few W/cm{sup 3}. The utmost plasma current density and B/R ratio among spherical tokamaks allow operation in the range of high plasma densities {approx} 10{sup 20} m{sup -3}. This feature results in big power density loads to the first wall due to small plasma-wall spacing. The area of the first wall amour was gradually increased during few years since 2003, and nowadays reaches almost 90% of the inner vessel surface faced to plasma. Plasma facing protecting tiles are manufactured from recrystallized graphite doped by different elements (Ti, Si, B). Additionally the plasma facing surface was protected by films deposited during boronization. The tendency of short time and long time scale plasma parameters variation are discussed including the plasma performance improvement with increase of protected area. Technology of tiles preparation before installation into the tokamak vessel is briefly described, as well as technology of plasma facing armor preparation before the plasma experiments. Few protecting tiles doped by different elements which were exposed to plasma fluxes of dissimilar power densities for a long time were extracted from the vacuum vessel. The analysis of tiles material (RGT-91) to hold (accumulate) deuterium was made. The distribution of absorbed deuterium concentration along poloidal coordinate was measured. The elementary composition of the films deposited on the tiles was studied by Rutherford back scattering technique and by nuclear resonance reaction method. Other modern methods of surface and structural analysis of material

  6. A case study for cloud based high throughput analysis of NGS data using the globus genomics system

    Directory of Open Access Journals (Sweden)

    Krithika Bhuvaneshwar

    2015-01-01

    Full Text Available Next generation sequencing (NGS technologies produce massive amounts of data requiring a powerful computational infrastructure, high quality bioinformatics software, and skilled personnel to operate the tools. We present a case study of a practical solution to this data management and analysis challenge that simplifies terabyte scale data handling and provides advanced tools for NGS data analysis. These capabilities are implemented using the “Globus Genomics” system, which is an enhanced Galaxy workflow system made available as a service that offers users the capability to process and transfer data easily, reliably and quickly to address end-to-endNGS analysis requirements. The Globus Genomics system is built on Amazon's cloud computing infrastructure. The system takes advantage of elastic scaling of compute resources to run multiple workflows in parallel and it also helps meet the scale-out analysis needs of modern translational genomics research.

  7. Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility.

    Science.gov (United States)

    Pancera, Marie; Majeed, Shahzad; Ban, Yih-En Andrew; Chen, Lei; Huang, Chih-chin; Kong, Leopold; Kwon, Young Do; Stuckey, Jonathan; Zhou, Tongqing; Robinson, James E; Schief, William R; Sodroski, Joseph; Wyatt, Richard; Kwong, Peter D

    2010-01-19

    The viral spike of HIV-1 is composed of three gp120 envelope glycoproteins attached noncovalently to three gp41 transmembrane molecules. Viral entry is initiated by binding to the CD4 receptor on the cell surface, which induces large conformational changes in gp120. These changes not only provide a model for receptor-triggered entry, but affect spike sensitivity to drug- and antibody-mediated neutralization. Although some of the details of the CD4-induced conformational change have been visualized by crystal structures and cryoelectron tomograms, the critical gp41-interactive region of gp120 was missing from previous atomic-level characterizations. Here we determine the crystal structure of an HIV-1 gp120 core with intact gp41-interactive region in its CD4-bound state, compare this structure to unliganded and antibody-bound forms to identify structurally invariant and plastic components, and use ligand-oriented cryoelectron tomograms to define component mobility in the viral spike context. Newly defined gp120 elements proximal to the gp41 interface complete a 7-stranded beta-sandwich, which appeared invariant in conformation. Loop excursions emanating from the sandwich form three topologically separate--and structurally plastic--layers, topped off by the highly glycosylated gp120 outer domain. Crystal structures, cryoelectron tomograms, and interlayer chemistry were consistent with a mechanism in which the layers act as a shape-changing spacer, facilitating movement between outer domain and gp41-associated beta-sandwich and providing for conformational diversity used in immune evasion. A "layered" gp120 architecture thus allows movement among alternative glycoprotein conformations required for virus entry and immune evasion, whereas a beta-sandwich clamp maintains gp120-gp41 interaction and regulates gp41 transitions.

  8. Pathological bolus exposure may define gastro-esophageal reflux better than pathological acid exposure in patients with globus.

    Science.gov (United States)

    Sinn, Dong Hyun; Kim, Beom Jin; Son, Hee Jung; Kim, Jae J; Rhee, Jong Chul; Rhee, Poong-Lyul

    2012-01-01

    Conventionally, pathological acid exposure (PAE), defined by acid reflux only, is used to identify gastro-esophageal reflux disease (GERD). However, weak acid reflux or non-acid reflux also induces reflux symptoms. Defining abnormal reflux based on all reflux episodes may better identify GERD and would be more useful among patients with atypical GERD symptoms, such as globus. Impedance-pHmetry results of 31 globus patients, off acid suppressants, were analysed. A median of 24 episodes of reflux were observed. Of the reflux episodes, 54% were non-acid reflux and 50% reached the proximal extent. PAE was observed in 6 patients (19%). For 5 patients (16%) without PAE, there was evidence of increased bolus exposure compared to normal controls (an intraesophageal bolus exposure for more than 1.4% of the recording time, defined as pathological bolus exposure, PBE). When GERD was defined by PAE or esophagitis, the prevalence of GERD was 29%. When GERD was defined by PBE, PAE or esophagitis, the prevalence was 42%. PBE identified 13% of the patients who otherwise would have been missed. A significant proportion of patients without PAE had evidence of PBE. PBE may be a more useful definition for identifying patients with abnormal increase in reflux in patients with globus. Further studies are warranted.

  9. Association between patients' recommendation of their GP and their evaluation of the GP.

    Science.gov (United States)

    Vedsted, Peter; Heje, Hanne N

    2008-01-01

    Patient priorities and patient evaluations indicate that accessibility should receive more attention to increase quality in general practice. The definition of family medicine emphasizes the patient-centred approach, communication skills, continuity, and clinical skills. We aimed to explore the associations between the 23 items in the Europep questionnaire measuring patient evaluation of general practice and the patients' recommendation of their general practitioner (GP) to friends and to study the relationship of these items with the core competences of family medicine. Cross-sectional study where patients aged 18 years and over attending the practice were included. Patients completed the Danish version of the 23 item Europep questionnaire and an additional item about the degree to which they could recommend their GP to friends. Danish general practice (the DanPEP study). A total of 50 191 patients and 690 GPs were included in the analyses. For each item, associations were calculated between a positive answer and the degree to which the patient could recommend the GP. Analyses were made at patient and GP levels. We found 12 items that covered the 10 most strongly associated items from both analyses: four of six items from the "doctor-patient relationship", two of five items from "medical care", and all items from "information and support" and "organization of services". No items from "accessibility" were among the 12 items. Recommending the GP to others was most strongly associated with the "emphatic", "patient-oriented", "informative and coordinating", and "competent/skilled" GP and to a lesser degree with accessibility to general practice.

  10. Plasma formation and first OH experiments in GLOBUS-M tokamak

    International Nuclear Information System (INIS)

    Gusev, V.K.; Aleksandrov, S.V.; Burtseva, T.A.

    2001-01-01

    The paper reports results of experimental campaigns on plasma ohmic heating, performed during 1999-2000 on the spherical tokamak Globus-M. Later experimental results with tokamak fed by thyristor rectifiers are presented in detail. The toroidal magnetic field and plasma pulse duration in these experiments were significantly increased. The method of stray magnetic field compensation is described. The technology of vacuum vessel conditioning, including boronization of the vessel performed at the end of the experiments, is briefly discussed. Also discussed is the influence of ECR preioniziation on the breakdown conditions. Experimental data on plasma column formation and current ramp-up in different regimes of operation with the magnetic flux of the central solenoid (CS) limited to ∼100 mVs are presented. Ramp-up of the plasma current of 0.25 MA for the time interval ∼0.03 s with about 0.02 s flat-top at the toroidal field (TF) strength of 0.35 T allows the conclusion that power supplies, control system and wall conditioning work well. The same conclusion can be drawn from observation of plasma density behavior the density is completely controlled with external gas puff and the influence of the wall is negligible after boronization. The magnetic flux consumption efficiency is discussed. The results of magnetic equilibrium simulations are presented and compared with experiment. (author)

  11. Continuous cultivation of a thermophilic bacterium Aeribacillus pallidus 418 for production of an exopolysaccharide applicable in cosmetic creams.

    Science.gov (United States)

    Radchenkova, N; Panchev, I; Vassilev, S; Kuncheva, M; Dobreva, S; Kambourova, M

    2015-11-01

    The aim of this study was to evaluate the effectiveness of continuous cultivation approach for exopolysaccharide (EPS) production by a thermophilic micro-organism and the potential of the synthesized EPS for application in cosmetic industry. Study on the ability of Aeribacillus pallidus 418, isolated as a good EPS producer, to synthesize the polymer in continuous cultures showed higher production in comparison with batch cultures. The degree of the EPS in the precipitate after continuous cultivation significantly increased. Non-Newtonian pseudoplastic and thixotropic behaviour of EPS determines the ability of the received cream to become more fluid after increasing time of application on the skin. This study demonstrates a highly efficient way for production of EPS from a continuous growth culture of A. pallidus 418 that have many advantages and can outperform batch culture by eliminating time for cleaning and sterilization of the vessel and the comparatively long lag phases before the organisms enter a brief period of high productivity. The valuable physico-chemical properties of the synthesized EPS influenced positively the properties of a commercial cream. EPSs from thermophilic micro-organisms are of special interest due to the advantages of the thermophilic processes and nonpathogenic nature of the polymer molecules. However, their industrial application is hindered by the comparatively low biomass and correspondingly EPS yield. Suggested continuous approach for EPS could have an enormous economic potential for an industrial scale production of thermophilic EPSs. © 2015 The Society for Applied Microbiology.

  12. Study of Globus-M Tokamak Poloidal System and Plasma Position Control

    Science.gov (United States)

    Dokuka, V. N.; Korenev, P. S.; Mitrishkin, Yu. V.; Pavlova, E. A.; Patrov, M. I.; Khayrutdinov, R. R.

    2017-12-01

    In order to provide efficient performance of tokamaks with vertically elongated plasma position, control systems for limited and diverted plasma configuration are required. The accuracy, stability, speed of response, and reliability of plasma position control as well as plasma shape and current control depend on the performance of the control system. Therefore, the problem of the development of such systems is an important and actual task in modern tokamaks. In this study, the measured signals from the magnetic loops and Rogowski coils are used to reconstruct the plasma equilibrium, for which linear models in small deviations are constructed. We apply methods of the H∞-optimization theory to the synthesize control system for vertical and horizontal position of plasma capable to working with structural uncertainty of the models of the plant. These systems are applied to the plasma-physical DINA code which is configured for the tokamak Globus-M plasma. The testing of the developed systems applied to the DINA code with Heaviside step functions have revealed the complex dynamics of plasma magnetic configurations. Being close to the bifurcation point in the parameter space of unstable plasma has made it possible to detect an abrupt change in the X-point position from the top to the bottom and vice versa. Development of the methods for reconstruction of plasma magnetic configurations and experience in designing plasma control systems with feedback for tokamaks provided an opportunity to synthesize new digital controllers for plasma vertical and horizontal position stabilization. It also allowed us to test the synthesized digital controllers in the closed loop of the control system with the DINA code as a nonlinear model of plasma.

  13. Prediction of the Secondary Structure of HIV-1 gp120

    DEFF Research Database (Denmark)

    Hansen, Jan; Lund, Ole; Nielsen, Jens O.

    1996-01-01

    Fourier transform infrared spectroscopy. The predicted secondary structure of gp120 compared well with data from NMR analysis of synthetic peptides from the V3 loop and the C4 region. As a first step towards modeling the tertiary structure of gp120, the predicted secondary structure may guide the design......The secondary structure of HIV-1 gp120 was predicted using multiple alignment and a combination of two independent methods based on neural network and nearest-neighbor algorithms. The methods agreed on the secondary structure for 80% of the residues in BH10 gp120. Six helices were predicted in HIV...

  14. Draft Genome Sequence of Aeribacillus pallidus Strain 8m3, a Thermophilic Hydrocarbon-Oxidizing Bacterium Isolated from the Dagang Oil Field (China).

    Science.gov (United States)

    Poltaraus, Andrey B; Sokolova, Diyana S; Grouzdev, Denis S; Ivanov, Timophey M; Malakho, Sophia G; Korshunova, Alena V; Rozanov, Aleksey S; Tourova, Tatiyana P; Nazina, Tamara N

    2016-06-09

    The draft genome sequence of Aeribacillus pallidus strain 8m3, a thermophilic aerobic oil-oxidizing bacterium isolated from production water from the Dagang high-temperature oil field, China, is presented here. The genome is annotated to provide insights into the genomic and phenotypic diversity of the genus Aeribacillus. Copyright © 2016 Poltaraus et al.

  15. Draft Genome Sequence of Aeribacillus pallidus Strain 8m3, a Thermophilic Hydrocarbon-Oxidizing Bacterium Isolated from the Dagang Oil Field (China)

    OpenAIRE

    Poltaraus, Andrey B.; Sokolova, Diyana S.; Grouzdev, Denis S.; Ivanov, Timophey M.; Malakho, Sophia G.; Korshunova, Alena V.; Rozanov, Aleksey S.; Tourova, Tatiyana P.; Nazina, Tamara N.

    2016-01-01

    The draft genome sequence of Aeribacillus pallidus strain 8m3, a thermophilic aerobic oil-oxidizing bacterium isolated from production water from the Dagang high-temperature oil field, China, is presented here. The genome is annotated to provide insights into the genomic and phenotypic diversity of the genus Aeribacillus.

  16. Concurrent Presentation of Burning Mouth Syndrome and Globus Pharyngis in Enugu, Nigeria: A Ten-year Clinical Evaluation.

    Science.gov (United States)

    Chukwuneke, Felix; Akpe, James; Okoye, Linda; Ekwueme, Christian; Obiakor, Anthonia; Amobi, Emmanuel; Egbunike, Doris

    2014-01-01

    To review 22 patients with globus pharyngis among a group of 39 patients who presented with burning mouth syndrome and to highlight the clinical presentation and treatment outcome of these oropharyngeal symptoms, often ignored by practicing oral surgeons. We carried out a retrospective review of 39 patients with burning mouth syndrome seen at oral surgery units of three specialist hospitals in Enugu, Nigeria between 2001 and 2010. The focus was on the 22 of these patients with burning mouth syndrome and globus pharyngis (the persistent sensation of having phlegm, a pill or some other sort of obstruction in the throat when there is none). Relevant information included patients' oral habits and dental status, past medical history, sociodemographic data, onset of symptoms and treatment outcome. Amongst the 22 patients, 8 (36.4%) were males while 14 (63.6%) were females, giving a male to female ratio of 1:1.8. Of the 8 male patients, 3 (37.5%) were retrenched workers, 2 (25%) were drug addicts, 2 (25%) had a history of psychiatric problems and 1 (12.5%) had post-radiation therapy due to diagnosis of adenocystic carcinoma. Amongst the 14 female patients, 6 (42.8%) were divorcees, 3 (21.4%) were unemployed and unmarried, 2 (14.3%) had menopausal problems, 2 (14.3%) had dental prostheses and 1 (7.2%) had a history of mental disorder. Globus pharyngis can present at the same time in some individuals with burning mouth syndrome. The emotional aetiological factor in this unusual ailment calls for proper examinations and a multidisciplinary approach in the management of patients who presented with burning mouth syndrome, especially with a history of depression.

  17. End-To-End Solution for Integrated Workload and Data Management using GlideinWMS and Globus Online

    International Nuclear Information System (INIS)

    Mhashilkar, Parag; Miller, Zachary; Weiss, Cathrin; Kettimuthu, Rajkumar; Garzoglio, Gabriele; Holzman, Burt; Duan, Xi; Lacinski, Lukasz

    2012-01-01

    Grid computing has enabled scientific communities to effectively share computing resources distributed over many independent sites. Several such communities, or Virtual Organizations (VO), in the Open Science Grid and the European Grid Infrastructure use the GlideinWMS system to run complex application work-flows. GlideinWMS is a pilot-based workload management system (WMS) that creates an on-demand, dynamically-sized overlay Condor batch system on Grid resources. While the WMS addresses the management of compute resources, however, data management in the Grid is still the responsibility of the VO. In general, large VOs have resources to develop complex custom solutions, while small VOs would rather push this responsibility to the infrastructure. The latter requires a tight integration of the WMS and the data management layers, an approach still not common in modern Grids. In this paper we describe a solution developed to address this shortcoming in the context of Center for Enabling Distributed Peta-scale Science (CEDPS) by integrating GlideinWMS with Globus Online (GO). Globus Online is a fast, reliable file transfer service that makes it easy for any user to move data. The solution eliminates the need for the users to provide custom data transfer solutions in the application by making this functionality part of the GlideinWMS infrastructure. To achieve this, GlideinWMS uses the file transfer plug-in architecture of Condor. The paper describes the system architecture and how this solution can be extended to support data transfer services other than Globus Online when used with Condor or GlideinWMS.

  18. The quaternary structure of the amidase from Geobacillus pallidus RAPc8 is revealed by its crystal packing

    International Nuclear Information System (INIS)

    Agarkar, Vinod B.; Kimani, Serah W.; Cowan, Donald A.; Sayed, Muhammed F.-R.; Sewell, B. Trevor

    2006-01-01

    The amidase from G. pallidus RAPc8, a moderate thermophile, converts amides to the corresponding acids and ammonia and has application as an industrial catalyst. RAPc8 amidase has been cloned, expressed and purified, and then crystallized using the hanging-drop vapour-diffusion method. The amidase from Geobacillus pallidus RAPc8, a moderate thermophile, is a member of the nitrilase enzyme superfamily. It converts amides to the corresponding acids and ammonia and has application as an industrial catalyst. RAPc8 amidase has been cloned and functionally expressed in Escherichia coli and has been purified by heat treatment and a number of chromatographic steps. The enzyme was crystallized using the hanging-drop vapour-diffusion method. Crystals produced in the presence of 1.2 M sodium citrate, 400 mM NaCl, 100 mM sodium acetate pH 5.6 were selected for X-ray diffraction studies. A data set having acceptable statistics to 1.96 Å resolution was collected under cryoconditions using an in-house X-ray source. The space group was determined to be primitive cubic P4 2 32, with unit-cell parameter a = 130.49 (±0.05) Å. The structure was solved by molecular replacement using the backbone of the hypothetical protein PH0642 from Pyrococcus horikoshii (PDB code 1j31) with all non-identical side chains substituted with alanine as a probe. There is one subunit per asymmetric unit. The subunits are packed as trimers of dimers with D3 point-group symmetry around the threefold axis in such a way that the dimer interface seen in the homologues is preserved

  19. 77 FR 73635 - Northwest Storage GP, LLC; Notice of Application

    Science.gov (United States)

    2012-12-11

    ...) 1254 to a proposed 346-megawatt (MW) power plant located within the north industrial area of the Port...] Northwest Storage GP, LLC; Notice of Application Take notice that on November 21, 2012, Northwest Storage GP, LLC. (Northwest) filed with the Federal Energy Regulatory Commission an application under section 7 of...

  20. Internalization and Axonal Transport of the HIV Glycoprotein gp120

    Science.gov (United States)

    Berth, Sarah; Caicedo, Hector Hugo; Sarma, Tulika; Morfini, Gerardo

    2015-01-01

    The HIV glycoprotein gp120, a neurotoxic HIV glycoprotein that is overproduced and shed by HIV-infected macrophages, is associated with neurological complications of HIV such as distal sensory polyneuropathy, but interactions of gp120 in the peripheral nervous system remain to be characterized. Here, we demonstrate internalization of extracellular gp120 in a manner partially independent of binding to its coreceptor CXCR4 by F11 neuroblastoma cells and cultured dorsal root ganglion neurons. Immunocytochemical and pharmacological experiments indicate that gp120 does not undergo trafficking through the endolysosomal pathway. Instead, gp120 is mainly internalized through lipid rafts in a cholesterol-dependent manner, with a minor fraction being internalized by fluid phase pinocytosis. Experiments using compartmentalized microfluidic chambers further indicate that, after internalization, endocytosed gp120 selectively undergoes retrograde but not anterograde axonal transport from axons to neuronal cell bodies. Collectively, these studies illuminate mechanisms of gp120 internalization and axonal transport in peripheral nervous system neurons, providing a novel framework for mechanisms for gp120 neurotoxicity. PMID:25636314

  1. Selection for Dutch postgraduate GP training; time for improvement

    NARCIS (Netherlands)

    Vermeulen, M.I.; Kuyvenhoven, M.M.; Zuithoff, N.P.; Tromp, F.; Graaf, Y. van der; Pieters, R.H.

    2012-01-01

    Background: In the Netherlands we select candidates for the postgraduate GP training by assessing personal qualities in interviews. Because of differences in the ratio of number of candidates and number of vacancies between the eight departments of GP training we questioned whether the risk of being

  2. Scotland's GP paediatric scholarship: an evaluation.

    Science.gov (United States)

    MacVicar, Ronald; Borland, Lyndsey; McHale, Sharon; Goh, Dayeel; Potter, Alex

    2018-05-01

    In a previous publication we described the implementation and early evaluation of general practice paediatric scholarships in Scotland. We suggested that it was too early to be able to determine whether this significant investment will produce a return for Scotland in terms of enhanced roles in providing, leading or developing children's services in primary care or at the primary care/secondary care interface. This paper presents the results of a survey of the impact of the scholarship for the first six cohorts of the scholarship (119 General Practitioners). The response rate was 76%. Of the 90 respondents, almost half (44) have developed roles or areas of special paediatric interest either within or out with the practice, or in three cases both within and out with the practice. A total of 37 (43%) of those that continue to work within general practice reported that they have developed areas of special interest of benefit to the practice. Qualitative analysis of free text questions suggested that scholars had benefited from their experience in terms of increased confidence in dealing with child health problems, developing links with secondary care colleagues, and personal gain with respect to role development. What is already known in this area: Changes in GP Training have been suggested in order to provide a workforce that can meet the needs of infants, children and young people. Studies have shown a positive impact of paediatric trainees and GP trainees learning together. Little attention has however been given to the potential to support trained GPs to develop their expertise in child health. What this work adds: Early evaluation of the Scottish Paediatric Scholarship suggested a high degree of satisfaction. This more robust evaluation suggests that almost half (44/90 respondents) have developed roles or areas of special paediatric interest either within or out with the practice, or in three cases both within and out with the practice. Suggestions for future

  3. Educational CPD: how UK GP trainers develop themselves as teachers.

    Science.gov (United States)

    Waters, Mark; Wall, David

    2007-09-01

    There is little in the literature giving the perspective of UK General Practice (GP) trainers on their development as teachers. What motivates GP trainers develop themselves as teachers? What obstacles to their professional development do GP trainers perceive? A questionnaire to all GP trainers in the West Midlands Deanery in 2004. 360/444 (81%) questionnaires were returned. 56.6% of GP trainers had another educational role in addition to training GP Registrars in the practice. 15.8% of trainers possessed an educational qualification. 13 had completed a Certificate in Medical Education and 28 were engaged in study towards that qualification. Trainers wanted more time to spend on their development as teachers than they presently have, and would then be interested in a wider variety of learning methods. However, 56.6% of trainers would still not choose to undertake a university-accredited course. Female GP trainers perceived more difficulty in obtaining protected time for their development as teachers (Educational CPD) (p = 0.021), were significantly less sure of their partners' support for this development (p = 0.033), and were more likely to agree with trainers undertaking a Certificate in Medical Education (p = 0.003). Having an additional educational role did not affect trainers' ability to take protected time, but significantly increased the amount of time aspired to (p = 0.005). Nothing made more difference to trainers' perception of their ability to undertake Educational CPD than did the perceived attitude of their partners. Educational CPD was very important to GP trainers, but getting protected time was difficult. Consideration of the needs and opinions of partners was a very strong barrier to trainers taking sufficient protected time. Given more available time, GP trainers would be more likely to consider gaining academic qualifications in education. However, this was not be something that all trainers wanted.

  4. Enhanced energy efficiency by means of low temperature differences. Subcritical CO{sub 2} cascade in Globus Handelshof Saarbruecken-Guedingen; Hohe Energieeffizienz durch kleine Temperaturdifferenzen. Unterkritische CO{sub 2}-Kaskade im Globus Handelshof Saarbruecken-Guedingen

    Energy Technology Data Exchange (ETDEWEB)

    Schmid, Wolfgang [Wolfgang Schmid Pressebuero fuer Technische Gebaeudeausruestung, Muenchen (Germany)

    2011-06-15

    Green coldness is on the advance for the most German grocery chains. Especially, in the course of the R22 exit, more and more shopping centers opt for natural refrigerants or for a cascade solution with CO{sub 2} for the deep freezing and R404a for a normal refrigeration and air conditioning. Elektro-Kaeltebau Moersch GmbH (Saarburg, Federal Republic of Germany) is one of the green refrigeration system builders from the first hour in the implementation of energy-efficient and climate friendly refrigeration plants in the food sector. One of the current projects is the incorporation of a CO{sub 2}/R404A cascade during the operation in the Globus Handelshof in Saarbruecken-Guedingen (Federal Republic of Germany).

  5. 77 FR 20807 - Northwest Pipeline GP; Notice of Application

    Science.gov (United States)

    2012-04-06

    ... diameter pipelines away from an adjacent surface coal mine west of Kemmerer, Wyoming. Northwest also... directed to Pam Barnes, Manager Certificates and Tariffs, Northwest Pipeline GP, 295 Chipeta Way, Salt Lake...

  6. Leukemia: Derived heat shock protein gp96-peptide complex ...

    African Journals Online (AJOL)

    Jane

    2011-06-27

    Jun 27, 2011 ... Leukemia is a malignant clonal disease in hematopoietic stem cells that is typically treated with chemotherapy and radiotherapy. However ..... with autologous tumor-derived heatshock protein gp96 after liver resection for ...

  7. Videofluoroscopy of the pharynx and esophagus in patients with globus pharyngis. Comparison with static radiography; Die radiologische Abklaerung des Globus pharyngis. Vergleich der diagnostischen Wertigkeit von konventionellem Roentgen mit der Videokinematographie

    Energy Technology Data Exchange (ETDEWEB)

    Schober, E. [Abt. Roentgen fuer Konservative Faecher, Universitaetsklinik fuer Radiodiagnostik, Wien (Austria); Schima, W. [Abt. Roentgen fuer Konservative Faecher, Universitaetsklinik fuer Radiodiagnostik, Wien (Austria); Pokieser, P. [Abt. Roentgen fuer Chirurgische Faecher, Universitaetsklinik fuer Radiodiagnostik, Wien (Austria)

    1995-10-01

    The symptom is associated with a multitude of pharyngoesophageal abnormalities. Our study compares the diagnostic yield of videofluoroscopy to that of static radiography in patients suffering from globus pharnygis. A total of 150 consecutive patients complaining of a lump in the throat, but without evidence of dysphagia, were studied in a standardized fashion with both methods. Videofluoroscopy combined with static radiography revealed morphological or functional abnormalities in 75% of our patients. The combination of the two methods yielded significantly more abnormalities in the pharynx and esophagus than videofluoroscopy or static radiography alone. Esophageal motor disorders, pharyngoesophageal sphincter dysfunction and pharyngeal residue of contrast material proved to be the most common abnormalities. In conclusion, videofluoroscopy combined with static radiography is mandatory in the radiological assessment of patients suffering from the globus sensation. (orig.) [Deutsch] Unsere Studie vergleicht die diagnostische Wertigkeit des konventionellen Roentgens mit jener der Videokineamtographie von Pharynx und Oesophagus bei der Abklaerung des Globusgefuehls. Wir haben 150 konsekutive Patienten mit Globusgefuehl, jedoch ohne Dysphagie mit beiden Methoden nach einem standardisierten Protokoll untersucht. Mittels der Kombination von konventionellem Roentgen mit der Videokinematographie fanden sich bei 75% der Patienten pathologische Veraenderungen. Durch die Kombination beider Methoden konnten signifikant mehr morphologische und funktionelle Stoerungen des Pharynx sowie Oesophagus aufgezeigt werden, als mit der alleinigen konventionellen Technik oder der alleinigen Videokinematographie. Die haeufigsten pathologischen Veraenderungen in unserem Kollektiv waren Oesophagusmotilitaetsstoerungen, eine Dyskinesie des pharyngooesophagealen Sphinkters sowie eine abnorme pharyngeale Kontrastmittelretention. Unsere Ergebnisse belegen eindeutig, dass die radiologische

  8. Exploring resilience in rural GP registrars ? implications for training

    OpenAIRE

    Walters, Lucie; Laurence, Caroline O.; Dollard, Joanne; Elliott, Taryn; Eley, Diann S.

    2015-01-01

    Background Resilience can be defined as the ability to rebound from adversity and overcome difficult circumstances. General Practice (GP) registrars face many challenges in transitioning into general practice, and additional stressors and pressures apply for those choosing a career in rural practice. At this time of international rural generalist medical workforce shortages, it is important to focus on the needs of rural GP registrars and how to support them to become resilient health care pr...

  9. GP registrar well-being: a cross-sectional survey

    OpenAIRE

    Schattner, Peter; Mazalin, Dennis; Pier, Ciaran; Wainer, Jo; Ling, Mee Yoke

    2010-01-01

    Abstract Objectives To investigate the major stressors affecting GP registrars, how those at risk can be best identified and the most useful methods of managing or reducing their stress. Design, setting and participants Cross-sectional postal questionnaire of all GP registrars in one large regional training provider's catchment area. Main outcome measures The Depression, Anxiety and Stress Scale (DASS), a specifically developed Registrar Stressor Scale consisting of five subscales of potentia...

  10. Hypothalamic projections to the ventral medulla oblongata in the rat, with special reference to the nucleus raphe pallidus: a study using autoradiographic and HRP techniques

    Energy Technology Data Exchange (ETDEWEB)

    Hosoya, Yasuhiko

    1985-10-07

    Hypothalamic descending projections to the medullary ventral surface were studied autoradiographically in the rat. A small amount of (/sup 3/H)leucine was injected unilaterally into various parts of the hypothalamus by air pressure. Abundant and characteristic terminal labelings were observed bilaterally in the nucleus raphe pallidus, the ventral surface to the pyramidal tract and the nucleus interfascicularis hypoglossi, after injections into the dorsal posterior hypothalamic area caudal to the paraventricular hypothalamic nucleus. Conspicuous, but less numerous labelings were observed in the nucleus raphe obscurus and the ipsilateral raphe magnus. After an injection of (/sup 3/H)leucine into the hypothalamus and injections of horseradish peroxidase (HRP) into the spinal cord in the same animal, silver grains were densely distributed around HRP-labeled neurons in the nucleus raphe pallidus including the nucleus interfascicularis hypoglossi. The present results suggest that the dorsal posterior hypothalamic area projects directly to the spinal-projecting neurons of the nucleus raphe pallidus. 53 refs.; 9 figs.

  11. Exploring resilience in rural GP registrars--implications for training.

    Science.gov (United States)

    Walters, Lucie; Laurence, Caroline O; Dollard, Joanne; Elliott, Taryn; Eley, Diann S

    2015-07-02

    Resilience can be defined as the ability to rebound from adversity and overcome difficult circumstances. General Practice (GP) registrars face many challenges in transitioning into general practice, and additional stressors and pressures apply for those choosing a career in rural practice. At this time of international rural generalist medical workforce shortages, it is important to focus on the needs of rural GP registrars and how to support them to become resilient health care providers. This study sought to explore GP registrars' perceptions of their resilience and strategies they used to maintain resilience in rural general practice. In this qualitative interpretive research, semi-structured interviews were recorded, transcribed and analysed using an inductive approach. Initial coding resulted in a coding framework which was refined using constant comparison and negative case analysis. Authors developed consensus around the final conceptual model. Eighteen GP registrars from: Australian College of Rural and Remote Medicine Independent Pathway, and three GP regional training programs with rural training posts. Six main themes emerged from the data. Firstly, rural GP registrars described four dichotomous tensions they faced: clinical caution versus clinical courage; flexibility versus persistence; reflective practice versus task-focused practice; and personal connections versus professional commitment. Further themes included: personal skills for balance which facilitated resilience including optimistic attitude, self-reflection and metacognition; and finally GP registrars recognised the role of their supervisors in supporting and stretching them to enhance their clinical resilience. Resilience is maintained as on a wobble board by balancing professional tensions within acceptable limits. These limits are unique to each individual, and may be expanded through personal growth and professional development as part of rural general practice training.

  12. Axial complex and associated structures of the sea urchin Strongylocentrotus pallidus (Sars, G.O. 1871) (Echinodermata: Echinoidea).

    Science.gov (United States)

    Ezhova, Olga Vladimirovna; Malakhov, Vladimir Vasil'yevich; Egorova, Ekaterina Alekseevna

    2018-06-01

    Studies of echinoid microscopic anatomy over the last two centuries have created a number of inaccuracies and mistakes that have accumulated in the descriptions of the intricate organization of the coelomic system of Echinoidea. To clarify the situation, we reconstructed the axial complex and radial complex of the echinoid Strongylocentrotus pallidus. The water ring is located between the perivisceral coelom and the perioral coelom. The oral haemal ring lies between the coelothelia of the water-vascular, perivisceral, and perioral rings. The axial part of the axial organ communicates with the oral haemal ring in interradius CD, but the axial coelom does not form the axocoelomic perihaemal ring. The ventral intestinal haemal vessel originates from the oral haemal ring in radius A, and then branches into a network of capillaries, from which the dorsal intestinal vessel starts. The pericardial coelom envelopes the pericardial part of the axial organ, the lacunae of which communicate with the haemocoel of the body wall and with the axial part of the axial organ. The genital haemal ring and the dorsal intestinal vessel communicate with the axial organ. The genital coelom passes in the CD interradius on the side opposite to the hindgut. There is a somatocoelomic perihaemal ring, which sends a pair of coelomic outgrowths into each radius, accompanied by a radial haemal vessel in the oral part. The mistakes and inaccuracies of early descriptions of the echinoid axial complex are listed. The axial complex and associated structures of sea urchins are compared with other eleutherozoans. © 2018 Wiley Periodicals, Inc.

  13. Patient influences on satisfaction and loyalty for GP services.

    Science.gov (United States)

    Rundle-Thiele, Sharyn; Russell-Bennett, Rebekah

    2010-04-01

    Little is known about the influence that patients themselves have on their loyalty to a general practitioner (GP). Consequently, a theoretical framework that draws on diverse literature is proposed to suggest that along with satisfaction, patient loyalty is an important outcome for GPs. Comprising 174 Australian patients, this study identified that knowledgeable patients reported lower levels of loyalty while older patients and patients visiting a GP more frequently reported higher levels of loyalty. The results suggest that extending patient-centered care practices to encompass all patients may be warranted in order to improve patient satisfaction and loyalty. Further, future research opportunities abound, with intervention and dyadic research methodologies recommended.

  14. Yellow fever 17D-vectored vaccines expressing Lassa virus GP1 and GP2 glycoproteins provide protection against fatal disease in guinea pigs.

    Science.gov (United States)

    Jiang, Xiaohong; Dalebout, Tim J; Bredenbeek, Peter J; Carrion, Ricardo; Brasky, Kathleen; Patterson, Jean; Goicochea, Marco; Bryant, Joseph; Salvato, Maria S; Lukashevich, Igor S

    2011-02-01

    Yellow Fever (YF) and Lassa Fever (LF) are two prevalent hemorrhagic fevers co-circulating in West Africa and responsible for thousands of deaths annually. The YF vaccine 17D has been used as a vector for the Lassa virus glycoprotein precursor (LASV-GPC) or their subunits, GP1 (attachment glycoprotein) and GP2 (fusion glycoprotein). Cloning shorter inserts, LASV-GP1 and -GP2, between YF17D E and NS1 genes enhanced genetic stability of recombinant viruses, YF17D/LASV-GP1 and -GP2, in comparison with YF17D/LASV-GPC recombinant. The recombinant viruses were replication competent and properly processed YF proteins and LASV GP antigens in infected cells. YF17D/LASV-GP1 and -GP2 induced specific CD8+ T cell responses in mice and protected strain 13 guinea pigs against fatal LF. Unlike immunization with live attenuated reassortant vaccine ML29, immunization with YF17D/LASV-GP1 and -GP2 did not provide sterilizing immunity. This study demonstrates the feasibility of YF17D-based vaccine to control LF in West Africa. Copyright © 2010 Elsevier Ltd. All rights reserved.

  15. Yellow fever 17D-vectored vaccines expressing Lassa virus GP1 and GP2 glycoproteins provide protection against fatal disease in guinea pigs

    Science.gov (United States)

    Jiang, Xiaohong; Dalebout, Tim J.; Bredenbeek, Peter J.; Carrion, Ricardo; Brasky, Kathleen; Patterson, Jean; Goicochea, Marco; Bryant, Joseph; Salvato, Maria S.; Lukashevich, Igor S.

    2010-01-01

    Yellow Fever (YF) and Lassa Fever (LF) are two prevalent hemorrhagic fevers co-circulating in West Africa and responsible for thousands of deaths annually. The YF vaccine 17D has been used as a vector for the Lassa virus glycoprotein precursor (LASV-GPC) or their subunits, GP1 (attachment glycoprotein) and GP2 (fusion glycoprotein). Cloning shorter inserts, LASV GP1 and GP2, between YF17D E and NS1 genes enhanced genetic stability of recombinant viruses, YF17D/LASV-GP1 and –GP2, in comparison with YF17D/LASV-GPC recombinant. The recombinant viruses were replication competent and properly processed YF and LASV GP proteins in infected cells. YF17D/LASV-GP1&GP2 induced specific CD8+ T cell responses in mice and protected strain 13 guinea pigs against fatal LF. Unlike immunization with live attenuated reassortant vaccine ML29, immunization with YF17D/LASV-GP1&GP2 did not provide sterilizing immunity. This study demonstrates the feasibility of YF17D-based vaccine to control LF in West Africa. PMID:21145373

  16. A comparative immunogenicity study in rabbits of disulfide-stabilized, proteolytically cleaved, soluble trimeric human immunodeficiency virus type 1 gp140, trimeric cleavage-defective gp140 and monomeric gp120

    International Nuclear Information System (INIS)

    Beddows, Simon; Franti, Michael; Dey, Antu K.; Kirschner, Marc; Iyer, Sai Prasad N.; Fisch, Danielle C.; Ketas, Thomas; Yuste, Eloisa; Desrosiers, Ronald C.; Klasse, Per Johan; Maddon, Paul J.; Olson, William C.; Moore, John P.

    2007-01-01

    The human immunodeficiency virus type 1 (HIV-1) surface envelope glycoprotein (Env) complex, a homotrimer containing gp120 surface glycoprotein and gp41 transmembrane glycoprotein subunits, mediates the binding and fusion of the virus with susceptible target cells. The Env complex is the target for neutralizing antibodies (NAbs) and is the basis for vaccines intended to induce NAbs. Early generation vaccines based on monomeric gp120 subunits did not confer protection from infection; one alternative approach is therefore to make and evaluate soluble forms of the trimeric Env complex. We have directly compared the immunogenicity in rabbits of two forms of soluble trimeric Env and monomeric gp120 based on the sequence of HIV-1 JR-FL . Both protein-only and DNA-prime, protein-boost immunization formats were evaluated, DNA-priming having little or no influence on the outcome. One form of trimeric Env was made by disrupting the gp120-gp41 cleavage site by mutagenesis (gp140 UNC ), the other contains an intramolecular disulfide bond to stabilize the cleaved gp120 and gp41 moieties (SOSIP.R6 gp140). Among the three immunogens, SOSIP.R6 gp140 most frequently elicited neutralizing antibodies against the homologous, neutralization-resistant strain, HIV-1 JR-FL . All three proteins induced NAbs against more sensitive strains, but the breadth of activity against heterologous primary isolates was limited. When antibodies able to neutralize HIV-1 JR-FL were detected, antigen depletion studies showed they were not directed at the V3 region but were targeted at other, undefined gp120 and also non-gp120 epitopes

  17. Optional part-time and longer GP training modules in GP practices associated with more trainees becoming GPs - a cohort study in Switzerland.

    Science.gov (United States)

    Studerus, Lara; Ahrens, Regina; Häuptle, Christian; Goeldlin, Adrian; Streit, Sven

    2018-01-05

    Switzerland, like many other countries, has a shortage of General Practitioners (GPs). Optional GP training modules in GP practices were offered during the at least 5-year GP training program to increase student and trainee interest in becoming a GP. The training modules had not yet been evaluated. We determined how many Swiss GP trainees became practicing GPs after they completed optional training modules, and if longer modules were associated with higher rates of GP specialization. In this population-based cohort study, we included GP trainees who chose an optional GP training module in GP practice, provided by the Foundation to Promote Training in General Practice (WHM) between 2006 and 2015. GP trainees were invited to complete an online survey to assess the primary outcome (becoming a practicing GP by 2016). Data on non-responders was collected via an internet search. We calculated univariate time-to-event curves to become a practicing GP, stratified by trainee's gender, length, part-time training, and number of years after graduation until training modules were completed. We used a multivariate model to adjust for characteristics of participants, training, and satisfaction with training modules. We assessed primary outcome for 351 (92.1%) of 381 former GP trainees who participated in a WHM program between 2006 and 2015. Of these 218 (57%) were practicing GPs by 2016. When focusing on the trainees who had completed training between 2006 and 2010, the rate of practicing GPs was even 73%. Longer (p = 0.018) and part-time training modules (p = 0.003) were associated with higher rates of being a practicing GP. Most (81%) practicing GPs thought their optional GP training module was (very) important in their choice of specialty. GP trainees who spent more time training in a GP practice, or who trained part-time were more likely to become practicing GPs. Most (80%) rated their training module as (very) important in their choice of career, highlighting that

  18. Potable Water Treatment Facility General Permit (PWTF GP) ...

    Science.gov (United States)

    2017-08-28

    The Final PWTF GP establishes permit eligibility conditions, Notice of Intent (NOI) requirements, effluent limitations, standards, prohibitions, and best management practices for facilities that discharge to waters in the Commonwealth of Massachusetts (including both Commonwealth and Indian country lands) and the State of New Hampshire.

  19. GP registrar well-being: a cross-sectional survey

    Directory of Open Access Journals (Sweden)

    Schattner Peter

    2010-02-01

    Full Text Available Abstract Objectives To investigate the major stressors affecting GP registrars, how those at risk can be best identified and the most useful methods of managing or reducing their stress. Design, setting and participants Cross-sectional postal questionnaire of all GP registrars in one large regional training provider's catchment area. Main outcome measures The Depression, Anxiety and Stress Scale (DASS, a specifically developed Registrar Stressor Scale consisting of five subscales of potential stressors, plus closed questions on how to identify and manage stress in GP registrars. Results Survey response rate of 51% (102/199. Rural difficulties followed by achieving a work/life balance were the principal stressors. Ten percent of registrars were mildly or moderately depressed or anxious (DASS and 7% mild to moderately anxious (DASS. Registrars preferred informal means of identifying those under stress (a buddy system and talks with their supervisors; similarly, they preferred to manage stress by discussions with family and friends, debriefing with peers and colleagues, or undertaking sport and leisure activities. Conclusions This study supports research which confirms that poor psychological well-being is an important issue for a significant minority of GP trainees. Regional training providers should ensure that they facilitate formal and informal strategies to identify those at risk and assist them to cope with their stress.

  20. Do practice nurse solve future GP capacity problems?

    NARCIS (Netherlands)

    Lamkaddem, M.; Haan, J. de; Bakker, D. de

    2003-01-01

    Background: Task delegation is viewed as an important policy instrument to counter foreseen future shortages in GP capacity in the Netherlands. Therefore, a national programme to introduce practice nurses in general practice was launched in 1998 by the National Association of General Practice. In

  1. GP registrar well-being: a cross-sectional survey.

    Science.gov (United States)

    Schattner, Peter; Mazalin, Dennis; Pier, Ciaran; Wainer, Jo; Ling, Mee Yoke

    2010-02-09

    To investigate the major stressors affecting GP registrars, how those at risk can be best identified and the most useful methods of managing or reducing their stress. Cross-sectional postal questionnaire of all GP registrars in one large regional training provider's catchment area. The Depression, Anxiety and Stress Scale (DASS), a specifically developed Registrar Stressor Scale consisting of five subscales of potential stressors, plus closed questions on how to identify and manage stress in GP registrars. Survey response rate of 51% (102/199). Rural difficulties followed by achieving a work/life balance were the principal stressors. Ten percent of registrars were mildly or moderately depressed or anxious (DASS) and 7% mild to moderately anxious (DASS). Registrars preferred informal means of identifying those under stress (a buddy system and talks with their supervisors); similarly, they preferred to manage stress by discussions with family and friends, debriefing with peers and colleagues, or undertaking sport and leisure activities. This study supports research which confirms that poor psychological well-being is an important issue for a significant minority of GP trainees. Regional training providers should ensure that they facilitate formal and informal strategies to identify those at risk and assist them to cope with their stress.

  2. Blended learning in CME: the perception of GP trainers

    NARCIS (Netherlands)

    te Pas, E.; Meinema, J. G.; Visser, M. R. M.; van Dijk, N.

    2016-01-01

    Blended learning (the combination of electronic methods with traditional teaching methods) has the potential to combine the best of traditional education with the best of computer-mediated training. We chose to develop such an intervention for GP trainers who were undertaking a Continuing Medical

  3. Assessment of reliability of Greulich and Pyle (gp) method for ...

    African Journals Online (AJOL)

    Background: Greulich and Pyle standards are the most widely used age estimation standards all over the world. The applicability of the Greulich and Pyle standards to populations which differ from their reference population is often questioned. This study aimed to assess the reliability of Greulich and Pyle (GP) method for ...

  4. Numerical study of the elastic-plastic cyclic deformation of the ''GLOBUS-M'' compact tokamak central solenoid

    International Nuclear Information System (INIS)

    Bykov, V.; Kavin, A.; Krivchenkov, Y.; Panin, A.

    1996-01-01

    The ''GLOBUS-M'' is a compact resistive tokamak with a central solenoid (CS) wound around the inner portion of the toroidal field coils. The magnetic field at the solenoid axis amounts to 8.3 T. The CS incorporates two layers of conductor (CuCr copper alloy) baked into insulation. The solenoid is designed to sustain 80,000 energizing. During each loading cycle the solenoid is subjected to the radial forces accompanied with the vertical compression. The most loaded region has been considered and modeled with the use of 2D axisymmetric finite element (FE) model. The model includes two conductor turns baked into insulation compound, copper cooling tubes and solder. The stress analysis shows that there is some plastic deformation in the copper tube and solder during loading and there is some back plastic deformation in the solder during unloading. The reloading does not cause any change in the solenoid stress-strain state in comparison with the case of loading. The number of cycles to failure has been simulated for all metallic components of the solenoid

  5. An Extended Design of the "Grid-Enabled SEE++ System" Based on Globus Toolkit 4 and gLite Conference

    CERN Document Server

    Schreiner, W.; Buchberger, M.; Kaltofen, T.

    2006-01-01

    "Grid-Enabled SEE++" based on the SEE++ software system for the biomechanical 3D simulation of the human eye and its muscles. SEE++ simulates the common eye muscle surgery techniques in a graphic interactive way that is familiar to an experienced surgeon. The goal of "Grid-Enabled SEE++" is to adapt and to extend SEE++ in several steps and to develop an efficient grid-based tool for "Evidence Based Medicine", which supports the surgeons in choosing optimal surgery techniques for the treatments of different syndromes of strabismus. In our previous work, we combined the SEE++ software with the Globus (pre-Web Service) middleware and developed a parallel version of the simulation of the "Hess-Lancaster test" (typical medical examination). By this, we demonstrated how a noticeable speedup can be achieved in SEE++ by the exploitation of the computational power of the Grid. Furthermore, we reported the prototype implementation of a medical database component for "Grid-Enabled SEE++". Finally, we designed a so calle...

  6. Managerialism and the British GP: the GP as manager and as managed.

    Science.gov (United States)

    Warwicker, T

    1998-01-01

    The focus of the paper is on the relationship between General Practitioners (GPs) and central government. This relationship dates from the introduction of national health insurance in the UK. From the outset it had an impact on GPs' medical role, their professional status and income. The structure created in 1911 meant that GPs operated as franchisees and, notwithstanding Labour's policy objective of creating a salaried service, this role continued, effectively unchanged, after the creation of the National Health Service (NHS) in 1948. General practice was also the poor relation in contrast to hospital medicine, a feature intensified by the priorities of the NHS. These forces meant that GPs had a dual role: that of clinician and gatekeeper to specialist hospital services, a role in which they exercised substantial clinical freedom: and running a small business, a feature which was exaggerated by the absence of grant aid to improve premises prior to the Family Doctor Charter of 1965. This structural relationship has been progressively transformed by changes in the 1980s and 1990s. On the one hand the emphasis on cost control has seen central government attempting to combine a financial with a clinical gate-keeping keeping role. The crucial change in this respect is the creation of GP fundholding which, in turn, could be seen to have implications for the subordinate status of GPs within the medical profession. However, this has been combined with trends to greater measures of control over GPs. Of central importance in this respect were the changes introduced by the 1990 GP contract. The contract involved an attempt to substantially reduce clinical autonomy by building in much more detailed contractual duties with respect, for example, to health promotion activities. This was combined with the use of financial incentives to reach, for example, immunization targets. Control over clinical autonomy has also involved constraints over prescribing and the shift from Family

  7. CGP lil-gp 2.1;1.02 User's Manual

    Science.gov (United States)

    Janikow, Cezary Z.; DeWeese, Scott W.

    1997-01-01

    This document describes extensions provided to lil-gp facilitating dealing with constraints. This document deals specifically with lil-gp 1.02, and the resulting extension is referred to as CGP lil-gp 2.1; 1.02 (the first version is for the extension, the second for the utilized lil-gp version). Unless explicitly needed to avoid confusion, version numbers are omitted.

  8. Attitudes towards obesity treatment in GP training practices: a focus group study

    NARCIS (Netherlands)

    Jochemsen-van der Leeuw, H. G. A.; van Dijk, N.; Wieringa-de Waard, M.

    2011-01-01

    Both patients and government expect the GP to treat obesity. Previous studies reported a negative attitude of GPs towards this task. Little is known about the attitude of GP trainees. To assess the attitude and other factors that influence the willingness and ability of GP trainees to provide

  9. Why are some patients in treatment for advanced cancer reluctant to consult their GP?

    DEFF Research Database (Denmark)

    Åbom, Birgit; Pfeiffer, Per

    2009-01-01

    and therefore consulted the doctor or the staff at the cancer treatment centre before seeking advice from their GP. Some patients found that the GP was not familiar enough with the treatments given; others that they did not want to inconvenience the busy GP with what they perceived to be minor non...

  10. Low-frequency stimulation of the external globus palladium produces anti-epileptogenic and anti-ictogenic actions in rats.

    Science.gov (United States)

    Cheng, Hui; Kuang, Yi-fang; Liu, Yang; Wang, Yi; Xu, Zheng-hao; Gao, Feng; Zhang, Shi-hong; Ding, Mei-ping; Chen, Zhong

    2015-08-01

    To investigate the anti-epileptic effects of deep brain stimulation targeting the external globus palladium (GPe) in rats. For inducing amygdala kindling and deep brain stimulation, bipolar stainless-steel electrodes were implanted in SD rats into right basolateral amygdala and right GPe, respectively. The effects of deep brain stimulation were evaluated in the amygdala kindling model, maximal electroshock model (MES) and pentylenetetrazole (PTZ) model. Moreover, the background EEGs in the amygdala and GPe were recorded. Low-frequency stimulation (0.1 ms, 1 Hz, 15 min) at the GPe slowed the progression of seizure stages and shortened the after-discharge duration (ADD) during kindling acquisition. Furthermore, low-frequency stimulation significantly decreased the incidence of generalized seizures, suppressed the average stage, and shortened the cumulative ADD and generalized seizure duration in fully kindled rats. In addition, low-frequency stimulation significantly suppressed the average stage of MES-induced seizures and increased the latency to generalized seizures in the PTZ model. High-frequency stimulation (0.1 ms, 130 Hz, 5 min) at the GPe had no anti-epileptic effect and even aggravated epileptogenesis induced by amygdala kindling. EEG analysis showed that low-frequency stimulation at the GPe reversed the increase in delta power, whereas high-frequency stimulation at the GPe had no such effect. Low-frequency stimulation, but not high-frequency stimulation, at the GPe exerts therapeutic effect on temporal lobe epilepsy and tonic-colonic generalized seizures, which may be due to interference with delta rhythms. The results suggest that modulation of GPe activity using low-frequency stimulation or drugs may be a promising epilepsy treatment.

  11. Lessons learned from an Internet GP information system.

    Science.gov (United States)

    Briggs, J S; Bradley, M P

    1998-01-01

    We describe the prototype of an application that in actual use would allow GPs to find out more information about consultants at hospitals. This would aid the GP in making the decision about which consultant a patient should be referred to. The requirements of the application from the GP's perspective are described, together with some of the issues that have to be resolved before hospitals can provide the necessary information in a standard format. The application is implemented as a client--server system using standard Internet technologies such as Java and HTML. This architecture has a number of advantages but also revealed some issues concerning security and the format of data, among other things. The project showed that there is a desire for such a system and that that desire can be fulfilled at a relatively low cost.

  12. HIV-gp120 and physical dependence to buprenorphine.

    Science.gov (United States)

    Palma, J; Abood, M E; Benamar, K

    2015-05-01

    Opioids are among the most effective and commonly used analgesics in clinical practice for severe pain. However, the use of opioid medications is clinically limited by several adverse properties including dependence. While opioid dependence is a complex health condition, the treatment of HIV-infected individuals with opioid dependence presents additional challenges. The goal of this study was to examine the physical dependence to buprenorphine in the context of HIV. Young adult male rats (Sprague-Dawley) were pretreated with HIV-1 envelope glycoprotein 120 (gp120) injected into the periaqueductal gray area (PAG) and we examined the impact on physical dependence to opioid. It was found that the physical dependence to methadone occurred earlier than that to buprenorphine, and that gp120 did not enhance or precipitate the buprenorphine withdrawal. The results suggest that buprenorphine could be the better therapeutic option to manage opioid dependence in HIV. Copyright © 2015. Published by Elsevier Ireland Ltd.

  13. Anti-HIV double variable domain immunoglobulins binding both gp41 and gp120 for targeted delivery of immunoconjugates.

    Directory of Open Access Journals (Sweden)

    Ryan B Craig

    Full Text Available BACKGROUND: Anti-HIV immunoconjugates targeted to the HIV envelope protein may be used to eradicate the latent reservoir of HIV infection using activate-and-purge protocols. Previous studies have identified the two target epitopes most effective for the delivery of cytotoxic immunoconjugates the CD4-binding site of gp120, and the hairpin loop of gp41. Here we construct and test tetravalent double variable domain immunoglobulin molecules (DVD-Igs that bind to both epitopes. METHODS: Synthetic genes that encode DVD-Igs utilizing V-domains derived from human anti-gp120 and anti-gp41 Abs were designed and expressed in 293F cells. A series of constructs tested different inter-V-linker domains and orientations of the two V domains. Antibodies were tested for binding to recombinant Ag and native Env expressed on infected cells, for neutralization of infectious HIV, and for their ability to deliver cytotoxic immunoconjugates to infected cells. FINDINGS: The outer V-domain was the major determinant of binding and functional activity of the DVD-Ig. Function of the inner V-domain and bifunctional binding required at least 15 AA in the inter-V-domain linker. A molecular model showing the spatial orientation of the two epitopes is consistent with this observation. Linkers that incorporated helical domains (A[EAAAK](nA resulted in more effective DVD-Igs than those based solely on flexible domains ([GGGGS](n. In general, the DVD-Igs outperformed the less effective parental antibody and equaled the activity of the more effective. The ability of the DVD-Igs to deliver cytotoxic immunoconjugates in the absence of soluble CD4 was improved over that of either parent. CONCLUSIONS: DVD-Igs can be designed that bind to both gp120 and gp41 on the HIV envelope. DVD-Igs are effective in delivering cytotoxic immunoconjugates. The optimal design of these DVD-Igs, in which both domains are fully functional, has not yet been achieved.

  14. Blended learning in CME: the perception of GP trainers.

    Science.gov (United States)

    Te Pas, E; Meinema, J G; Visser, M R M; van Dijk, N

    2016-05-01

    Blended learning (the combination of electronic methods with traditional teaching methods) has the potential to combine the best of traditional education with the best of computer-mediated training. We chose to develop such an intervention for GP trainers who were undertaking a Continuing Medical Education (CME) course in evidence-based medicine (EBM). This study reports on our experience and investigated the factors influencing the perception on usefulness and logistics of blended learning for learners in CME. In total, 170 GP trainers participated in the intervention. We used questionnaires, observations during the four face-to-face meetings and evaluations in the e-course over one year. Additionally we organised focus groups to gain insight in some of the outcomes of the questionnaires and interpretations of the observations. The GP trainers found the design and the educational method (e-course in combination with meetings) attractive, instructive and complementary. Factors influencing their learning were (1) educational design, (2) educational method, (3) topic of the intervention, (4) time (planning), (5) time (intervention), (6) learning style, (7) technical issues, (8) preconditions and (9) level of difficulty. A close link between daily practice and the educational intervention was considered an important precondition for the success of the intervention in this group of learners. GP trainers were positive about blended learning: they found e-learning a useful way to gain knowledge and the meetings a pleasant way of transferring the knowledge into practice. Although some preconditions should be taken into consideration during its development and implementation, they would participate in similarly designed learning in the future.

  15. GP140/CDCPI in the Development of Prostate Cancer Metastasis

    Science.gov (United States)

    2013-09-01

    localization of Gp140 to the plasma membrane of prostate epithelial cells is decreased or lost in PIN, invasive and metastatic prostate cancers when...Matrigel (BD Biosciences, Franklin Lakes, NJ) at 2000 cells per well. Spheroid structures were extracted and expanded in regu- lar tissue culture, and...cell surface (Figure 2A). Some surface-negative cells express E-cadherin in the cytoplasm. Cells were cultured in Matrigel, and spheroid structures

  16. Basket Option Pricing Using GP-GPU Hardware Acceleration

    KAUST Repository

    Douglas, Craig C.

    2010-08-01

    We introduce a basket option pricing problem arisen in financial mathematics. We discretized the problem based on the alternating direction implicit (ADI) method and parallel cyclic reduction is applied to solve the set of tridiagonal matrices generated by the ADI method. To reduce the computational time of the problem, a general purpose graphics processing units (GP-GPU) environment is considered. Numerical results confirm the convergence and efficiency of the proposed method. © 2010 IEEE.

  17. Membrane topology analysis of HIV-1 envelope glycoprotein gp41

    Directory of Open Access Journals (Sweden)

    Xiao Dan

    2010-11-01

    Full Text Available Abstract Background The gp41 subunit of the HIV-1 envelope glycoprotein (Env has been widely regarded as a type I transmembrane protein with a single membrane-spanning domain (MSD. An alternative topology model suggested multiple MSDs. The major discrepancy between the two models is that the cytoplasmic Kennedy sequence in the single MSD model is assigned as the extracellular loop accessible to neutralizing antibodies in the other model. We examined the membrane topology of the gp41 subunit in both prokaryotic and mammalian systems. We attached topological markers to the C-termini of serially truncated gp41. In the prokaryotic system, we utilized a green fluorescent protein (GFP that is only active in the cytoplasm. The tag protein (HaloTag and a membrane-impermeable ligand specific to HaloTag was used in the mammalian system. Results In the absence of membrane fusion, both the prokaryotic and mammalian systems (293FT cells supported the single MSD model. In the presence of membrane fusion in mammalian cells (293CD4 cells, the data obtained seem to support the multiple MSD model. However, the region predicted to be a potential MSD is the highly hydrophilic Kennedy sequence and is least likely to become a MSD based on several algorithms. Further analysis revealed the induction of membrane permeability during membrane fusion, allowing the membrane-impermeable ligand and antibodies to cross the membrane. Therefore, we cannot completely rule out the possible artifacts. Addition of membrane fusion inhibitors or alterations of the MSD sequence decreased the induction of membrane permeability. Conclusions It is likely that a single MSD model for HIV-1 gp41 holds true even in the presence of membrane fusion. The degree of the augmentation of membrane permeability we observed was dependent on the membrane fusion and sequence of the MSD.

  18. Impact of Leishmania metalloprotease GP63 on macrophage signaling

    Science.gov (United States)

    Isnard, Amandine; Shio, Marina T.; Olivier, Martin

    2012-01-01

    The intramacrophage protozoan parasites of Leishmania genus have developed sophisticated ways to subvert the innate immune response permitting their infection and propagation within the macrophages of the mammalian host. Several Leishmania virulence factors have been identified and found to be of importance for the development of leishmaniasis. However, recent findings are now further reinforcing the critical role played by the zinc-metalloprotease GP63 as a virulence factor that greatly influence host cell signaling mechanisms and related functions. GP63 has been found to be involved not only in the cleavage and degradation of various kinases and transcription factors, but also to be the major molecule modulating host negative regulatory mechanisms involving for instance protein tyrosine phosphatases (PTPs). Those latter being well recognized for their pivotal role in the regulation of a great number of signaling pathways. In this review article, we are providing a complete overview about the role of Leishmania GP63 in the mechanisms underlying the subversion of macrophage signaling and functions. PMID:22919663

  19. Structural Basis for Species Selectivity in the HIV-1 gp120-CD4 Interaction: Restoring Affinity to gp120 in Murine CD4 Mimetic Peptides

    Directory of Open Access Journals (Sweden)

    Kristin Kassler

    2011-01-01

    Full Text Available The first step of HIV-1 infection involves interaction between the viral glycoprotein gp120 and the human cellular receptor CD4. Inhibition of the gp120-CD4 interaction represents an attractive strategy to block HIV-1 infection. In an attempt to explore the known lack of affinity of murine CD4 to gp120, we have investigated peptides presenting the putative gp120-binding site of murine CD4 (mCD4. Molecular modeling indicates that mCD4 protein cannot bind gp120 due to steric clashes, while the larger conformational flexibility of mCD4 peptides allows an interaction. This finding is confirmed by experimental binding assays, which also evidenced specificity of the peptide-gp120 interaction. Molecular dynamics simulations indicate that the mCD4-peptide stably interacts with gp120 via an intermolecular β-sheet, while an important salt-bridge formed by a C-terminal lysine is lost. Fixation of the C-terminus by introducing a disulfide bridge between the N- and C-termini of the peptide significantly enhanced the affinity to gp120.

  20. Conceptualising GP teachers' knowledge: a pedagogical content knowledge perspective.

    Science.gov (United States)

    Cantillon, Peter; de Grave, Willem

    2012-05-01

    Most teacher development initiatives focus on enhancing knowledge of teaching (pedagogy), whilst largely ignoring other important features of teacher knowledge such as subject matter knowledge and awareness of the learning context. Furthermore, teachers' ability to learn from faculty development interventions is limited by their existing (often implicit) pedagogical knowledge and beliefs. Pedagogical content knowledge (PCK) represents a model of teacher knowledge incorporating what they know about subject matter, pedagogy and context. PCK can be used to explore teachers' prior knowledge and to structure faculty development programmes so that they take account of a broader range of teachers' knowledge. We set out to examine the application of a PCK model in a general practice education setting. This study is part of a larger study that employed a mixed method approach (concept mapping, phenomenological interviews and video-stimulated recall) to explore features of GP teachers' subject matter knowledge, pedagogical knowledge and knowledge of the learning environment in the context of a general practice tutorial. This paper presents data on GP teachers' pedagogical and context knowledge. There was considerable overlap between different GP teachers' knowledge and beliefs about learners and the clinical learning environment (i.e. knowledge of context). The teachers' beliefs about learners were largely based on assumptions derived from their own student experiences. There were stark differences, however, between teachers in terms of pedagogical knowledge, particularly in terms of their teaching orientations (i.e. transmission or facilitation orientation) and this was manifest in their teaching behaviours. PCK represents a useful model for conceptualising clinical teacher prior knowledge in three domains, namely subject matter, learning context and pedagogy. It can and should be used as a simple guiding framework by faculty developers to inform the design and delivery of

  1. The GP problem: quantifying gene-to-phenotype relationships.

    Science.gov (United States)

    Cooper, Mark; Chapman, Scott C; Podlich, Dean W; Hammer, Graeme L

    2002-01-01

    In this paper we refer to the gene-to-phenotype modeling challenge as the GP problem. Integrating information across levels of organization within a genotype-environment system is a major challenge in computational biology. However, resolving the GP problem is a fundamental requirement if we are to understand and predict phenotypes given knowledge of the genome and model dynamic properties of biological systems. Organisms are consequences of this integration, and it is a major property of biological systems that underlies the responses we observe. We discuss the E(NK) model as a framework for investigation of the GP problem and the prediction of system properties at different levels of organization. We apply this quantitative framework to an investigation of the processes involved in genetic improvement of plants for agriculture. In our analysis, N genes determine the genetic variation for a set of traits that are responsible for plant adaptation to E environment-types within a target population of environments. The N genes can interact in epistatic NK gene-networks through the way that they influence plant growth and development processes within a dynamic crop growth model. We use a sorghum crop growth model, available within the APSIM agricultural production systems simulation model, to integrate the gene-environment interactions that occur during growth and development and to predict genotype-to-phenotype relationships for a given E(NK) model. Directional selection is then applied to the population of genotypes, based on their predicted phenotypes, to simulate the dynamic aspects of genetic improvement by a plant-breeding program. The outcomes of the simulated breeding are evaluated across cycles of selection in terms of the changes in allele frequencies for the N genes and the genotypic and phenotypic values of the populations of genotypes.

  2. Determinants of a GP visit and cervical cancer screening examination in Great Britain.

    Directory of Open Access Journals (Sweden)

    Alexander Michael Labeit

    Full Text Available In the UK, women are requested to attend a cervical cancer test every 3 years as part of the NHS Cervical Screening Programme. This analysis compares the determinants of a cervical cancer screening examination with the determinants of a GP visit in the same year and investigates if cervical cancer screening participation is more likely for women who visit their GP.A recursive probit model was used to analyse the determinants of GP visits and cervical cancer screening examinations. GP visits were considered to be endogenous in the cervical cancer screening examination. The analysed sample consisted of 52,551 observations from 8,386 women of the British Household Panel Survey.The analysis showed that a higher education level and a worsening self-perceived health status increased the probability of a GP visit, whereas smoking decreased the probability of a GP visit. GP visits enhanced the uptake of a cervical cancer screening examination in the same period. The only variables which had the same positive effect on both dependent variables were higher education and living with a partner. The probability of a cervical cancer screening examination increased also with previous cervical cancer screening examinations and being in the recommended age groups. All other variables had different results for the uptake of a GP visit or a cervical cancer screening examination.Most of the determinants of visiting a GP and cervical cancer screening examination differ from each other and a GP visit enhances the uptake of a smear test.

  3. Parallelized Local Volatility Estimation Using GP-GPU Hardware Acceleration

    KAUST Repository

    Douglas, Craig C.

    2010-01-01

    We introduce an inverse problem for the local volatility model in option pricing. We solve the problem using the Levenberg-Marquardt algorithm and use the notion of the Fréchet derivative when calculating the Jacobian matrix. We analyze the existence of the Fréchet derivative and its numerical computation. To reduce the computational time of the inverse problem, a GP-GPU environment is considered for parallel computation. Numerical results confirm the validity and efficiency of the proposed method. ©2010 IEEE.

  4. "Zolotoi globus" dostalsja "Vaviljonu"

    Index Scriptorium Estoniae

    2007-01-01

    Kuldse Gloobuse auhinna draamakategoorias sai mängufilm "Paabel" ("Babel") : režissöör Alejandro Gonzalez Inarritu : Ameerika Ühendriigid - Mehhiko, 2006. Ka teised Golden Globe filmiauhinna saajad

  5. Cannabidiol changes P-gp and BCRP expression in trophoblast cell lines

    Directory of Open Access Journals (Sweden)

    Valeria Feinshtein

    2013-09-01

    Full Text Available Objectives. Marijuana is the most commonly used illicit drug during pregnancy. Due to high lipophilicity, cannabinoids can easily penetrate physiological barriers like the human placenta and jeopardize the developing fetus. We evaluated the impact of cannabidiol (CBD, a major non-psychoactive cannabinoid, on P-glycoprotein (P-gp and Breast Cancer Resistance Protein (BCRP expression, and P-gp function in a placental model, BeWo and Jar choriocarcinoma cell lines (using P-gp induced MCF7 cells (MCF7/P-gp for comparison. Study design. Following the establishment of the basal expression of these transporters in the membrane fraction of all three cell lines, P-gp and BCRP protein and mRNA levels were determined following chronic (24–72 h exposure to CBD, by Western Blot and qPCR. CBD impact on P-gp efflux function was examined by uptake of specific P-gp fluorescent substrates (calcein-AM, DiOC2(3 and rhodamine123(rh123. Cyclosporine A (CsA served as a positive control. Results. Chronic exposure to CBD resulted in significant changes in the protein and mRNA levels of both transporters. While P-gp was down-regulated, BCRP levels were up-regulated in the choriocarcinoma cell lines. CBD had a remarkably different influence on P-gp and BCRP expression in MCF7/P-gp cells, demonstrating that these are cell type specific effects. P-gp dependent efflux (of calcein, DiOC2(3 and rh123 was inhibited upon short-term exposure to CBD. Conclusions. Our study shows that CBD might alter P-gp and BCRP expression in the human placenta, and inhibit P-gp efflux function. We conclude that marijuana use during pregnancy may reduce placental protective functions and change its morphological and physiological characteristics.

  6. A study into the effectiveness of unqualified GP assistants.

    Science.gov (United States)

    Philip, Marilyn; Turnbull, Betty

    This article aims to address the potential shortfall in care provision offered by general practitioners (GPs) resulting from pending retirement and the retention and recruitment crisis. An educational module was developed that offered both theory and practise to unqualified general practice assistants. The module content was determined following discussion with local GPs. A small qualitative study of six students was carried out to review efficacy of participants in their new role. Using a grounded theory approach, participant and supervisor views of course content and delivery, role preparation diversity were analysed and compared. Tape-recorded interviews were conducted and analysis carried out employing the constant comparative method. Data were coded and emergent themes categorized. Overall, participants agreed that the module had strengthened their knowledge, added new skills, heightened their job satisfaction, added significant diversity to their role and enhanced their employability potential. Five participants communicated that they were more confident in performing clinical skills and advising health improvement techniques. Supervisors also reported that participants displayed a more competent and professional approach to health care, which was complementary to the role of the GP and practice nurse. Ultimately this allowed both GP and practice nurse to focus on dealing with chronic illness targets, as required in the new directive (Scottish Executive, 2004).

  7. Asthma control in general practice -- GP and patient perspectives compared.

    Science.gov (United States)

    Henderson, Joan; Hancock, Kerry L; Armour, Carol; Harrison, Christopher; Miller, Graeme

    2013-10-01

    How general practitioners (GPs) and patients perceive asthma control, and concordance between these perceptions, may influence asthma management and medication adherence. The aims of this study were to determine asthma prevalence in adult patients, measure patient asthma control and the correlation between GP and patient perceptions of asthma control or impact. A Supplementary Analysis of Nominated Data (SAND) sub-study of the Bettering the Evaluation and Care of Health (BEACH) program surveyed 2563 patients from 103 GPs. Asthma control was measured using the Asthma Control Questionnaire 5-item version (ACQ-5), and medication adherence by patient self-report. Survey procedures in SAS software and Pearson's correlation statistics were used. Asthma prevalence was 12.7% (95% confidence interval: 10.9-14.5), with good correlation between GP and patient perceptions of asthma control/impact, and with raw ACQ-5 scores. Grouped ACQ-5 scores showed higher levels of uncontrolled asthma. Medication adherence was sub-optimal. The ACQ-5 questions are useful for assessing asthma control, for prompting medication reviews, and for reinforcing benefits of medication compliance to improve long-term asthma control.

  8. Proteomics computational analyses suggest that baculovirus GP64 superfamily proteins are class III penetrenes

    Directory of Open Access Journals (Sweden)

    Garry Robert F

    2008-02-01

    Full Text Available Abstract Background Members of the Baculoviridae encode two types of proteins that mediate virus:cell membrane fusion and penetration into the host cell. Alignments of primary amino acid sequences indicate that baculovirus fusion proteins of group I nucleopolyhedroviruses (NPV form the GP64 superfamily. The structure of these viral penetrenes has not been determined. The GP64 superfamily includes the glycoprotein (GP encoded by members of the Thogotovirus genus of the Orthomyxoviridae. The entry proteins of other baculoviruses, group II NPV and granuloviruses, are class I penetrenes. Results Class III penetrenes encoded by members of the Rhabdoviridae and Herpesviridae have an internal fusion domain comprised of beta sheets, other beta sheet domains, an extended alpha helical domain, a membrane proximal stem domain and a carboxyl terminal anchor. Similar sequences and structural/functional motifs that characterize class III penetrenes are located collinearly in GP64 of group I baculoviruses and related glycoproteins encoded by thogotoviruses. Structural models based on a prototypic class III penetrene, vesicular stomatitis virus glycoprotein (VSV G, were established for Thogoto virus (THOV GP and Autographa california multiple NPV (AcMNPV GP64 demonstrating feasible cysteine linkages. Glycosylation sites in THOV GP and AcMNPV GP64 appear in similar model locations to the two glycosylation sites of VSV G. Conclusion These results suggest that proteins in the GP64 superfamily are class III penetrenes.

  9. The pancreatic zymogen granule membrane protein, GP2, binds Escherichia coli type 1 Fimbriae

    Directory of Open Access Journals (Sweden)

    Lowe Anson W

    2009-07-01

    Full Text Available Abstract Background GP2 is the major membrane protein present in the pancreatic zymogen granule, and is cleaved and released into the pancreatic duct along with exocrine secretions. The function of GP2 is unknown. GP2's amino acid sequence is most similar to that of uromodulin, which is secreted by the kidney. Recent studies have demonstrated uromodulin binding to bacterial Type 1 fimbria. The fimbriae serve as adhesins to host receptors. The present study examines whether GP2 also shares similar binding properties to bacteria with Type 1 fimbria. Commensal and pathogenic bacteria, including E. coli and Salmonella, express type 1 fimbria. Methods An in vitro binding assay was used to assay the binding of recombinant GP2 to defined strains of E. coli that differ in their expression of Type 1 fimbria or its subunit protein, FimH. Studies were also performed to determine whether GP2 binding is dependent on the presence of mannose residues, which is a known determinant for FimH binding. Results GP2 binds E. coli that express Type 1 fimbria. Binding is dependent on GP2 glycosylation, and specifically the presence of mannose residues. Conclusion GP2 binds to Type 1 fimbria, a bacterial adhesin that is commonly expressed by members of the Enterobacteriacae family.

  10. Reduction of cerebral glucose utilization by the HIV envelope glycoprotein Gp-120

    Energy Technology Data Exchange (ETDEWEB)

    Kimes, A.S.; London, E.D.; Szabo, G.; Raymon, L.; Tabakoff, B. (Neuropharmacology Laboratory, National Institute on Drug Abuse, Baltimore, MD (USA))

    1991-05-01

    Gp-120 is a glycoprotein constituent of the human immunodeficiency virus (HIV) envelope. The effects of gp-120 on cerebral glucose utilization in rats were studied by the quantitative 2-deoxy-D-(1-14C) glucose method. Intracerebroventricular injection of gp-120 significantly reduced glucose utilization in the lateral habenula and the suprachiasmatic nucleus and decreased the global cerebral metabolic rate for glucose. The findings suggest that gp-120 and closely related peptides can alter neuronal function, thereby contributing to the sequelae of HIV infection.

  11. Reduction of cerebral glucose utilization by the HIV envelope glycoprotein Gp-120

    International Nuclear Information System (INIS)

    Kimes, A.S.; London, E.D.; Szabo, G.; Raymon, L.; Tabakoff, B.

    1991-01-01

    Gp-120 is a glycoprotein constituent of the human immunodeficiency virus (HIV) envelope. The effects of gp-120 on cerebral glucose utilization in rats were studied by the quantitative 2-deoxy-D-[1-14C] glucose method. Intracerebroventricular injection of gp-120 significantly reduced glucose utilization in the lateral habenula and the suprachiasmatic nucleus and decreased the global cerebral metabolic rate for glucose. The findings suggest that gp-120 and closely related peptides can alter neuronal function, thereby contributing to the sequelae of HIV infection

  12. Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Jinghe; Kang, Byong H.; Pancera, Marie; Lee, Jeong Hyun; Tong, Tommy; Feng, Yu; Imamichi, Hiromi; Georgiev, Ivelin S.; Chuang, Gwo-Yu; Druz, Aliaksandr; Doria-Rose, Nicole A.; Laub, Leo; Sliepen, Kwinten; van Gils, Marit J.; de la Peña, Alba Torrents; Derking, Ronald; Klasse, Per-Johan; Migueles, Stephen A.; Bailer, Robert T.; Alam, Munir; Pugach, Pavel; Haynes, Barton F.; Wyatt, Richard T.; Sanders, Rogier W.; Binley, James M.; Ward, Andrew B.; Mascola, John R.; Kwong, Peter D.; Connors, Mark [NIH

    2015-10-15

    The isolation of human monoclonal antibodies is providing important insights into the specificities that underlie broad neutralization of HIV-1 (reviewed in ref. 1). Here we report a broad and extremely potent HIV-specific monoclonal antibody, termed 35O22, which binds a novel HIV-1 envelope glycoprotein (Env) epitope. 35O22 neutralized 62% of 181 pseudoviruses with a half-maximum inhibitory concentration (IC50) <50 μg ml-1. The median IC50 of neutralized viruses was 0.033 μg ml-1, among the most potent thus far described. 35O22 did not bind monomeric forms of Env tested, but did bind the trimeric BG505 SOSIP.664. Mutagenesis and a reconstruction by negative-stain electron microscopy of the Fab in complex with trimer revealed that it bound to a conserved epitope, which stretched across gp120 and gp41. The specificity of 35O22 represents a novel site of vulnerability on HIV Env, which serum analysis indicates to be commonly elicited by natural infection. Binding to this new site of vulnerability may thus be an important complement to current monoclonal-antibody-based approaches to immunotherapies, prophylaxis and vaccine design.

  13. Vertical integration - Reducing the load on GP teachers.

    Science.gov (United States)

    Anderson, Katrina; Thomson, Jennifer

    2009-11-01

    With the increased medical student numbers in Australia there is an expectation that general practice will train students, junior doctors and registrars, and the teaching burden for busy general practitioners will rise. We discuss the model of vertical integration of general practice education set up at the Australian National University Medical School in the Australian Capital Territory and southeast New South Wales. This model of vertical integration is unique. It could be adapted in a range of vocational settings and spans medical student, prevocational doctor, registrar and international medical graduate teaching. A key aim of these strategies is to reduce the load on the clinical GP teacher as sustaining their contribution is crucial to the future of training in general practice.

  14. A multi-system approach assessing the interaction of anticonvulsants with P-gp.

    Directory of Open Access Journals (Sweden)

    David Dickens

    Full Text Available 30% of epilepsy patients receiving antiepileptic drugs (AEDs are not fully controlled by therapy. The drug transporter hypothesis for refractory epilepsy proposes that P-gp is over expressed at the epileptic focus with a role of P-gp in extruding AEDs from the brain. However, there is controversy regarding whether all AEDs are substrates for this transporter. Our aim was to investigate transport of phenytoin, lamotrigine and carbamazepine by using seven in-vitro transport models. Uptake assays in CEM/VBL cell lines, oocytes expressing human P-gp and an immortalised human brain endothelial cell line (hCMEC/D3 were carried out. Concentration equilibrium transport assays were performed in Caco-2, MDCKII ±P-gp and LLC-PK1±P-gp in the absence or presence of tariquidar, an inhibitor of P-gp. Finally, primary porcine brain endothelial cells were used to determine the apparent permeability (Papp of the three AEDs in the absence or presence of P-gp inhibitors. We detected weak transport of phenytoin in two of the transport systems (MDCK and LLC-PK1 cells transfected with human P-gp but not in the remaining five. No P-gp interaction was observed for lamotrigine or carbamazepine in any of the seven validated in-vitro transport models. Neither lamotrigine nor carbamazepine was a substrate for P-gp in any of the model systems tested. Our data suggest that P-gp is unlikely to contribute to the pathogenesis of refractory epilepsy through transport of carbamazepine or lamotrigine.

  15. Binding kinetics of aptamers to gp120 derived from HIV-1 subtype C

    CSIR Research Space (South Africa)

    Millroy, L

    2011-02-01

    Full Text Available aptamers with specific and strong affinity to the HIV-1 envelope glycoprotein gp120 and act as novel HIV-1 entry inhibitor drugs or as targeted drug delivery systems to HIV-1 infected cells. Prior to any downstream applications, novel gp120 aptamers need...

  16. Admission and poor performance of trainees in the postgraduate GP training in the Netherlands

    NARCIS (Netherlands)

    Vermeulen, M.I.

    2014-01-01

    Until 2014 the selection for the Dutch postgraduate GP training was conducted locally, on the eight GP departments. The procedure consisted of a letter of application and a semi-structured interview. We investigated to what extend department of choice, candidates’ characteristics and qualities

  17. A functional F analogue of AcMNPV GP64 is from the Agrotis segetum granulovirus

    NARCIS (Netherlands)

    Yin, F.; Wang, M.; Tan, Y.; Deng, F.; Vlak, J.M.; Hu, Z.H.; Wang, H.

    2008-01-01

    The envelope fusion protein F of Plutella xylostella granulovirus is a computational analogue of the GP64 envelope fusion protein of Autographa californica nucleopolyhedrovirus (AcMNPV). Granulovirus (GV) F proteins were thought to be unable to functionally replace GP64 in the AcMNPV pseudotyping

  18. Selected Thermophysical Properties of 2,2 Dimethylcyclopentyl Methylphosphonofluoridate (GP) and 2,2 Dimethylcyclopentanol (DMCP)

    Science.gov (United States)

    2016-09-01

    chromatography using a thermal conductivity detector (GC-TCD). Table 1. Sample Information for GP and DMCP Chemical Name Mole Fraction Purity...Proving Ground, MD, 1983; UNCLASSIFIED Report (ADC033491). 23. Weast, R.C. CRC Handbook of Chemistry and Physics, 53rd ed.; CRC Press: Boca Raton, FL...gas chromatography GD pinacolyl methylphosphonofluoridate GF cyclohexyl methylphosphonofluoridate GP 2,2-dimethylcyclopentyl

  19. Triage of febrile children at a GP cooperative : determinants of a consultation

    NARCIS (Netherlands)

    Monteny, Miriam; Berger, Marjolein Y.; van der Wouden, Johannes C.; Broekman, Berth J.; Koes, Bart W.

    Background Most febrile children contacting a GP cooperative are seen by a GP, although the incidence of serious illness is low. The guidelines for triage might not be suitable in primary care. Aim To investigate the determinants related to the outcome of triage in febrile children. Design of study

  20. Screening and Identification of ssDNA Aptamer for Human GP73

    Directory of Open Access Journals (Sweden)

    Jingchun Du

    2015-01-01

    Full Text Available As one tumor marker of HCC, Golgi Protein 73 (GP73 is given more promise in the early diagnosis of HCC, and aptamers have been developed to compete with antibodies as biorecognition probes in different detection system. In this study, we utilized GP73 to screen specific ssDNA aptamers by SELEX technique. First, GP73 proteins were expressed and purified by prokaryotic expression system and Nickle ion affinity chromatography, respectively. At the same time, the immunogenicity of purified GP73 was confirmed by Western blotting. The enriched ssDNA library with high binding capacity for GP73 was obtained after ten rounds of SELEX. Then, thirty ssDNA aptamers were sequenced, in which two ssDNA aptamers with identical DNA sequence were confirmed, based on the alignment results, and designated as A10-2. Furthermore, the specific antibody could block the binding of A10-2 to GP73, and the specific binding of A10-2 to GP73 was also supported by the observation that several tumor cell lines exhibited variable expression level of GP73. Significantly, the identified aptamer A10-2 could distinguish normal and cancerous liver tissues. So, our results indicate that the aptamer A10-2 might be developed into one molecular probe to detect HCC from normal liver specimens.

  1. The effect of gender medicine education in GP training: a prospective cohort study.

    Science.gov (United States)

    Dielissen, Patrick; Verdonk, Petra; Waard, Magreet Wieringa-de; Bottema, Ben; Lagro-Janssen, Toine

    2014-11-01

    The purpose of this study is to compare the change in general practitioner (GP) trainees' gender awareness following a modular gender medicine programme or a mainstream gender medicine programme. In 2007, a prospective study was conducted in three cohorts of in total 207 GP trainees who entered GP training in the Netherlands. The outcome measure was the Nijmegen Gender Awareness in Medicine Scale and a 16-item gender knowledge questionnaire. Two gender medicine teaching methods were compared: a modular approach (n = 75) versus a mainstream approach (n = 72). Both strategies were compared with a control cohort (n = 60). Statistical analysis included analysis of variance and t-tests. The overall response rates for the modular, mainstream and control cohort were 78, 72 and 82 %, respectively. There was a significant difference in change in gender knowledge scores between the modular cohort compared with the mainstream and control cohort (p = 0.049). There were no statistical differences between the cohorts on gender sensitivity and gender role ideology. At entry and end, female GP trainees demonstrated significantly higher gender awareness than male GP trainees. A modular teaching method is not a more favourable educational method to teach gender medicine in GP training. Female GP trainees are more gender aware, but male GP trainees are not unaware of gender-related issues.

  2. Biochemical and microbiological evidence for fermentative digestion in free-living land iguanas (Conolophus pallidus) and marine iguanas (Amblyrhynchus cristatus) on the Galápagos archipelago.

    Science.gov (United States)

    Mackie, Roderick I; Rycyk, Mathew; Ruemmler, Rebecca L; Aminov, Rustam I; Wikelski, Martin

    2004-01-01

    Herbivorous lizards are potentially capable of high digestive efficiency, but the presence of an indigenous microbial population has been implied from measurements of activity rather than directly studied. This study is the first to provide direct biochemical and microbiological evidence for fermentative digestion in free-living land iguanas (Conolophus pallidus) and marine iguanas (Amblyrhynchus cristatus) from the Galapagos archipelago. In marine iguanas, the stomach and large capacious colon contained ca. 32% and 60%, respectively, of the weight of total gut content. Total volatile fatty acid concentration was ca. 150 and 180 mM, respectively, for marine and land iguanas. Molar proportions of acetate, propionate, and butyrate (80.3%, 9.5%, and 3.5%) in land iguana fecal samples were similar to those for marine iguanas. Examination of fecal samples using confocal and transmission electron microscopy, as well as cultivable counts, revealed a dense and diverse population of bacteria, with spores prominent. Total culturable counts of anaerobes (2.22x10(8) g(-1) wet weight of fecal material) outnumbered aerobes on average by a factor of ca. 700. Combined, these results strongly support the contention that these unique herbivorous lizards are largely dependent on the presence and metabolic activities of a resident bacterial population in order to hydrolyze and ferment plant polymers that are indigestible to the host.

  3. Utility of thermo-alkali-stable γ-CA from polyextremophilic bacterium Aeribacillus pallidus TSHB1 in biomimetic sequestration of CO2 and as a virtual peroxidase.

    Science.gov (United States)

    Bose, Himadri; Satyanarayana, Tulasi

    2017-04-01

    Aeribacillus pallidus TSHB1 polyextremophilic bacterium produces a γ-carbonic anhydrase (ApCA), which is a homotrimeric biocatalyst with a subunit molecular mass of 32 ± 2 kDa. The enzyme is stable in the pH range between 8.0 and 11.0 and thus alkali-stable and moderately thermostable with T 1/2 values of 40 ± 1, 15 ± 1, and 8 ± 0.5 min at 60, 70, and 80 °C, respectively. Activation energy for irreversible inactivation "E d " of carbonic anhydrase is 67.119 kJ mol -1 . The enzyme is stable in the presence of various flue gas contaminants such as SO 3 2- ,SO 4 2- , and NO 3 - and cations Mg 2+ , Mn 2+ , Ca 2+ , and Ba 2+ . Fluorescence studies in the presence of N-bromosuccinimide and fluorescence quenching using KI and acrylamide revealed the importance of tryptophan residues in maintaining the structural integrity of the enzyme. ApCA is more efficient than the commercially available bovine carbonic anhydrase (BCA) in CO 2 sequestration. The enzyme was successfully used in biomineralization of CO 2 from flue gas. Replacement of active site Zn 2+ with Mn 2+ enabled ApCA to function as a peroxidase which exhibited alkali-stability and moderate thermostability like ApCA.

  4. Purification and biochemical characterization of a novel thermostable serine alkaline protease from Aeribacillus pallidus C10: a potential additive for detergents.

    Science.gov (United States)

    Yildirim, Vildan; Baltaci, Mustafa Ozkan; Ozgencli, Ilknur; Sisecioglu, Melda; Adiguzel, Ahmet; Adiguzel, Gulsah

    2017-12-01

    An extracellular thermostable alkaline serine protease enzyme from Aeribacillus pallidus C10 (GenBank No: KC333049), was purified 4.85 and 17. 32-fold with a yield of 26.9 and 19.56%, respectively, through DE52 anion exchange and Probond affinity chromatography. The molecular mass of the enzyme was determined through sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), with approximately 38.35 kDa. The enzyme exhibited optimum activity at pH 9 and at temperature 60 °C. It was determined that the enzyme had remained stable at the range of pH 7.0-10.0, and that it had preserved more than 80% of its activity at a broad temperature range (20-80 °C). The enzyme activity was found to retain more than 70% and 55% in the presence of organic solvents and commercial detergents, respectively. In addition, it was observed that the enzyme activity had increased in the presence of 5% SDS. K M and V max values were calculated as 0.197 mg/mL and 7.29 μmol.mL - 1 .min - 1 , respectively.

  5. Innate immunity glycoprotein gp-340 variants may modulate human susceptibility to dental caries

    Directory of Open Access Journals (Sweden)

    Johansson Ingegerd

    2007-06-01

    Full Text Available Abstract Background Bacterial adhesion is an important determinant of colonization and infection, including dental caries. The salivary scavenger receptor cysteine-rich glycoprotein gp-340, which mediates adhesion of Streptococcus mutans (implicated in caries, harbours three major size variants, designated gp-340 I to III, each specific to an individual saliva. Here we have examined the association of the gp-340 I to III polymorphisms with caries experience and adhesion of S. mutans. Methods A case-referent study was performed in 12-year-old Swedish children with high (n = 19 or low (n = 19 caries experiences. We measured the gp-340 I to III saliva phenotypes and correlated those with multiple outcome measures for caries experience and saliva adhesion of S. mutans using the partial least squares (PLS multivariate projection technique. In addition, we used traditional statistics and 2-year caries increment to verify the established PLS associations, and bacterial adhesion to purified gp-340 I to III proteins to support possible mechanisms. Results All except one subject were typed as gp-340 I to III (10, 23 and 4, respectively. The gp-340 I phenotype correlated positively with caries experience (VIP = 1.37 and saliva adhesion of S. mutans Ingbritt (VIP = 1.47. The gp-340 II and III phenotypes tended to behave in the opposite way. Moreover, the gp-340 I phenotype tended to show an increased 2-year caries increment compared to phenotypes II/III. Purified gp-340 I protein mediated markedly higher adhesion of S. mutans strains Ingbritt and NG8 and Lactococcus lactis expressing AgI/II adhesins (SpaP or PAc compared to gp-340 II and III proteins. In addition, the gp-340 I protein appeared over represented in subjects positive for Db, an allelic acidic PRP variant associated with caries, and subjects positive for both gp-340 I and Db tended to experience more caries than those negative for both proteins. Conclusion Gp-340 I behaves as a caries

  6. Comprehensive functional analysis of N-linked glycans on Ebola virus GP1.

    Science.gov (United States)

    Lennemann, Nicholas J; Rhein, Bethany A; Ndungo, Esther; Chandran, Kartik; Qiu, Xiangguo; Maury, Wendy

    2014-01-28

    Ebola virus (EBOV) entry requires the virion surface-associated glycoprotein (GP) that is composed of a trimer of heterodimers (GP1/GP2). The GP1 subunit contains two heavily glycosylated domains, the glycan cap and the mucin-like domain (MLD). The glycan cap contains only N-linked glycans, whereas the MLD contains both N- and O-linked glycans. Site-directed mutagenesis was performed on EBOV GP1 to systematically disrupt N-linked glycan sites to gain an understanding of their role in GP structure and function. All 15 N-glycosylation sites of EBOV GP1 could be removed without compromising the expression of GP. The loss of these 15 glycosylation sites significantly enhanced pseudovirion transduction in Vero cells, which correlated with an increase in protease sensitivity. Interestingly, exposing the receptor-binding domain (RBD) by removing the glycan shield did not allow interaction with the endosomal receptor, NPC1, indicating that the glycan cap/MLD domains mask RBD residues required for binding. The effects of the loss of GP1 N-linked glycans on Ca(2+)-dependent (C-type) lectin (CLEC)-dependent transduction were complex, and the effect was unique for each of the CLECs tested. Surprisingly, EBOV entry into murine peritoneal macrophages was independent of GP1 N-glycans, suggesting that CLEC-GP1 N-glycan interactions are not required for entry into this important primary cell. Finally, the removal of all GP1 N-glycans outside the MLD enhanced antiserum and antibody sensitivity. In total, our results provide evidence that the conserved N-linked glycans on the EBOV GP1 core protect GP from antibody neutralization despite the negative impact the glycans have on viral entry efficiency. Filovirus outbreaks occur sporadically throughout central Africa, causing high fatality rates among the general public and health care workers. These unpredictable hemorrhagic fever outbreaks are caused by multiple species of Ebola viruses, as well as Marburg virus. While filovirus

  7. Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape

    Energy Technology Data Exchange (ETDEWEB)

    Wibmer, Constantinos Kurt; Gorman, Jason; Ozorowski, Gabriel; Bhiman, Jinal N.; Sheward, Daniel J.; Elliott, Debra H.; Rouelle, Julie; Smira, Ashley; Joyce, M. Gordon; Ndabambi, Nonkululeko; Druz, Aliaksandr; Asokan, Mangai; Burton, Dennis R.; Connors, Mark; Abdool Karim, Salim S.; Mascola, John R.; Robinson, James E.; Ward, Andrew B.; Williamson, Carolyn; Kwong, Peter D.; Morris, Lynn; Moore, Penny L.; Desrosiers, Ronald C.

    2017-01-11

    A comprehensive understanding of the regions on HIV-1 envelope trimers targeted by broadly neutralizing antibodies may contribute to rational design of an HIV-1 vaccine. We previously identified a participant in the CAPRISA cohort, CAP248, who developed trimer-specific antibodies capable of neutralizing 60% of heterologous viruses at three years post-infection. Here, we report the isolation by B cell culture of monoclonal antibody CAP248-2B, which targets a novel membrane proximal epitope including elements of gp120 and gp41. Despite low maximum inhibition plateaus, often below 50% inhibitory concentrations, the breadth of CAP248-2B significantly correlated with donor plasma. Site-directed mutagenesis, X-ray crystallography, and negative-stain electron microscopy 3D reconstructions revealed how CAP248-2B recognizes a cleavage-dependent epitope that includes the gp120 C terminus. While this epitope is distinct, it overlapped in parts of gp41 with the epitopes of broadly neutralizing antibodies PGT151, VRC34, 35O22, 3BC315, and 10E8. CAP248-2B has a conformationally variable paratope with an unusually long 19 amino acid light chain third complementarity determining region. Two phenylalanines at the loop apex were predicted by docking and mutagenesis data to interact with the viral membrane. Neutralization by CAP248-2B is not dependent on any single glycan proximal to its epitope, and low neutralization plateaus could not be completely explained by N- or O-linked glycosylation pathway inhibitors, furin co-transfection, or pre-incubation with soluble CD4. Viral escape from CAP248-2B involved a cluster of rare mutations in the gp120-gp41 cleavage sites. Simultaneous introduction of these mutations into heterologous viruses abrogated neutralization by CAP248-2B, but enhanced neutralization sensitivity to 35O22, 4E10, and 10E8 by 10-100-fold. Altogether, this study expands the region of the HIV-1 gp120-gp41 quaternary interface that is a target for broadly neutralizing

  8. Expression of HIV gp120 protein increases sensitivity to the rewarding properties of methamphetamine in mice

    Science.gov (United States)

    Kesby, James P.; Hubbard, David T.; Markou, Athina; Semenova, Svetlana

    2012-01-01

    Methamphetamine abuse and human immunodeficiency virus (HIV) infection induce neuropathological changes in corticolimbic brain areas involved in reward and cognitive function. Little is known about the combined effects of methamphetamine and HIV infection on cognitive and reward processes. The HIV/gp120 protein induces neurodegeneration in mice, similar to HIV-induced pathology in humans. We investigated the effects of gp120 expression on associative learning, preference for methamphetamine and non-drug reinforcers, and sensitivity to the conditioned rewarding properties of methamphetamine in transgenic (tg) mice expressing HIV/gp120 protein (gp120-tg). gp120-tg mice learned the operant response for food at the same rate as non-tg mice. In the two-bottle choice procedure with restricted access to drugs, gp120-tg mice exhibited greater preference for methamphetamine and saccharin than non-tg mice, whereas preference for quinine was similar between genotypes. Under conditions of unrestricted access to methamphetamine, the mice exhibited a decreased preference for increasing methamphetamine concentrations. However, male gp120-tg mice showed a decreased preference for methamphetamine at lower concentrations than non-tg male mice. gp120-tg mice developed methamphetamine-induced conditioned place preference at lower methamphetamine doses compared with non-tg mice. No differences in methamphetamine pharmacokinetics were found between genotypes. These results indicate that gp120-tg mice exhibit no deficits in associative learning or reward/motivational function for a natural reinforcer. Interestingly, gp120 expression resulted in increased preference for methamphetamine and a highly palatable non-drug reinforcer (saccharin) and increased sensitivity to methamphetamine-induced conditioned reward. These data suggest that HIV-positive individuals may have increased sensitivity to methamphetamine, leading to high methamphetamine abuse potential in this population. PMID

  9. The Influences of Glycosylation on the Antigenicity, Immunogenicity, and Protective Efficacy of Ebola Virus GP DNA Vaccines

    National Research Council Canada - National Science Library

    Dowling, William; Thompson, Elizabeth; Badger, Catherine; Mellquist, Jenny L; Garrison, Aura R; Smith, Jeffrey M; Paragas, Jason; Hogan, Robert J; Schmaljohn, Connie

    2006-01-01

    ... or with deletions in the central hypervariable mucin region. We showed that mutation of one of the two N-linked GP2 glycosylation sites was highly detrimental to the antigenicity and immunogenicity of GP...

  10. Classification as clustering: a Pareto cooperative-competitive GP approach.

    Science.gov (United States)

    McIntyre, Andrew R; Heywood, Malcolm I

    2011-01-01

    Intuitively population based algorithms such as genetic programming provide a natural environment for supporting solutions that learn to decompose the overall task between multiple individuals, or a team. This work presents a framework for evolving teams without recourse to prespecifying the number of cooperating individuals. To do so, each individual evolves a mapping to a distribution of outcomes that, following clustering, establishes the parameterization of a (Gaussian) local membership function. This gives individuals the opportunity to represent subsets of tasks, where the overall task is that of classification under the supervised learning domain. Thus, rather than each team member representing an entire class, individuals are free to identify unique subsets of the overall classification task. The framework is supported by techniques from evolutionary multiobjective optimization (EMO) and Pareto competitive coevolution. EMO establishes the basis for encouraging individuals to provide accurate yet nonoverlaping behaviors; whereas competitive coevolution provides the mechanism for scaling to potentially large unbalanced datasets. Benchmarking is performed against recent examples of nonlinear SVM classifiers over 12 UCI datasets with between 150 and 200,000 training instances. Solutions from the proposed coevolutionary multiobjective GP framework appear to provide a good balance between classification performance and model complexity, especially as the dataset instance count increases.

  11. Which positive factors determine the GP satisfaction in clinical practice? A systematic literature review.

    Science.gov (United States)

    Le Floch, B; Bastiaens, H; Le Reste, J Y; Lingner, H; Hoffman, R D; Czachowski, S; Assenova, R; Koskela, T H; Klemenc-Ketis, Z; Nabbe, P; Sowinska, A; Montier, T; Peremans, L

    2016-09-13

    Looking at what makes General Practitioners (GPs) happy in their profession, may be important in increasing the GP workforce in the future. The European General Practice Research Network (EGPRN) created a research team (eight national groups) in order to clarify the factors involved in GP job satisfaction throughout Europe. The first step of this study was a literature review to explore how the satisfaction of GPs had been studied before. The research question was "Which factors are related to GP satisfaction in Clinical Practice?" Systematic literature review according to the PRISMA statement. The databases searched were Pubmed, Embase and Cochrane. All articles were identified, screened and included by two separate research teams, according to inclusion or exclusion criteria. Then, a qualitative appraisal was undertaken. Next, a thematic analysis process was undertaken to capture any issue relevant to the research question. The number of records screened was 458. One hundred four were eligible. Finally, 17 articles were included. The data revealed 13 subthemes, which were grouped into three major themes for GP satisfaction. First there were general profession-related themes, applicable to many professions. A second group of issues related specifically to a GP setting. Finally, a third group was related to professional life and personal issues. A number of factors leading to GP job satisfaction, exist in literature They should be used by policy makers within Europe to increase the GP workforce. The research team needs to undertake qualitative studies to confirm or enhance those results.

  12. Esters of the Marine-Derived Triterpene Sipholenol A Reverse P-GP-Mediated Drug Resistance

    Directory of Open Access Journals (Sweden)

    Yongchao Zhang

    2015-04-01

    Full Text Available Our previous studies showed that several sipholane triterpenes, sipholenol A, sipholenone E, sipholenol L and siphonellinol D, have potent reversal effect for multidrug resistance (MDR in cancer cells that overexpressed P-glycoprotein (P-gp/ABCB1. Through comparison of cytotoxicity towards sensitive and multi-drug resistant cell lines, we identified that the semisynthetic esters sipholenol A-4-O-acetate and sipholenol A-4-O-isonicotinate potently reversed P-gp-mediated MDR but had no effect on MRP1/ABCC1 and BCRP/ABCG2-mediated MDR. The results from [3H]-paclitaxel accumulation and efflux studies suggested that these two triterpenoids were able to increase the intracellular accumulation of paclitaxel by inhibiting its active efflux. In addition, western blot analysis revealed that these two compounds did not alter the expression levels of P-gp when treated up to 72 h. These sipholenol derivatives also stimulated the ATPase activity of P-gp membranes, which suggested that they might be substrates of P-gp. Moreover, in silico molecular docking studies revealed the virtual binding modes of these two compounds into human homology model of P-gp. In conclusion, sipholenol A-4-O-acetate and sipholenol A-4-O-isonicotinate efficiently inhibit the P-gp and may represent potential reversal agents for the treatment of multidrug resistant cancers.

  13. Characterization of Human Colorectal Cancer MDR1/P-gp Fab Antibody

    Directory of Open Access Journals (Sweden)

    Xuemei Zhang

    2013-01-01

    Full Text Available In this study, the peptide sized 21 kDa covering P-gp transmembrane region was first prepared for generating a novel mouse monoclonal antibody Fab fragment with biological activity against multiple drug resistance protein P-gp21 by phage display technology. Phage-displayed antibody library prepared from mice spleen tissues was selected against the recombinant protein P-gp21 with five rounds of panning. A number of clones expressing Fab bound to P-gp21, showing neutralized activity in vitro, were isolated and screened by enzyme-linked immunosorbent assay based on its recognition properties to P-gp21 and human colorectal cancer tissue homogenate, resulting in identification of an optimal recombinant Fab clone (Number 29. Further characterization by recloning number 29 into an expression vector showed significant induction of the Fab antibody in the clone number 29 by Isopropyl β-D-1-thiogalactopyranoside (IPTG. After purified by HiTrap Protein L, the specificity of the Fab antibody to P-gp21 was also confirmed. Not only was the targeted region of this monoclonal Fab antibody identified as a 16-peptide epitope (ALKDKKELEGSGKIAT comprising residues 883–898 within the transmembrane (TM domain of human P-gp, but also the binding ability with it was verified. The clinical implication of our results for development of personalized therapy of colorectal cancer will be further studied.

  14. Are there practical opportunities for developing leadership skills during GP training and beyond? A survey of GP trainees and trainers in South East Scotland.

    Science.gov (United States)

    Curry, Nicola; Denney, MeiLing

    2016-01-01

    There is currently a lack of formal training in leadership skills, particularly during GP training. This study aimed to explore the current training and practical opportunities which exist, specifically exploring the views of GP trainees and trainers. An electronic questionnaire was sent to 266 GP trainees and trainers in south-east Scotland. Questions focused on respondents' experience of leadership-specific training and opportunities to engage with leadership roles. There were a total of 76 respondents (28.6% response rate). Response rate was 19.0% in trainees and 34.6% in trainers. A majority of respondents (80.0%) were established GPs. Of those who had received training in leadership, most (72.1%) underwent this after qualifying as a GP. Respondents identified a range of leadership roles within and outside the practice covering clinical and non-clinical areas. Most were interested in future leadership roles (46.7% moderately interested; 28% very interested). More time, training opportunities and the presence of GP role models were motivating factors in terms of participants' readiness to take on future leadership roles. Signposting trainees, trainers and general practitioners to leadership opportunities and training would be relatively easy but addressing a lack of motivating factors at a local level is essential. The effectiveness of such training and opportunities for experiential learning in leadership roles requires further research.

  15. Structural delineation of a quaternary, cleavage-dependent epitope at the gp41-gp120 interface on intact HIV-1 Env trimers.

    Science.gov (United States)

    Blattner, Claudia; Lee, Jeong Hyun; Sliepen, Kwinten; Derking, Ronald; Falkowska, Emilia; de la Peña, Alba Torrents; Cupo, Albert; Julien, Jean-Philippe; van Gils, Marit; Lee, Peter S; Peng, Wenjie; Paulson, James C; Poignard, Pascal; Burton, Dennis R; Moore, John P; Sanders, Rogier W; Wilson, Ian A; Ward, Andrew B

    2014-05-15

    All previously characterized broadly neutralizing antibodies to the HIV-1 envelope glycoprotein (Env) target one of four major sites of vulnerability. Here, we define and structurally characterize a unique epitope on Env that is recognized by a recently discovered family of human monoclonal antibodies (PGT151-PGT158). The PGT151 epitope is comprised of residues and glycans at the interface of gp41 and gp120 within a single protomer and glycans from both subunits of a second protomer and represents a neutralizing epitope that is dependent on both gp120 and gp41. Because PGT151 binds only to properly formed, cleaved trimers, this distinctive property, and its ability to stabilize Env trimers, has enabled the successful purification of mature, cleaved Env trimers from the cell surface as a complex with PGT151. Here we compare the structural and functional properties of membrane-extracted Env trimers from several clades with those of the soluble, cleaved SOSIP gp140 trimer. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. The Effects of IGF-1 on Trk Expressing DRG Neurons with HIV-gp120- Induced Neurotoxicity.

    Science.gov (United States)

    Li, Hao; Liu, Zhen; Chi, Heng; Bi, Yanwen; Song, Lijun; Liu, Huaxiang

    2016-01-01

    HIV envelope glycoprotein gp120 is the main protein that causes HIVassociated sensory neuropathy. However, the underlying mechanisms of gp120-induced neurotoxicity are still unclear. There are lack effective treatments for relieving HIV-related neuropathic symptoms caused by gp120-induced neurotoxicity. In the present study, tyrosine kinase receptor (Trk)A, TrkB, and TrkC expression in primary cultured dorsal root ganglion (DRG) neurons with gp120-induced neurotoxicity was investigated. The effects of IGF-1 on distinct Trk-positive DRG neurons with gp120-induced neurotoxicity were also determined. The results showed that gp120 not only dose-dependently induced DRG neuronal apoptosis and inhibited neuronal survival and neurite outgrowth, but also decreased distinct Trk expression levels. IGF-1 rescued DRG neurons from apoptosis and improved neuronal survival of gp120 neurotoxic DRG neurons in vitro. IGF-1 also improved TrkA and TrkB, but not TrkC, expression in gp120 neurotoxic conditions. The effects of IGF-1 could be blocked by preincubation with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. These results suggested that gp120 may have a wide range of neurotoxicity on different subpopulations of DRG neurons, while IGF-1 might only relieve some subpopulations of DRG neurons with gp120-induced neurotoxicity. These data provide novel information of mechanisms of gp120 neurotoxicity on primary sensory neurons and the potential therapeutic effects of IGF-1 on gp120-induced neurotoxicity.

  17. Induction of regulatory T cells by high-dose gp96 suppresses murine liver immune hyperactivation.

    Directory of Open Access Journals (Sweden)

    Xinghui Li

    Full Text Available Immunization with high-dose heat shock protein gp96, an endoplasmic reticulum counterpart of the Hsp90 family, significantly enhances regulatory T cell (Treg frequency and suppressive function. Here, we examined the potential role and mechanism of gp96 in regulating immune-mediated hepatic injury in mice. High-dose gp96 immunization elicited rapid and long-lasting protection of mice against concanavalin A (Con A-and anti-CD137-induced liver injury, as evidenced by decreased alanine aminotransaminase (ALT levels, hepatic necrosis, serum pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-6, and number of IFN-γ (+ CD4(+ and IFN-γ (+ CD8(+ T cells in the spleen and liver. In contrast, CD4(+CD25(+Foxp3(+ Treg frequency and suppressive function were both increased, and the protective effect of gp96 could be generated by adoptive transfer of Treg cells from gp96-immunized mice. In vitro co-culture experiments demonstrated that gp96 stimulation enhanced Treg proliferation and suppressive function, and up-regulation of Foxp3, IL-10, and TGF-β1 induced by gp96 was dependent on TLR2- and TLR4-mediated NF-κB activation. Our work shows that activation of Tregs by high-dose gp96 immunization protects against Con A- and anti-CD137-induced T cell-hepatitis and provides therapeutic potential for the development of a gp96-based anti-immune hyperactivation vaccine against immune-mediated liver destruction.

  18. Nuclear pore complex assembly and maintenance in POM121- and gp210-deficient cells

    DEFF Research Database (Denmark)

    Stavru, Fabrizia; Nautrup-Pedersen, Gitte; Cordes, Volker C

    2006-01-01

    So far, POM121 and gp210 are the only known anchoring sites of vertebrate nuclear pore complexes (NPCs) within the lipid bilayer of the nuclear envelope (NE) and, thus, are excellent candidates for initiating the NPC assembly process. Indeed, we demonstrate that POM121 can recruit several...... as depletion of POM121 from human fibroblasts, which do not express gp210, further suggest that NPCs can assemble or at least persist in a POM121- and gp210-free form. This points to extensive redundancies in protein-protein interactions within NPCs and suggests that vertebrate NPCs contain additional membrane...

  19. Cloning of gp-340, a putative opsonin receptor for lung surfactant protein D

    DEFF Research Database (Denmark)

    Holmskov, U; Mollenhauer, J; Madsen, J

    1999-01-01

    in a soluble form and in association with the membranes of alveolar macrophages. The primary structure of gp-340 has been established by molecular cloning, which yielded a 7,686-bp cDNA sequence encoding a polypeptide chain of 2, 413 amino acids. The domain organization features 13 scavenger receptor cysteine...... in a way that suggested capping, whereas other macrophages showed strong intracellular staining within the phagosome/phagolysosome compartments. In some macrophages, SP-D and gp-340 were located in the same cellular compartment. Immunoreactive gp-340 was also found in epithelial cells of the small...

  20. Exposure to the cytokine EGF leads to abnormal hyperactivity of pallidal GABA neurons: implications for schizophrenia and its modeling.

    Science.gov (United States)

    Sotoyama, Hidekazu; Namba, Hisaaki; Chiken, Satomi; Nambu, Atsushi; Nawa, Hiroyuki

    2013-08-01

    Previous studies on a cytokine model for schizophrenia reveal that the hyperdopaminergic innervation and neurotransmission in the globus pallidus (GP) is involved in its behavioral impairments. Here, we further explored the physiological consequences of the GP abnormality in the indirect pathway, using the same schizophrenia model established by perinatal exposure to epidermal growth factor (EGF). Single-unit recordings revealed that the neural activity from the lateral GP was elevated in EGF-treated rats in vivo and in vitro (i.e., slice preparations), whereas the central area of the GP exhibited no significant differences. The increase in the pallidal activity was normalized by subchronic treatment with risperidone, which is known to ameliorate their behavioral deficits. We also monitored extracellular GABA concentrations in the substantia nigra, one of the targets of pallidal efferents. There was a significant increase in basal GABA levels in EGF-treated rats, whereas high potassium-evoked GABA effluxes and glutamate levels were not affected. A neurotoxic lesion in the GP of EGF-treated rats normalized GABA concentrations to control levels. Corroborating our in vivo results, GABA release from GP slices was elevated in EGF-treated animals. These findings suggest that the hyperactivity and enhanced GABA release of GP neurons represent the key pathophysiological features of this cytokine-exposure model for schizophrenia. © 2013 International Society for Neurochemistry.

  1. Localization of Basal Ganglia and Thalamic Damage in Dyskinetic Cerebral Palsy.

    Science.gov (United States)

    Aravamuthan, Bhooma R; Waugh, Jeff L

    2016-01-01

    Dyskinetic cerebral palsy affects 15%-20% of patients with cerebral palsy. Basal ganglia injury is associated with dyskinetic cerebral palsy, but the patterns of injury within the basal ganglia predisposing to dyskinetic cerebral palsy are unknown, making treatment difficult. For example, deep brain stimulation of the globus pallidus interna improves dystonia in only 40% of patients with dyskinetic cerebral palsy. Basal ganglia injury heterogeneity may explain this variability. To investigate this, we conducted a qualitative systematic review of basal ganglia and thalamic damage in dyskinetic cerebral palsy. Reviews and articles primarily addressing genetic or toxic causes of cerebral palsy were excluded yielding 22 studies (304 subjects). Thirteen studies specified the involved basal ganglia nuclei (subthalamic nucleus, caudate, putamen, globus pallidus, or lentiform nuclei, comprised by the putamen and globus pallidus). Studies investigating the lentiform nuclei (without distinguishing between the putamen and globus pallidus) showed that all subjects (19 of 19) had lentiform nuclei damage. Studies simultaneously but independently investigating the putamen and globus pallidus also showed that all subjects (35 of 35) had lentiform nuclei damage (i.e., putamen or globus pallidus damage); this was followed in frequency by damage to the putamen alone (70 of 101, 69%), the subthalamic nucleus (17 of 25, 68%), the thalamus (88 of 142, 62%), the globus pallidus (7/35, 20%), and the caudate (6 of 47, 13%). Globus pallidus damage was almost always coincident with putaminal damage. Noting consistent involvement of the lentiform nuclei in dyskinetic cerebral palsy, these results could suggest two groups of patients with dyskinetic cerebral palsy: those with putamen-predominant damage and those with panlenticular damage involving both the putamen and the globus pallidus. Differentiating between these groups could help predict response to therapies such as deep brain

  2. Membrane insertion and assembly of epitope-tagged gp9 at the tip of the M13 phage

    Directory of Open Access Journals (Sweden)

    Kuhn Andreas

    2011-09-01

    Full Text Available Abstract Background Filamentous M13 phage extrude from infected Escherichia coli with a tip structure composed of gp7 and gp9. This tip structure is extended by the assembly of the filament composed of the major coat protein gp8. Finally, gp3 and gp6 terminate the phage structure at the proximal end. Up to now, gp3 has been the primary tool for phage display technology. However, gp7, gp8 and gp9 could also be used for phage display and these phage particles should bind to two different or more surfaces when the modified coat proteins are combined. Therefore, we tested here if the amino-terminal end of gp9 can be modified and whether the modified portion is exposed and detectable on the M13 phage particles. Results The amino-terminal region of gp9 was modified by inserting short sequences that encode antigenic epitopes. We show here that the modified gp9 proteins correctly integrate into the membrane using the membrane insertase YidC exposing the modified epitope into the periplasm. The proteins are then efficiently assembled onto the phage particles. Also extensions up to 36 amino acid residues at the amino-terminal end of gp9 did not interfere with membrane integration and phage assembly. The exposure of the antigenic tags on the phage was visualised with immunogold labelling by electron microscopy and verified by dot blotting with antibodies to the tags. Conclusions Our results suggest that gp9 at the phage tip is suitable for the phage display technology. The modified gp9 can be supplied in trans from a plasmid and fully complements M13 phage with an amber mutation in gene 9. The modified phage tip is very well accessible to antibodies.

  3. The impact of leadership development on GP mental health commissioning.

    Science.gov (United States)

    Dickerson, Emma; Fenge, Lee-Ann; Rosenorn-Lanng, Emily

    2017-07-03

    Purpose This paper aims to explore the learning needs of general practitioners (GPs) involved in commissioning mental health provision in England, and offer an evaluation of a leadership and commissioning skills development programme for Mental Health Commissioners. Design/methodology/approach Retrospective mixed method, including online mixed method survey, rating participants' knowledge, skills, abilities, semi-structured telephone interviews and third-party questionnaires were used. Results were analysed for significant differences using the Wilcoxon Signed Ranks test. Open-ended responses and interview transcripts were analysed thematically. Findings Indicative results showed that participants perceived significant impacts in ability across eight key question groups evaluated. Differences were found between the perceived and observed impact in relation to technical areas covered within the programme which were perceived as the highest scoring impacts by participants. Research limitations/implications The indicative results show a positive impact on practice has been both perceived and observed. Findings illustrate the value of this development programme on both the personal development of GP Mental Health Commissioners and commissioning practice. Although the findings of this evaluation increase understanding in relation to an important and topical area, larger scale, prospective evaluations are required. Impact evaluations could be embedded within future programmes to encourage higher participant and third-party engagement. Future evaluations would benefit from collection and analysis of attendance data. Further research could involve patient, service user and carer perspectives on mental health commissioning. Originality value Results of this evaluation could inform the development of future learning programmes for mental health commissioners as part of a national approach to improve mental health provision.

  4. The Astringency of the GP Algorithm for Forecasting Software Failure Data Series

    Directory of Open Access Journals (Sweden)

    Yong-qiang Zhang

    2007-05-01

    Full Text Available The forecasting of software failure data series by Genetic Programming (GP can be realized without any assumptions before modeling. This discovery has transformed traditional statistical modeling methods as well as improved consistency for model applicability. The individuals' different characteristics during the evolution of generations, which are randomly changeable, are treated as Markov random processes. This paper also proposes that a GP algorithm with "optimal individuals reserved strategy" is the best solution to this problem, and therefore the adaptive individuals finally will be evolved. This will allow practical applications in software reliability modeling analysis and forecasting for failure behaviors. Moreover it can verify the feasibility and availability of the GP algorithm, which is applied to software failure data series forecasting on a theoretical basis. The results show that the GP algorithm is the best solution for software failure behaviors in a variety of disciplines.

  5. Curcumin improves synaptic plasticity impairment induced by HIV-1gp120 V3 loop

    Directory of Open Access Journals (Sweden)

    Ling-ling Shen

    2015-01-01

    Full Text Available Curcumin has been shown to significantly improve spatial memory impairment induced by HIV-1 gp120 V3 in rats, but the electrophysiological mechanism remains unknown. Using extracellular microelectrode recording techniques, this study confirmed that the gp120 V3 loop could suppress long-term potentiation in the rat hippocampal CA1 region and synaptic plasticity, and that curcumin could antagonize these inhibitory effects. Using a Fura-2/AM calcium ion probe, we found that curcumin resisted the effects of the gp120 V3 loop on hippocampal synaptosomes and decreased Ca 2+ concentration in synaptosomes. This effect of curcumin was identical to nimodipine, suggesting that curcumin improved the inhibitory effects of gp120 on synaptic plasticity, ameliorated damage caused to the central nervous system, and might be a potential neuroprotective drug.

  6. A combined AHP-GP model to allocate internal auditing time to ...

    African Journals Online (AJOL)

    Analytic hierarchy process, goal programming, internal audit, risk assessment. ..... Services area and are listed, together with their associated management ..... [2] Badri MA, 2001, A combined AHP-GP model for quality control systems, Interna-.

  7. Analýza marketingové strategie společnosti GLOBUS ČR se zaměřením na nepotravinářskou část sortimentu

    OpenAIRE

    Falcmanová, Klára

    2012-01-01

    The bachelor's thesis is about the analysis of the marketing environment in retail in the Czech Republic. The thesis is concentrated on the influence of marketing environment on GLOBUS ČR and its marketing strategy. The first chapter is theoretical and describes marketing environment and marketing mix, SWOT analysis and market segmentation. In the second chapter are defined the forms and possibilities of marketing communication in the retail environment. The third chapter is practical and the...

  8. Engineering and exploitation of a fluorescent HIV-1 gp120 for live cell CD4 binding assays

    International Nuclear Information System (INIS)

    Costantini, Lindsey M.; Irvin, Susan C.; Kennedy, Steven C.; Guo, Feng; Goldstein, Harris; Herold, Betsy C.; Snapp, Erik L.

    2015-01-01

    The HIV-1 envelope glycoprotein, gp120, binds the host cell receptor, CD4, in the initial step of HIV viral entry and infection. This process is an appealing target for the development of inhibitory drugs and neutralizing antibodies. To study gp120 binding and intracellular trafficking, we engineered a fluorescent fusion of the humanized gp120 JRFL HIV-1 variant and GFP. Gp120-sfGFP is glycosylated with human sugars, robustly expressed, and secreted from cultured human cells. Protein dynamics, quality control, and trafficking can be visualized in live cells. The fusion protein can be readily modified with different gp120 variants or fluorescent proteins. Finally, secreted gp120-sfGFP enables a sensitive and easy binding assay that can quantitatively screen potential inhibitors of gp120-CD4 binding on live cells via fluorescence imaging or laser scanning cytometry. This adaptable research tool should aid in studies of gp120 cell biology and the development of novel anti-HIV drugs. - Highlights: • Development of fluorescent protein labeled HIV-1 envelope gp120. • Imaging of gp120 dynamics and trafficking in live cells. • Quantitative visual assay of antibody-mediated inhibition of gp120 binding to CD4 on live cells

  9. Engineering and exploitation of a fluorescent HIV-1 gp120 for live cell CD4 binding assays

    Energy Technology Data Exchange (ETDEWEB)

    Costantini, Lindsey M. [Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 (United States); Irvin, Susan C. [Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 (United States); Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 (United States); Kennedy, Steven C. [Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 (United States); Guo, Feng [Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 (United States); Goldstein, Harris; Herold, Betsy C. [Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 (United States); Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 (United States); Snapp, Erik L., E-mail: erik-lee.snapp@einstein.yu.edu [Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 (United States)

    2015-02-15

    The HIV-1 envelope glycoprotein, gp120, binds the host cell receptor, CD4, in the initial step of HIV viral entry and infection. This process is an appealing target for the development of inhibitory drugs and neutralizing antibodies. To study gp120 binding and intracellular trafficking, we engineered a fluorescent fusion of the humanized gp120 JRFL HIV-1 variant and GFP. Gp120-sfGFP is glycosylated with human sugars, robustly expressed, and secreted from cultured human cells. Protein dynamics, quality control, and trafficking can be visualized in live cells. The fusion protein can be readily modified with different gp120 variants or fluorescent proteins. Finally, secreted gp120-sfGFP enables a sensitive and easy binding assay that can quantitatively screen potential inhibitors of gp120-CD4 binding on live cells via fluorescence imaging or laser scanning cytometry. This adaptable research tool should aid in studies of gp120 cell biology and the development of novel anti-HIV drugs. - Highlights: • Development of fluorescent protein labeled HIV-1 envelope gp120. • Imaging of gp120 dynamics and trafficking in live cells. • Quantitative visual assay of antibody-mediated inhibition of gp120 binding to CD4 on live cells.

  10. Role for the disulfide-bonded region of human immunodeficiency virus type 1 gp41 in receptor-triggered activation of membrane fusion function

    International Nuclear Information System (INIS)

    Bellamy-McIntyre, Anna K.; Baer, Severine; Ludlow, Louise; Drummer, Heidi E.; Poumbourios, Pantelis

    2010-01-01

    The conserved disulfide-bonded region (DSR) of the human immunodeficiency virus type 1 (HIV-1) fusion glycoprotein, gp41, mediates association with the receptor-binding glycoprotein, gp120. Interactions between gp120, CD4 and chemokine receptors activate the fusion activity of gp41. The introduction of W596L and W610F mutations to the DSR of HIV-1 QH1549.13 blocked viral entry and hemifusion without affecting gp120-gp41 association. The fusion defect correlated with inhibition of CD4-triggered gp41 pre-hairpin formation, consistent with the DSR mutations having decoupled receptor-induced conformational changes in gp120 from gp41 activation. Our data implicate the DSR in sensing conformational changes in the gp120-gp41 complex that lead to fusion activation.

  11. Cognitive deficits associated with combined HIV gp120 expression and chronic methamphetamine exposure in mice

    Science.gov (United States)

    Kesby, James P.; Markou, Athina; Semenova, Svetlana

    2014-01-01

    Methamphetamine abuse is common among individuals infected by human immunodeficiency virus (HIV). Neurocognitive outcomes tend to be worse in methamphetamine users with HIV. However, it is unclear whether discrete cognitive domains are susceptible to impairment after combined HIV infection and methamphetamine abuse. The expression of HIV/gp120 protein induces neuropathology in mice similar to HIV-induced pathology in humans. We investigated the separate and combined effects of methamphetamine exposure and gp120 expression on cognitive function in transgenic (gp120-tg) and control mice. The mice underwent an escalating methamphetamine binge regimen and were tested in novel object/location recognition, object-in-place recognition, and Barnes maze tests. gp120 expression disrupted performance in the object-in-place test (i.e., similar time spent with all objects, regardless of location), indicating deficits in associative recognition memory. gp120 expression also altered reversal learning in the Barnes maze, suggesting impairments in executive function. Methamphetamine exposure impaired spatial strategy in the Barnes maze, indicating deficits in spatial learning. Methamphetamine-exposed gp120-tg mice had the lowest spatial strategy scores in the final acquisition trials in the Barnes maze, suggesting greater deficits in spatial learning than all of the other groups. Although HIV infection involves interactions between multiple proteins and processes, in addition to gp120, our findings in gp120-tg mice suggest that humans with the dual insult of HIV infection and methamphetamine abuse may exhibit a broader spectrum of cognitive deficits than those with either factor alone. Depending on the cognitive domain, the combination of both insults may exacerbate deficits in cognitive performance compared with each individual insult. PMID:25476577

  12. Using photography to enhance GP trainees’ reflective practice and professional development.

    OpenAIRE

    Rutherford,; Forde, Emer; Priego-Hernández, J.; Butcher, Aurelia; Wedderburn, Clare

    2018-01-01

    The capacity and the commitment to reflect are integral to the practice of medicine and are core components of most GP training programmes. Teaching through the Humanities is a growing area within medical education, but one which is often considered a voluntary ‘add on’ for the interested doctor. This article describes an evaluation of a highly innovative pedagogical project which used photography as a means to enhance GP trainees’ reflective capacity, self awareness and professional developm...

  13. Oncostatin M induces heat hypersensitivity by gp130-dependent sensitization of TRPV1 in sensory neurons

    Directory of Open Access Journals (Sweden)

    Langeslag Michiel

    2011-12-01

    Full Text Available Abstract Oncostatin M (OSM is a member of the interleukin-6 cytokine family and regulates eg. gene activation, cell survival, proliferation and differentiation. OSM binds to a receptor complex consisting of the ubiquitously expressed signal transducer gp130 and the ligand binding OSM receptor subunit, which is expressed on a specific subset of primary afferent neurons. In the present study, the effect of OSM on heat nociception was investigated in nociceptor-specific gp130 knock-out (SNS-gp130-/- and gp130 floxed (gp130fl/fl mice. Subcutaneous injection of pathophysiologically relevant concentrations of OSM into the hind-paw of C57BL6J wild type mice significantly reduced paw withdrawal latencies to heat stimulation. In contrast to gp130fl/fl mice, OSM did not induce heat hypersensitivity in vivo in SNS-gp130-/- mice. OSM applied at the receptive fields of sensory neurons in in vitro skin-nerve preparations showed that OSM significantly increased the discharge rate during a standard ramp-shaped heat stimulus. The capsaicin- and heat-sensitive ion channel TRPV1, expressed on a subpopulation of nociceptive neurons, has been shown to play an important role in inflammation-induced heat hypersensitivity. Stimulation of cultured dorsal root ganglion neurons with OSM resulted in potentiation of capsaicin induced ionic currents. In line with these recordings, mice with a null mutation of the TRPV1 gene did not show any signs of OSM-induced heat hypersensitivity in vivo. The present data suggest that OSM induces thermal hypersensitivity by directly sensitizing nociceptors via OSMR-gp130 receptor mediated potentiation of TRPV1.

  14. Study and preparation of 99Tcm-GP kit for lung ventilation imaging

    International Nuclear Information System (INIS)

    Zhu Lin; Meng Fanmin; Zhang Jihong; Hong Tao; Liu Yunzhong; Liu Xiujie

    1997-01-01

    The preparation of the lyophilizing reagent, D-glucose-l-phosphate (GP) kit and the method of using this kit to label 99 Tc m to form 99 Tc m -GP for lung ventilation imaging at room temperature in a simple, rapid procedure are described. The stability of the lyophilizing reagent kit under various stock conditions is examined. The results show that all of the 99 Tc m -GP yields by the lyophilizing reagent kit are above 95% at 4 degree C (cold), 20-25 degree C (room temperature) and 40 degree C (oven) for 180, 90 and 3 days, respectively. The clinical practice indicates that in comparison with 99 Tc m -DTPA, 99 Tc m -GP has remarkable difference (P 99 Tc m -GP is an ideal radioaerosol for SPECT studies of lung ventilation. It has high alveolar deposition rate but low adhesion in the major airways compared to those of 99 Tc m -DTPA. 99 Tc m -GP also features prolonged pulmonary clearance time

  15. HIV-1 gp120 and drugs of abuse: interactions in the central nervous system.

    Science.gov (United States)

    Silverstein, Peter S; Shah, Ankit; Weemhoff, James; Kumar, Santosh; Singh, D P; Kumar, Anil

    2012-07-01

    HIV-1 infection is a global public health problem with more than 34 million people living with HIV infection. Although great strides have been made in treating this epidemic with therapeutic agents, the increase in patient life span has been coincident with an increase in the prevalence of HIV-associated neurocognitive disorders (HAND). HAND is thought to result from the neurotoxic effects of viral proteins that are shed from HIV-infected microglial cells. One of the primary neurotoxins responsible for this effect is the HIV-1 glycoprotein gp120. Exposure of neurons to gp120 has been demonstrated to cause apoptosis in neurons, as well as numerous indirect effects such as an increase in inflammatory cytokines, an increase in oxidative stress, and an increase in permeability of the blood-brain barrier. In many patients, the use of drugs of abuse (DOA) exacerbates the neurotoxic effects of gp120. Cocaine, methamphetamine and morphine are three DOAs that are commonly used by those infected with HIV-1. All three of these DOAs have been demonstrated to increase oxidative stress in the CNS as well as to increase permeability of the blood-brain barrier. Numerous model systems have demonstrated that these DOAs have the capability of exacerbating the neurotoxic effects of gp120. This review will summarize the neurotoxic effects of gp120, the deleterious effects of cocaine, methamphetamine and morphine on the CNS, and the combined effects of gp120 in the context of these drugs.

  16. The characteristics of general practice and the attractiveness of working as a GP: medical students' views.

    Science.gov (United States)

    Landstrom, Bjorn; Mattsson, Bengt; Nordin, Per; Rudebeck, Carl E

    2014-03-15

    The aim of the study was to investigate medical students' views on general practice based on their experiences in training, and to find out whether there were certain views associated with the intention to become a GP. A questionnaire, based on our earlier studies about GP working behaviour, was handed out to medical students in terms 1, 3, 5, 7, 10 and 11 of undergraduate studies in Gothenburg, Sweden. The analysis comprised statistical descriptions and comparisons. The students regarded general practice positively. They found the work environment good, the GP's awareness of patients' living conditions necessary, and that GP work requires medical breadth. The status of the GP in the medical profession was not considered high. One-fourth of the students strongly agreed with the possibility of a future as a GP. This attitude was statistically associated with support to the statements that general practice offers a good work environment and should be a major component in undergraduate training. Students with a negative attitude to working as GPs were also negative to having a major component of general practice in undergraduate training. Medical students with a positive stated attitude towards becoming GPs support changes in undergraduate training to include more general practice. The risk of increasing a negative attitude should be considered when changes are discussed.

  17. How can educators support general practice (GP) trainees to develop resilience to prevent burnout?

    Science.gov (United States)

    Sales, Bryony; Macdonald, Alexandra; Scallan, Samantha; Crane, Sue

    2016-11-01

    Burnout impacts adversely on professional and personal life, and holds implications for patient care. Current research on burnout mainly focuses on established general practitioners but it is unclear how early the signs of burnout really start. This work seeks to identify whether specific GP trainee groups are particularly at risk of burnout and the aspects of training they find stressful. A longitudinal cohort study, collecting qualitative and quantitative data through a single mode of data collection (questionnaire) took place with trainees from all GP training years (ST1-3), across a vocational training scheme (n = 48). Data gathered included the Oldenburg Burnout Inventory (OLBI). Higher than anticipated levels of burnout were displayed by all trainees. A sub-group self reporting higher levels of burnout comprised all-female, UK-trained-at-undergraduate GP trainees, with a partner but no children. Top reported stressors included knowledge/uncertainty, workload/time pressures and ePortfolio. Less than 50% of trainees perceived their burnout levels to be as high as their OLBI showing potential lack of insight. This research demonstrates that high levels of burnout are experienced in GP trainees as early as the first year of training. Early identification of burnout amongst trainees is essential by GP educators to help protect the future GP workforce.

  18. The role of membrane microdomains in transmembrane signaling through the epithelial glycoprotein Gp140/CDCP1

    Science.gov (United States)

    Alvares, Stacy M.; Dunn, Clarence A.; Brown, Tod A.; Wayner, Elizabeth E.; Carter, William G.

    2008-01-01

    Cell adhesion to the extracellular matrix (ECM) via integrin adhesion receptors initiates signaling cascades leading to changes in cell behavior. While integrin clustering is necessary to initiate cell attachment to the matrix, additional membrane components are necessary to mediate the transmembrane signals and the cell adhesion response that alter downstream cell behavior. Many of these signaling components reside in glycosphingolipid-rich and cholesterol-rich membrane domains such as Tetraspanin Enriched Microdomains (TEMs)/Glycosynapse 3 and Detergent-Resistant Microdomains (DRMs), also known as lipid rafts. In the following article, we will review examples of how components in these membrane microdomains modulate integrin adhesion after initial attachment to the ECM. Additionally, we will present data on a novel adhesion-responsive transmembrane glycoprotein Gp140/CUB Domain Containing Protein 1, which clusters in epithelial cell-cell contacts. Gp140 can then be phosphorylated by Src Family Kinases at tyrosine 734 in response to outside-in signals- possibly through interactions involving the extracellular CUB domains. Data presented here suggests that outside-in signals through Gp140 in cell-cell contacts assemble membrane clusters that associate with membrane microdomains to recruit and activate SFKs. Active SFKs then mediate phosphorylation of Gp140, SFK and PKCδ with Gp140 acting as a transmembrane scaffold for these kinases. We propose that the clustering of Gp140 and signaling components in membrane microdomains in cell-cell contacts contributes to changes in cell behavior. PMID:18269919

  19. Cloning, expression and preliminary crystallographic analysis of the equine infectious anaemia virus (EIAV) gp45 ectodomain

    International Nuclear Information System (INIS)

    Sun, Pei-Long; Lv, Shu-Xia; Zhou, Jian-Hua; Liu, Xin-Qi

    2011-01-01

    The equine infectious anaemia virus gp45 ectodomain was cloned, expressed and crystallized. Preliminary crystallographic analysis showed that the protein belonged to space group P6 3 and contained one molecule per asymmetric unit. Like human immunodeficiency virus (HIV), equine infectious anaemia virus (EIAV) belongs to the lentivirus genus. The first successful lentiviral vaccine was developed for EIAV. Thus, EIAV may serve as a valuable model for HIV vaccine research. EIAV glycoprotein 45 (gp45) plays a similar role to gp41 in HIV by mediating virus–host membrane fusion. The gp45 ectodomain was constructed according to the structure of HIV gp41, with removal of the disulfide-bond loop region. The protein was expressed in Escherichia coli and crystallized following purification. However, most of the crystals grew as aggregates and could not be used for data collection. By extensively screening hundreds of crystals, a 2.7 Å resolution data set was collected from a single crystal. The crystal belonged to space group P6 3 , with unit-cell parameters a = b = 46.84, c = 101.61 Å, α = β = 90, γ = 120°. Molecular replacement was performed using the coordinates of various lengths of HIV gp41 as search models. A long bent helix was identified and a well defined electron-density map around the long helix was obtained. This primary model provided the starting point for further refinement

  20. A review of a GP registrar-run mobile health clinic for homeless people.

    Science.gov (United States)

    O'Carroll, A; Irving, N; O'Neill, J; Flanagan, E

    2017-08-01

    Homeless people have excessively high morbidity and mortality rates, yet they face barriers accessing primary care. A mobile health clinic, staffed by GP registrars, was developed to provide services to homeless people, particularly rough sleepers and sex workers. The aims were to improve access to primary care and to challenge the stereotypes and prejudices of GP registrars through direct contact with homeless people. This was a qualitative study; questionnaires were completed on the mobile health clinic and two focus groups were conducted. All service users were asked to complete a questionnaire over a 3 month period. Two focus groups were conducted with 6 and 14 GP registrars who had worked on the bus. There was an 80% response rate (116 of 145). Fifty-two percent had no Medical Card meaning that they had no way to access the free primary care to which they are entitled. Had the clinic not been available, over half would not have sought further treatment and 16% would have gone to an Emergency Department. Ninety-one percent of users rated the service 10/10. The focus groups found that GP registrars who worked on the mobile health clinic had decreased negative stereotypes, increased empathy, and more knowledge of homeless issues. Furthermore, they intended to ensure that homeless people will not face discrimination in their future practice. A GP Registrar-run Mobile Health Clinic achieved its aims of improving access to primary care for rough sleepers and sex workers, and challenging stereotypes of GP Registrars.

  1. Introducing a GP copayment in Australia: Who would carry the cost burden?

    Science.gov (United States)

    Elkins, Rosemary Kate; Schurer, Stefanie

    2017-05-01

    Recent policy changes designed to contain unsustainable health expenditure growth imply that many more Australians may soon be charged a copayment to consult a GP. We explore the distributional consequences associated with a range of hypothetical GP copayment scenarios using nationally-representative Australian survey data. For each scenario, we estimate the cost burden that individuals and households across the income distribution would need to absorb to maintain their current GP service utilisation. Even when concessional patients are charged a third or a quarter of the non-concessional copayment rate, the average estimated cost burden in the lowest income quartile is typically between three and six times that of the highest, and the average cost burden for women is significantly higher than for men within every income quartile. These disparities are intensified for those with a chronic illness. We conclude that the widespread implementation of GP copayments would disproportionately burden lower-income families, who experience higher rates of chronic illness, higher demand for GP services, and lower capacity to absorb price increases. The regressive nature of GP copayments is reduced when concessional and child patients are exempted entirely, highlighting the importance of supporting GPs-particularly in disadvantaged areas-to maintain bulk-billing arrangements for vulnerable patient groups. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. HIV-1 gp41 Fusion Intermediate: A Target for HIV Therapeutics

    Directory of Open Access Journals (Sweden)

    Chungen Pan

    2010-02-01

    Full Text Available Human immunodeficiency virus (HIV-1 infection is initiated by the binding of gp120 envelope glyco-protein to its cell receptor (CD4 and a coreceptor (CXCR4 or CCR5, followed by a series of conformational changes in the gp41 transmembrane subunit. These changes include insertion of fusion peptide into the target cell membrane and association of C-heptad repeat (CHR peptide with the N-heptad repeat (NHR trimer, a pre-hairpin fusion intermediate. A stable six-helix bundle core is then formed, bringing the viral envelope and target cell membrane into close proximity for fusion. Peptides derived from the CHR region, such as T20 and C34, inhibit HIV-1 fusion by interacting with the gp41 fusion intermediate. A number of anti-HIV-1 peptides and small molecule compounds targeting the gp41 NHR-trimer have been identified. By combining HIV fusion/entry inhibitors targeting different sites in the gp41 fusion intermediate, a potent synergistic effect takes place, resulting in a potential new therapeutic strategy for the HIV infection/AIDS. Here, we present an overview of the current development of anti-HIV drugs, particularly those targeting the gp41 fusion intermediate.

  3. Insight derived from molecular dynamics simulations into molecular motions, thermodynamics and kinetics of HIV-1 gp120.

    Directory of Open Access Journals (Sweden)

    Peng Sang

    Full Text Available Although the crystal structures of the HIV-1 gp120 core bound and pre-bound by CD4 are known, the details of dynamics involved in conformational equilibrium and transition in relation to gp120 function have remained elusive. The homology models of gp120 comprising the N- and C-termini and loops V3 and V4 in the CD4-bound and CD4-unbound states were built and subjected to molecular dynamics (MD simulations to investigate the differences in dynamic properties and molecular motions between them. The results indicate that the CD4-bound gp120 adopted a more compact and stable conformation than the unbound form during simulations. For both the unbound and bound gp120, the large concerted motions derived from essential dynamics (ED analyses can influence the size/shape of the ligand-binding channel/cavity of gp120 and, therefore, were related to its functional properties. The differences in motion direction between certain structural components of these two forms of gp120 were related to the conformational interconversion between them. The free energy calculations based on the metadynamics simulations reveal a more rugged and complex free energy landscape (FEL for the unbound than for the bound gp120, implying that gp120 has a richer conformational diversity in the unbound form. The estimated free energy difference of ∼-6.0 kJ/mol between the global minimum free energy states of the unbound and bound gp120 indicates that gp120 can transform spontaneously from the unbound to bound states, revealing that the bound state represents a high-probability "ground state" for gp120 and explaining why the unbound state resists crystallization. Our results provide insight into the dynamics-and-function relationship of gp120, and facilitate understandings of the thermodynamics, kinetics and conformational control mechanism of HIV-1 gp120.

  4. 'Just a GP': a mixed method study of undermining of general practice as a career choice in the UK.

    Science.gov (United States)

    Alberti, Hugh; Banner, Kimberley; Collingwood, Helen; Merritt, Kymberlee

    2017-11-03

    Failure to recruit sufficient applicants to general practice (GP) training has been a problem both nationally and internationally for many years and undermining of GP is one possible contributing factor. The aim of our study was to ascertain what comments, both negative and positive, are being made in UK clinical settings to GP trainees about GP and to further explore these comments and their influence on career choice. We conducted a mixed methods study. We surveyed all foundation doctors and GP trainees within one region of Health Education England regarding any comments they experienced relating to a career in GP. We also conducted six focus groups with early GP trainees to discuss any comments that they experienced and whether these comments had any influence on their or others career choice. Positive comments reported by trainees centred around the concept that choosing GP is a positive, family-focused choice which facilities a good work-life balance. Workload was the most common negative comment, alongside the notion of being 'just a GP'; the belief that GP is boring, a waste of training and a second-class career choice. The reasons for and origin of the comments are multifactorial in nature. Thematic analysis of the focus groups identified key factors such as previous exposure to and experience of GP, family members who were GPs, GP role models, demographics of the clinician and referral behaviour. Trainees perceived that negative comments may be discouraging others from choosing GP as a career. Our study demonstrates that negative comments towards GP as a career do exist within clinical settings and are having a potential impact on poor recruitment rates to GP training. We have identified areas in which further negative comments could be prevented by changing perceptions of GP as a career. Additional time spent in GP as undergraduates and postgraduates, and positive GP role models, could particularly benefit recruitment. We recommend that undermining of GP

  5. Resistance of a human immunodeficiency virus type 1 isolate to a small molecule CCR5 inhibitor can involve sequence changes in both gp120 and gp41

    International Nuclear Information System (INIS)

    Anastassopoulou, Cleo G.; Ketas, Thomas J.; Depetris, Rafael S.; Thomas, Antonia M.; Klasse, Per Johan; Moore, John P.

    2011-01-01

    Here, we describe the genetic pathways taken by a human immunodeficiency virus type 1 (HIV-1) isolate, D101.12, to become resistant to the small molecule CCR5 inhibitor, vicriviroc (VCV), in vitro. Resistant D101.12 variants contained at least one substitution in the gp120 V3 region (H308P), plus one of two patterns of gp41 sequence changes involving the fusion peptide (FP) and a downstream residue: G514V+V535M or M518V+F519L+V535M. Studies of Env-chimeric and point-substituted viruses in peripheral blood mononuclear cells (PBMC) and TZM-bl cells showed that resistance can arise from the cooperative action of gp120 and gp41 changes, while retaining CCR5 usage. Modeling the VCV inhibition data from the two cell types suggests that D101.12 discriminates between high- and low-VCV affinity forms of CCR5 less than D1/85.16, a resistant virus with three FP substitutions.

  6. Transport inhibition of digoxin using several common P-gp expressing cell lines is not necessarily reporting only on inhibitor binding to P-gp.

    Directory of Open Access Journals (Sweden)

    Annie Albin Lumen

    Full Text Available We have reported that the P-gp substrate digoxin required basolateral and apical uptake transport in excess of that allowed by digoxin passive permeability (as measured in the presence of GF120918 to achieve the observed efflux kinetics across MDCK-MDR1-NKI (The Netherlands Cancer Institute confluent cell monolayers. That is, GF120918 inhibitable uptake transport was kinetically required. Therefore, IC50 measurements using digoxin as a probe substrate in this cell line could be due to inhibition of P-gp, of digoxin uptake transport, or both. This kinetic analysis is now extended to include three additional cell lines: MDCK-MDR1-NIH (National Institute of Health, Caco-2 and CPT-B2 (Caco-2 cells with BCRP knockdown. These cells similarly exhibit GF120918 inhibitable uptake transport of digoxin. We demonstrate that inhibition of digoxin transport across these cell lines by GF120918, cyclosporine, ketoconazole and verapamil is greater than can be explained by inhibition of P-gp alone. We examined three hypotheses for this non-P-gp inhibition. The inhibitors can: (1 bind to a basolateral digoxin uptake transporter, thereby inhibiting digoxin's cellular uptake; (2 partition into the basolateral membrane and directly reduce membrane permeability; (3 aggregate with digoxin in the donor chamber, thereby reducing the free concentration of digoxin, with concomitant reduction in digoxin uptake. Data and simulations show that hypothesis 1 was found to be uniformly acceptable. Hypothesis 2 was found to be uniformly unlikely. Hypothesis 3 was unlikely for GF120918 and cyclosporine, but further studies are needed to completely adjudicate whether hetero-dimerization contributes to the non-P-gp inhibition for ketoconazole and verapamil. We also find that P-gp substrates with relatively low passive permeability such as digoxin, loperamide and vinblastine kinetically require basolateral uptake transport over that allowed by +GF120918 passive permeability, while

  7. 'I need her to be a doctor': patients' experiences of presenting health information from the internet in GP consultations.

    Science.gov (United States)

    Bowes, Parvathy; Stevenson, Fiona; Ahluwalia, Sanjiv; Murray, Elizabeth

    2012-11-01

    Patients are increasingly using the internet for health-related information and may bring this to a GP consultation. There is scant information about why patients do this and what they expect from their GP. The aim was to explore patients' motivation in presenting information, their perception of the GP's response and what they wanted from their doctor. Qualitative study based in North London involving patients with experience of bringing health information from the internet to their GP. Semi-structured face-to-face and telephone interviews using a critical incident technique, recorded, transcribed verbatim, and subjected to thematic analysis by a multidisciplinary team of researchers. Twenty-six interviews were completed. Participants reported using the internet to become better informed about their health and hence make best use of the limited time available with the GP and to enable the GP to take their problem more seriously. Patients expected their GP to acknowledge the information; discuss, explain, or contextualise it; and offer a professional opinion. Patients tended to prioritise the GP opinion over the internet information. However, if the GP appeared disinterested, dismissive or patronising patients reported damage to the doctor-patient relationship, occasionally to the extent of seeking a second opinion or changing their doctor. This is the first in-depth qualitative study to explore why patients present internet information to their GP within the consultation and what they want when they do this. This information should help GPs respond appropriately in such circumstances.

  8. CXCL10 Decreases GP73 Expression in Hepatoma Cells at the Early Stage of Hepatitis C Virus (HCV Infection

    Directory of Open Access Journals (Sweden)

    Yuan Liu

    2013-12-01

    Full Text Available Golgi protein 73 (GP73, which is up-regulated in hepatocellular carcinoma (HCC, has recently been identified as a novel serum marker for HCC diagnosis. Several reports also noted the increased levels of GP73 expression in chronic liver disease in patients with acute hepatitis of various etiologies, chronic Hepatitis C virus (HCV infection and alcoholic liver disease. The molecular mechanisms of GP73 expression in HCV related liver disease still need to be determined. In this study, we aimed to evaluate the effect of HCV infection on GP73 expression. GP73 was highly expressed in Huh7, Hep3B, 293T and HUVEC cells, and was low-expressed in HepG2 cells. HCV infection led to down-regulation of GP73 in Huh7 and HepG2/CD81 cells at the early stage of infection. CXCL10 decreased GP73 expression in Huh7 and HepG2 cells. Up-regulation of GP73 was noted in hepatocytes with cytopathic effect at advanced stage of HCV infection, and further research is needed to determine the unknown factors affecting GP73 expression. In conclusion, our study provided additional evidence for the roles of GP73 in liver disease.

  9. Conserved region at the COOH terminus of human immunodeficiency virus gp120 envelope protein contains an immunodominant epitope

    International Nuclear Information System (INIS)

    Palker, T.J.; Matthews, T.J.; Clark, M.E.

    1987-01-01

    A highly immunogenic epitope from a conserved COOH-terminal region of the human immunodeficiency virus (HIV) gp120 envelope protein has been identified with antisera from HIV-seropositive subjects and a synthetic peptide (SP-22) containing 15 amino acids from this region (Ala-Pro-Thr-Lys-Ala-Lys-Arg-Arg-Val-Val-Gln-Arg-Glu-Lys-Arg). Peptide SP-22 absorbed up to 100% of anti-gp120 antibody reactivity from select HIV + patient sera in immunoblot assays and up to 79% of serum anti-gp120 antibody reactivity in competition RIA. In RIA, 45% of HIV-seropositive subjects had antibodies that bound to peptide SP-22. Human anti-SP-22 antibodies that bound to and were eluted from an SP-22 affinity column reacted with gp120 in RIA and immunoblot assays but did not neutralize HIV or inhibit HIV-induced syncytium formation in vitro, even though these antibodies comprised 70% of all anti-gp120 antibodies in the test serum. In contrast, the remaining 30% of SP-22 nonreactive anti-gp120 antibodies did not react with gp120 in immunoblot assays but did react in RIA and neutralized HIV in vitro. Thus, ≅ 50% of HIV-seropositive patients make high titers of nonneutralizing antibodies to an immunodominant antigen on gp120 defined by SP-22. Moreover, the COOH terminus of gp120 contains the major antigen or antigens identified by human anti-gp120 antibodies in immunoblot assays

  10. Gp120 stability on HIV-1 virions and Gag-Env pseudovirions is enhanced by an uncleaved Gag core

    International Nuclear Information System (INIS)

    Hammonds, Jason; Chen Xuemin; Ding Lingmei; Fouts, Timothy; De Vico, Anthony; Megede, Jan zur; Barnett, Susan; Spearman, Paul

    2003-01-01

    Human immunodeficiency virus type-1 (HIV-1) particles incorporate a trimeric envelope complex (Env) made of gp120 (SU) and gp41 (TM) heterodimers. It has been previously established that soluble CD4 (sCD4) interaction leads to shedding of gp120 from viral particles, and that gp120 may also be easily lost from virions during incubation or particle purification procedures. In the design of HIV particle or pseudovirion-based HIV vaccines, it may be important to develop strategies to maximize the gp120 content of particles. We analyzed the gp120 retention of HIV-1 laboratory-adapted isolates and primary isolates following incubation with sCD4 and variations in temperature. NL4-3 shed gp120 readily in a temperature- and sCD4-dependent manner. Surprisingly, inactivation of the viral protease led to markedly reduced shedding of gp120. Gp120 shedding was shown to vary markedly between HIV-1 strains, and was not strictly determined by whether the isolate was adapted to growth on immortalized T cell lines or was a primary isolate. Pseudovirions produced by expression of codon-optimized gag and env genes also demonstrated enhanced gp120 retention when an immature core structure was maintained. Pseudovirions of optimal stability were produced through a combination of an immature Gag protein core and a primary isolate Env. These results support the feasibility of utilizing pseudovirion particles as immunogens for the induction of humoral responses directed against native envelope structures

  11. Clinicopathological correlations of podoplanin (gp38 expression in rheumatoid synovium and its potential contribution to fibroblast platelet crosstalk.

    Directory of Open Access Journals (Sweden)

    Manuel J Del Rey

    Full Text Available Synovial fibroblasts (SF undergo phenotypic changes in rheumatoid arthritis (RA that contribute to inflammatory joint destruction. This study was undertaken to evaluate the clinical and functional significance of ectopic podoplanin (gp38 expression by RA SF.Expression of gp38 and its CLEC2 receptor was analyzed by immunohistochemistry in synovial arthroscopic biopsies from RA patients and normal and osteoarthritic controls. Correlation between gp38 expression and RA clinicopathological variables was analyzed. In patients rebiopsied after anti-TNF-α therapy, changes in gp38 expression were determined. Platelet-SF coculture and gp38 silencing in SF were used to analyze the functional contribution of gp38 to SF migratory and invasive properties, and to SF platelet crosstalk.gp38 was abundantly but variably expressed in RA, and it was undetectable in normal synovial tissues. Among clinicopathologigal RA variables, significantly increased gp38 expression was only found in patients with lymphoid neogenesis (LN, and RF or ACPA autoantibodies. Cultured synovial but not dermal fibroblasts showed strong constitutive gp38 expression that was further induced by TNF-α. In RA patients, anti-TNF-α therapy significantly reduced synovial gp38 expression. In RA synovium, CLEC2 receptor expression was only observed in platelets. gp38 silencing in cultured SF did not modify their migratory and invasive properties but reduced the expression of IL-6 and IL-8 genes induced by SF-platelet interaction.In RA, synovial expression of gp38 is strongly associated to LN and it is reduced after anti-TNF-α therapy. Interaction between gp38 and CLEC2 platelet receptor is feasible in RA synovium in vivo and can specifically contribute to gene expression by SF.

  12. Alphavirus Replicon DNA Vectors Expressing Ebola GP and VP40 Antigens Induce Humoral and Cellular Immune Responses in Mice

    Directory of Open Access Journals (Sweden)

    Shoufeng Ren

    2018-01-01

    Full Text Available Ebola virus (EBOV causes severe hemorrhagic fevers in humans, and no approved therapeutics or vaccine is currently available. Glycoprotein (GP is the major protective antigen of EBOV, and can generate virus-like particles (VLPs by co-expression with matrix protein (VP40. In this study, we constructed a recombinant Alphavirus Semliki Forest virus (SFV replicon vector DREP to express EBOV GP and matrix viral protein (VP40. EBOV VLPs were successfully generated and achieved budding from 293 cells after co-transfection with DREP-based GP and VP40 vectors (DREP-GP+DREP-VP40. Vaccination of BALB/c mice with DREP-GP, DREP-VP40, or DREP-GP+DREP-VP40 vectors, followed by immediate electroporation resulted in a mixed IgG subclass production, which recognized EBOV GP and/or VP40 proteins. This vaccination regimen also led to the generation of both Th1 and Th2 cellular immune responses in mice. Notably, vaccination with DREP-GP and DREP-VP40, which produces both GP and VP40 antigens, induced a significantly higher level of anti-GP IgG2a antibody and increased IFN-γ secreting CD8+ T-cell responses relative to vaccination with DREP-GP or DREP-VP40 vector alone. Our study indicates that co-expression of GP and VP40 antigens based on the SFV replicon vector generates EBOV VLPs in vitro, and vaccination with recombinant DREP vectors containing GP and VP40 antigens induces Ebola antigen-specific humoral and cellular immune responses in mice. This novel approach provides a simple and efficient vaccine platform for Ebola disease prevention.

  13. Crystallogenesis of bacteriophage P22 tail accessory factor gp26 at acidic and neutral pH

    Energy Technology Data Exchange (ETDEWEB)

    Cingolani, Gino, E-mail: cingolag@upstate.edu; Andrews, Dewan [Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210 (United States); Casjens, Sherwood [Department of Pathology, Division of Cell Biology and Immunology, University of Utah Medical School, Salt Lake City, UT 84112 (United States); Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210 (United States)

    2006-05-01

    The crystallogenesis of bacteriophage P22 tail-fiber gp26 is described. To study possible pH-induced conformational changes in gp26 structure, native trimeric gp26 has been crystallized at acidic pH (4.6) and a chimera of gp26 fused to maltose-binding protein (MBP-gp26) has been crystallized at neutral and alkaline pH (7-10). Gp26 is one of three phage P22-encoded tail accessory factors essential for stabilization of viral DNA within the mature capsid. In solution, gp26 exists as an extended triple-stranded coiled-coil protein which shares profound structural similarities with class I viral membrane-fusion protein. In the cryo-EM reconstruction of P22 tail extracted from mature virions, gp26 forms an ∼220 Å extended needle structure emanating from the neck of the tail, which is likely to be brought into contact with the cell’s outer membrane when the viral DNA-injection process is initiated. To shed light on the potential role of gp26 in cell-wall penetration and DNA injection, gp26 has been crystallized at acidic, neutral and alkaline pH. Crystals of native gp26 grown at pH 4.6 diffract X-rays to 2.0 Å resolution and belong to space group P2{sub 1}, with a dimer of trimeric gp26 molecules in the asymmetric unit. To study potential pH-induced conformational changes in the gp26 structure, a chimera of gp26 fused to maltose-binding protein (MBP-gp26) was generated. Hexagonal crystals of MBP-gp26 were obtained at neutral and alkaline pH using the high-throughput crystallization robot at the Hauptman–Woodward Medical Research Institute, Buffalo, NY, USA. These crystals diffract X-rays to beyond 2.0 Å resolution. Structural analysis of gp26 crystallized at acidic, neutral and alkaline pH is in progress.

  14. Mutations in gp41 are correlated with coreceptor tropism but do not improve prediction methods substantially.

    Science.gov (United States)

    Thielen, Alexander; Lengauer, Thomas; Swenson, Luke C; Dong, Winnie W Y; McGovern, Rachel A; Lewis, Marilyn; James, Ian; Heera, Jayvant; Valdez, Hernan; Harrigan, P Richard

    2011-01-01

    The main determinants of HIV-1 coreceptor usage are located in the V3-loop of gp120, although mutations in V2 and gp41 are also known. Incorporation of V2 is known to improve prediction algorithms; however, this has not been confirmed for gp41 mutations. Samples with V3 and gp41 genotypes and Trofile assay (Monogram Biosciences, South San Francisco, CA, USA) results were taken from the HOMER cohort (n=444) and from patients screened for the MOTIVATE studies (n=1,916; 859 with maraviroc outcome data). Correlations of mutations with tropism were assessed using Fisher's exact test and prediction models trained using support vector machines. Models were validated by cross-validation, by testing models from one dataset on the other, and by analysing virological outcome. Several mutations within gp41 were highly significant for CXCR4 usage; most strikingly an insertion occurring in 7.7% of HOMER-R5 and 46.3% of HOMER-X4 samples (MOTIVATE 5.7% and 25.2%, respectively). Models trained on gp41 sequence alone achieved relatively high areas under the receiver-operating characteristic curve (AUCs; HOMER 0.713 and MOTIVATE 0.736) that were almost as good as V3 models (0.773 and 0.884, respectively). However, combining the two regions improved predictions only marginally (0.813 and 0.902, respectively). Similar results were found when models were trained on HOMER and validated on MOTIVATE or vice versa. The difference in median log viral load decrease at week 24 between patients with R5 and X4 virus was 1.65 (HOMER 2.45 and MOTIVATE 0.79) for V3 models, 1.59 for gp41-models (2.42 and 0.83, respectively) and 1.58 for the combined predictor (2.44 and 0.86, respectively). Several mutations within gp41 showed strong correlation with tropism in two independent datasets. However, incorporating gp41 mutations into prediction models is not mandatory because they do not improve substantially on models trained on V3 sequences alone.

  15. Enhancing field GP engagement in hospital-based studies. Rationale, design, main results and participation in the diagest 3-GP motivation study

    Directory of Open Access Journals (Sweden)

    Berkhout Christophe

    2012-06-01

    Full Text Available Abstract Background Diagest 3 was a study aimed at lowering the risk of developing type 2 diabetes within 3 years after childbirth. Women with gestational diabetes were enrolled in the study. After childbirth, the subjects showed little interest in the structured education programme and did not attend workshops. Their general practitioners (GPs were approached to help motivate the subjects to participate in Diagest 3, but the GPs were reluctant. The present study aimed to understand field GPs’ attitudes towards hospital-based studies, and to develop strategies to enhance their involvement and reduce subject drop-out rates. Methods We used a three-step process: step one used a phenomenological approach exploring the beliefs, attitudes, motivations and environmental factors contributing to the GPs’ level of interest in the study. Data were collected in face-to-face interviews and coded by hand and with hermeneutic software to develop distinct GP profiles. Step two was a cross-sectional survey by questionnaire to determine the distribution of the profiles in the GP study population and whether completion of an attached case report form (CRF was associated with a particular GP profile. In step three, we assessed the impact of the motivation study on participation rates in the main study. Results Fifteen interviews were conducted to achieve data saturation. Theorisation led to the definition of 4 distinct GP profiles. The response rate to the questionnaire was 73%, but dropped to 52% when a CRF was attached. The link between GP profiles and the rate of CRF completion remains to be verified. The GPs provided data on the CRF that was of comparable quality to those collected in the main trial. Our analysis showed that the motivation study increased overall participation in the main study by 23%, accounting for 16% (24/152 of all final visits for 536 patients who were initially enrolled in the Diagest 3 study. Conclusions When a hospital-led study

  16. Enhancing field GP engagement in hospital-based studies. Rationale, design, main results and participation in the Diagest 3-GP motivation study.

    Science.gov (United States)

    Berkhout, Christophe; Vandaele-Bétancourt, Marie; Robert, Stéphane; Lespinasse, Solène; Mitha, Gamil; Bradier, Quentin; Vambergue, Anne; Fontaine, Pierre

    2012-06-21

    Diagest 3 was a study aimed at lowering the risk of developing type 2 diabetes within 3 years after childbirth. Women with gestational diabetes were enrolled in the study. After childbirth, the subjects showed little interest in the structured education programme and did not attend workshops. Their general practitioners (GPs) were approached to help motivate the subjects to participate in Diagest 3, but the GPs were reluctant. The present study aimed to understand field GPs' attitudes towards hospital-based studies, and to develop strategies to enhance their involvement and reduce subject drop-out rates. We used a three-step process: step one used a phenomenological approach exploring the beliefs, attitudes, motivations and environmental factors contributing to the GPs' level of interest in the study. Data were collected in face-to-face interviews and coded by hand and with hermeneutic software to develop distinct GP profiles. Step two was a cross-sectional survey by questionnaire to determine the distribution of the profiles in the GP study population and whether completion of an attached case report form (CRF) was associated with a particular GP profile. In step three, we assessed the impact of the motivation study on participation rates in the main study. Fifteen interviews were conducted to achieve data saturation. Theorisation led to the definition of 4 distinct GP profiles. The response rate to the questionnaire was 73%, but dropped to 52% when a CRF was attached. The link between GP profiles and the rate of CRF completion remains to be verified. The GPs provided data on the CRF that was of comparable quality to those collected in the main trial. Our analysis showed that the motivation study increased overall participation in the main study by 23%, accounting for 16% (24/152) of all final visits for 536 patients who were initially enrolled in the Diagest 3 study. When a hospital-led study explores issues in primary care, its design must anticipate GP

  17. P-gp expression in brown trout erythrocytes: evidence of a detoxification mechanism in fish erythrocytes.

    Science.gov (United States)

    Valton, Emeline; Amblard, Christian; Wawrzyniak, Ivan; Penault-Llorca, Frederique; Bamdad, Mahchid

    2013-12-05

    Blood is a site of physiological transport for a great variety of molecules, including xenobiotics. Blood cells in aquatic vertebrates, such as fish, are directly exposed to aquatic pollution. P-gp are ubiquitous "membrane detoxification proteins" implicated in the cellular efflux of various xenobiotics, such as polycyclic aromatic hydrocarbons (PAHs), which may be pollutants. The existence of this P-gp detoxification system inducible by benzo [a] pyrene (BaP), a highly cytotoxic PAH, was investigated in the nucleated erythrocytes of brown trout. Western blot analysis showed the expression of a 140-kDa P-gp in trout erythrocytes. Primary cultures of erythrocytes exposed to increasing concentrations of BaP showed no evidence of cell toxicity. Yet, in the same BaP-treated erythrocytes, P-gp expression increased significantly in a dose-dependent manner. Brown trout P-gp erythrocytes act as membrane defence mechanism against the pollutant, a property that can be exploited for future biomarker development to monitor water quality.

  18. Immunizing Patients With Metastatic Melanoma Using Recombinant Adenoviruses Encoding MART-1 or gp100 Melanoma Antigens

    Science.gov (United States)

    Rosenberg, Steven A.; Zhai, Yifan; Yang, James C.; Schwartzentruber, Douglas J.; Hwu, Patrick; Marincola, Francesco M.; Topalian, Suzanne L.; Restifo, Nicholas P.; Seipp, Claudia A.; Einhorn, Jan H.; Roberts, Bruce; White, Donald E.

    2008-01-01

    Background: The characterization of the genes encoding melanoma-associated antigens MART-1 or gp100, recognized by T cells, has opened new possibilities for the development of immunization strategies for patients with metastatic melanoma. With the use of recombinant adenoviruses expressing either MART-1 or gp100 to immunize patients with metastatic melanoma, we evaluated the safety, immunologic, and potential therapeutic aspects of these immunizations. Methods: In phase I studies, 54 patients received escalating doses (between 107 and 1011 plaque-forming units) of recombinant adenovirus encoding either MART-1 or gp100 melanoma antigen administered either alone or followed by the administration of interleukin 2 (IL-2). The immunologic impact of these immunizations on the development of cellular and antibody reactivity was assayed. Results: Recombinant adenoviruses expressing MART-1 or gp100 were safely administered. One of 16 patients with metastatic melanoma receiving the recombinant adenovirus MART-1 alone experienced a complete response. Other patients achieved objective responses, but they had received IL-2 along with an adenovirus, and their responses could be attributed to the cytokine. Immunologic assays showed no consistent immunization to the MART-1 or gp100 transgenes expressed by the recombinant adenoviruses. High levels of neutralizing antibody were found in the pretreatment sera of the patients. Conclusions: High doses of recombinant adenoviruses could be safely administered to cancer patients. High levels of neutralizing antibody present in patients' sera prior to treatment may have impaired the ability of these viruses to immunize patients against melanoma antigens. PMID:9862627

  19. GP and pharmacist inter-professional learning - a grounded theory study.

    Science.gov (United States)

    Cunningham, David E; Ferguson, Julie; Wakeling, Judy; Zlotos, Leon; Power, Ailsa

    2016-05-01

    Practice Based Small Group Learning (PBSGL) is an established learning resource for primary care clinicians in Scotland and is used by one-third of general practitioners (GPs). Scottish Government and UK professional bodies have called for GPs and pharmacists to work more closely together to improve care. To gain GPs' and pharmacists' perceptions and experiences of learning together in an inter-professional PBSGL pilot. Qualitative research methods involving established GP PBSGL groups in NHS Scotland recruiting one or two pharmacists to join them. A grounded theory method was used. GPs were interviewed in focus groups by a fellow GP, and pharmacists were interviewed individually by two researchers, neither being a GP or a pharmacist. Interviews were audio-recorded, transcribed and analysed using grounded theory methods. Data saturation was achieved and confirmed. Three themes were identified: GPs' and pharmacists' perceptions and experiences of inter-professional learning; Inter-professional relationships and team-working; Group identity and purpose of existing GP groups. Pharmacists were welcomed into GP groups and both professions valued inter-professional PBSGL learning. Participants learned from each other and both professions gained a wider perspective of the NHS and of each others' roles in the organisation. Inter-professional relationships, communication and team-working were strengthened and professionals regarded each other as peers and friends.

  20. Comparative Glycoprofiling of HIV gp120 Immunogens by Capillary Electrophoresis and MALDI Mass Spectrometry

    Science.gov (United States)

    Guttman, Miklós; Váradi, Csaba; Lee, Kelly K.; Guttman, András

    2015-01-01

    The Human Immunodeficiency Virus (HIV) envelope glycoprotein (Env) is the primary antigenic feature on the surface of the virus and is of key importance in HIV vaccinology. Vaccine trials with the gp120 subunit of Env are ongoing with the recent RV144 trial showing moderate efficacy. gp120 is densely covered with N-linked glycans that are thought to help evade the host's humoral immune response. To assess how the global glycosylation patterns vary between gp120 constructs, the glycan profiles of several gp120s were examined by capillary electrophoresis with laser induced fluorescence detection and MALDI-MS. The glycosylation profiles were found to be similar for chronic vs. transmitter/founder isolates and only varied moderately between gp120s from different clades. This study revealed that the addition of specific tags, such as the gD tag used in the RV144 trial, had significant effects on the overall glycosylation patterns. Such effects are likely to influence the immunogenicity of various Env immunogens and should be considered for future vaccine strategies, emphasizing the importance of the glycosylation analysis approach described in this paper. PMID:25809283

  1. Strategies for induction of catalytic antibodies toward HIV-1 glycoprotein gp120 in autoimmune prone mice.

    Science.gov (United States)

    Durova, Oxana M; Vorobiev, Ivan I; Smirnov, Ivan V; Reshetnyak, Andrew V; Telegin, Georgy B; Shamborant, Olga G; Orlova, Nadezda A; Genkin, Dmitry D; Bacon, Andrew; Ponomarenko, Natalia A; Friboulet, Alain; Gabibov, Alexander G

    2009-11-01

    Tremendous efforts to produce an efficient vaccine for HIV infection have been unsuccessful. The ability of HIV to utilize sophisticated mechanisms to escape killing by host immune system rises dramatic problems in the development of antiviral therapeutics. The HIV infection proceeds by interaction of coat viral glycoprotein gp120 trimer with CD4(+) receptor of the lymphocyte. Thus this surface antigen may be regarded as a favorable target for immunotherapy. In the present study, we have developed three different strategies to produce gp120-specific response in autoimmune prone mice (SJL strain) as potential tools for production "catalytic vaccine". Therefore (i) reactive immunization by peptidylphosphonate, structural part of the coat glycoprotein, (ii) immunization by engineered fused epitopes of gp120 and encephalogenic peptide, a part of myelin basic protein, and (iii) combined vaccination by DNA and corresponding gp120 fragments incorporated into liposomes were investigated. In the first two cases monoclonal antibodies and their recombinant fragments with amidolytic and gp120-specific proteolytic activities were characterized. In the last case, catalytic antibodies with virus neutralizing activity proved in cell line models were harvested.

  2. Serological responses in chimpanzees inoculated with human immunodeficiency virus glycoprotein (gp120) subunit vaccine

    International Nuclear Information System (INIS)

    Arthur, L.O.; Pyle, S.W.; Nara, P.L.

    1987-01-01

    The major envelope glycoprotein of a human immunodeficiency virus (HIV) has been purified and was utilized as a prototype vaccine in chimpanzees. The 120,000-dalton glycoprotein (gp120) was purified from membranes of human T-lymphotropic virus (HTLV)-IIIB-infected cells and the final preparation contained low levels to no detectable HTLV-IIIB core antigen (p24) and low levels of endotoxin. Chimpanzees inoculated with gp120 responded by developing antibodies that precipitated radiolabeled gp120 and neutralized in vitro infection of HTLV-IIIB. Antibodies to HTLV-IIIB p24 were not detected in the gp120-immunized chimpanzees. Peripheral blood leukocytes from the vaccinated animals were examined for T4 + and T8 + cells, and no decrease in the T4/T8 ratio was found, indicating that immunization with a ligand (gp120) that binds to T4 has not detectable adverse effect on the population of T4 + cells. The only current animal model that can be reproducibly infected with HIV is the chimpanzee. Immunization of chimpanzees with HIV proteins will provide an experimental system for testing the effectiveness of prototype vaccines for preventing HIV infection in vivo

  3. Leishmania major surface protease Gp63 interferes with the function of human monocytes and neutrophils in vitro

    DEFF Research Database (Denmark)

    Sørensen, A L; Hey, A S; Kharazmi, A

    1994-01-01

    In the present study the effect of Leishmania major surface protease Gp63 on the chemotaxis and oxidative burst response of human peripheral blood monocytes and neutrophils was investigated. It was shown that prior incubation of cells with Gp63 inhibited chemotaxis of neutrophils but not monocytes...... towards the chemotactic peptide f-met-leu-phe. On the other hand, chemotaxis of both neutrophils and monocytes towards zymosan-activated serum containing C5a was inhibited by Gp63. Monocyte and neutrophil chemiluminescence response to opsonized zymosan was reduced by preincubation of the cells with Gp63...... in a concentration-dependent manner. Notably, monocytes were inhibited to a much greater degree than neutrophils by a given concentration of Gp63, and they were also inhibited at much lower concentrations of the protease. The inhibitory effect of Gp63 on chemotaxis and chemiluminescence was completely abolished...

  4. 65 nm LP/GP mix low cost platform for multi-media wireless and consumer applications

    Science.gov (United States)

    Tavel, B.; Duriez, B.; Gwoziecki, R.; Basso, M. T.; Julien, C.; Ortolland, C.; Laplanche, Y.; Fox, R.; Sabouret, E.; Detcheverry, C.; Boeuf, F.; Morin, P.; Barge, D.; Bidaud, M.; Biénacel, J.; Garnier, P.; Cooper, K.; Chapon, J. D.; Trouiller, Y.; Belledent, J.; Broekaart, M.; Gouraud, P.; Denais, M.; Huard, V.; Rochereau, K.; Difrenza, R.; Planes, N.; Marin, M.; Boret, S.; Gloria, D.; Vanbergue, S.; Abramowitz, P.; Vishnubhotla, L.; Reber, D.; Stolk, P.; Woo, M.; Arnaud, F.

    2006-04-01

    A complete 65 nm CMOS platform, called LP/GP Mix, has been developed employing thick oxide transistor (IO), Low Power (LP) and General Purpose (GP) devices on the same chip. Dedicated to wireless multi-media and consumer applications, this new triple gate oxide platform is low cost (+1mask only) and saves over 35% of dynamic power with the use of the low operating voltage GP. The LP/GP mix shows competitive digital performance with a ring oscillator (FO = 1) speed equal to 7 ps per stage (GP) and 6T-SRAM static power lower than 10 pA/cell (LP). Compatible with mixed-signal design requirements, transistors show high voltage gain, low mismatch factor and low flicker noise. Moreover, to address mobile phone demands, excellent RF performance has been achieved with FT = 160 GHz for LP and 280 GHz for GP nMOS transistors.

  5. Crystal Structure of the Carboxy-Terminal Region of the Bacteriophage T4 Proximal Long Tail Fiber Protein Gp34

    Directory of Open Access Journals (Sweden)

    Meritxell Granell

    2017-06-01

    Full Text Available Long tail fibers of bacteriophage T4 are formed by proteins gp34, gp35, gp36, and gp37, with gp34 located at the phage-proximal end and gp37 at the phage-distal, receptor-binding end. We have solved the structure of the carboxy-terminal region of gp34, consisting of amino acids 894–1289, by single-wavelength anomalous diffraction and extended the structure to amino acids 744–1289 using data collected from crystals containing longer gp34-fragments. The structure reveals three repeats of a mixed α-β fibrous domain in residues 744 to 877. A triple-helical neck connects to an extended triple β-helix domain (amino acids 900–1127 punctuated by two β-prism domains. Next, a β-prism domain decorated with short helices and extended β-helices is present (residues 1146–1238, while the C-terminal end is capped with another short β-helical region and three β-hairpins. The structure provides insight into the stability of the fibrous gp34 protein.

  6. Incorporating and evaluating an integrated gender-specific medicine curriculum: a survey study in Dutch GP training

    Science.gov (United States)

    Dielissen, Patrick W; Bottema, Ben JAM; Verdonk, Petra; Lagro-Janssen, Toine LM

    2009-01-01

    Background We recently set standards for gender-specific medicine training as an integrated part of the GP training curriculum. This paper describes the programme and evaluation of this training. Methods The programme is designed for GP registrars throughout the 3-year GP training. The modules emphasize interaction, application, and clinically integrated learning and teaching methods in peer groups. In 2005 - 2008, after completion of each tutorial, GP registrars were asked to fill in a questionnaire on a 5-point Likert scale to assess the programme's methods and content. GP registrars were also asked to identify two learning points related to the programme. Results The teaching programme consists of five 3-hour modules that include gender themes related to and frequently seen by GPs such as in doctor-patient communication and cardiovascular disease. GP registrars evaluated the training course positively. The written learning points suggest that GP registrars have increased their awareness of why attention to gender-specific information is relevant. Conclusion In summary, gender-specific medicine training has been successfully integrated into an existing GP training curriculum. The modules and teaching methods are transferable to other training institutes for postgraduate training. The evaluation of the teaching programme shows a positive impact on GP registrars' gender awareness. PMID:19737396

  7. Incorporating and evaluating an integrated gender-specific medicine curriculum: a survey study in Dutch GP training

    Directory of Open Access Journals (Sweden)

    Lagro-Janssen Toine LM

    2009-09-01

    Full Text Available Abstract Background We recently set standards for gender-specific medicine training as an integrated part of the GP training curriculum. This paper describes the programme and evaluation of this training. Methods The programme is designed for GP registrars throughout the 3-year GP training. The modules emphasize interaction, application, and clinically integrated learning and teaching methods in peer groups. In 2005 - 2008, after completion of each tutorial, GP registrars were asked to fill in a questionnaire on a 5-point Likert scale to assess the programme's methods and content. GP registrars were also asked to identify two learning points related to the programme. Results The teaching programme consists of five 3-hour modules that include gender themes related to and frequently seen by GPs such as in doctor-patient communication and cardiovascular disease. GP registrars evaluated the training course positively. The written learning points suggest that GP registrars have increased their awareness of why attention to gender-specific information is relevant. Conclusion In summary, gender-specific medicine training has been successfully integrated into an existing GP training curriculum. The modules and teaching methods are transferable to other training institutes for postgraduate training. The evaluation of the teaching programme shows a positive impact on GP registrars' gender awareness.

  8. Medical students' and GP registrars' accommodation needs in the rural community: insight from a Victorian study.

    Science.gov (United States)

    Han, Gil-Soo; Wearne, Ben; O'Meara, Peter; McGrail, Matthew; Chesters, Janice

    2003-01-01

    Medical education in Australia is currently entering a new era, including support for the significant extension of medical students and general practitioner (GP) registrars' training programs in rural communities. This commitment to rural medical student and general practitioner recruitment and retention has made the provision of accommodation in rural communities a vital issue. This study has found that approximately half of all medical students on placement with rural GPs are currently accommodated with their GP supervisor or with other practice staff. This is a burden for many GPs and when the anticipated increase in the frequency and length of rural placements occurs what is currently a burden will become unsustainable. The changing gender and cultural demographics of medical students and rural general practitioners will also contribute to stresses on this accommodation system. It is important to have a systematic approach towards more appropriate and sustainable models of accommodation for both medical students and GP registrars.

  9. Effect of Ebola virus proteins GP, NP and VP35 on VP40 VLP morphology

    Directory of Open Access Journals (Sweden)

    Harty Ronald N

    2006-05-01

    Full Text Available Abstract Recently we described a role for Ebola virus proteins, NP, GP, and VP35 in enhancement of VP40 VLP budding. To explore the possibility that VLP structure was altered by co-expression of EBOV proteins leading to the observed enhancement of VP40 VLP budding, we performed density gradient analysis as well as electron microscopy studies. Our data suggest that VP40 is the major determinant of VLP morphology, as co-expression of NP, GP and VP35 did not significantly change VLP density, length, and diameter. Ultra-structural changes were noted in the core of the VLPs when NP was co-expressed with VP40. Overall, these findings indicate that major changes in morphology of VP40 VLPs were likely not responsible for enhanced budding of VP40 VLPs in the presence of GP, NP and/or VP35.

  10. Influences on GP coping and resilience: a qualitative study in primary care.

    Science.gov (United States)

    Cheshire, Anna; Ridge, Damien; Hughes, John; Peters, David; Panagioti, Maria; Simon, Chantal; Lewith, George

    2017-06-01

    'Neoliberal' work policies, austerity, NHS restructuring, and increased GP consultation rates provide the backdrop against increasing reports of GP burnout and an impending shortage of GPs. To explore GPs' experiences of workplace challenges and stresses, and their coping strategies, particularly focusing on understanding the impact of recent NHS workplace change. Study design was qualitative, with data collected from two focus groups and seven one-to-one telephone interviews. Focus groups and one-to-one telephone interviews explored the experiences of GPs currently practising in England, recruited through convenience sampling. Data were collected using a semi-structured interview approach and analysed using thematic analysis. There were 22 GP participants recruited: focus groups ( n = 15) and interviews ( n = 7). Interviewees understood GPs to be under intense and historically unprecedented pressures, which were tied to the contexts in which they work, with important moral implications for 'good' doctoring. Many reported that being a full-time GP was too stressful: work-related stress led to mood changes, sleep disruption, increases in anxiety, and tensions with loved ones. Some had subsequently sought ways to downsize their clinical workload. Workplace change resulted in little time for the things that helped GP resilience: a good work-life balance and better contact with colleagues. Although some GPs were coping better than others, GPs acknowledged that there was only so much an individual GP could do to manage their stress, given the external work issues they faced. GPs experience their emotional lives and stresses as being meaningfully shaped by NHS factors. To support GPs to provide effective care, resilience building should move beyond the individual to include systemic work issues. © British Journal of General Practice 2017.

  11. GPs' experiences with out-of-hours GP cooperatives: a survey study from the Netherlands.

    Science.gov (United States)

    Smits, Marleen; Keizer, Ellen; Huibers, Linda; Giesen, Paul

    2014-09-01

    Out-of-hours primary care has been provided by general practitioner (GP) cooperatives since the year 2000 in the Netherlands. Early studies in countries with similar organizational structures showed positive GP experiences. However, nowadays it is said that GPs experience a high workload at the cooperative and that they outsource a considerable part of their shifts. To examine positive and negative experiences of GPs providing out-of-hours primary care, and the frequency and reasons for outsourcing shifts. A cross-sectional observational survey among 688 GPs connected to six GP cooperatives in the Netherlands, using a web-based questionnaire. The response was 55% (n = 378). The main reasons for working in GP cooperatives were to retain registration as GP (79%) and remain experienced in acute care (74%). GPs considered the peak hours (81%) and the high number of patients (73%) as the most negative aspects. Most GPs chose to provide the out-of-hours shifts themselves: 85% outsourced maximally 25% of their shifts. The percentage of outsourced shifts increased with age. Main reasons for outsourcing were the desire to have more private time (76%); the high workload in daytime practice (71%); and less the workload during out-of-hours (46%). GPs are motivated to work in out-of-hours GP cooperatives, and they outsource few shifts. GPs consider the peak load and the large number of (non-urgent) help requests as the most negative aspects. To motivate and involve GPs for 7 × 24-h primary care, it is important to set limits on their workload.

  12. Thalamic involvement in a patient with kernicterus

    Energy Technology Data Exchange (ETDEWEB)

    Yilmaz, Yueksel [Department of Pediatrics, Marmara University School of Medicine, Istanbul (Turkey); Ekinci, Gazanfer [Department of Radiology, Marmara University School of Medicine, Istanbul (Turkey)

    2002-07-01

    We report the MR imaging findings of a 16-month-old boy with dyskinetic cerebral palsy resulting from kernicterus. T2-weighted images showed symmetric bilateral hyperintensity in the thalamus in addition to the globus pallidus. (orig.)

  13. Structural Findings in the Brain MRI of Patients with Acute Carbon Monoxide Poisoning

    Directory of Open Access Journals (Sweden)

    Yasmin Davoudi

    2014-09-01

    Conclusion: The white matter and globus pallidus were the most common affected regions in brain following acute CO poisoning. Signal abnormalities and restricted diffusion in MRI were correlated with duration of exposure to CO but not with the carboxyhemoglobin levels.

  14. Family effects on the rurality of GP's work location: a longitudinal panel study.

    Science.gov (United States)

    McGrail, Matthew R; Russell, Deborah J; O'Sullivan, Belinda G

    2017-10-19

    Reduced opportunities for children's schooling and spouse's/partner's employment are identified internationally as key barriers to general practitioners (GPs) working rurally. This paper aims to measure longitudinal associations between the rurality of GP work location and having (i) school-aged children and (ii) a spouse/partner in the workforce. Participants included 4377 GPs responding to at least two consecutive annual surveys of the Medicine in Australia: Balancing Employment and Life (MABEL) national longitudinal study between 2008 and 2014. The main outcome, GP work location, was categorised by remoteness and population size. Five sequential binary school-age groupings were defined according to whether a GP had no children, only preschool children (aged 0-4 years), at least one primary-school child (aged 5-11 years), at least one child in secondary school (aged 12-18 years), and all children older than secondary school (aged ≥ 19). Partner in the workforce was defined by whether a GP had a partner who was either currently working or looking for work, or not. Separate generalised estimating equation models, which aggregated consecutive annual observations per GP, tested associations between work location and (i) educational stages and (ii) partner employment, after adjusting for key covariates. Male GPs with children in secondary school were significantly less likely to work rurally (inclusive of > 50 000 regional centres through to the smallest rural towns of locations were not significantly associated with the educational stage of their children. Having a partner in the workforce was not associated with work location for male GPs, whereas female GPs with a partner in the workforce were significantly less likely to work in smaller rural/remote communities (location is related to key family needs which differ according to GP gender and educational stages of children. Such non-professional factors are likely to be dynamic across the GP's lifespan and

  15. Gravity Probe-B (GP-B) Mission and Tracking, Telemetry and Control Subsystem Overview

    Science.gov (United States)

    Kennedy, Paul; Bell, Joseph L. (Technical Monitor)

    2001-01-01

    The National Aeronautics and Space Administration's (NASA) Marshall Space Flight Center (MSFC) in Huntsville, Alabama will launch the Gravity Probe B (GP-B) space experiment in the Fall of 2002. The GP-B spacecraft was developed to prove Einstein's theory of General Relativity. This paper will provide an overview of the GPB mission and will discuss the design, and test of the spacecraft Tracking, Telemetry and Control (TT&C) subsystem which incorporates NASA's latest generation standard transponder for use with the NASA Tracking and Data Relay Satellite System (TDRSS).

  16. Identification of active pocket and protein druggability within envelope glycoprotein GP2 from Ebola virus

    Directory of Open Access Journals (Sweden)

    Beuy Joob

    2014-12-01

    Full Text Available The drug searching for combating the present outbreak of Ebola virus infection is the urgent activity at present. Finding the new effective drug at present must base on the molecular analysis of the pathogenic virus. The in-depth analysis of the viral protein to find the binding site, active pocket is needed. Here, the authors analyzed the envelope glycoprotein GP2 from Ebola virus. Identification of active pocket and protein druggability within envelope glycoprotein GP2 from Ebola virus was done. According to this assessment, 7 active pockets with varied druggability could be identified.

  17. Council tax valuation bands and contacts with a GP out-of-hours service.

    Science.gov (United States)

    Beale, Norman; Taylor, Gordon; Gwynne, Mark; Peart, Carole

    2006-04-01

    UK GPs are no longer responsible for the organisation of out-of-hours care for their patients, but resources remains capitation-based. This cross-sectional study tests whether council tax valuation bands can predict the demand for such services. All out-of-hours contacts made by patients in North Wiltshire over 4 months were classified by council tax band; frequencies compared with official population statistics. Council tax band predicts out-of-hours GP workload irrespective of age and sex: the more modest the home, the higher the GP contact rate. It may prove more difficult to sustain out-of-hours services in deprived parts of the UK.

  18. Neurotensin effects on N-type calcium currents among rat pallidal neurons: an electrophysiological and immunohistochemical study.

    Science.gov (United States)

    Martorana, Alessandro; Martella, Giuseppina; D'Angelo, Vincenza; Fusco, Francesca Romana; Spadoni, Francesca; Bernardi, Giorgio; Stefani, Alessandro

    2006-10-01

    The tridecapeptide neurotensin (NT) is involved in the modulation of dopamine (DA)-mediated functions in the nigrostriatal and mesocorticolimbic pathways. Its relevance in mammalian globus pallidus (GP) is questioned. A recent electrophysiological study on GP slices described NT-mediated robust membrane depolarization, depending upon the suppression of potassium conductance and/or the activation of cation current. Here, we have studied whether NT also affected high-voltage-activated calcium (Ca(2+)) currents, by means of whole-cell recordings on isolated GP neurons. In our hands, the full peptide and the segment NT8-13 reversibly inhibited N-like Ca(2+) current in about 60% of the recorded dissociated neurons, irrespective of their capacitance. The NT-mediated modulation showed no desensitization and was antagonized by the NT1 antagonists SR48692 and SR142948. These results imply an abundant expression of NTS(1) on GP cell somata. Then, we performed a light and immunofluorescence-confocal microscopy study of NTS(1) localization among GP neurons. We found that NTS(1) is localized in about 56% of GP neurons in both subpopulations of neurons, namely parvalbumin positive and negative. We conclude that NT, likely released from the striatal terminals in GP, acts through the postsynaptic NTS(1) preferentially localized in the lateral aspects of the GP. These data suggest a new implication (neither merely presynaptic nor simply "excitatory") for NT in the modulation of GP firing pattern. In addition, NT might have a role in affecting the interplay among the endogenous release of GABA/glutamate and DA. This hypothesis might have implications on both sensori-motor and associative functions of the GP and should be tested in DA-denervated disease models.

  19. Immunodiagnosis of paracoccidioidomycosis due to Paracoccidioides brasiliensis using a latex test: detection of specific antibody anti-gp43 and specific antigen gp43.

    Directory of Open Access Journals (Sweden)

    Priscila Oliveira Dos Santos

    2015-02-01

    Full Text Available Paracoccidioidomycosis (PCM is a life-threatening systemic disease and is a neglected public health problem in many endemic regions of Latin America. Though several diagnostic methods are available, almost all of them present with some limitations.A latex immunoassay using sensitized latex particles (SLPs with gp43 antigen, the immunodominant antigen of Paracoccidioides brasiliensis, or the monoclonal antibody mAb17c (anti-gp43 was evaluated for antibody or antigen detection in sera, cerebrospinal fluid (CSF, and bronchoalveolar lavage (BAL from patients with PCM due to P. brasiliensis. The gp43-SLPs performed optimally to detect specific antibodies with high levels of sensitivity (98.46%, 95% CI 91.7-100.0, specificity (93.94%, 95% CI 87.3-97.7, and positive (91.4% and negative (98.9% predictive values. In addition, we propose the use of mAb17c-SLPs to detect circulating gp43, which would be particularly important in patients with immune deficiencies who fail to produce normal levels of immunoglobulins, achieving good levels of sensitivity (96.92%, 95% CI 89.3-99.6, specificity (88.89%, 95% CI 81.0-94.3, and positive (85.1% and negative (97.8% predictive values. Very good agreement between latex tests and double immune diffusion was observed for gp43-SLPs (k = 0.924 and mAb17c-SLPs (k = 0.850, which reinforces the usefulness of our tests for the rapid diagnosis of PCM in less than 10 minutes. Minor cross-reactivity occurred with sera from patients with other fungal infections. We successfully detected antigens and antibodies from CSF and BAL samples. In addition, the latex test was useful for monitoring PCM patients receiving therapy.The high diagnostic accuracy, low cost, reduced assay time, and simplicity of this new latex test offer the potential to be commercialized and makes it an attractive diagnostic assay for use not only in clinics and medical mycology laboratories, but mainly in remote locations with limited laboratory infrastructure

  20. Membrane binding properties of EBV gp110 C-terminal domain; evidences for structural transition in the membrane environment

    International Nuclear Information System (INIS)

    Park, Sung Jean; Seo, Min-Duk; Lee, Suk Kyeong; Lee, Bong Jin

    2008-01-01

    Gp110 of Epstein-Barr virus (EBV) mainly localizes on nuclear/ER membranes and plays a role in the assembly of EBV nucleocapsid. The C-terminal tail domain (gp110 CTD) is essential for the function of gp110 and the nuclear/ER membranes localization of gp110 is ruled by its C-terminal unique nuclear localization signal (NLS), consecutive four arginines. In the present study, the structural properties of gp110 CTD in membrane mimics were investigated using CD, size-exclusion chromatography, and NMR, to elucidate the effect of membrane environment on the structural transition and to compare the structural feature of the protein in the solution state with that of the membrane-bound form. CD and NMR analysis showed that gp110 CTD in a buffer solution appears to adopt a stable folding intermediate which lacks compactness, and a highly helical structure is formed only in membrane environments. The helical content of gp110 CTD was significantly affected by the negative charge as well as the size of membrane mimics. Based on the elution profiles of the size-exclusion chromatography, we found that gp110 CTD intrinsically forms a trimer, revealing that a trimerization region may exist in the C-terminal domain of gp110 like the ectodomain of gp110. The mutation of NLS (RRRR) to RTTR does not affect the overall structure of gp110 CTD in membrane mimics, while the helical propensity in a buffer solution was slightly different between the wild-type and the mutant proteins. This result suggests that not only the helicity induced in membrane environment but also the local structure around NLS may be related to trafficking to the nuclear membrane. More detailed structural difference between the wild-type and the mutant in membrane environment was examined using synthetic two peptides including the wild-type NLS and the mutant NLS

  1. Simultaneous Activation of Multiple Memory Systems during Learning: Insights from Electrophysiology and Modeling

    Science.gov (United States)

    2010-06-01

    autonomic and pain functions, and facilitating/inhibiting voluntary movements. The external segment of the globus pallidus (globus pallidus externa, GPe...or less responsive to pain stimuli. 1.2.4. Other cortico-basal ganglia loops Alexander, Strick and colleagues have additionally defined a number of... orofacial loop and loops through inferotemporal and posterior parietal cortical areas have also been defined. 1.2.5. Interactions between loops Once

  2. Altered effective connectivity network of the basal ganglia in low-grade hepatic encephalopathy: a resting-state fMRI study with Granger causality analysis.

    Directory of Open Access Journals (Sweden)

    Rongfeng Qi

    Full Text Available BACKGROUND: The basal ganglia often show abnormal metabolism and intracranial hemodynamics in cirrhotic patients with hepatic encephalopathy (HE. Little is known about how the basal ganglia affect other brain system and is affected by other brain regions in HE. The purpose of this study was to investigate whether the effective connectivity network associated with the basal ganglia is disturbed in HE patients by using resting-state functional magnetic resonance imaging (rs-fMRI. METHODOLOGY/PRINCIPAL FINDINGS: Thirty five low-grade HE patients and thirty five age- and gender- matched healthy controls participated in the rs-fMRI scans. The effective connectivity networks associated with the globus pallidus, the primarily affected region within basal ganglia in HE, were characterized by using the Granger causality analysis and compared between HE patients and healthy controls. Pearson correlation analysis was performed between the abnormal effective connectivity and venous blood ammonia levels and neuropsychological performances of all HE patients. Compared with the healthy controls, patients with low-grade HE demonstrated mutually decreased influence between the globus pallidus and the anterior cingulate cortex (ACC, cuneus, bi-directionally increased influence between the globus pallidus and the precuneus, and either decreased or increased influence from and to the globus pallidus in many other frontal, temporal, parietal gyri, and cerebellum. Pearson correlation analyses revealed that the blood ammonia levels in HE patients negatively correlated with effective connectivity from the globus pallidus to ACC, and positively correlated with that from the globus pallidus to precuneus; and the number connectivity test scores in patients negatively correlated with the effective connectivity from the globus pallidus to ACC, and from superior frontal gyrus to globus pallidus. CONCLUSIONS/SIGNIFICANCE: Low-grade HE patients had disrupted effective

  3. Small-angle scattering from GP zones in Al–Cu alloy

    Indian Academy of Sciences (India)

    Administrator

    ficial aging, which are extensively used in commercial practice. It is well established ... Cu system shows the variety of metastable states follow- ing the sequence SSS .... the model for spinodal decomposition of GP 1 zones in. Al–Cu system ...

  4. Study of coherence strain of GP II zones in an aged aluminum composite

    International Nuclear Information System (INIS)

    Hernández-Rivera, J.L.; Rivera, J.J. Cruz; Koch, C.T.; Özdöl, V.B.; Martínez-Sánchez, R.

    2012-01-01

    Highlights: ► Precipitation sequence was changed in 2024 Al alloy. ► Image artifacts ought to the mask size and shape increased the real strain value. ► The strain distribution around experimental GP area was non uniform and more complex than reference. ► The origin of this strain distribution are related to mechanisms by which GP precipitates lose coherence. - Abstract: Strain mapping using the geometric phase analysis (GPA) technique was applied to Al–GP II (Guinier–Preston) nanoscale precipitates, using both high resolution transmission electron microscopy (HRTEM) micrographs as well as the exit wave function (EWF) obtained by focal series reconstruction. The experimental strain results were compared with strain maps obtained from an atomic model which consisted of an Al supercell containing a GP II precipitate. It was built as a reference from literature data. The experimental results demonstrate a complex strain distribution and larger fluctuations than the reference strain maps. These differences were found to be partly a consequence of image artifacts produced by the technique as well as complex microstructural events which were present at the development stage studied.

  5. GP-initiated preconception counselling in a randomised controlled trial does not induce anxiety

    NARCIS (Netherlands)

    de Jong-Potjer, L. C.; Elsinga, J.; le Cessie, S.; van der Pal-de Bruin, K. M.; Neven, A. Knuistingh; Buitendijk, S. E.; Assendelft, W. J. J.

    2006-01-01

    BACKGROUND: Preconception counselling (PCC) can reduce adverse pregnancy outcome by addressing risk factors prior to pregnancy. This study explores whether anxiety is induced in women either by the offer of PCC or by participation with GP-initiated PCC. METHODS: Randomised trial of usual care versus

  6. GP-initiated preconception counselling in a randomised controlled trial does not induce anxiety

    NARCIS (Netherlands)

    Jong-Potjer, L.C. de; Elsinga, J.; Cessie, S. le; Pal-de Bruin, K.M. van der; Knuistingh Neven, A.; Buitendijk, S.E.; Assendelft, W.J.J.

    2006-01-01

    Background: Preconception counselling (PCC) can reduce adverse pregnancy outcome by addressing risk factors prior to pregnancy. This study explores whether anxiety is induced in women either by the offer of PCC or by participation with GP-initiated PCC. Methods: Randomised trial of usual care versus

  7. GP-initiated preconception counselling in a randomised controlled trial does not induce anxiety

    Directory of Open Access Journals (Sweden)

    Neven A Knuistingh

    2006-11-01

    Full Text Available Abstract Background Preconception counselling (PCC can reduce adverse pregnancy outcome by addressing risk factors prior to pregnancy. This study explores whether anxiety is induced in women either by the offer of PCC or by participation with GP-initiated PCC. Methods Randomised trial of usual care versus GP-initiated PCC for women aged 18–40, in 54 GP practices in the Netherlands. Women completed the six-item Spielberger State Trait Anxiety Inventory (STAI before PCC (STAI-1 and after (STAI-2. After pregnancy women completed a STAI focusing on the first trimester of pregnancy (STAI-3. Results The mean STAI-1-score (n = 466 was 36.4 (95% CI 35.4 – 37.3. Following PCC there was an average decrease of 3.6 points in anxiety-levels (95% CI, 2.4 – 4.8. Mean scores of the STAI-3 were 38.5 (95% CI 37.7 – 39.3 in the control group (n = 1090 and 38.7 (95% CI 37.9 – 39.5 in the intervention group (n = 1186. Conclusion PCC from one's own GP reduced anxiety after participation, without leading to an increase in anxiety among the intervention group during pregnancy. We therefore conclude that GPs can offer PCC to the general population without fear of causing anxiety. Trial Registration: ISRCTN53942912

  8. Identification of megalin/gp330 as a receptor for lipoprotein(a) in vitro

    DEFF Research Database (Denmark)

    Niemeier, A; Willnow, T; Dieplinger, H

    1999-01-01

    for both LRP and megalin/gp330 were compared with regard to their ability to bind, internalize, and degrade dioctadecyltetramethylindocarbocyanine perchlorate (DiI)-fluorescence-labeled Lp(a) as well as equimolar amounts of 125I-labeled Lp(a) and LDL. Uptake and degradation of radiolabeled Lp...

  9. Working as a locum GP: their professional role in organizational context.

    NARCIS (Netherlands)

    Batenburg, R.; Hassel, D. van; Velden, L. van der

    2012-01-01

    Context: The workforce of General Practitioners (GPs) in the Netherlands is closely monitored and planned to ensure their pivotal role in primary care and the Dutch health care system. While the majority of GPs have their own practice or are employed by other GP practices or health community

  10. Functional cloning of a gp100-reactive T-cell receptor from vitiligo patient skin

    NARCIS (Netherlands)

    Klarquist, Jared; Eby, Jonathan M.; Henning, Steven W.; Li, Mingli; Wainwright, Derek A.; Westerhof, Wiete; Luiten, Rosalie M.; Nishimura, Michael I.; Le Poole, I. Caroline

    2016-01-01

    We isolated gp100-reactive T cells from perilesional skin of a patient with progressive vitiligo with superior reactivity toward melanoma cells compared with tumor-infiltrating lymphocytes 1520, a melanoma-derived T-cell line reactive with the same cognate peptide. After dimer enrichment and limited

  11. Defamation on facebook: Isparta V Richter 2013 6 SA 529 (GP ...

    African Journals Online (AJOL)

    In this case discussion, a brief overview is given of the few cases already reported, but in the main the case of Isparta v Richter 2013 6 SA 4529 (GP) is discussed. In this case a South African court for the first time awarded damages to the plaintiff for defamatory comments made on Facebook. The questions that confronted ...

  12. Small-angle scattering from GP zones in Al–Cu alloy

    Indian Academy of Sciences (India)

    ... and smallangle scattering experiments were carried on the powdered samples as a function of time during artificial aging. Small-angle scattering data were analysed, and evidence has been obtained for the occurrence of spinodal decomposition as the mechanism responsible in the early stages of formation of GP zones.

  13. Speeding up IA mechanically-steered multistatic radar scheduling with GP-GPUs

    CSIR Research Space (South Africa)

    Focke, RW

    2016-07-01

    Full Text Available In this paper, the authors investigate speeding up the execution time of Interval Algebra (IA) mechanically-steered multistatic and multisite radar scheduling using a general-purpose graphical processing unit (GP-GPU). Multistatic/multisite radar...

  14. Degradation of 1,2-Dibromoethane by Mycobacterium sp. Strain GP1

    NARCIS (Netherlands)

    Poelarends, Gerrit J.; van Hylckama Vlieg, Johannes; Marchesi, Julian R.; Freitas dos Santos, Luisa M.; Janssen, Dick B.

    The newly isolated bacterial strain GP1 can utilize 1,2-dibromoethane as the sole carbon and energy source. On the basis of 16S rRNA gene sequence analysis, the organism was identified as a member of the subgroup which contains the fast-growing mycobacteria, The first step in 1,2-dibromoethane

  15. Determining the Structure of an Unliganded and Fully Glycosylated SIV gp120 Envelope Glycoprotein

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Bing; Vogan, Erik M.; Gong, Haiyun; Skehel, John J.; Wiley, Don C.; Harrison, Stephen C. (Harvard-Med); (NIMR)

    2010-07-13

    HIV/SIV envelope glycoproteins mediate the first steps in viral infection. They are trimers of a membrane-anchored polypeptide chain, cleaved into two fragments known as gp120 and gp41. The structure of HIV gp120 bound with receptor (CD4) has been known for some time. We have now determined the structure of a fully glycosylated SIV gp120 envelope glycoprotein in an unliganded conformation by X-ray crystallography at 4.0 {angstrom} resolution. We describe here our experimental and computational approaches, which may be relevant to other resolution-limited crystallographic problems. Key issues were attention to details of beam geometry mandated by small, weakly diffracting crystals, and choice of strategies for phase improvement, starting with two isomorphous derivatives and including multicrystal averaging. We validated the structure by analyzing composite omit maps, averaged among three distinct crystal lattices, and by calculating model-based, SeMet anomalous difference maps. There are at least four ordered sugars on many of the thirteen oligosaccharides.

  16. The assessment of genetic risk of breast cancer : a set of GP guidelines

    NARCIS (Netherlands)

    de Bock, GH; Vlieland, TPMV; Hageman, GCHA; Oosterwijk, JC; Springer, MP; Kievit, J

    Background. Assessing a genetic risk for developing breast cancer is not an easy task for a GP. Current expert guidelines for referring and counselling women with a family history positive for breast cancer are complex and difficult to apply in general practice, and have only two strategies (to

  17. Antibiotics in Dutch general practice: nationwide electronic GP database and national reimbursement rates.

    NARCIS (Netherlands)

    Akkerman, A.E.; Kuyvenhoven, M.M.; Verheij, T.J.M.; Dijk, L. van

    2008-01-01

    PURPOSE: In order to assess whether different databases generate information which can be reliable compared with each other, this study aimed to assess to which degree prescribing rates for systemic antibiotics from a nationwide electronic general practitioner (GP) database correspond with national

  18. An optimized D2Q37 Lattice Boltzmann code on GP-GPUs

    NARCIS (Netherlands)

    Biferale, L.; Mantovani, F.; Pivanti, M.; Pozzati, F.; Sbragaglia, M.; Scagliarini, Andrea; Schifano, S.F.; Toschi, F.

    2013-01-01

    We describe the implementation of a thermal compressible Lattice Boltzmann algorithm on an NVIDIA Tesla C2050 system based on the Fermi GP-GPU. We consider two different versions, including and not including reactive effects. We describe the overall organization of the algorithm and give details on

  19. How Do Gut Feelings Feature in Tutorial Dialogues on Diagnostic Reasoning in GP Traineeship?

    Science.gov (United States)

    Stolper, C. F.; Van de Wiel, M. W. J.; Hendriks, R. H. M.; Van Royen, P.; Van Bokhoven, M. A.; Van der Weijden, T.; Dinant, G. J.

    2015-01-01

    Diagnostic reasoning is considered to be based on the interaction between analytical and non-analytical cognitive processes. Gut feelings, a specific form of non-analytical reasoning, play a substantial role in diagnostic reasoning by general practitioners (GPs) and may activate analytical reasoning. In GP traineeships in the Netherlands, trainees…

  20. The bacteria binding glycoprotein salivary agglutinin (SAG/gp340) activates complement via the lectin pathway

    NARCIS (Netherlands)

    Leito, Jelani T. D.; Ligtenberg, Antoon J. M.; van Houdt, Michel; van den Berg, Timo K.; Wouters, Diana

    2011-01-01

    Salivary agglutinin (SAG), also known as gp-340 and Deleted in Malignant Brain Tumours 1, is a glycoprotein that is present in tears, lung fluid and mucosal surfaces along the gastrointestinal tract. It is encoded by the Deleted in Malignant Brain Tumours 1 gene, a member of the Scavenger Receptor

  1. Binding of radiolabeled asbestos fibers to guinea pig (gp) alveolar macrophages (AM)

    International Nuclear Information System (INIS)

    Giannotti, M.A.; Tewson, T.J.; Francsechini, M.P.; Scheule, R.K.; Holian, A.

    1990-01-01

    The mechanism by which fibrogenic particulates cause pulmonary fibrosis in humans is not understood, but is likely to involve the AM. Using two fibrogenic particulates, namely, chrysotile (CHR) and crocidolite (CRO) asbestos and gpAM as components of an in vitro model system, the authors have shown that CHR stimulates the gpAM to release superoxide anion, but CRO does not. To examine whether this difference in stimulatory abilities is a result of differences in cell-asbestos binding they have developed an efficient procedure that radiolabels asbestos fibers while retaining their bioactivity. The fibers are labeled with 68 Ge. The 68 Ge decays into 68 Ga, which then can be detected by its characteristic position emission. Both CHR and CRO asbestos were radiolabled successfully. Mild reaction conditions and short reaction times were found under which >90% of the added 68 Ge and 68 Ga bound to the fibers. The radiolabel was retained even after washing the fibers extensively with physiologic buffers. A density gradient procedure was developed to quantitate the binding of asbestos to gpAM in suspension. The binding of both fibers increased with time over one hr. Thus, these results indicate that although both CHR and CRO interact with the gpAM, only CHR interacts productively to stimulate superoxide anion release

  2. Epidemiology and resistance patterns in urinary pathogens from long-term care facilities and GP populations.

    LENUS (Irish Health Repository)

    Brabazon, E D

    2012-06-01

    Urinary tract infections (UTIs) are a major source of antimicrobial prescribing in the clinical setting and a potential reservoir for the emergence of resistant organisms. Although studies have been published on resistance rates for urinary pathogens from both hospital and general practitioner (GP) settings, there is little information from Long-Term Care Facilities (LTCFs) in Ireland. This study aimed to document the epidemiology and resistance rates in urinary isolates, in the LTCF and GP setting, from samples submitted to a typical microbiology laboratory. In 2010, there were 963 urinary isolates from LTCFs and 1,169 urinary isolates from GPs, identified from patients 65 years and over, with cytology suggestive of infection. E. coil was the most common causative organism identified. There were significantly higher levels of resistance to ampicillin, co-amoxiclav, ciprofloxacin, nitrofurantoin, trimethoprim, and piperacillin\\/tazobactam in the LTCF population compared to the GP population (e.g. for E. coli, 86%-v-69%; 30%-v- 21%; 58%-v-26%, 10%-v-3%, 68%-v-48%, 10%-v- 4% respectively). Isolates with resistance mechanisms to beta-lactams, were identified in both populations. Results presented in this paper demonstrate significant differences between resistance rates in LTCF and GP populations which suggest that there are implications for empiric antimicrobial prescribing for UTIs in the LTCF setting.

  3. Extending an Afrikaans pronunciation dictionary using Dutch resources and P2P/GP2P

    CSIR Research Space (South Africa)

    Loots, L

    2010-11-01

    Full Text Available . This is compared to the more common approach of extending the Afrikaans dictionary by means of graphemeto-phoneme (G2P) conversion. The results indicate that the Afrikaans pronunciations obtained by P2P and GP2P from the Dutch dictionary are more accurate than...

  4. Validating glycoprotein non-metastatic melanoma B (gpNMB, osteoactivin), a new biomarker of Gaucher disease.

    Science.gov (United States)

    Murugesan, Vagishwari; Liu, Jun; Yang, Ruhua; Lin, Haiquin; Lischuk, Andrew; Pastores, Gregory; Zhang, Xiaokui; Chuang, Wei-Lien; Mistry, Pramod K

    2018-02-01

    In the spleens of Gaucher disease mice and patients, there is a striking elevation of expression of glycoprotein non-Metastatic Melanoma B (gpNMB). We conducted a study in a large cohort of patients with Gaucher disease to assess the utility of serum levels of soluble fragment of gpNMB as a biomarker of disease activity. There was >15-fold elevation of gpNMB in sera of untreated patients with Gaucher disease. gpNMB levels correlated with overall disease severity as well as the severity of individual organ compartments: liver, spleen, bone and hematological disease. Imiglucerase enzyme replacement therapy resulted in significant reduction of gpNMB. Serum levels of gpNMB were highly correlated with accumulation of bioactive lipid substrate of Gaucher disease, glucosylsphingosine as well as established biomarkers, chitotriosidase and chemokine, CCL18. Our results suggest utility of gpNMB as a biomarker of Gaucher disease to monitor individual patients and cohorts of patients for disease progression or response to therapy. Investigation of gpNMB in Gaucher disease pathophysiology is likely to illuminate our understanding disease mechanisms. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Structural and functional characterization of EIAV gp45 fusion peptide proximal region and asparagine-rich layer

    Energy Technology Data Exchange (ETDEWEB)

    Duan, Liangwei; Du, Jiansen [State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071 (China); Wang, Xuefeng; Zhou, Jianhua; Wang, Xiaojun [State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150001 (China); Liu, Xinqi, E-mail: liu2008@nankai.edu.cn [State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071 (China)

    2016-04-15

    Equine infectious anaemia virus (EIAV) and human immunodeficiency virus (HIV) are members of the lentiviral genus. Similar to HIV gp41, EIAV gp45 is a fusogenic protein that mediates fusion between the viral particle and the host cell membrane. The crystal structure of gp45 reported reveals a different conformation in the here that includes the fusion peptide proximal region (FPPR) and neighboring asparagine-rich layer compared with previous HIV-1 gp41 structures. A complicated hydrogen-bond network containing a cluster of solvent molecules appears to be critical for the stability of the gp45 helical bundle. Interestingly, viral replication was relatively unaffected by site-directed mutagenesis of EIAV, in striking contrast to that of HIV-1. Based on these observations, we speculate that EIAV is more adaptable to emergent mutations, which might be important for the evolution of EIAV as a quasi-species, and could potentially contribute to the success of the EIAV vaccine. - Highlights: • The crystal structure of EIAV gp45 was determined. • The fusion peptide proximal region adopts a novel conformation different to HIV-1. • The asparagine-rich layer includes an extensive hydrogen-bond network. • These regions of EIAV are highly tolerant to mutations. • The results provide insight into the mechanism of gp41/gp45-mediated membrane fusion.

  6. Characterisation of different forms of the accessory gp3 canine coronavirus type I protein identified in cats.

    Science.gov (United States)

    d'Orengiani, Anne-Laure Pham-Hung d'Alexandry; Duarte, Lidia; Pavio, Nicole; Le Poder, Sophie

    2015-04-16

    ORF3 is a supplemental open reading frame coding for an accessory glycoprotein gp3 of unknown function, only present in genotype I canine strain (CCoV-I) and some atypical feline FCoV strains. In these latter hosts, the ORF3 gene systematically displays one or two identical deletions leading to the synthesis of truncated proteins gp3-Δ1 and gp3-Δ2. As deletions in CoV accessory proteins have already been involved in tissue or host switch, studies of these different gp3 proteins were conducted in canine and feline cell. All proteins oligomerise through covalent bonds, are N-glycosylated and are maintained in the ER in non-infected but also in CCoV-II infected cells, without any specific retention signal. However, deletions influence their level of expression. In canine cells, all proteins are expressed with similar level whereas in feline cells, the expression of gp3-Δ1 is higher than the two other forms of gp3. None of the gp3 proteins modulate the viral replication cycle of heterologous genotype II CCoV in canine cell line, leading to the conclusion that the gp3 proteins are probably advantageous only for CCoV-I and atypical FCoV strains. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. DMPD: Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signalingpathways. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 12960231 Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited sign...82. Epub 2003 Jul 22. (.png) (.svg) (.html) (.csml) Show Macrophage activation through CCR5- and CXCR4-media...on through CCR5- and CXCR4-mediated gp120-elicited signalingpathways. Authors Lee C, Liu QH, Tomkowicz B, Yi

  8. Characterization of humoral responses to soluble trimeric HIV gp140 from a clade A Ugandan field isolate

    DEFF Research Database (Denmark)

    Visciano, Maria Luisa; Tagliamonte, Maria; Stewart-Jones, Guillaume

    2013-01-01

    Trimeric soluble forms of HIV gp140 envelope glycoproteins represent one of the closest molecular structures compared to native spikes present on intact virus particles. Trimeric soluble gp140 have been generated by several groups and such molecules have been shown to induce antibodies with neutr...

  9. Autographa californica multiple nucleopolyhedrovirus GP64 protein: Analysis of domain I and V amino acid interactions and membrane fusion activity

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Qianlong [State Key Laboratory of Crop Stress Biology for Arid Areas, Key Laboratory of Northwest Loess Plateau Crop Pest Management of Ministry of Agriculture, College of Plant Protection, Northwest A& F University, Yangling, Shaanxi 712100 (China); Blissard, Gary W. [Boyce Thompson Institute, Cornell University, Ithaca, NY 14853, United State (United States); Liu, Tong-Xian [State Key Laboratory of Crop Stress Biology for Arid Areas, Key Laboratory of Northwest Loess Plateau Crop Pest Management of Ministry of Agriculture, College of Plant Protection, Northwest A& F University, Yangling, Shaanxi 712100 (China); Li, Zhaofei, E-mail: zhaofeili73@outlook.com [State Key Laboratory of Crop Stress Biology for Arid Areas, Key Laboratory of Northwest Loess Plateau Crop Pest Management of Ministry of Agriculture, College of Plant Protection, Northwest A& F University, Yangling, Shaanxi 712100 (China)

    2016-01-15

    The Autographa californica multiple nucleopolyhedrovirus GP64 is a class III viral fusion protein. Although the post-fusion structure of GP64 has been solved, its pre-fusion structure and the detailed mechanism of conformational change are unknown. In GP64, domain V is predicted to interact with two domain I segments that flank fusion loop 2. To evaluate the significance of the amino acids involved in these interactions, we examined 24 amino acid positions that represent interacting and conserved residues within domains I and V. In several cases, substitution of a single amino acid involved in a predicted interaction disrupted membrane fusion activity, but no single amino acid pair appears to be absolutely required. We identified 4 critical residues in domain V (G438, W439, T452, and T456) that are important for membrane fusion, and two residues (G438 and W439) that appear to be important for formation or stability of the pre-fusion conformation of GP64. - Highlights: • The baculovirus envelope glycoprotein GP64 is a class III viral fusion protein. • The detailed mechanism of conformational change of GP64 is unknown. • We analyzed 24 positions that might stabilize the post-fusion structure of GP64. • We identified 4 residues in domain V that were critical for membrane fusion. • Two residues are critical for formation of the pre-fusion conformation of GP64.

  10. CD4-binding site alterations in CCR5-using HIV-1 envelopes influencing gp120-CD4 interactions and fusogenicity

    International Nuclear Information System (INIS)

    Sterjovski, Jasminka; Churchill, Melissa J.; Roche, Michael; Ellett, Anne; Farrugia, William; Wesselingh, Steven L.; Cunningham, Anthony L.; Ramsland, Paul A.; Gorry, Paul R.

    2011-01-01

    CD4-binding site (CD4bs) alterations in gp120 contribute to different pathophysiological phenotypes of CCR5-using (R5) HIV-1 strains, but the potential structural basis is unknown. Here, we characterized functionally diverse R5 envelope (Env) clones (n = 16) to elucidate potential structural alterations within the gp120 CD4bs that influence Env function. Initially, we showed that the magnitude of gp120-CD4-binding correlates with increased fusogenicity and reduced CD4 dependence. Analysis of three-dimensional gp120 structural models revealed two CD4bs variants, D279 and N362, that were associated with reduced CD4 dependence. Further structural analysis showed that a wider aperture of the predicted CD4bs cavity, as constrained by the inner-most atoms at the gp120 V1V2 stem and the V5 loop, was associated with amino acid alterations within V5 and correlated with increased gp120-CD4 binding and increased fusogenicity. Our results provide evidence that the gp120 V5 loop may alter CD4bs conformation and contribute to increased gp120-CD4 interactions and Env fusogenicity.

  11. Human antibody response to a strain-specific HIV-1 gp120 epitope associated with cell fusion inhibition

    NARCIS (Netherlands)

    Goudsmit, J.; Boucher, C. A.; Meloen, R. H.; Epstein, L. G.; Smit, L.; van der Hoek, L.; Bakker, M.

    1988-01-01

    PEPSCAN analysis, performed using 536 overlapping nonapeptides derived from the HTLV-III B nucleotide sequence of the region encoding the external envelope protein of 120 kDa (gp120), identified in the V3 region of gp120 a major binding site for antibodies of HIV-1-infected humans. The minimal amino

  12. Frequency and persistency of DNA vaccine encoding GP25 by oral on common carp

    Directory of Open Access Journals (Sweden)

    Sri Nuryati

    2015-05-01

    Full Text Available ABSTRACT Koi herpesvirus (KHV is a major viral pathogen that infects common carp and koi. KHV disease outbreak is happened in almost all centre of common carp culture in Indonesia and caused mass mortality. Deoxyribonucleic acid (DNA vaccination method is one of ways to cope with KHV infection. Vaccines were commonly given by injection. The aim of this research was to get frequency and persistency of DNA vaccine encoding GP25 given by oral delivery method in common carp. This research would like to determine dose, frequency of vaccination, persistency of DNA vaccine and culture medium for the bacterial host. DNA vaccine persistency test was done by using polymerase chain reaction (PCR method with the specific primer for GP25 gene. The results showed that level of DNA vaccine that could be detected in feed was 7.56 ng (equal to 1.598×1010 copies. Efficient culture medium for Escherichia coli DH5α carrying DNA vaccine was LB triptone. Feeding fish with diet supplemented with 1 mL E. coli DH5α containing DNA vaccine for each fish and two times a week allowed persistence of DNA vaccine in kindney and spleen. Keywords: common carp, KHV, DNA vaccine, GP25, persistance  ABSTRAK Koi herpesvirus (KHV adalah virus patogen utama yang menginfeksi ikan mas dan ikan koi. Wabah penyakit KHV terjadi di hampir semua sentra budidaya ikan mas di Indonesia dan menyebabkan kematian massal ikan. Metode vaksinasi DNA merupakan salah satu cara yang dapat dilakukan untuk menanggulangi serangan KHV. Pemberian vaksin umumnya dilakukan dengan cara injeksi. Tujuan penelitian ini adalah untuk menguji frekuensi dan persistensi vaksin DNA GP25 antivirus KHV yang diberikan melalui oral pada ikan mas. Pada penelitian ini dilakukan uji dosis, frekuensi pemberian vaksin, persistensi vaksin DNA, dan media kultur bakteri inang. Persistensi vaksin DNA dianalisis menggunakan metode PCR dengan primer spesifik gen GP25. Hasil penelitian menunjukkan bahwa dosis vaksin DNA yang

  13. Values of serum AFP, GGTⅡ and GP73 in diagnosis of primary hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    ZHU Chen

    2014-10-01

    Full Text Available ObjectiveTo explore the early diagnostic values of serum alpha-fetoprotein (AFP, gamma-glutamyltransferase Ⅱ (GGTⅡ, and Golgi protein 73 (GP73 in patients with primary hepatocellular carcinoma (PHC. MethodsThe serum specimens of 100 patients with liver diseases (50 cases of hepatitis and liver cirrhosis and 50 cases of PHC and 50 healthy people were collected in our hospital from February 2013 to February 2014. Electrochemical luminescence technique, specific immuno-membrane adsorption assay, and enzyme-linked immunosorbent assay were used to measure the serum levels of AFP, GGTⅡ, and GP73. Comparison of continuous data between multiple groups was made by analysis of variance, and comparison between two groups was made by q test. The receiver operating characteristic (ROC curves of single or combined test results were made, and the areas under the ROC curves (AUCs were calculated. The sensitivity, specificity, and AUCs of AFP, GGTⅡ, GP73, and the combined test were analyzed and compared. ResultsThe level of serum GGTⅡ in the PHC group was significantly different compared with those in the other two groups (F=16.224, P<0.05, but there was no significant difference between the normal group and the hepatitis and liver cirrhosis group (P>0.05. Significant differences in serum levels of AFP and GP73 were observed by paired comparison between the PHC group, hepatitis and liver cirrhosis group, and normal group (F=193.128, F=20.231, P<0.05 for both. When assayed alone, the specificities of GP73, GGTⅡ, and AFP were 69%, 64% and 51%, respectively, and the sensitivities were 92%, 84%, and 76%, respectively. In combined test, the specificity was 94.6% and the sensitivity was 98.8%. ConclusionThe GP73 test is the best performer in the single assays. Combined test of serum AFP, GGTⅡ, and GP73 shows a good diagnostic value for PHC with greatly improved specificity and sensitivity.

  14. Antioxidant enzyme gene delivery to protect from HIV-1 gp120-induced neuronal apoptosis.

    Science.gov (United States)

    Agrawal, L; Louboutin, J-P; Reyes, B A S; Van Bockstaele, E J; Strayer, D S

    2006-12-01

    Human immunodeficiency virus-1 (HIV-1) infection in the central nervous system (CNS) may lead to neuronal loss and progressively deteriorating CNS function: HIV-1 gene products, especially gp120, induce free radical-mediated apoptosis. Reactive oxygen species (ROS), are among the potential mediators of these effects. Neurons readily form ROS after gp120 exposure, and so might be protected from ROS-mediated injury by antioxidant enzymes such as Cu/Zn-superoxide dismutase (SOD1) and/or glutathione peroxidase (GPx1). Both enzymes detoxify oxygen free radicals. As they are highly efficient gene delivery vehicles for neurons, recombinant SV40-derived vectors were used for these studies. Cultured mature neurons derived from NT2 cells and primary fetal neurons were transduced with rSV40 vectors carrying human SOD1 and/or GPx1 cDNAs, then exposed to gp120. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. Transduction efficiency of both neuron populations was >95%, as assayed by immunostaining. Transgene expression was also ascertained by Western blotting and direct assays of enzyme activity. Gp120 induced apoptosis in a high percentage of unprotected NT2-N. Transduction with SV(SOD1) and SV(GPx1) before gp120 challenge reduced neuronal apoptosis by >90%. Even greater protection was seen in cells treated with both vectors in sequence. Given singly or in combination, they protect neuronal cells from HIV-1-gp120 induced apoptosis. We tested whether rSV40 s can deliver antioxidant enzymes to the CNS in vivo: intracerebral injection of SV(SOD1) or SV(GPx1) into the caudate putamen of rat brain yielded excellent transgene expression in neurons. In vivo transduction using SV(SOD1) also protected neurons from subsequent gp120-induced apoptosis after injection of both into the caudate putamen of rat brain. Thus, SOD1 and GPx1 can be delivered by SV40 vectors in vitro or in vivo. This approach may merit consideration for

  15. Antiviral Activity of HIV gp120 Targeting Bispecific T Cell Engager (BiTE®) Antibody Constructs.

    Science.gov (United States)

    Brozy, Johannes; Schlaepfer, Erika; Mueller, Christina K S; Rochat, Mary-Aude; Rampini, Silvana K; Myburgh, Renier; Raum, Tobias; Kufer, Peter; Baeuerle, Patrick A; Muenz, Markus; Speck, Roberto F

    2018-05-02

    Today's gold standard in HIV therapy is the combined antiretroviral therapy (cART). It requires strict adherence by patients and life-long medication, which can lower the viral load below detection limits and prevent HIV-associated immunodeficiency, but cannot cure patients. The bispecific T cell engaging (BiTE®) antibody technology has demonstrated long-term relapse-free outcomes in patients with relapsed and refractory acute lymphocytic leukemia. We here generated BiTE® antibody constructs that target the HIV-1 envelope protein gp120 (HIV gp120) using either the scFv B12 or VRC01, the first two extracellular domains (1+2) of human CD4 alone or joined to the single chain variable fragment (scFv) of the antibody 17b fused to an anti-human CD3ϵ scFv. These engineered human BiTE® antibody constructs showed engagement of T cells for redirected lysis of HIV gp120-transfected CHO cells. Furthermore, they substantially inhibited HIV-1 replication in PBMCs as well as in macrophages co-cultured with autologous CD8+ T-cells, the most potent being the human CD4(1+2) BiTE® antibody construct and the CD4(1+2)L17b BiTE® antibody construct. The CD4(1+2) h BiTE® antibody construct promoted HIV infection of human CD4-/CD8+ T cells. In contrast, the neutralizing B12 and the VRC01 BiTE® antibody constructs as well as the CD4(1+2)L17b BiTE® antibody construct did not. Thus, BiTE® antibody constructs targeting HIV gp120 are very promising for constraining HIV and warrant further development as novel antiviral therapy with curative potential. Importance HIV is a chronic infection well controlled with the current cART. However, we lack cure of HIV, and the HIV pandemic goes on. Here we showed in vitro and ex vivo t hat a bispecific T-cell engaging (BiTE®) antibody construct targeting HIV gp120 resulted in substantially reduced HIV replication. In addition, these BiTE® antibody constructs display efficient killing of gp120 expressing cells and inhibited replication in ex vivo

  16. Critical review and hydrologic application of threshold detection methods for the generalized Pareto (GP) distribution

    Science.gov (United States)

    Mamalakis, Antonios; Langousis, Andreas; Deidda, Roberto

    2016-04-01

    Estimation of extreme rainfall from data constitutes one of the most important issues in statistical hydrology, as it is associated with the design of hydraulic structures and flood water management. To that extent, based on asymptotic arguments from Extreme Excess (EE) theory, several studies have focused on developing new, or improving existing methods to fit a generalized Pareto (GP) distribution model to rainfall excesses above a properly selected threshold u. The latter is generally determined using various approaches, such as non-parametric methods that are intended to locate the changing point between extreme and non-extreme regions of the data, graphical methods where one studies the dependence of GP distribution parameters (or related metrics) on the threshold level u, and Goodness of Fit (GoF) metrics that, for a certain level of significance, locate the lowest threshold u that a GP distribution model is applicable. In this work, we review representative methods for GP threshold detection, discuss fundamental differences in their theoretical bases, and apply them to 1714 daily rainfall records from the NOAA-NCDC open-access database, with more than 110 years of data. We find that non-parametric methods that are intended to locate the changing point between extreme and non-extreme regions of the data are generally not reliable, while methods that are based on asymptotic properties of the upper distribution tail lead to unrealistically high threshold and shape parameter estimates. The latter is justified by theoretical arguments, and it is especially the case in rainfall applications, where the shape parameter of the GP distribution is low; i.e. on the order of 0.1 ÷ 0.2. Better performance is demonstrated by graphical methods and GoF metrics that rely on pre-asymptotic properties of the GP distribution. For daily rainfall, we find that GP threshold estimates range between 2÷12 mm/d with a mean value of 6.5 mm/d, while the existence of quantization in the

  17. A single-neuron tracing study of arkypallidal and prototypic neurons in healthy rats.

    Science.gov (United States)

    Fujiyama, Fumino; Nakano, Takashi; Matsuda, Wakoto; Furuta, Takahiro; Udagawa, Jun; Kaneko, Takeshi

    2016-12-01

    The external globus pallidus (GP) is known as a relay nucleus of the indirect pathway of the basal ganglia. Recent studies in dopamine-depleted and healthy rats indicate that the GP comprises two main types of pallidofugal neurons: the so-called "prototypic" and "arkypallidal" neurons. However, the reconstruction of complete arkypallidal neurons in healthy rats has not been reported. Here we visualized the entire axonal arborization of four single arkypallidal neurons and six single prototypic neurons in rat brain using labeling with a viral vector expressing membrane-targeted green fluorescent protein and examined the distribution of axon boutons in the target nuclei. Results revealed that not only the arkypallidal neurons but nearly all of the prototypic neurons projected to the striatum with numerous axon varicosities. Thus, the striatum is a major target nucleus for pallidal neurons. Arkypallidal and prototypic GP neurons located in the calbindin-positive and calbindin-negative regions mainly projected to the corresponding positive and negative regions in the striatum. Because the GP and striatum calbindin staining patterns reflect the topographic organization of the striatopallidal projection, the striatal neurons in the sensorimotor and associative regions constitute the reciprocal connection with the GP neurons in the corresponding regions.

  18. Surfactant protein D binds to human immunodeficiency virus (HIV) envelope protein gp120 and inhibits HIV replication

    DEFF Research Database (Denmark)

    Meschi, Joseph; Crouch, Erika C; Skolnik, Paul

    2005-01-01

    The envelope protein (gp120) of human immunodeficiency virus (HIV) contains highly conserved mannosylated oligosaccharides. These glycoconjugates contribute to resistance to antibody neutralization, and binding to cell surface lectins on macrophages and dendritic cells. Mannose-binding lectin (MBL......) binds to gp120 and plays a role in defence against the virus. In this study it is demonstrated that surfactant protein D (SP-D) binds to gp120 and inhibits HIV infectivity at significantly lower concentrations than MBL. The binding of SP-D was mediated by its calcium-dependent carbohydrate......-binding activity and was dependent on glycosylation of gp120. Native dodecameric SP-D bound to HIV gp120 more strongly than native trimeric SP-D. Since one common polymorphic form of SP-D is predominantly expressed as trimers and associated with lower blood levels, these individuals may have less effective innate...

  19. Using photography to enhance GP trainees' reflective practice and professional development.

    Science.gov (United States)

    Rutherford; Forde, Emer; Priego-Hernandez, Jacqueline; Butcher, Aurelia; Wedderburn, Clare

    2018-02-08

    The capacity and the commitment to reflect are integral to the practice of medicine and are core components of most general practitioners (GP) training programmes. Teaching through the humanities is a growing area within medical education, but one which is often considered a voluntary 'add-on' for the interested doctor. This article describes an evaluation of a highly innovative pedagogical project which used photography as a means to enhance GP trainees' reflective capacity, self-awareness and professional development. Photography was used as a tool to develop GP trainees' skills in recognising and articulating the attitudes, feelings and values that might impact on their clinical work and to enhance their confidence in their ability to deal with these concerns/issues. We submit that photography is uniquely well suited for facilitating insight and self-reflection because it provides the ability to record 'at the touch of a button' those scenes and images to which our attention is intuitively drawn without the need for-or the interference of-conscious decisions. This allows us the opportunity to reflect later on the reasons for our intuitive attraction to these scenes. These photography workshops were a compulsory part of the GP training programme and, despite the participants' traditional scientific backgrounds, the results clearly demonstrate the willingness of participants to accept-even embrace-the use of art as a tool for learning. The GP trainees who took part in this project acknowledged it to be beneficial for both their personal and professional development. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  20. Value of combined detection of serum AFP and GP73 in early diagnosis of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    GAO Haifeng

    2014-07-01

    Full Text Available ObjectiveTo investigate the value of combined detection of serum alpha-fetoprotein (AFP and Golgi protein-73 (GP73 in the diagnosis of hepatocellular carcinoma (HCC and to provide a basis for early diagnosis and differential diagnosis of HCC. MethodsA total of 408 patients hospitalized in Baoji Central Hospital from June 2012 to May 2013, as well as healthy persons who had normal test results in physical examination, were included in the study, and their specimens were collected. These patients were classified into HCC group (n=142, chronic hepatitis group (n=156, and liver cirrhosis group (n=110. Serum levels of AFP and GP73 in the three groups were measured by electrochemiluminescence immunoassay and double-antibody sandwich enzyme-linked immunosorbent assay, respectively. Comparison of test results between groups was made by analysis of variance, and comparison of rates was made by chi-square test. The sensitivity and specificity of the two indicators for the diagnosis of HCC were calculated using MedCalc statistical software. ResultsThe HCC group had significantly higher serum AFP and GP73 levels than the liver cirrhosis group and chronic hepatitis group (P<0.05; the liver cirrhosis group had significantly higher serum AFP and GP73 levels than the chronic hepatitis group (P<0.05. The sensitivity and specificity of the two indicators for the diagnosis of HCC were 95.8% and 98.6%, respectively, showing significant differences compared with those of each indicator alone (P<0.05. ConclusionCombined detection of serum AFP and GP73 has high diagnostic value and clinical significance for HCC, and they can be used as indicators for early diagnosis and differential diagnosis of HCC.

  1. Patient satisfaction with out-of-hours GP cooperatives: a longitudinal study.

    Science.gov (United States)

    Smits, Marleen; Huibers, Linda; Oude Bos, Anita; Giesen, Paul

    2012-12-01

    For over a decade, out-of-hours primary care in the Netherlands has been provided by general practitioner (GP) cooperatives. In the past years, quality improvements have been made and patients have become acquainted with the service. This may have increased patient satisfaction. The objective of this study was to examine changes in patient satisfaction with GP cooperatives over time. Longitudinal observational study. A validated patient satisfaction questionnaire was distributed in 2003-2004 (T1) and 2007-2008 (T2). Items were rated on a scale from 0 to 10 (1 = very bad; 10 = excellent). Eight GP cooperatives in the Netherlands. Stratified sample of 9600 patients. Response was 55% at T1 (n = 2634) and 51% at T2 (n = 2462). Expectations met; satisfaction with triage nurses, GPs, and organization. For most patients the care received at the GP cooperative met their expectations (T1: 86.1% and T2: 88.4%). Patients were satisfied with the triage nurses (overall grade T1: 7.73 and T2: 7.99), GPs (T1: 8.04 and T2: 8.25), and organization (overall grade T1: 7.60 and T2: 7.78). Satisfaction with triage nurses showed the largest increase over time. The quality and effectiveness of advice or treatment were given relatively low grades. Of all organizational aspects, the lowest grades were given for waiting times and information about the cooperative. In general, patients were initially satisfied with GP cooperatives and satisfaction had even increased four years later. However, there is room for improvement in the content of the advice, waiting times, and information supply. More research is needed into satisfaction of specific patient groups.

  2. Correlation between the GP78 Gene Polymorphism and Coronary Atherosclerotic Heart Disease

    Directory of Open Access Journals (Sweden)

    Long Wang

    2018-01-01

    Full Text Available Objective: To study the correlation between the GP78 gene polymorphism and blood fat, blood glucose, blood pressure and coronary atherosclerotic heart disease. Methods: A total of 72 patients with coronary atherosclerotic heart disease were selected as the observation group, and 68 healthy participants were selected as the control group. The gp78 gene polymorphism of both groups was studied via polymerase chain reaction-restriction fragment length polymorphism (RFLP. At the same time, the multiple expression quantities of the GP78 gene in the tissues of both groups were tested via fluorogenic quantitative PCR, enzyme-linked immunosorbent assay (ELISA and Western-blotting assay. Furthermore, the blood fat, blood glucose and blood pressure of subjects in both groups were tested. Results: The percentages of the gp78 gene polymorphisms of Arg/Arg, Arg/Gly and Gly/Gly at the 145 locus of the study subjects in the observation group were 12.3%, 43.2% and 44.5%, respectively, while those in the control group were 74.3%, 11.2% and 14.5%, respectively, and there were significant differences between both groups. Based on the test results of the blood fat, blood glucose and blood pressure of the objects in the observation group and control group, significant differences were found between the two groups (P<0.05. Conclusion: There was a significant correlation between the 145 locus of the gp89 gene and coronary atherosclerotic heart disease, indexes of blood fat, blood glucose and blood pressure. Keywords: blood fat, blood glucose, blood pressure, coronary sclerosis, heart disease

  3. Striking HIV-1 Entry by Targeting HIV-1 gp41. But, Where Should We Target?

    Directory of Open Access Journals (Sweden)

    Cátia Teixeira

    Full Text Available HIV-1 gp41 facilitates the viral fusion through a conformational switch involving the association of three C-terminal helices along the conserved hydrophobic grooves of three N-terminal helices coiled-coil. The control of these structural rearrangements is thought to be central to HIV-1 entry and, therefore, different strategies of intervention are being developed. Herewith, we describe a procedure to simulate the folding of an HIV-1 gp41 simplified model. This procedure is based on the construction of plausible conformational pathways, which describe protein transition between non-fusogenic and fusogenic conformations. The calculation of the paths started with 100 molecular dynamics simulations of the non-fusogenic conformation, which were found to converge to different intermediate states. Those presenting defined criteria were selected for separate targeted molecular dynamics simulations, subjected to a force constant imposing a movement towards the gp41 fusogenic conformation. Despite significant diversity, a preferred sequence of events emerged when the simulations were analyzed in terms of the formation, breakage and evolution of the contacts. We pointed out 29 residues as the most relevant for the movement of gp41; also, 2696 possible interactions were reduced to only 48 major interactions, which reveals the efficiency of the method. The analysis of the evolution of the main interactions lead to the detection of four main behaviors for those contacts: stable, increasing, decreasing and repulsive interactions. Altogether, these results suggest a specific small cavity of the HIV-1 gp41 hydrophobic groove as the preferred target to small molecules.

  4. Complete dissociation of the HIV-1 gp41 ectodomain and membrane proximal regions upon phospholipid binding

    International Nuclear Information System (INIS)

    Roche, Julien; Louis, John M.; Aniana, Annie; Ghirlando, Rodolfo; Bax, Ad

    2015-01-01

    The envelope glycoprotein gp41 mediates the process of membrane fusion that enables entry of the HIV-1 virus into the host cell. Strong lipid affinity of the ectodomain suggests that its heptad repeat regions play an active role in destabilizing membranes by directly binding to the lipid bilayers and thereby lowering the free-energy barrier for membrane fusion. In such a model, immediately following the shedding of gp120, the N-heptad and C-heptad helices dissociate and melt into the host cell and viral membranes, respectively, pulling the destabilized membranes into juxtaposition, ready for fusion. Post-fusion, reaching the final 6-helix bundle (6HB) conformation then involves competition between intermolecular interactions needed for formation of the symmetric 6HB trimer and the membrane affinity of gp41’s ectodomain, including its membrane-proximal regions. Our solution NMR study of the structural and dynamic properties of three constructs containing the ectodomain of gp41 with and without its membrane-proximal regions suggests that these segments do not form inter-helical interactions until the very late steps of the fusion process. Interactions between the polar termini of the heptad regions, which are not associating with the lipid surface, therefore may constitute the main driving force initiating formation of the final post-fusion states. The absence of significant intermolecular ectodomain interactions in the presence of dodecyl phosphocholine highlights the importance of trimerization of gp41’s transmembrane helix to prevent complete dissociation of the trimer during the course of fusion

  5. Complete dissociation of the HIV-1 gp41 ectodomain and membrane proximal regions upon phospholipid binding

    Energy Technology Data Exchange (ETDEWEB)

    Roche, Julien; Louis, John M.; Aniana, Annie [National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Chemical Physics (United States); Ghirlando, Rodolfo [National Institutes of Health, Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases (United States); Bax, Ad, E-mail: bax@nih.gov [National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Chemical Physics (United States)

    2015-04-15

    The envelope glycoprotein gp41 mediates the process of membrane fusion that enables entry of the HIV-1 virus into the host cell. Strong lipid affinity of the ectodomain suggests that its heptad repeat regions play an active role in destabilizing membranes by directly binding to the lipid bilayers and thereby lowering the free-energy barrier for membrane fusion. In such a model, immediately following the shedding of gp120, the N-heptad and C-heptad helices dissociate and melt into the host cell and viral membranes, respectively, pulling the destabilized membranes into juxtaposition, ready for fusion. Post-fusion, reaching the final 6-helix bundle (6HB) conformation then involves competition between intermolecular interactions needed for formation of the symmetric 6HB trimer and the membrane affinity of gp41’s ectodomain, including its membrane-proximal regions. Our solution NMR study of the structural and dynamic properties of three constructs containing the ectodomain of gp41 with and without its membrane-proximal regions suggests that these segments do not form inter-helical interactions until the very late steps of the fusion process. Interactions between the polar termini of the heptad regions, which are not associating with the lipid surface, therefore may constitute the main driving force initiating formation of the final post-fusion states. The absence of significant intermolecular ectodomain interactions in the presence of dodecyl phosphocholine highlights the importance of trimerization of gp41’s transmembrane helix to prevent complete dissociation of the trimer during the course of fusion.

  6. Constrained Combinatorial Libraries of Gp2 Proteins Enhance Discovery of PD-L1 Binders.

    Science.gov (United States)

    Kruziki, Max A; Sarma, Vidur; Hackel, Benjamin J

    2018-06-05

    Engineered protein ligands are used for molecular therapy, diagnostics, and industrial biotechnology. The Gp2 domain is a 45-amino acid scaffold that has been evolved for specific, high-affinity binding to multiple targets by diversification of two solvent-exposed loops. Inspired by sitewise enrichment of select amino acids, including cysteine pairs, in earlier Gp2 discovery campaigns, we hypothesized that the breadth and efficiency of de novo Gp2 discovery will be aided by sitewise amino acid constraint within combinatorial library design. We systematically constructed eight libraries and comparatively evaluated their efficacy for binder discovery via yeast display against a panel of targets. Conservation of a cysteine pair at the termini of the first diversified paratope loop increased binder discovery 16-fold ( p libraries with conserved cysteine pairs, within the second loop or an interloop pair, did not aid discovery thereby indicating site-specific impact. Via a yeast display protease resistance assay, Gp2 variants from the loop one cysteine pair library were 3.3 ± 2.1-fold ( p = 0.005) more stable than nonconstrained variants. Sitewise constraint of noncysteine residues-guided by previously evolved binders, natural Gp2 homology, computed stability, and structural analysis-did not aid discovery. A panel of binders to programmed death ligand 1 (PD-L1), a key target in cancer immunotherapy, were discovered from the loop 1 cysteine constraint library. Affinity maturation via loop walking resulted in strong, specific cellular PD-L1 affinity ( K d = 6-9 nM).

  7. Re-Audit of the Contents of GP Referral letters to General Adult Community Psychiatrists.

    Science.gov (United States)

    Odelola, Catherine; Jabbar, Farid

    2017-09-01

    The quality of information provided by referring general practitioners to secondary care mental health services are crucial elements in the effective management of patients. In order to establish effective communication, both primary and secondary care health professionals should contribute to planning and organising this process taking into account their different opinions and views. Anonymous questionnaire was designed to collect information on items that GPs and psychiatrist rated as most important items in GP referral letters to psychiatrists. The questionnaires were sent out electronically. Each item was scored using a rating scale where 0 was least important and 10 was most important. Items that scored 8 and above were agreed by all as the most important items. 76 GP letters were audited using a devised checklist of the identified most important items. Data was collected and analysed using a devised data collection tool. A re-audit was done 6months later. A response rate of 70% was obtained for both psychiatrists and GPs. Reasons for referral were described in almost all GP referral letters (95%). Only 24% referral letters had details about current physical health which improved to 59%. Concerns about risk were described in only 47% of letters and treatment provided by GP in 50% of letters. These improved in 79% and 71% of letters respectively in the re-audit. The involvement of professionals in devising a standardised approach for referral letters has improved communication in this re-audit between GPs and Psychiatrists. This is evident in the improvement in key aspects of the referral letters: past medical history, past psychiatric history, current physical health, treatment provided by GP. Efficient communication between GPs and psychiatrists improves the quality of health care for patients.

  8. Brain MR imaging in patients with hepatic cirrhosis: relationship between high intensity signal in basal ganglia on T1-weighted images and elemental concentrations in brain

    International Nuclear Information System (INIS)

    Maeda, H.; Sato, M.; Yoshikawa, A.; Kimura, M.; Sonomura, T.; Terada, M.; Kishi, K.

    1997-01-01

    In patients with hepatic cirrhosis, the globus pallidus and putamen show high intensity on T1-weighted MRI. While the causes of this high signal have been thought to include paramagnetic substances, especially manganese, no evidence for this has been presented. Autopsy in four cases of hepatic cirrhosis permitted measurement of metal concentrations in brain and histopathological examination. In three cases the globus pallidus showed high intensity on T1-weighted images. Mean manganese concentrations in globus pallidus, putamen and frontal white matter were 3.03 ± 0.38, 2.12 ± 0.37, and 1.38 ± 0.24 (μg/g wet weight), respectively, being approximately four- to almost ten-fold the normal values. Copper concentrations in globus pallidus and putamen were also high, 50 % more than normal. Calcium, iron, zinc and magnesium concentrations were all normal. The fourth case showed no abnormal intensity in the basal ganglia and brain metal concentrations were all normal. Histopathologically, cases with showing high signal remarkable atrophy, necrosis, and deciduation of nerve cells and proliferation of glial cells and microglia in globus pallidus. These findings were similar to those in chronic manganese poisoning. On T1-weighted images, copper deposition shows no abnormal intensity. It is therefore inferred that deposition of highly concentrations of manganese may caused high signal on T1-weighted images and nerve cell death in the globus pallidus. (orig.). With 2 figs., 2 tabs

  9. A single amino acid substitution modulates low-pH-triggered membrane fusion of GP64 protein in Autographa californica and Bombyx mori nucleopolyhedroviruses

    International Nuclear Information System (INIS)

    Katou, Yasuhiro; Yamada, Hayato; Ikeda, Motoko; Kobayashi, Michihiro

    2010-01-01

    We have previously shown that budded viruses of Bombyx mori nucleopolyhedrovirus (BmNPV) enter the cell cytoplasm but do not migrate into the nuclei of non-permissive Sf9 cells that support a high titer of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) multiplication. Here we show, using the syncytium formation assay, that low-pH-triggered membrane fusion of BmNPV GP64 protein (Bm-GP64) is significantly lower than that of AcMNPV GP64 protein (Ac-GP64). Mutational analyses of GP64 proteins revealed that a single amino acid substitution between Ac-GP64 H155 and Bm-GP64 Y153 can have significant positive or negative effects on membrane fusion activity. Studies using bacmid-based GP64 recombinant AcMNPV harboring point-mutated ac-gp64 and bm-gp64 genes showed that Ac-GP64 H155Y and Bm-GP64 Y153H substitutions decreased and increased, respectively, the multiplication and cell-to-cell spread of progeny viruses. These results indicate that Ac-GP64 H155 facilitates the low-pH-triggered membrane fusion reaction between virus envelopes and endosomal membranes.

  10. iP-gp , a novel cell line with tight barrier function and expression of human P-glycoprotein (ABCB1) for drug screening

    DEFF Research Database (Denmark)

    Brodin, Birger; Ozgür, Burak; Saaby, Lasse

    that new API's are evaluated with respect to P-gp interactions.  Aim : The aim of the present work was to validate the suitability of the newly developed iP-gp cell line for investigating P-gp interactions with human P-gp. Methods: IPEC-J2 MDR1 (iP-gp) cells were cultured on permeable supports for 17......Background : The efflux transporter P-glycoprotein (P-gp, product of the MDR1/ABCB1 gene) hinders uptake of drug compounds to the brain, limits intestinal uptake, is a cause of resistance to chemoterapeutics and a potential "site" for drug-drug interaction. Regulatory agencies therefore recommend.......04 +/- 0.01 µM in transport experiments including digoxin and rhodamine 123, respectively. Summary/Conclusion : The iP-gp cell line may become a useful screening tool for interactions between drug compounds and human P-gp....

  11. Attenuated Human Parainfluenza Virus Type 1 Expressing Ebola Virus Glycoprotein GP Administered Intranasally Is Immunogenic in African Green Monkeys.

    Science.gov (United States)

    Lingemann, Matthias; Liu, Xueqiao; Surman, Sonja; Liang, Bo; Herbert, Richard; Hackenberg, Ashley D; Buchholz, Ursula J; Collins, Peter L; Munir, Shirin

    2017-05-15

    The recent 2014-2016 Ebola virus (EBOV) outbreak prompted increased efforts to develop vaccines against EBOV disease. We describe the development and preclinical evaluation of an attenuated recombinant human parainfluenza virus type 1 (rHPIV1) expressing the membrane-anchored form of EBOV glycoprotein GP, as an intranasal (i.n.) EBOV vaccine. GP was codon optimized and expressed either as a full-length protein or as an engineered chimeric form in which its transmembrane and cytoplasmic tail (TMCT) domains were replaced with those of the HPIV1 F protein in an effort to enhance packaging into the vector particle and immunogenicity. GP was inserted either preceding the N gene (pre-N) or between the N and P genes (N-P) of rHPIV1 bearing a stabilized attenuating mutation in the P/C gene (C Δ170 ). The constructs grew to high titers and efficiently and stably expressed GP. Viruses were attenuated, replicating at low titers over several days, in the respiratory tract of African green monkeys (AGMs). Two doses of candidates expressing GP from the pre-N position elicited higher GP neutralizing serum antibody titers than the N-P viruses, and unmodified GP induced higher levels than its TMCT counterpart. Unmodified EBOV GP was packaged into the HPIV1 particle, and the TMCT modification did not increase packaging or immunogenicity but rather reduced the stability of GP expression during in vivo replication. In conclusion, we identified an attenuated and immunogenic i.n. vaccine candidate expressing GP from the pre-N position. It is expected to be well tolerated in humans and is available for clinical evaluation. IMPORTANCE EBOV hemorrhagic fever is one of the most lethal viral infections and lacks a licensed vaccine. Contact of fluids from infected individuals, including droplets or aerosols, with mucosal surfaces is an important route of EBOV spread during a natural outbreak, and aerosols also might be exploited for intentional virus spread. Therefore, vaccines that protect

  12. Analysis of purified gp96 preparations from rat and mouse livers using 2-D gel electrophoresis and tandem mass spectrometry.

    Science.gov (United States)

    Fairburn, B; Muthana, M; Hopkinson, K; Slack, L K; Mirza, S; Georgiou, A S; Espigares, E; Wong, C; Pockley, A G

    2006-09-01

    The stress protein gp96 exhibits a number of immunological activities, the majority of studies into which have used gp96 purified from a variety of tissues. On the basis of 1-D gel electrophoresis, the purity of these preparations has been reported to range between 70% and 99%. This study analyzed gp96 preparations from rat and mouse livers using 2-D gel electrophoresis and liquid chromatography electrospray ionization tandem mass spectrometry (MS-MS). The procedure for purifying gp96 was reproducible, as similar protein profiles were observed in replicate gels of gp96 preparations. The purity of the preparations was typically around 70%, with minor co-purified proteins of varying molecular weights and mobilities being present. Dominant bands at 95-100 kDa in preparations from Wistar rats and C57BL/6 mice were identified as gp96 by ECL Western blotting. Multiple bands having similar, yet distinct molecular weights and differing pI mobility on ECL Western blots were confirmed as being gp96 in preparations from Wistar rats using MS-MS. The most striking feature of the 2-D gel analysis was the presence of additional dominant bands at 55 kDa in preparations from Wistar rats, and at 75-90 kDa in preparations from C57BL/6 mice. These were identified as gp96 by ECL Western blotting and, in the case of preparations from Wistar rats, by MS-MS. Although the lower molecular weight, gp96-related molecules might be partially degraded gp96, their reproducible presence, definition and characteristics suggest that they are alternative, species-specific isoforms of the molecule. A 55 kDa protein which exhibited a lower pI value than gp96 was present in all preparations and this was identified as calreticulin, another putative immunoregulatory molecule. This study confirms the reproducibility of the gp96 purification protocol and reveals the presence of multiple gp96 isoforms, some of which likely result from post-translational modifications such as differential glycosylation and

  13. Construction and Characterization of a Humanized Anti-Epstein-Barr Virus gp350 Antibody with Neutralizing Activity in Cell Culture

    Directory of Open Access Journals (Sweden)

    Jerome E. Tanner

    2018-04-01

    Full Text Available Acute Epstein-Barr virus (EBV infection in immunosuppressed transplant patients can give rise to a malignant B-cell proliferation known as post-transplant lymphoproliferative disease (PTLD. The EBV major virion surface glycoprotein (gp350 is a principal target of naturally occurring neutralizing antibodies and is viewed as the best target to prevent acute infection and PTLD in at-risk transplant recipients. We have constructed a humanized (hu version of the murine anti-gp350 neutralizing monoclonal antibody 72a1. The hu72a1 IgG1 antibody displayed no significant anti-mouse activity, recognized both gp350 and its splice variant gp220 as well as a gp350 peptide that was shown to constitute the principal EBV gp350 neutralizing epitope when tested in immunoassays. Hu72a1 antibody blocked in vitro EBV infection of B cells at a level which equaled that of a mouse-human chimeric 72a1 antibody construct. This work provides a further structural and immunological understanding of the 72a1 antibody interaction with EBV gp350, and constitutes a launch point for future anti-EBV therapeutic antibodies designed to block EBV infection and prevent PTLD while eliminating the deleterious antigenic murine features of the original 72a1 antibody.

  14. Phosphorylation of varicella-zoster virus glycoprotein gpI by mammalian casein kinase II and casein kinase I

    International Nuclear Information System (INIS)

    Grose, C.; Jackson, W.; Traugh, J.A.

    1989-01-01

    Varicella-zoster virus (VZV) glycoprotein gpI is the predominant viral glycoprotein within the plasma membranes of infected cells. This viral glycoprotein is phosphorylated on its polypeptide backbone during biosynthesis. In this report, the authors investigated the protein kinases which participate in the phosphorylation events. Under in vivo conditions, VZV gpI was phosphorylated on its serine and threonine residues by protein kinases present within lysates of either VZV-infected or uninfected cells. Because this activity was diminished by heparin, a known inhibitor of casein kinase II, isolated gpI was incubated with purified casein kinase II and shown to be phosphorylated in an in vitro assay containing [γ- 32 P]ATP. The same glycoprotein was phosphorylated when [ 32 P]GTP was substituted for [ 32 P]ATP in the protein kinase assay. They also tested whether VZV gpI was phosphorylated by two other ubiquitous mammalian protein kinases--casein kinase I and cyclic AMP-dependent kinase--and found that only casein kinase I modified gpI. When the predicted 623-amino-acid sequence of gpI was examined, two phosphorylation sites known to be optimal for casein kinase II were observed. In summary, this study showed that VZV gpI was phosphorylated by each of two mammalian protein kinases (casein kinase I and casein kinase II) and that potential serine-threonine phosphorylation sites for each of these two kinases were present in the viral glycoprotein

  15. Genome profiling (GP method based classification of insects: congruence with that of classical phenotype-based one.

    Directory of Open Access Journals (Sweden)

    Shamim Ahmed

    Full Text Available Ribosomal RNAs have been widely used for identification and classification of species, and have produced data giving new insights into phylogenetic relationships. Recently, multilocus genotyping and even whole genome sequencing-based technologies have been adopted in ambitious comparative biology studies. However, such technologies are still far from routine-use in species classification studies due to their high costs in terms of labor, equipment and consumables.Here, we describe a simple and powerful approach for species classification called genome profiling (GP. The GP method composed of random PCR, temperature gradient gel electrophoresis (TGGE and computer-aided gel image processing is highly informative and less laborious. For demonstration, we classified 26 species of insects using GP and 18S rDNA-sequencing approaches. The GP method was found to give a better correspondence to the classical phenotype-based approach than did 18S rDNA sequencing employing a congruence value. To our surprise, use of a single probe in GP was sufficient to identify the relationships between the insect species, making this approach more straightforward.The data gathered here, together with those of previous studies show that GP is a simple and powerful method that can be applied for actually universally identifying and classifying species. The current success supported our previous proposal that GP-based web database can be constructible and effective for the global identification/classification of species.

  16. A Critical View on In Vitro Analysis of P-glycoprotein (P-gp) Transport Kinetics.

    Science.gov (United States)

    Saaby, Lasse; Brodin, Birger

    2017-09-01

    Transport proteins expressed in the different barriers of the human body can have great implications on absorption, distribution, and excretion of drug compounds. Inhibition or saturation of a transporter can potentially alter these absorbtion, distribution, metabolism and elimination properties and thereby also the pharmacokinetic profile and bioavailability of drug compounds. P-glycoprotein (P-gp, ABCB1) is an efflux transporter which is present in most of the barriers of the body, including the small intestine, the blood-brain barrier, the liver, and the kidney. In all these tissues, P-gp may mediate efflux of drug compounds and may also be a potential site for drug-drug interactions. Consequently, there is a need to be able to predict the saturation and inhibition of P-gp and other transporters in vivo. For this purpose, Michaelis-Menten steady-state analysis has been applied to estimate kinetic parameters, such as K m and V max , for carrier-mediated transport, whereas half-maximal inhibitor concentration (IC 50 ) and the disassociation constant for an inhibitor/P-gp complex (K i ) have been determined to estimate P-gp inhibition. This review addresses in vitro methods commonly used to study P-gp transport kinetics and aims at providing a critical evaluation of the application of steady-state Michaelis-Menten analysis of kinetic parameters for substrate/P-gp interactions. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  17. FDG-PET study of the bilateral subthalamic nucleus stimulation effects on the regional cerebral metabolism in advanced Parkinson disease

    International Nuclear Information System (INIS)

    Li, D.; Shen, J.; Zan, S.; Sun, B.; Zuo, C.; Guan, Y.; Zhao, Y.

    2006-01-01

    The aim of the study was to evaluate the changes in regional cerebral metabolic rate of glucose (rCMRGIu) induced by bilateral subthalamic nucleus (STN) stimulation in advanced Parkinson's disease (PD). 18 F-Fluorodeoxyglucose (FDG) PET data obtained before and one month after stimulation were analyzed with statistical parametric mapping (SPM). As a result of clinically effective bilateral STN stimulation, rCMRGIu increased in lateral globus pallidus (GP), upper brain stem, dorsolateral prefrontal cortex (DLPFC) and posterior parietal-occipital cortex, and decreased in the orbital frontal cortex and parahippocampus gyrus (p <0.001). We conclude that the alleviation of clinical symptoms in advanced PD by bilateral STN stimulation may be the result of activation of both ascending and descending pathways from STN and of restoration of the impaired higher-order cortex functions. (author)

  18. Energetics of dendrimer binding to HIV-1 gp120-CD4 complex and mechanismic aspects of its role as an entry-inhibitor

    International Nuclear Information System (INIS)

    Saurabh, Suman; Sahoo, Anil Kumar; Maiti, Prabal K.

    2016-01-01

    Experiments and computational studies have established that de-protonated dendrimers (SPL7013 and PAMAM) act as entry-inhibitors of HIV. SPL7013 based Vivagel is currently under clinical development. The dendrimer binds to gp120 in the gp120-CD4 complex, destabilizes it by breaking key contacts between gp120 and CD4 and prevents viral entry into target cells. In this work, we provide molecular details and energetics of the formation of the SPL7013-gp120-CD4 ternary complex and decipher modes of action of the dendrimer in preventing viral entry. It is also known from experiments that the dendrimer binds weakly to gp120 that is not bound to CD4. It binds even more weakly to the CD4-binding region of gp120 and thus cannot directly block gp120-CD4 complexation. In this work, we examine the feasibility of dendrimer binding to the gp120-binding region of CD4 and directly blocking gp120-CD4 complex formation. We find that the process of the dendrimer binding to CD4 can compete with gp120-CD4 binding due to comparable free energy change for the two processes, thus creating a possibility for the dendrimer to directly block gp120-CD4 complexation by binding to the gp120-binding region of CD4. (paper)

  19. Energetics of dendrimer binding to HIV-1 gp120-CD4 complex and mechanismic aspects of its role as an entry-inhibitor

    Science.gov (United States)

    Saurabh, Suman; Sahoo, Anil Kumar; Maiti, Prabal K.

    2016-10-01

    Experiments and computational studies have established that de-protonated dendrimers (SPL7013 and PAMAM) act as entry-inhibitors of HIV. SPL7013 based Vivagel is currently under clinical development. The dendrimer binds to gp120 in the gp120-CD4 complex, destabilizes it by breaking key contacts between gp120 and CD4 and prevents viral entry into target cells. In this work, we provide molecular details and energetics of the formation of the SPL7013-gp120-CD4 ternary complex and decipher modes of action of the dendrimer in preventing viral entry. It is also known from experiments that the dendrimer binds weakly to gp120 that is not bound to CD4. It binds even more weakly to the CD4-binding region of gp120 and thus cannot directly block gp120-CD4 complexation. In this work, we examine the feasibility of dendrimer binding to the gp120-binding region of CD4 and directly blocking gp120-CD4 complex formation. We find that the process of the dendrimer binding to CD4 can compete with gp120-CD4 binding due to comparable free energy change for the two processes, thus creating a possibility for the dendrimer to directly block gp120-CD4 complexation by binding to the gp120-binding region of CD4.

  20. The Ixodes scapularis Salivary Protein, Salp15, Prevents the Association of HIV-1 gp120 and CD4

    OpenAIRE

    Juncadella, Ignacio J.; Garg, Renu; Bates, Tonya C.; Olivera, Elias R.; Anguita, Juan

    2007-01-01

    Ixodes scapularis salivary protein, Salp15, inhibits CD4+ T cell activation by binding to the most-extracellular domains of the CD4 molecule, potentially overlapping with the gp120-binding region. We now show that Salp15 inhibits the interaction of gp120 and CD4. Furthermore, Salp15 prevents syncytia formation between HL2/3 (a stable HeLa cell line expressing the envelope protein) and CD4-expressing cells. Salp15 prevented gp120-CD4 interaction at least partially through its direct interactio...

  1. Social relationships and GP use of middle-aged and older adults in Europe: a moderator analysis.

    Science.gov (United States)

    Bremer, Daniel; Lüdecke, Daniel; Vonneilich, Nico; von dem Knesebeck, Olaf

    2018-04-07

    This paper investigates (1) how social relationships (SRs) relate to the frequency of general practitioner (GP) visits among middle-aged and older adults in Europe, (2) if SRs moderate the association between self-rated health and GP visits, and (3) how the associations vary regarding employment status. Data stem from the Survey of Health, Ageing and Retirement in Europe project (wave 4, 56 989 respondents, 50 years or older). GP use was assessed by frequency of contacts with GPs in the last 12 months. Predictors were self-rated health and structural (Social Integration Index (SII), social contact frequency) and functional (emotional closeness) aspects of SR. Regressions were used to measure the associations between GP use and those predictors. Sociodemographic and socioeconomic factors were used as covariates. Additional models were computed with interactions. Analyses did not reveal significant associations of functional and structural aspects of SR with frequency of GP visits (SII: incidence rate ratio (IRR)=0.99, 95% CI 0.97 to 1.01, social contact frequency: IRR=1.04, 95% CI 1.00 to 1.07, emotional closeness: IRR=1.02, 95% CI 1.00 to 1.04). Moderator analyses showed that 'high social contact frequency people' with better health had more statistically significant GP visits than 'low social contact frequency people' with better health. Furthermore, people with poor health and an emotionally close network showed a significantly higher number of GP visits compared with people with same health, but less close networks. Three-way interaction analyses indicated employment status specific behavioural patterns with regard to SR and GP use, but coefficients were mostly not significant. All in all, the not employed groups showed a higher number of GP visits. Different indicators of SR showed statistically insignificantly associations with GP visits. Consequently, the relevance of SR may be rated rather low in quantitative terms for investigating GP use behaviour

  2. Determination of the minimal fusion peptide of bovine leukemia virus gp30

    International Nuclear Information System (INIS)

    Lorin, Aurelien; Lins, Laurence; Stroobant, Vincent; Brasseur, Robert; Charloteaux, Benoit

    2007-01-01

    In this study, we determined the minimal N-terminal fusion peptide of the gp30 of the bovine leukemia virus on the basis of the tilted peptide theory. We first used molecular modelling to predict that the gp30 minimal fusion peptide corresponds to the 15 first residues. Liposome lipid-mixing and leakage assays confirmed that the 15-residue long peptide induces fusion in vitro and that it is the shortest peptide inducing optimal fusion since longer peptides destabilize liposomes to the same extent but not shorter ones. The 15-residue long peptide can thus be considered as the minimal fusion peptide. The effect of mutations reported in the literature was also investigated. Interestingly, mutations related to glycoproteins unable to induce syncytia in cell-cell fusion assays correspond to peptides predicted as non-tilted. The relationship between obliquity and fusogenicity was also confirmed in vitro for one tilted and one non-tilted mutant peptide

  3. Evaluation of "credit card" libraries for inhibition of HIV-1 gp41 fusogenic core formation.

    Science.gov (United States)

    Xu, Yang; Lu, Hong; Kennedy, Jack P; Yan, Xuxia; McAllister, Laura A; Yamamoto, Noboru; Moss, Jason A; Boldt, Grant E; Jiang, Shibo; Janda, Kim D

    2006-01-01

    Protein-protein interactions are of critical importance in biological systems, and small molecule modulators of such protein recognition and intervention processes are of particular interest. To investigate this area of research, we have synthesized small-molecule libraries that can disrupt a number of biologically relevant protein-protein interactions. These library members are designed upon planar motif, appended with a variety of chemical functions, which we have termed "credit-card" structures. From two of our "credit-card" libraries, a series of molecules were uncovered which act as inhibitors against the HIV-1 gp41 fusogenic 6-helix bundle core formation, viral antigen p24 formation, and cell-cell fusion at low micromolar concentrations. From the high-throughput screening assays we utilized, a selective index (SI) value of 4.2 was uncovered for compound 2261, which bodes well for future structure activity investigations and the design of more potent gp41 inhibitors.

  4. Biodegradation waste of the stations service by Rhodococcus erythropolis ohp-al-gp

    International Nuclear Information System (INIS)

    Pucci, Oscar Hector; Acuna, Adrian Javier; Pucci, Graciela Natalia

    2013-01-01

    The strain Rhodococcus erythropolis ohp-al-gp was isolated from turbine oil contaminated soil from northern Santa Cruz province, Argentina. Because of its potential in bioremediation, the aim was to know the abilities for degradation of pure compounds and mixtures of hydrocarbons, as well as degradation in the presence and absence of diesel nitrogen measured by gas chromatography. The strain possesses the ability to use diesel, kerosene, lubricating oil, pristane, hexane, heptane, octane, pentadecane and hexadecane. R. erythropolis ohp-al-gp has excellent potential for bioremediation of hydrocarbons, which are conflictive as lubricating oils, their potential use in removing mud from washing engines or gas stations would be its most important application. The degradation rate in optimal culture conditions, gives it an additional advantage. It also has a low degradation in the absence of nitrogen, a frequent limiting factor in Patagonian soils.

  5. Characterization of the immuno dominant regions within gp41 of env gene of HIV in Pakistan

    International Nuclear Information System (INIS)

    Nisar, L.; Qadir, M.I.; Nisa, T.; Malik, S.A.; Tabassum, N.

    2011-01-01

    Objective of the present study was to characterize the immuno dominant sequences of gp41 in HIV strain in Pakistani population so that vaccine may be prepared based upon these regions. A total of 25 specimens were collected from HIV patients of different areas of Pakistan. The viral RNA was isolated using QIAamp MinElute Spin Kit manufactured by Quiagen, California, USA. RT-PCR was done for amplification of the required region and confirmed by gel electrophoresis. The nucleotides of the required regions were sequenced using Big Dye terminator. Less than 20% of the specimens had mutations in immuno dominant regions, so it may be concluded that immuno dominant regions of gp41 in HIV strain in Pakistani population are conservatives and vaccine based upon these regions may prove active immunization against the disease. (author)

  6. Characterization of the immuno dominant regions within gp41 of env gene of HIV in Pakistan

    Energy Technology Data Exchange (ETDEWEB)

    Nisar, L; Qadir, M I; Nisa, T; Malik, S A; Tabassum, N

    2011-08-15

    Objective of the present study was to characterize the immuno dominant sequences of gp41 in HIV strain in Pakistani population so that vaccine may be prepared based upon these regions. A total of 25 specimens were collected from HIV patients of different areas of Pakistan. The viral RNA was isolated using QIAamp MinElute Spin Kit manufactured by Quiagen, California, USA. RT-PCR was done for amplification of the required region and confirmed by gel electrophoresis. The nucleotides of the required regions were sequenced using Big Dye terminator. Less than 20% of the specimens had mutations in immuno dominant regions, so it may be concluded that immuno dominant regions of gp41 in HIV strain in Pakistani population are conservatives and vaccine based upon these regions may prove active immunization against the disease. (author)

  7. GP supervisors--an investigation into their motivations and teaching activities.

    Science.gov (United States)

    Ingham, Gerard; O'Meara, Peter; Fry, Jennifer; Crothers, Natalie

    2014-11-01

    There is little empirical information on how general practitioner (GP) supervisors teach and the reasons for the variation in their teaching methods. Could the variation be due to differing motivations to teach? Supervisors from one regional training provider who attended educational workshops in 2013 were surveyed, seeking infor-mation on their motivation to become and remain a supervisor, and the frequency of use of selected teaching activities. The majority of respondents cited intrinsic motivators, including enjoying teaching (84%), contribution to the profession and community (82%), adding variety (78%) and workforce/succession planning (69%), as reasons for becoming GP supervisors. The expected relationships between motivations and teaching activities were not found. Variation in teaching activities used by supervisors does not appear to be associated with differing motivations. Measuring the use of teaching activities is not a mechanism to determine a supervisor's commitment to teaching.

  8. Reasons for elderly patients GP visits: results of a cross-sectional study

    OpenAIRE

    Frese, Thomas; Mahlmeister, Jarmila; Deutsch, Tobias; Sandholzer, Hagen

    2016-01-01

    Thomas Frese, Jarmila Mahlmeister, Tobias Deutsch, Hagen Sandholzer Department of General Practice, Medical Faculty, University of Leipzig, Leipzig, Germany Objective: The aim of this study is to describe the frequency of reasons for elderly patients visits to a general practice (GP) setting. Subjects and methods: Cross-sectional data from 8,877 randomly selected patients were assessed during a 1-year period by 209 GPs in the German federal state of Saxony. The reasons for visits, performed...

  9. How international medical graduates view their learning needs for UK GP training.

    Science.gov (United States)

    Warwick, Christopher

    2014-03-01

    International medical graduates (IMGs) form a vital group of general practitioners (GPs) in the NHS. They are known to face additional challenges above and beyond those faced by UK medical graduates in the course of their GP training. Whilst they are a heterogeneous group of professionals, their views on what they need to learn, and how they are supported, are often distant from those of the educators responsible for planning their education. This study was undertaken, through narrative-based focus groups, to explore the issues which matter to the IMGs, in an attempt to empower their voices about their experiences in GP training, and to see what lessons could be drawn from these views. The findings confirmed the central importance, and considerable challenge involved, in making an effective transition into the culture of the NHS and UK general practice. The IMGs felt that induction needed to be an on-going, iterative process of learning which continued throughout training, with a more effective individualised learning needs analysis at the start of GP training. Lack of sophisticated language skills was highlighted as a real concern. Recognition that their lack of knowledge about the NHS at the start of training should not be seen as an indicator of deficiency, but a clue to what they needed to learn were also key messages. IMGs also felt the earlier in their training they undertook a GP placement, the quicker they would start to understand the culture of general practice in the UK. Further work following on from this research should include how to manage change in the educational network for these barriers to be overcome.

  10. A study of role expansion: a new GP role in cardiology care

    Science.gov (United States)

    2014-01-01

    Background The National Health Service is reconfiguring health care services in order to meet the increasing challenge of providing care for people with long-term conditions and to reduce the demand on specialised outpatient hospital services by enhancing primary care. A review of cardiology referrals to specialised care and the literature on referral management inspired the development of a new GP role in Cardiology. This new extended role was developed to enable GPs to diagnose and manage patients with mild to moderate heart failure or atrial fibrillation and to use a range of diagnostics effectively in primary care. This entailed GPs participating in a four-session short course with on-going clinical supervision. The new role was piloted in a small number of GP practices in one county in England for four months. This study explores the impact of piloting the Extended Cardiology role on the GP’s role, patients’ experience, service delivery and quality. Methods A mixed methods approach was employed including semi-structured interviews with GPs, a patient experience survey, a quality review of case notes, and analysis on activity and referral data. Results The participating GPs perceived the extended GP role as a professional development opportunity that had the potential to reduce healthcare utilisation and costs, through a reduction in referrals, whilst meeting the patient’s wishes for the provision of care closer to home. Patient experience of the new GP service was positive. The standard of clinical practice was judged acceptable. There was a fall in referrals during the study period. Conclusion This new role in cardiology was broadly welcomed as a model of care by the participating GPs and by patients, because of the potential to improve the quality of care for patients in primary care and reduce costs. As this was a pilot study further development and continuing evaluation of the model is recommended. PMID:24885826

  11. Positive evolution of the glycoprotein (GP) gene is related to transmission of the Ebola virus.

    Science.gov (United States)

    Jing, Y X; Wang, L N; Wu, X M; Song, C X

    2016-03-28

    Ebola hemorrhagic fever is a fatal disease caused by the negative-strand RNA of the Ebola virus. A high-intensity outbreak of this fever was reported in West Africa last year; however, there is currently no definitive treatment strategy available for this disease. In this study, we analyzed the molecular evolutionary history and attempted to determine the positive selection sites in the Ebola genes using multiple-genomic sequences of the various Ebola virus subtypes, in order to gain greater clarity into the evolution of the virus and its various subtypes. Only the glycoprotein (GP) gene was positively selected among the 8 Ebola genes, with the other genes remaining in the purification stage. The positive selection sites in the GP gene were identified by a random-site model; these sites were found to be located in the mucin-like region, which is associated with transmembrane protein binding. Additionally, different branches of the phylogenetic tree displayed different positive sites, which in turn was responsible for differences in the cell adhesion ability of the virus. In conclusion, the pattern of positive sites in the GP gene is associated with the epidemiology and prevalence of Ebola in different areas.

  12. Commissioning of the iGp Feedback System at DAΦNE

    International Nuclear Information System (INIS)

    Drago, A.; Fox, J.D.; Teytelman, D.; Tobiyama, M.

    2011-01-01

    The iGp (Integrated Gigasample Processor) is an innovative digital bunch-by-bunch feedback system developed by a KEK / SLAC / INFN-LNF joint collaboration. The processing unit can sample at 500 MHz and compute the bunch-by-bunch output signal for up to ∼5000 bunches. The feedback gateware code is implemented inside just one FPGA (Field Programmable Gate Array) chip, a Xilinx Virtex-II. The FPGA implements two banks of 16-tap FIR (Finite Impulse Response) filters. Each filter is realtime programmable through the operator interface. At DAΦNE, the Frascati Φ-Factory, two iGp units have been commissioned in the April 2007. The iGp systems have substituted the previous betatron feedback systems. This insertion has been very fast and has shown no problems involving just a substitution of the old, less flexible, digital systems, letting unchanged the baseband analog frontend and backend. The commissioning has been very simple, due to the complete and powerful EPICS operator interface, working well in local and remote operations. The software includes also tools for analyzing post processor data. A description of the commissioning with the operations done is reported.

  13. Observing the temperature dependent transition of the GP2 peptide using terahertz spectroscopy.

    Directory of Open Access Journals (Sweden)

    Yiwen Sun

    Full Text Available The GP2 peptide is derived from the Human Epidermal growth factor Receptor 2 (HER2/nue, a marker protein for breast cancer present in saliva. In this paper we study the temperature dependent behavior of hydrated GP2 at terahertz frequencies and find that the peptide undergoes a dynamic transition between 200 and 220 K. By fitting suitable molecular models to the frequency response we determine the molecular processes involved above and below the transition temperature (T(D. In particular, we show that below T(D the dynamic transition is dominated by a simple harmonic vibration with a slow and temperature dependent relaxation time constant and that above T(D, the dynamic behavior is governed by two oscillators, one of which has a fast and temperature independent relaxation time constant and the other of which is a heavily damped oscillator with a slow and temperature dependent time constant. Furthermore a red shifting of the characteristic frequency of the damped oscillator was observed, confirming the presence of a non-harmonic vibration potential. Our measurements and modeling of GP2 highlight the unique capabilities of THz spectroscopy for protein characterization.

  14. [Eukaryotic Expression and Immunogenic Research of Recombination Ebola Virus Membrane Protein Gp-Fc].

    Science.gov (United States)

    Zhang, Xiaoguang; Yang, Ren; Wang, Jiao; Wang, Xuan; Hou, Mieling; An, Lina; Zhu, Ying; Cao, Yuxi; Zeng, Yi

    2016-01-01

    We used 293 cells to express the recombinant membrane protein of the Ebola virus. Then, the immunogenicity of the recombinant protein was studied by immunized BALB/c mice. According to the codon use frequency of humans, the gene encoding the extracellular domain of the Ebola virus membrane protein was optimized, synthesized, and inserted into the eukaryotic expression plasmid pXG-Fc to construct the human IgG Fc and Ebola GP fusion protein expression plasmid pXG-modGP-Fc. To achieve expression, the fusion protein expression vector was transfected into high-density 293 cells using transient transfection technology. The recombinant protein was purified by protein A affinity chromatography. BALB/c mice were immunized with the purified fusion protein, and serum antibody titers evaluated by an indirect enzyme-linked immunosorbent assay (ELISA). Purification and analyses of the protein revealed that the eukaryotic expression vector could express the recombinant protein GP-Fc effectively, and that the recombinant protein in the supernatant of the cell culture was present as a dimer. After immunization with the purified recombinant protein, a high titer of antigen-specific IgG could be detected in the serum of immunized mice by indirect ELISA, showing that the recombinant protein had good immunogenicity. These data suggest that we obtained a recombinant protein with good immunogenicity. Our study is the basis for development of a vaccine against the Ebola virus and for screening of monoclonal antibodies.

  15. Supply and demand in physician markets: a panel data analysis of GP services in Australia.

    Science.gov (United States)

    McRae, Ian; Butler, James R G

    2014-09-01

    To understand the trends in any physician services market it is necessary to understand the nature of both supply and demand, but few studies have jointly examined supply and demand in these markets. This study uses aggregate panel data on general practitioner (GP) services at the Statistical Local Area level in Australia spanning eight years to estimate supply and demand equations for GP services. The structural equations of the model are estimated separately using population-weighted fixed effects panel modelling with the two stage least squares formulation of the generalised method of moments approach (GMM (2SLS)). The estimated price elasticity of demand of [Formula: see text] is comparable with other studies. The direct impact of GP density on demand, while significant, proves almost immaterial in the context of near vertical supply curves. Supply changes are therefore due to shifts in the position of the curves, partly determined by a time trend. The model is validated by comparing post-panel model predictions with actual market outcomes over a period of three years and is found to provide surprisingly accurate projections over a period of significant policy change. The study confirms the need to jointly consider supply and demand in exploring the behaviour of physician services markets.

  16. Solution Structure and Membrane Interaction of the Cytoplasmic Tail of HIV-1 gp41 Protein.

    Science.gov (United States)

    Murphy, R Elliot; Samal, Alexandra B; Vlach, Jiri; Saad, Jamil S

    2017-11-07

    The cytoplasmic tail of gp41 (gp41CT) remains the last HIV-1 domain with an unknown structure. It plays important roles in HIV-1 replication such as mediating envelope (Env) intracellular trafficking and incorporation into assembling virions, mechanisms of which are poorly understood. Here, we present the solution structure of gp41CT in a micellar environment and characterize its interaction with the membrane. We show that the N-terminal 45 residues are unstructured and not associated with the membrane. However, the C-terminal 105 residues form three membrane-bound amphipathic α helices with distinctive structural features such as variable degree of membrane penetration, hydrophobic and basic surfaces, clusters of aromatic residues, and a network of cation-π interactions. This work fills a major gap by providing the structure of the last segment of HIV-1 Env, which will provide insights into the mechanisms of Gag-mediated Env incorporation as well as the overall Env mobility and conformation on the virion surface. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Characteristics and career intentions of Scottish rural and urban GP registrars: cause for concern?

    Science.gov (United States)

    Ross, S; Gillies, J C

    1999-01-01

    To investigate the differences between the characteristics and career intentions of GP registrars in urban and rural areas, and to make recommendations to reduce a potential work force crisis in rural practice. Postal survey. All general practices in Scotland. In February 1996, 40/196 (20%) of urban and 45/150 (30%) of rural GP registrar places available in Scotland, were vacant (chi 2 = 4.22, df = 1, p = 0.02). Postal questionnaires were sent to all 261 GP registrars in post. Of 235 respondents (90%), the majority wished to remain in general practice (63% of urban and 53% of rural registrars), but only 22% of urban and 18% of rural registrars intended to apply for principal posts immediately after training. Fewer urban (8%) than rural registrars (21%) stated an intention to go abroad to work after training. Rural registrars tended to want to work in rural areas, and vice versa. Part-time and job-sharing were attractive employment options for both groups, and more flexible career structures were favoured by over 80%. Though much more attention has been paid to recruitment in inner cities, the findings from this study suggest that in Scotland difficulties in finding principals may occur first in rural areas. As general practitioners have an extended role in rural areas, including that of emergency care, shortages could have a serious impact on patient care.

  18. Intrapulmonary Versus Nasal Transduction of Murine Airways With GP64-pseudotyped Viral Vectors

    Directory of Open Access Journals (Sweden)

    Mayumi Oakland

    2013-01-01

    Full Text Available Persistent viral vector-mediated transgene expression in the airways requires delivery to cells with progenitor capacity and avoidance of immune responses. Previously, we observed that GP64-pseudotyped feline immunodeficiency virus (FIV-mediated gene transfer was more efficient in the nasal airways than the large airways of the murine lung. We hypothesized that in vivo gene transfer was limited by immunological and physiological barriers in the murine intrapulmonary airways. Here, we systematically investigate multiple potential barriers to lentiviral gene transfer in the airways of mice. We show that GP64-FIV vector transduced primary cultures of well-differentiated murine nasal epithelia with greater efficiency than primary cultures of murine tracheal epithelia. We further demonstrate that neutrophils, type I interferon (IFN responses, as well as T and B lymphocytes are not the major factors limiting the transduction of murine conducting airways. In addition, we observed better transduction of GP64-pseudotyped vesicular stomatitis virus (VSV in the nasal epithelia compared with the intrapulmonary airways in mice. VSVG glycoprotein pseudotyped VSV transduced intrapulmonary epithelia with similar efficiency as nasal epithelia. Our results suggest that the differential transduction efficiency of nasal versus intrapulmonary airways by FIV vector is not a result of immunological barriers or surface area, but rather differential expression of cellular factors specific for FIV vector transduction.

  19. Patients' perceptions of GP non-verbal communication: a qualitative study.

    Science.gov (United States)

    Marcinowicz, Ludmila; Konstantynowicz, Jerzy; Godlewski, Cezary

    2010-02-01

    During doctor-patient interactions, many messages are transmitted without words, through non-verbal communication. To elucidate the types of non-verbal behaviours perceived by patients interacting with family GPs and to determine which cues are perceived most frequently. In-depth interviews with patients of family GPs. Nine family practices in different regions of Poland. At each practice site, interviews were performed with four patients who were scheduled consecutively to see their family doctor. Twenty-four of 36 studied patients spontaneously perceived non-verbal behaviours of the family GP during patient-doctor encounters. They reported a total of 48 non-verbal cues. The most frequent features were tone of voice, eye contact, and facial expressions. Less frequent were examination room characteristics, touch, interpersonal distance, GP clothing, gestures, and posture. Non-verbal communication is an important factor by which patients spontaneously describe and evaluate their interactions with a GP. Family GPs should be trained to better understand and monitor their own non-verbal behaviours towards patients.

  20. [Characteristics of beneficiaries of a GP-centred health care contract in Germany].

    Science.gov (United States)

    Freund, Tobias; Szecsenyi, Joachim; Ose, Dominik

    2010-11-01

    Since 2004, primary care in Germany has increasingly been provided in special general practitioner (GP)-centred health care contracts (HZV). To date there is limited evidence about the characteristics of their beneficiaries regarding morbidity burden and health care utilization. We analysed insurance claims data from all beneficiaries of the "Allgemeine Ortskrankenkasse (AOK) Baden-Württemberg" listed in 10 general practices that contracted in a special GP-centred health care contract (HZV). We compared beneficiaries enrolled in the HZV with those who were not enrolled in the contract. Comparisons included the number of hospital admissions in 2007-2008 and the Charlson comorbidity index. Insurance claims data of 6,026 beneficiaries were available for analysis. In the third quarter of 2009, 51% (3,066) of the beneficiaries were enrolled in the HZV. They were significantly older (mean 61 years [SD 18 years] vs. 49 years [SD 22 years]; p contract tended to be older and suffered from a higher morbidity burden when compared with beneficiaries of the same health care fund who were not enrolled in the contract. Besides, beneficiaries of the contract had higher numbers of hospital admissions during the two year period before enrolment. These findings have substantial implications for individualized care management approaches that may be offered to beneficiaries of GP-centred health care contracts.

  1. Efficient Generation of Glucose-Responsive Beta Cells from Isolated GP2+ Human Pancreatic Progenitors

    Directory of Open Access Journals (Sweden)

    Jacqueline Ameri

    2017-04-01

    Full Text Available Stem cell-based therapy for type 1 diabetes would benefit from implementation of a cell purification step at the pancreatic endoderm stage. This would increase the safety of the final cell product, allow the establishment of an intermediate-stage stem cell bank, and provide a means for upscaling β cell manufacturing. Comparative gene expression analysis revealed glycoprotein 2 (GP2 as a specific cell surface marker for isolating pancreatic endoderm cells (PECs from differentiated hESCs and human fetal pancreas. Isolated GP2+ PECs efficiently differentiated into glucose responsive insulin-producing cells in vitro. We found that in vitro PEC proliferation declines due to enhanced expression of the cyclin-dependent kinase (CDK inhibitors CDKN1A and CDKN2A. However, we identified a time window when reducing CDKN1A or CDKN2A expression increased proliferation and yield of GP2+ PECs. Altogether, our results contribute tools and concepts toward the isolation and use of PECs as a source for the safe production of hPSC-derived β cells.

  2. Antigenicity and Immunogenicity of RV144 Vaccine AIDSVAX Clade E Envelope Immunogen Is Enhanced by a gp120 N-Terminal Deletion

    Science.gov (United States)

    Liao, Hua-Xin; Tomaras, Georgia D.; Bonsignori, Mattia; Tsao, Chun-Yen; Hwang, Kwan-Ki; Chen, Haiyan; Lloyd, Krissey E.; Bowman, Cindy; Sutherland, Laura; Jeffries, Thomas L.; Kozink, Daniel M.; Stewart, Shelley; Anasti, Kara; Jaeger, Frederick H.; Parks, Robert; Yates, Nicole L.; Overman, R. Glenn; Sinangil, Faruk; Berman, Phillip W.; Pitisuttithum, Punnee; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Karasavva, Nicos; Rerks-Ngarm, Supachai; Kim, Jerome H.; Michael, Nelson L.; Zolla-Pazner, Susan; Santra, Sampa; Letvin, Norman L.; Harrison, Stephen C.

    2013-01-01

    An immune correlates analysis of the RV144 HIV-1 vaccine trial revealed that antibody responses to the gp120 V1/V2 region correlated inversely with infection risk. The RV144 protein immunogens (A244-rp120 and MN-rgp120) were modified by an N-terminal 11-amino-acid deletion (Δ11) and addition of a herpes simplex virus (HSV) gD protein-derived tag (gD). We investigated the effects of these modifications on gp120 expression, antigenicity, and immunogenicity by comparing unmodified A244 gp120 with both Δ11 deletion and gD tag and with Δ11 only. Analysis of A244 gp120, with or without Δ11 or gD, demonstrated that the Δ11 deletion, without the addition of gD, was sufficient for enhanced antigenicity to gp120 C1 region, conformational V2, and V1/V2 gp120 conformational epitopes. RV144 vaccinee serum IgGs bound more avidly to A244 gp120 Δ11 than to the unmodified gp120, and their binding was blocked by C1, V2, and V1/V2 antibodies. Rhesus macaques immunized with the three different forms of A244 gp120 proteins gave similar levels of gp120 antibody titers, although higher antibody titers developed earlier in A244 Δ11 gp120-immunized animals. Conformational V1/V2 monoclonal antibodies (MAbs) gave significantly higher levels of blocking of plasma IgG from A244 Δ11 gp120-immunized animals than IgG from animals immunized with unmodified A244 gp120, thus indicating a qualitative difference in the V1/V2 antibodies induced by A244 Δ11 gp120. These results demonstrate that deletion of N-terminal residues in the RV144 A244 gp120 immunogen improves both envelope antigenicity and immunogenicity. PMID:23175357

  3. Fusion proteins of HIV-1 envelope glycoprotein gp120 with CD4-induced antibodies showed enhanced binding to CD4 and CD4 binding site antibodies

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Weizao, E-mail: chenw3@mail.nih.gov [Protein Interactions Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); Feng, Yang [Protein Interactions Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); Wang, Yanping [Protein Interactions Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); The Basic Research Program, Science Applications International Corporation-Frederick, Inc., National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); Zhu, Zhongyu; Dimitrov, Dimiter S. [Protein Interactions Group, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer Some recombinant HIV-1 gp120s do not preserve their conformations on gp140s. Black-Right-Pointing-Pointer We hypothesize that CD4i antibodies could induce conformational changes in gp120. Black-Right-Pointing-Pointer CD4i antibodies enhance binding of CD4 and CD4bs antibodies to gp120. Black-Right-Pointing-Pointer CD4i antibody-gp120 fusion proteins could have potential as vaccine immunogens. -- Abstract: Development of successful AIDS vaccine immunogens continues to be a major challenge. One of the mechanisms by which HIV-1 evades antibody-mediated neutralizing responses is the remarkable conformational flexibility of its envelope glycoprotein (Env) gp120. Some recombinant gp120s do not preserve their conformations on gp140s and functional viral spikes, and exhibit decreased recognition by CD4 and neutralizing antibodies. CD4 binding induces conformational changes in gp120 leading to exposure of the coreceptor-binding site (CoRbs). In this study, we test our hypothesis that CD4-induced (CD4i) antibodies, which target the CoRbs, could also induce conformational changes in gp120 leading to better exposed conserved neutralizing antibody epitopes including the CD4-binding site (CD4bs). We found that a mixture of CD4i antibodies with gp120 only weakly enhanced CD4 binding. However, such interactions in single-chain fusion proteins resulted in gp120 conformations which bound to CD4 and CD4bs antibodies better than the original or mutagenically stabilized gp120s. Moreover, the two molecules in the fusion proteins synergized with each other in neutralizing HIV-1. Therefore, fusion proteins of gp120 with CD4i antibodies could have potential as components of HIV-1 vaccines and inhibitors of HIV-1 entry, and could be used as reagents to explore the conformational flexibility of gp120 and mechanisms of entry and immune evasion.

  4. Conformational alterations in the CD4 binding cavity of HIV-1 gp120 influencing gp120-CD4 interactions and fusogenicity of HIV-1 envelopes derived from brain and other tissues

    Directory of Open Access Journals (Sweden)

    Ramsland Paul A

    2011-06-01

    Full Text Available Abstract Background CD4-binding site (CD4bs alterations in gp120 contribute to HIV-1 envelope (Env mediated fusogenicity and the ability of gp120 to utilize low levels of cell-surface CD4. In a recent study, we constructed three-dimensional models of gp120 to illustrate CD4bs conformations associated with enhanced fusogenicity and enhanced CD4-usage of a modestly-sized panel of blood-derived HIV-1 Envs (n = 16. These conformations were characterized by a wider aperture of the CD4bs cavity, as constrained by the inner-most atoms at the gp120 V1V2 stem and the V5 loop. Here, we sought to provide further validation of the utility of these models for understanding mechanisms that influence Env function, by characterizing the structure-function relationships of a larger panel of Envs derived from brain and other tissues (n = 81. Findings Three-dimensional models of gp120 were generated by our recently validated homology modelling protocol. Analysis of predicted CD4bs structures showed correlations between the aperture width of the CD4bs cavity and ability of the Envs to mediate cell-cell fusion, scavenge low-levels of cell-surface CD4, bind directly to soluble CD4, and bind to the Env mAb IgG1b12 whose epitope overlaps the gp120 CD4bs. These structural alterations in the CD4bs cavity were associated with repositioning of the V5 loop. Conclusions Using a large, independent panel of Envs, we can confirm the utility of three-dimensional gp120 structural models for illustrating CD4bs alterations that can affect Env function. Furthermore, we now provide new evidence that these CD4bs alterations augment the ability of gp120 to interact with CD4 by increasing the exposure of the CD4bs.

  5. Carnauba wax nanoparticles enhance strong systemic and mucosal cellular and humoral immune responses to HIV-gp140 antigen.

    Science.gov (United States)

    Arias, Mauricio A; Loxley, Andrew; Eatmon, Christy; Van Roey, Griet; Fairhurst, David; Mitchnick, Mark; Dash, Philip; Cole, Tom; Wegmann, Frank; Sattentau, Quentin; Shattock, Robin

    2011-02-01

    Induction of humoral responses to HIV at mucosal compartments without inflammation is important for vaccine design. We developed charged wax nanoparticles that efficiently adsorb protein antigens and are internalized by DC in the absence of inflammation. HIV-gp140-adsorbed nanoparticles induced stronger in vitro T-cell proliferation responses than antigen alone. Such responses were greatly enhanced when antigen was co-adsorbed with TLR ligands. Immunogenicity studies in mice showed that intradermal vaccination with HIV-gp140 antigen-adsorbed nanoparticles induced high levels of specific IgG. Importantly, intranasal immunization with HIV-gp140-adsorbed nanoparticles greatly enhanced serum and vaginal IgG and IgA responses. Our results show that HIV-gp140-carrying wax nanoparticles can induce strong cellular/humoral immune responses without inflammation and may be of potential use as effective mucosal adjuvants for HIV vaccine candidates. Copyright © 2010 Elsevier Ltd. All rights reserved.

  6. Th1-like human T-cell clones recognizing Leishmania gp63 inhibit Leishmania major in human macrophages

    DEFF Research Database (Denmark)

    Kemp, M; Hey, A S; Bendtzen, K

    1994-01-01

    The major surface protease of Leishmania major, gp63, has been suggested as a vaccine candidate for cutaneous leishmaniasis. In this study gp63 was purified from L. major promastigotes. A panel of human T-cell clones recognizing this protein were generated from individuals who had previously had...... resembling Th1 cells. Autologous mononuclear cells and Epstein-Barr virus-transformed B cell lines were equally efficient in presenting the antigen to the T cells. The gp63 reactive T cells induced resistance to infection in cultured human macrophages by L. major. The data confirm that human CD4+ T cells...... recognizing gp63 can take part in the host defence against L. major infections....

  7. GP50 as a promising early diagnostic antigen for Taenia multiceps infection in goats by indirect ELISA.

    Science.gov (United States)

    Huang, Xing; Xu, Jing; Wang, Yu; Guo, Cheng; Chen, Lin; Gu, Xiaobin; Lai, Weimin; Peng, Xuerong; Yang, Guangyou

    2016-12-01

    Coenurosis is caused by coenurus, the metacestode of Taenia multiceps, which mainly parasitizes the brain and spinal cord of cattle, sheep and goats. To date, no widely-approved methods are available to identify early coenurus infection. In this study, we identified a full-length cDNA that encodes GP50 (TmGP50) from the transcriptome of T. multiceps, and then cloned and expressed in E. coli. The native proteins in adult stage and coenurus were located via immunofluorescence assays, while the potential of recombinant TmGP50 protein (rTmGP50) for indirect ELISA-based serodiagnostics was assessed using native goat sera. In addition, we orally infected 20 goats with mature T. multiceps eggs. Praziquantel (10%) was given to 10 of the goats 45 days post-infection (p.i.). Blood samples were collected for 17 weeks p.i. from the 20 goats and anti-rTmGP50 antibodies were evaluated using the indirect ELISA established here. The TmGP50 contains an 897 bp open reading frame, in which signal sequence resides in 1 ~ 48 sites and mature polypeptide consists of 282 amino acid residues. Immunofluorescence staining showed that native TmGP50 was localized to the microthrix and parenchymatous zone of the adult parasite and coenurus, and the coenurus cystic wall. The indirect ELISA based on rTmGP50 exhibited a sensitivity of 95.0% and a specificity of 92.6% when detecting GP50 antibodies in sera of naturally infected goats and sheep. In goats experimentally infected with T. multiceps, anti-TmGP50 antibody was detectable from 2 to 17 weeks p.i. in the control group, while the antibody fell below the cut-off value about 3 weeks after praziquantel treatment. Our results indicate that recombinant TmGP50 is a suitable early diagnostic antigen for coenurus infection in goats.

  8. Human salivary agglutinin binds to lung surfactant protein-D and is identical with scavenger receptor protein gp-340

    DEFF Research Database (Denmark)

    Ligtenberg, T J; Bikker, F J; Groenink, J

    2001-01-01

    bound in a similar way to Streptococcus mutans and surfactant protein-D. Histochemically, the distribution of gp-340 in the submandibular salivary glands was identical with the agglutinin distribution, as shown in a previous paper [Takano, Bogert, Malamud, Lally and Hand (1991) Anat. Rec. 230, 307......-318]. We conclude that agglutinin is identical with gp-340, and that this molecule interacts with S. mutans and surfactant protein-D....

  9. In vitro and in vivo evaluation of the effects of piperine on P-gp function and expression

    International Nuclear Information System (INIS)

    Han Yi; Chin Tan, Theresa May; Lim, Lee-Yong

    2008-01-01

    Piperine, a major component of black pepper, is used as spice and nutrient enhancer. The purpose of the present study was to evaluate the effects of acute and prolonged piperine exposure on cellular P-gp expression and function in vitro and in vivo. Piperine at concentrations ranging from 10 to 100 μM, determined by MTT assay to be non-cytotoxic, was observed to inhibit P-gp mediated efflux transport of [ 3 H]-digoxin across L-MDR1 and Caco-2 cell monolayers. The acute inhibitory effect was dependent on piperine concentration, with abolishment of [ 3 H]-digoxin polarized transport attained at 50 μM of piperine. In contrast, prolonged (48 and 72 h) co-incubation of Caco-2 cell monolayers with piperine (50 and 100 μM) increased P-gp activity through an up-regulation of cellular P-gp protein and MDR1 mRNA levels. The up-regulated protein was functionally active, as demonstrated by a higher degree of [ 3 H]-digoxin efflux across the cell monolayers, but the induction was readily reversed by the removal of the spice from the culture medium. Peroral administration of piperine at the dose of 112 μg/kg body weight/day to male Wistar rats for 14 consecutive days also led to increased intestinal P-gp levels. However, there was a concomitant reduction in the rodent liver P-gp although the kidney P-gp level was unaffected. Our data suggest that caution should be exercised when piperine is to be co-administered with drugs that are P-gp substrates, particularly for patients whose diet relies heavily on pepper

  10. Applying the trigger review method after a brief educational intervention: potential for teaching and improving safety in GP specialty training?

    OpenAIRE

    McKay, John; de Wet, Carl; Kelly, Moya; Bowie, Paul

    2013-01-01

    Background:\\ud The Trigger Review Method (TRM) is a structured approach to screening clinical records for undetected patient safety incidents (PSIs) and identifying learning and improvement opportunities. In Scotland, TRM participation can inform GP appraisal and has been included as a core component of the national primary care patient safety programme that was launched in March 2013. However, the clinical workforce needs up-skilled and the potential of TRM in GP training has yet to be teste...

  11. Curcumin protects microglia and primary rat cortical neurons against HIV-1 gp120-mediated inflammation and apoptosis.

    Directory of Open Access Journals (Sweden)

    Luyan Guo

    Full Text Available Curcumin is a molecule found in turmeric root that has anti-inflammatory, antioxidant, and anti-tumor properties and has been widely used as both an herbal drug and a food additive to treat or prevent neurodegenerative diseases. To explore whether curcumin is able to ameliorate HIV-1-associated neurotoxicity, we treated a murine microglial cell line (N9 and primary rat cortical neurons with curcumin in the presence or absence of neurotoxic HIV-1 gp120 (V3 loop protein. We found that HIV-1 gp120 profoundly induced N9 cells to produce reactive oxygen species (ROS, tumor necrosis factor-α (TNF-α and monocyte chemoattractant protein-1 (MCP-1. HIV-1 gp120 also induced apoptosis of primary rat cortical neurons. Curcumin exerted a powerful inhibitory effect against HIV-1 gp120-induced neuronal damage, reducing the production of ROS, TNF-α and MCP-1 by N9 cells and inhibiting apoptosis of primary rat cortical neurons. Curcumin may exert its biological activities through inhibition of the delayed rectification and transient outward potassium (K(+ current, as curcumin effectively reduced HIV-1 gp120-mediated elevation of the delayed rectification and transient outward K(+ channel current in neurons. We conclude that HIV-1 gp120 increases ROS, TNF-α and MCP-1 production in microglia, and induces cortical neuron apoptosis by affecting the delayed rectification and transient outward K(+ channel current. Curcumin reduces production of ROS and inflammatory mediators in HIV-1-gp120-stimulated microglia, and protects cortical neurons against HIV-1-mediated apoptosis, most likely through inhibition of HIV-1 gp120-induced elevation of the delayed rectification and transient outward K(+ current.

  12. Sex Commonalities and Differences in Obesity-Related Alterations in Intrinsic Brain Activity and Connectivity.

    Science.gov (United States)

    Gupta, Arpana; Mayer, Emeran A; Labus, Jennifer S; Bhatt, Ravi R; Ju, Tiffany; Love, Aubrey; Bal, Amanat; Tillisch, Kirsten; Naliboff, Bruce; Sanmiguel, Claudia P; Kilpatrick, Lisa A

    2018-02-01

    This study aimed to characterize obesity-related sex differences in the intrinsic activity and connectivity of the brain's reward networks. Eighty-six women (n = 43) and men (n = 43) completed a 10-minute resting functional magnetic resonance imaging scan. Sex differences and commonalities in BMI-related frequency power distribution and reward seed-based connectivity were investigated by using partial least squares analysis. For whole-brain activity in both men and women, increased BMI was associated with increased slow-5 activity in the left globus pallidus (GP) and substantia nigra. In women only, increased BMI was associated with increased slow-4 activity in the right GP and bilateral putamen. For seed-based connectivity in women, increased BMI was associated with reduced slow-5 connectivity between the left GP and putamen and the emotion and cortical regulation regions, but in men, increased BMI was associated with increased connectivity with the medial frontal cortex. In both men and women, increased BMI was associated with increased slow-4 connectivity between the right GP and bilateral putamen and the emotion regulation and sensorimotor-related regions. The stronger relationship between increased BMI and decreased connectivity of core reward network components with cortical and emotion regulation regions in women may be related to the greater prevalence of emotional eating. The present findings suggest the importance of personalized treatments for obesity that consider the sex of the affected individual. © 2017 The Obesity Society.

  13. MRI of bilirubin encephalopathy (kernicterus: A case series of 4 patients from Sub-Saharan Africa, May 2017

    Directory of Open Access Journals (Sweden)

    Getachew Assefa Neknek, MD

    2018-06-01

    Full Text Available Characteristic magnetic resonance imaging (MRI findings in patients with chronic kernicterus are bilateral and symmetric T2-weighted hyperintensities in the globus pallidus. We report 4 cases of infants with clinical, laboratory, and MRI findings of kernicterus in this case series. This is the first MRI report of kernicterus in Ethiopia. Awareness of the disease is raised in this report, and the role of magnetic resonance in detecting signal abnormalities associated with kernicterus in the globus pallidi is underscored. We recommend MRI to be part of the investigation in neonates with jaundice. Keywords: Kernicterus, Globus pallidus, MRI

  14. Effects of local application of methylprednisolone delivered by the C/GP-hydrogel on the recovery of facial nerves.

    Science.gov (United States)

    Chao, Xiuhua; Fan, Zhaomin; Han, Yuechen; Wang, Yan; Li, Jianfeng; Chai, Renjie; Xu, Lei; Wang, Haibo

    2015-01-01

    Local administration of MP delivered by the C/GP-MP-hydrogel can improve the recovery of facial nerve following crush injury. The findings suggested that locally injected MP delivered by C/GP-hydrogel might be a promising treatment for facial nerve damage. In this study, the aim is to assess the effectiveness of locally administrating methylprednisolone(MP) loaded by chitosan-β-glycerophosphate hydrogel (C/GP-hydrogel) on the regeneration of facial nerve crush injury. After the crush of left facial nerves, Wistar rats were randomly divided into four different groups. Then, four different therapies were used to treat the damaged facial nerves. At the 1(st), 2(nd), 3(rd), and 4(th) week after injury, the functional recovery of facial nerves and the morphological changes of facial nerves were assessed. The expression of growth associated protein-43 (GAP-43) protein in the facial nucleus were also evaluated. Locally injected MP delivered by C/GP-hydrogel effectively accelerated the facial functional recovery. In addition, the regenerated facial nerves in the C/GP-MP group were more mature than those in the other groups. The expression of GAP-43 protein was also improved by the MP, especially in the C/GP-MP group.

  15. User Fees in General Practice: Willingness to Pay and Potential Substitution Patterns-Results from a Danish GP Patient Survey.

    Science.gov (United States)

    Kronborg, Christian; Pedersen, Line Bjørnskov; Fournaise, Anders; Kronborg, Christel Nøhr

    2017-10-01

    Increases in public expenditures to general practitioner (GP) services and specialist care have spurred debate over whether to implement user fees for healthcare services such as GP consultations in Denmark. The objective of this study was to examine Danish patients' attitudes towards user fees and their willingness to pay (WTP) for a consultation, and to investigate how user charges may impact patients' behaviour. A questionnaire survey was conducted in a GP clinic. A total of 343 individual persons answered the questionnaire. One hundred and seventy (50%) persons were not willing to pay for a consultation. Among patients reporting positive WTP values, the mean WTP was 137 (standard deviation 140) Danish kroner (DKK). Patients who were 65 years old or older were more likely to be willing to pay for a GP consultation than patients under the age of 65 years. Furthermore, patients with a personal annual income of more than 200,000 DKK were more likely to be willing to pay for a consultation than other income groups. With respect to patients with a positive WTP value, their own assessment of the seriousness of the consultation and their self-assessed health influenced the amount they would be willing to pay. Finally, we observed a stated willingness to substitute GP consultations with alternatives that are free of charge. About half of the patients with an appointment for a GP consultation are willing to pay for the consultation. User charges may potentially influence the patients' behaviour. ClinicalTrials.gov NCT01784731.

  16. Characterization of humoral responses to soluble trimeric HIV gp140 from a clade A Ugandan field isolate.

    Science.gov (United States)

    Visciano, Maria Luisa; Tagliamonte, Maria; Stewart-Jones, Guillaume; Heyndrickx, Leo; Vanham, Guido; Jansson, Marianne; Fomsgaard, Anders; Grevstad, Berit; Ramaswamy, Meghna; Buonaguro, Franco M; Tornesello, Maria Lina; Biswas, Priscilla; Scarlatti, Gabriella; Buonaguro, Luigi

    2013-07-08

    Trimeric soluble forms of HIV gp140 envelope glycoproteins represent one of the closest molecular structures compared to native spikes present on intact virus particles. Trimeric soluble gp140 have been generated by several groups and such molecules have been shown to induce antibodies with neutralizing activity against homologous and heterologous viruses. In the present study, we generated a recombinant trimeric soluble gp140, derived from a previously identified Ugandan A-clade HIV field isolate (gp14094UG018). Antibodies elicited in immunized rabbits show a broad binding pattern to HIV envelopes of different clades. An epitope mapping analysis reveals that, on average, the binding is mostly focused on the C1, C2, V3, V5 and C5 regions. Immune sera show neutralization activity to Tier 1 isolates of different clades, demonstrating cross clade neutralizing activity which needs to be further broadened by possible structural modifications of the clade A gp14094UG018. Our results provide a rationale for the design and evaluation of immunogens and the clade A gp14094UG018 shows promising characteristics for potential involvement in an effective HIV vaccine with broad activity.

  17. Glial TNFα in the spinal cord regulates neuropathic pain induced by HIV gp120 application in rats

    Directory of Open Access Journals (Sweden)

    Ouyang Handong

    2011-05-01

    Full Text Available Abstract Background HIV-associated sensory neuropathy (HIV-SN is one of the most common forms of peripheral neuropathy, affecting about 30% of people with acquired immune deficiency syndrome (AIDS. The symptoms of HIV-SN are dominated by neuropathic pain. Glia activation in the spinal cord has become an attractive target for attenuating chronic pain. This study will investigate the role of spinal TNFα released from glia in HIV-related neuropathic pain. Results Peripheral gp120 application into the rat sciatic nerve induced mechanical allodynia for more than 7 weeks, and upregulated the expression of spinal TNFα in the mRNA and the protein levels at 2 weeks after gp120 application. Spinal TNFα was colocalized with GFAP (a marker of astrocytes and Iba1 (a marker of microglia in immunostaining, suggesting that glia produce TNFα in the spinal cord in this model. Peripheral gp120 application also increased TNFα in the L4/5 DRG. Furthermore, intrathecal administration of TNFα siRNA or soluble TNF receptor reduced gp120 application-induced mechanical allodynia. Conclusions Our results indicate that TNFα in the spinal cord and the DRG are involved in neuropathic pain, following the peripheral HIV gp120 application, and that blockade of the glial product TNFα reverses neuropathic pain induced by HIV gp120 application.

  18. HIV-1 specific IgA detected in vaginal secretions of HIV uninfected women participating in a microbicide trial in Southern Africa are primarily directed toward gp120 and gp140 specificities.

    Directory of Open Access Journals (Sweden)

    Kelly E Seaton

    Full Text Available Many participants in microbicide trials remain uninfected despite ongoing exposure to HIV-1. Determining the emergence and nature of mucosal HIV-specific immune responses in such women is important, since these responses may contribute to protection and could provide insight for the rational design of HIV-1 vaccines.We first conducted a pilot study to compare three sampling devices (Dacron swabs, flocked nylon swabs and Merocel sponges for detection of HIV-1-specific IgG and IgA antibodies in vaginal secretions. IgG antibodies from HIV-1-positive women reacted broadly across the full panel of eight HIV-1 envelope (Env antigens tested, whereas IgA antibodies only reacted to the gp41 subunit. No Env-reactive antibodies were detected in the HIV-negative women. The three sampling devices yielded equal HIV-1-specific antibody titers, as well as total IgG and IgA concentrations. We then tested vaginal Dacron swabs archived from 57 HIV seronegative women who participated in a microbicide efficacy trial in Southern Africa (HPTN 035. We detected vaginal IgA antibodies directed at HIV-1 Env gp120/gp140 in six of these women, and at gp41 in another three women, but did not detect Env-specific IgG antibodies in any women.Vaginal secretions of HIV-1 infected women contained IgG reactivity to a broad range of Env antigens and IgA reactivity to gp41. In contrast, Env-binding antibodies in the vaginal secretions of HIV-1 uninfected women participating in the microbicide trial were restricted to the IgA subtype and were mostly directed at HIV-1 gp120/gp140.

  19. [Expression and significance of P-gp/mdr1 mRNA, MRP and LRP in non-Hodgkin's lymphoma].

    Science.gov (United States)

    Li, Le; Su, Li-ping; Ma, Li; Zhao, Jin; Zhu, Lei; Zhou, Yong-an

    2009-03-01

    To explore the expression and clinical significance of P-glycoprotein (P-gp)/mdr1mRNA, multidrug resistance-associated protein (MRP) and lung resistance protein (LRP) in newly diagnosed non-Hodgkin's lymphoma. mdr1 mRNA of in 41 patients with non-Hodgkin's lymphoma was assayed by semi-quantitative RT-PCR. The expressions of P-gp, MRP and LRP proteins in lymph node viable blasts were identified by flow cytometry. The results were compared with those obtained from control cases, and the correlation of the changes with clinical outcomes was analyzed. (1) Among the 41 cases, the positive expression of P-gp protein was detected in 8 cases, MRP in 7 cases, LRP in 15 cases, and mdr 1 mRNA in 11 cases. (2) The P-gp and LRP levels in NHL were significantly higher than those in control group, but MRP wasn't. The P-gp over-expression was significantly associated with mdr1mRNA (r = 0.396, P = 0.01). No correlation was showed among the expressions of P-gp, MRP and LRP. (3) Patients with P-gp expression had a poorer outcome of chemotherapy than those with P-gp-negative (P = 0.005). P-gp expression was significantly associated with higher clinical stage (P = 0.046) and elevated serum lactate dehydrogenase level (P = 0.032), but not associated with malignant degree (P = 0.298). MRP had no impact on the outcome of chemotherapy (P = 0.212), and wasn't significantly associated with higher clinical stage (P = 0.369), elevated LDH (P = 0.762) and higher malignant degree (P = 0.451). Patients with LRP expression had a poorer outcome of chemotherapy than those LRP-negative (P = 0.012). LRP expression was significantly associated with higher clinical stage (P = 0.0019), elevated LDH (P = 0.02) and higher malignant degree (P = 0.01). The data of this study indicate that P-gp and LRP expressions but not MRP expression are important in the mechanism of drug resistance associated with a poor clinical outcome in previously untreated NHL.

  20. N-acetylcysteine prevents HIV gp 120-related damage of human cultured astrocytes: correlation with glutamine synthase dysfunction

    Directory of Open Access Journals (Sweden)

    Costa Nicola

    2007-12-01

    Full Text Available Abstract Background HIV envelope gp 120 glycoprotein is released during active HIV infection of brain macrophages thereby generating inflammation and oxidative stress which contribute to the development of the AIDS-Dementia Complex (ADC. Gp120 has also been found capable to generate excitotoxic effect on brain tissue via enhancement of glutamatergic neurotransmission, leading to neuronal and astroglial damage, though the mechanism is still to be better understood. Here we investigated on the effect of N-acetylcysteine (NAC, on gp120-induced damage in human cultured astroglial cells and the possible contribution of gp120-related reacting oxygen species (ROS in the imbalanced activity of glutamine synthase (GS, the enzyme that metabolizes glutamate into glutamine within astroglial cells playing a neuroprotective role in brain disorders. Results Incubation of Lipari human cultured astroglial cells with gp 120 (0.1–10 nM produced a significant reduction of astroglial cell viability and apoptosis as evaluated by TUNEL reaction and flow cytometric analysis (FACS. This effect was accompanied by lipid peroxidation as detected by means of malondialdehyde assay (MDA. In addition, gp 120 reduced both glutamine concentration in astroglial cell supernatants and GS expression as detected by immunocytochemistry and western blotting analysis. Pre-treatment of cells with NAC (0.5–5 mM, dose-dependently antagonised astroglial apoptotic cell death induced by gp 120, an effect accompanied by significant attenuation of MDA accumulation. Furthermore, both effects were closely associated with a significant recovery of glutamine levels in cell supernatants and by GS expression, thus suggesting that overproduction of free radicals might contribute in gp 120-related dysfunction of GS in astroglial cells. Conclusion In conclusion, the present experiments demonstrate that gp 120 is toxic to astroglial cells, an effect accompanied by lipid peroxidation and by altered

  1. A complete solution for GP-B's gyroscopic precession by retarded gravitational theory

    Science.gov (United States)

    Tang, Keyun

    Mainstream physicists generally believe that Mercury’s Perihelion precession and GP-B’ gyroscopic precession are two of the strongest evidences supporting Einstein’ curved spacetime and general relativity. However, most classical literatures and textbooks (e.g. Ohanain: Gravitation and Spacetime) paint an incorrect picture of Mercury’s orbit anomaly, namely Mercury’s perihelion precessed 43 arc-seconds per century; a correct picture should be that Mercury rotated 43 arc-seconds per century more than along Newtonian theoretical orbit. The essence of Le Verrier’s and Newcomb’s observation and analysis is that the angular speed of Mercury is slightly faster than the Newtonian theoretical value. The complete explanation to Mercury’s orbit anomaly should include two factors, perihelion precession is one of two factors, in addition, the change of orbital radius will also cause a change of angular speed, which is another component of Mercury's orbital anomaly. If Schwarzschild metric is correct, then the solution of the Schwarzschild orbit equation must contain three non-ignorable items. The first corresponds to Newtonian ellipse; the second is a nonlinear perturbation with increasing amplitude, which causes the precession of orbit perihelion; this is just one part of the angular speed anomaly of Mercury; the third part is a linear perturbation, corresponding to a similar figure of the Newton's ellipse, but with a minimal radius; this makes no contribution to the perihelion precession of the Schwarzschild orbit, but makes the Schwarzschild orbital radius slightly smaller, leading to a slight increase in Mercury’s angular speed. All classical literatures of general relativity ignored this last factor, which is a gross oversight. If you correctly take all three factors into consideration, the final result is that the difference between the angles rotated along Schwarzschild’s orbit and the angle rotated along Newton’s orbit for one hundred years should

  2. Antibody to gp41 MPER alters functional properties of HIV-1 Env without complete neutralization.

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    Arthur S Kim

    2014-07-01

    Full Text Available Human antibody 10E8 targets the conserved membrane proximal external region (MPER of envelope glycoprotein (Env subunit gp41 and neutralizes HIV-1 with exceptional potency. Remarkably, HIV-1 containing mutations that reportedly knockout 10E8 binding to linear MPER peptides are partially neutralized by 10E8, producing a local plateau in the dose response curve. Here, we found that virus partially neutralized by 10E8 becomes significantly less neutralization sensitive to various MPER antibodies and to soluble CD4 while becoming significantly more sensitive to antibodies and fusion inhibitors against the heptad repeats of gp41. Thus, 10E8 modulates sensitivity of Env to ligands both pre- and post-receptor engagement without complete neutralization. Partial neutralization by 10E8 was influenced at least in part by perturbing Env glycosylation. With unliganded Env, 10E8 bound with lower apparent affinity and lower subunit occupancy to MPER mutant compared to wild type trimers. However, 10E8 decreased functional stability of wild type Env while it had an opposite, stabilizing effect on MPER mutant Envs. Clade C isolates with natural MPER polymorphisms also showed partial neutralization by 10E8 with altered sensitivity to various gp41-targeted ligands. Our findings suggest a novel mechanism of virus neutralization by demonstrating how antibody binding to the base of a trimeric spike cross talks with adjacent subunits to modulate Env structure and function. The ability of an antibody to stabilize, destabilize, partially neutralize as well as alter neutralization sensitivity of a virion spike pre- and post-receptor engagement may have implications for immunotherapy and vaccine design.

  3. Sickness certification for common mental disorders and GP return-to-work advice.

    Science.gov (United States)

    Gabbay, Mark; Shiels, Chris; Hillage, Jim

    2016-09-01

    Aim To report the types and duration of sickness certification for different common mental disorders (CMDs) and the prevalence of GP advice aimed at returning the patient to work. In the United Kingdom, common mental health problems, such and depression and stress, have become the main reasons for patients requesting a sickness certificate to abstain from usual employment. Increasing attention is being paid to mental health and its impact on employability and work capacity in all parts of the welfare system. However, relatively little is known about the extent to which different mental health diagnoses impact upon sickness certification outcomes, and how the GP has used the new fit note (introduced in 2010) to support a return to work for patients with mental health diagnoses. Sickness certification data was collected from 68 UK-based general practices for a period of 12 months. Findings The study found a large part of all sickness absence certified by GPs was due to CMDs (29% of all sickness absence episodes). Females, younger patients and those living in deprived areas were more likely to receive a fit note for a CMD (compared with one for a physical health problem). The highest proportion of CMD fit notes were issued for 'stress'. However, sickness certification for depression contributed nearly half of all weeks certified for mental health problems. Only 7% of CMD fit notes included any 'may be fit' advice from the GP, with type of advice varying by mental health diagnostic category. Patients living in the most socially deprived neighbourhoods were less likely to receive 'may be fit' advice on their CMD fit notes.

  4. Activated Rac1 requires gp130 for Stat3 activation, cell proliferation and migration

    Energy Technology Data Exchange (ETDEWEB)

    Arulanandam, Rozanne; Geletu, Mulu [Departments of Microbiology and Immunology and Pathology and Molecular Medicine, and Queen' s University Cancer Institute, Queen' s University, Botterell Hall, Rm. 713, Kingston, Ontario, Canada K7L 3N6 (Canada); Feracci, Helene [Universite Bordeaux 1, Centre de Recherche Paul Pascal, CNRS UPR 8641, 33600 Pessac (France); Raptis, Leda, E-mail: raptisl@queensu.ca [Departments of Microbiology and Immunology and Pathology and Molecular Medicine, and Queen' s University Cancer Institute, Queen' s University, Botterell Hall, Rm. 713, Kingston, Ontario, Canada K7L 3N6 (Canada)

    2010-03-10

    Rac1 (Rac) is a member of the Rho family of small GTPases which controls cell migration by regulating the organization of actin filaments. Previous results suggested that mutationally activated forms of the Rho GTPases can activate the Signal Transducer and Activator of Transcription-3 (Stat3), but the exact mechanism is a matter of controversy. We recently demonstrated that Stat3 activity of cultured cells increases dramatically following E-cadherin engagement. To better understand this pathway, we now compared Stat3 activity levels in mouse HC11 cells before and after expression of the mutationally activated Rac1 (Rac{sup V12}), at different cell densities. The results revealed for the first time a dramatic increase in protein levels and activity of both the endogenous Rac and Rac{sup V12} with cell density, which was due to inhibition of proteasomal degradation. In addition, Rac{sup V12}-expressing cells had higher Stat3, tyrosine-705 phosphorylation and activity levels at all densities, indicating that Rac{sup V12} is able to activate Stat3. Further examination of the mechanism of Stat3 activation showed that Rac{sup V12} expression caused a surge in mRNA of Interleukin-6 (IL6) family cytokines, known potent Stat3 activators. Knockdown of gp130, the common subunit of this family reduced Stat3 activity, indicating that these cytokines may be responsible for the Stat3 activation by Rac{sup V12}. The upregulation of IL6 family cytokines was required for cell migration and proliferation induced by Rac{sup V12}, as shown by gp130 knockdown experiments, thus demonstrating that the gp130/Stat3 axis represents an essential effector of activated Rac for the regulation of key cellular functions.

  5. Activated Rac1 requires gp130 for Stat3 activation, cell proliferation and migration

    International Nuclear Information System (INIS)

    Arulanandam, Rozanne; Geletu, Mulu; Feracci, Helene; Raptis, Leda

    2010-01-01

    Rac1 (Rac) is a member of the Rho family of small GTPases which controls cell migration by regulating the organization of actin filaments. Previous results suggested that mutationally activated forms of the Rho GTPases can activate the Signal Transducer and Activator of Transcription-3 (Stat3), but the exact mechanism is a matter of controversy. We recently demonstrated that Stat3 activity of cultured cells increases dramatically following E-cadherin engagement. To better understand this pathway, we now compared Stat3 activity levels in mouse HC11 cells before and after expression of the mutationally activated Rac1 (Rac V12 ), at different cell densities. The results revealed for the first time a dramatic increase in protein levels and activity of both the endogenous Rac and Rac V12 with cell density, which was due to inhibition of proteasomal degradation. In addition, Rac V12 -expressing cells had higher Stat3, tyrosine-705 phosphorylation and activity levels at all densities, indicating that Rac V12 is able to activate Stat3. Further examination of the mechanism of Stat3 activation showed that Rac V12 expression caused a surge in mRNA of Interleukin-6 (IL6) family cytokines, known potent Stat3 activators. Knockdown of gp130, the common subunit of this family reduced Stat3 activity, indicating that these cytokines may be responsible for the Stat3 activation by Rac V12 . The upregulation of IL6 family cytokines was required for cell migration and proliferation induced by Rac V12 , as shown by gp130 knockdown experiments, thus demonstrating that the gp130/Stat3 axis represents an essential effector of activated Rac for the regulation of key cellular functions.

  6. Structural and biochemical characterization of phage λ FI protein (gpFI) reveals a novel mechanism of DNA packaging chaperone activity.

    Science.gov (United States)

    Popovic, Ana; Wu, Bin; Arrowsmith, Cheryl H; Edwards, Aled M; Davidson, Alan R; Maxwell, Karen L

    2012-09-14

    One of the final steps in the morphogenetic pathway of phage λ is the packaging of a single genome into a preformed empty head structure. In addition to the terminase enzyme, the packaging chaperone, FI protein (gpFI), is required for efficient DNA packaging. In this study, we demonstrate an interaction between gpFI and the major head protein, gpE. Amino acid substitutions in gpFI that reduced the strength of this interaction also decreased the biological activity of gpFI, implying that this head binding activity is essential for the function of gpFI. We also show that gpFI is a two-domain protein, and the C-terminal domain is responsible for the head binding activity. Using nuclear magnetic resonance spectroscopy, we determined the three-dimensional structure of the C-terminal domain and characterized the helical nature of the N-terminal domain. Through structural comparisons, we were able to identify two previously unannotated prophage-encoded proteins with tertiary structures similar to gpFI, although they lack significant pairwise sequence identity. Sequence analysis of these diverse homologues led us to identify related proteins in a variety of myo- and siphophages, revealing that gpFI function has a more highly conserved role in phage morphogenesis than was previously appreciated. Finally, we present a novel model for the mechanism of gpFI chaperone activity in the DNA packaging reaction of phage λ.

  7. The GP tests of competence assessment: which part best predicts fitness to practise decisions?

    Science.gov (United States)

    Jayaweera, Hirosha Keshani; Potts, Henry W W; Keshwani, Karim; Valerio, Chris; Baker, Magdalen; Mehdizadeh, Leila; Sturrock, Alison

    2018-01-02

    The General Medical Council (GMC) conducts Tests of Competence (ToC) for doctors referred for Fitness to Practise (FtP) issues. GPs take a single best answer knowledge test, an Objective Structured Clinical Examination (OSCE), and a Simulated Surgery (SimSurg) assessment which is a simulated GP consultation. The aim of this study was to examine the similarities between OSCEs and SimSurg to determine whether each assessment contributed something unique to GP ToCs. A mixed methods approach was used. Data were collated on 153 GPs who were required to undertake a ToC as a part of being investigated for FtP issues between February 2010 and October 2016. Using correlation analysis, we examined to what degree performance on the knowledge test, OSCE, and SimSurg related to case examiner recommendations and FtP outcomes, including the unique predictive power of these three assessments. The outcome measures were case examiner recommendations (i) not fit to practise; ii) fit to practise on a limited basis; or iii) fit to practise) as well as FtP outcomes (i) erased/removed from the register; ii) having restrictions/conditions; or iii) be in good standing). For the qualitative component, 45 GP assessors were asked to rate whether they assess the same competencies and which assessment provides better feedback about candidates. There was significant overlap between OSCEs and SimSurg, p < 0.001. SimSurg had additional predictive power in the presence of OSCEs and the knowledge test (p = 0.030) in distinguishing doctors from different FtP categories, while OSCEs did not (p = 0.080). Both the OSCEs (p = 0.004) and SimSurg (p < 0.001) had significant negative correlations with case examiner recommendations when accounting for the effects of the other two assessments. Inductive thematic analysis of the responses to the questionnaire showed that assessors perceived OSCEs to be better suited to target specific knowledge and skills. SimSurg was thought to produce a

  8. A combined AHP-GP model to allocate internal auditing time to projects

    Directory of Open Access Journals (Sweden)

    HA Kruger

    2006-06-01

    Full Text Available The optimal allocation of internal auditing time among competing projects is a multi-criteria problem that includes both qualitative and quantitative factors. This paper discusses an integrated approach where the analytic hierarchy process (AHP is used to deal with qualitative risk assessments and a goal programming (GP model to distribute available hours in such a way that risk is minimised. Additional considerations, such as maximum and minimum allowable project hours, risk reducing factors and risk levels, are also taken into account. Following a description of the models and framework, a brief case study is presented in which the framework was empirically evaluated.

  9. A mircocontroller MC68HC908GP32 based intelligent scalar

    International Nuclear Information System (INIS)

    Liu Huiying

    2001-01-01

    A Mircocontroller MC68HC908GP32 based intelligent scalar is presented. By replacing traditional IC modular with Mircocontroller, the new type scalar can provide new functions, such as countering rate measurement, control signal output, LCD display, PC control, etc., in addition to traditional functions of normal scalar. This intelligent scalar achieved comprehensive technical innovation to the traditional nuclear electronic instrument, with regard to the design methodology, structure and functions. In this way, the overall technical performance of the new type scalar, such as counting rate, accuracy, volume, cost and operation, etc., has been improved obviously, with bright prospects for application and dissemination

  10. Implementation of the G8GP program on physical protection - experiences and results

    International Nuclear Information System (INIS)

    Hagemann, A.

    2006-01-01

    At the Kananaskis Summit in June 2002, G8 Leaders launched the Global Partnership against the Spread of Weapons and Materials of Mass Destruction committing to support projects to issues of non-proliferation, disarmament, counter terrorism and nuclear safety in Russia. Since then progress has been made in implementing projects. The German Federal Foreign Office contracted GRS to implement a program for improving the physical protection of nuclear or highly radioactive materials of relevance at facilities in the Russian Federation. This paper reports about this G8GP Program on physical protection, its implementation, gained experiences, current achievements and results. (author)

  11. Association between general practice characteristics and use of out-of-hours GP cooperatives.

    Science.gov (United States)

    Smits, Marleen; Peters, Yvonne; Broers, Sanne; Keizer, Ellen; Wensing, Michel; Giesen, Paul

    2015-05-01

    The use of out-of-hours healthcare services for non-urgent health problems is believed to be related to the organisation of daytime primary care but insight into underlying mechanisms is limited. Our objective was to examine the association between daytime general practice characteristics and the use of out-of-hours care GP cooperatives. A cross-sectional observational study in 100 general practices in the Netherlands, connected to five GP cooperatives. In each GP cooperative, we took a purposeful sample of the 10 general practices with the highest use of out-of-hours care and the 10 practices with the lowest use. Practice and population characteristics were obtained by questionnaires, interviews, data extraction from patient registration systems and telephone accessibility measurements. To examine which aspects of practice organisation were associated with patients' use of out-of-hours care, we performed logistic regression analyses (low versus high out-of-hours care use), correcting for population characteristics. The mean out-of-hours care use in the high use group of general practices was 1.8 times higher than in the low use group. Day time primary care practices with more young children and foreigners in their patient populations and with a shorter distance to the GP cooperative had higher out-of-hours primary care use. In addition, longer telephone waiting times and lower personal availability for palliative patients in daily practice were associated with higher use of out-of-hours care. Moreover, out-of-hours care use was higher when practices performed more diagnostic tests and therapeutic procedures and had more assistant employment hours per 1000 patients. Several other aspects of practice management showed some non-significant trends: high utilising general practices tended to have longer waiting times for non-urgent appointments, lower availability of a telephone consulting hour, lower availability for consultations after 5 p.m., and less frequent

  12. Platelet GP II b/III a inhibitors in neurointervention therapeutics

    International Nuclear Information System (INIS)

    Wang Kuizhong; Huang Qinghai; Liu Jianmin

    2007-01-01

    The platelet glucoprotein (GP) II b/III a inhibitors prossess inhibiting platelet aggregation effectly. As new drugs of antiplatelet, they are different in mechanism with action, application and dosage between the II b/III a inhibitors and other tradional antiplatelet drugs such as aspirin or clopidogrel. In familiar with the pharmacologic action and clinical application of II b/III a inhibitors is important for endovascular interventional radiology, especially with important significance for obtaining high quality neuro-endovascular stenting in the perioperative period. (authors)

  13. N-terminal substitutions in HIV-1 gp41 reduce the expression of non-trimeric envelope glycoproteins on the virus

    International Nuclear Information System (INIS)

    Dey, Antu K.; David, Kathryn B.; Ray, Neelanjana; Ketas, Thomas J.; Klasse, Per J.; Doms, Robert W.; Moore, John P.

    2008-01-01

    The native, functional HIV-1 envelope glycoprotein (Env) complex is a trimer of two non-covalently associated subunits: the gp120 surface glycoprotein and the gp41 transmembrane glycoprotein. However, various non-functional forms of Env are present on virus particles and HIV-1-infected cells, some of which probably arise as the native complex decays. The aberrant forms include gp120-gp41 monomers and oligomers, as well as gp41 subunits from which gp120 has dissociated. The presence of non-functional Env creates binding sites for antibodies that do not recognize native Env complexes and that are, therefore, non-neutralizing. Non-native Env forms (monomers, dimers, tetramers and aggregates) can also arise when soluble gp140 proteins, lacking the cytoplasmic and transmembrane domains of gp41, are expressed for vaccine studies. We recently identified five amino acids in the gp41 N-terminal region (I535, Q543, S553, K567 and R588) that promote gp140 trimerization. We have now studied their influence on the function and antigenic properties of JR-FL Env expressed on the surfaces of pseudoviruses and Env-transfected cells. The 5 substitutions in gp41 reduce the expression of non-trimeric gp160s, without affecting trimer levels. Pseudovirions bearing the mutant Env are fully infectious with similar kinetics of Env-mediated fusion. Various non-neutralizing antibodies bind less strongly to the Env mutant, but neutralizing antibody binding is unaffected. Hence the gp41 substitutions do not adversely affect Env structure, supporting their use for making new Env-based vaccines. The mutant Env might also help in studies intended to correlate antibody binding to virus neutralization. Of note is that the 5 residues are much more frequent, individually or collectively, in viruses from subtypes other than B

  14. Host-Primed Ebola Virus GP Exposes a Hydrophobic NPC1 Receptor-Binding Pocket, Revealing a Target for Broadly Neutralizing Antibodies.

    Science.gov (United States)

    Bornholdt, Zachary A; Ndungo, Esther; Fusco, Marnie L; Bale, Shridhar; Flyak, Andrew I; Crowe, James E; Chandran, Kartik; Saphire, Erica Ollmann

    2016-02-23

    The filovirus surface glycoprotein (GP) mediates viral entry into host cells. Following viral internalization into endosomes, GP is cleaved by host cysteine proteases to expose a receptor-binding site (RBS) that is otherwise hidden from immune surveillance. Here, we present the crystal structure of proteolytically cleaved Ebola virus GP to a resolution of 3.3 Å. We use this structure in conjunction with functional analysis of a large panel of pseudotyped viruses bearing mutant GP proteins to map the Ebola virus GP endosomal RBS at molecular resolution. Our studies indicate that binding of GP to its endosomal receptor Niemann-Pick C1 occurs in two distinct stages: the initial electrostatic interactions are followed by specific interactions with a hydrophobic trough that is exposed on the endosomally cleaved GP1 subunit. Finally, we demonstrate that monoclonal antibodies targeting the filovirus RBS neutralize all known filovirus GPs, making this conserved pocket a promising target for the development of panfilovirus therapeutics. Ebola virus uses its glycoprotein (GP) to enter new host cells. During entry, GP must be cleaved by human enzymes in order for receptor binding to occur. Here, we provide the crystal structure of the cleaved form of Ebola virus GP. We demonstrate that cleavage exposes a site at the top of GP and that this site binds the critical domain C of the receptor, termed Niemann-Pick C1 (NPC1). We perform mutagenesis to find parts of the site essential for binding NPC1 and map distinct roles for an upper, charged crest and lower, hydrophobic trough in cleaved GP. We find that this 3-dimensional site is conserved across the filovirus family and that antibody directed against this site is able to bind cleaved GP from every filovirus tested and neutralize viruses bearing those GPs. Copyright © 2016 Bornholdt et al.

  15. Structure-based, targeted deglycosylation of HIV-1 gp120 and effects on neutralization sensitivity and antibody recognition

    International Nuclear Information System (INIS)

    Koch, Markus; Pancera, Marie; Kwong, Peter D.; Kolchinsky, Peter; Grundner, Christoph; Wang Liping; Hendrickson, Wayne A.; Sodroski, Joseph; Wyatt, Richard

    2003-01-01

    The human immunodeficiency virus (HIV-1) exterior envelope glycoprotein, gp120, mediates receptor binding and is the major target for neutralizing antibodies. Primary HIV-1 isolates are characteristically more resistant to broadly neutralizing antibodies, although the structural basis for this resistance remains obscure. Most broadly neutralizing antibodies are directed against functionally conserved gp120 regions involved in binding to either the primary virus receptor, CD4, or the viral coreceptor molecules that normally function as chemokine receptors. These antibodies are known as CD4 binding site (CD4BS) and CD4-induced (CD4i) antibodies, respectively. Inspection of the gp120 crystal structure reveals that although the receptor-binding regions lack glycosylation, sugar moieties lie proximal to both receptor-binding sites on gp120 and thus in proximity to both the CD4BS and the CD4i epitopes. In this study, guided by the X-ray crystal structure of gp120, we deleted four N-linked glycosylation sites that flank the receptor-binding regions. We examined the effects of selected changes on the sensitivity of two prototypic HIV-1 primary isolates to neutralization by antibodies. Surprisingly, removal of a single N-linked glycosylation site at the base of the gp120 third variable region (V3 loop) increased the sensitivity of the primary viruses to neutralization by CD4BS antibodies. Envelope glycoprotein oligomers on the cell surface derived from the V3 glycan-deficient virus were better recognized by a CD4BS antibody and a V3 loop antibody than were the wild-type glycoproteins. Absence of all four glycosylation sites rendered a primary isolate sensitive to CD4i antibody-mediated neutralization. Thus, carbohydrates that flank receptor-binding regions on gp120 protect primary HIV-1 isolates from antibody-mediated neutralization

  16. The Pathogenicity of Anti-β2GP1-IgG Autoantibodies Depends on Fc Glycosylation

    Directory of Open Access Journals (Sweden)

    Christoph Fickentscher

    2015-01-01

    Full Text Available To analyze the glycosylation of anti-β2GP1, we investigated purified IgG from healthy children, patients with APS, and asymptomatic adult carriers of antiphospholipid antibodies. We observed that in the sera of healthy children and of patients with APS, IgG3 and IgG2 were predominant, respectively. The potentially protective anti-β2GP1-IgM was lower in the sera of healthy children. Although anti-β2GP1-associated C1q did not differ between children and patients with antiphospholipid syndrome, the associated C3c was significantly higher in the sera of healthy children. This indicates a more efficient clearance of anti-β2GP1 immune complexes in the healthy children. This clearance is not accompanied by inflammation or coagulatory events. It is likely that the most important pathogenic factor of the anti-β2GP1-IgG is related to the different glycosylation observed in healthy and diseased individuals. We detected a significantly higher sialylation of anti-β2GP1-IgG isolated from the sera of healthy children and asymptomatic adults when compared with that of patients with clinically apparent antiphospholipid syndrome. Low sialylated IgG reportedly ameliorates inflammation and inflammation promotes hyposialylation. Thus, both reactions create a vicious circle that precipitates the pathology of the antiphospholipid syndrome including thrombus-formation. We conclude that the increased sialylation of anti-β2GP1-IgG of sera of healthy individuals limits their pathogenicity.

  17. DNA unwinding by ring-shaped T4 helicase gp41 is hindered by tension on the occluded strand.

    Science.gov (United States)

    Ribeck, Noah; Saleh, Omar A

    2013-01-01

    The replicative helicase for bacteriophage T4 is gp41, which is a ring-shaped hexameric motor protein that achieves unwinding of dsDNA by translocating along one strand of ssDNA while forcing the opposite strand to the outside of the ring. While much study has been dedicated to the mechanism of binding and translocation along the ssDNA strand encircled by ring-shaped helicases, relatively little is known about the nature of the interaction with the opposite, 'occluded' strand. Here, we investigate the interplay between the bacteriophage T4 helicase gp41 and the ss/dsDNA fork by measuring, at the single-molecule level, DNA unwinding events on stretched DNA tethers in multiple geometries. We find that gp41 activity is significantly dependent on the geometry and tension of the occluded strand, suggesting an interaction between gp41 and the occluded strand that stimulates the helicase. However, the geometry dependence of gp41 activity is the opposite of that found previously for the E. coli hexameric helicase DnaB. Namely, tension applied between the occluded strand and dsDNA stem inhibits unwinding activity by gp41, while tension pulling apart the two ssDNA tails does not hinder its activity. This implies a distinct variation in helicase-occluded strand interactions among superfamily IV helicases, and we propose a speculative model for this interaction that is consistent with both the data presented here on gp41 and the data that had been previously reported for DnaB.

  18. Development of a novel, guinea pig-specific IFN-γ ELISPOT assay and characterization of guinea pig cytomegalovirus GP83-specific cellular immune responses following immunization with a modified vaccinia virus Ankara (MVA)-vectored GP83 vaccine.

    Science.gov (United States)

    Gillis, Peter A; Hernandez-Alvarado, Nelmary; Gnanandarajah, Josephine S; Wussow, Felix; Diamond, Don J; Schleiss, Mark R

    2014-06-30

    The guinea pig (Cavia porcellus) provides a useful animal model for studying the pathogenesis of many infectious diseases, and for preclinical evaluation of vaccines. However, guinea pig models are limited by the lack of immunological reagents required for characterization and quantification of antigen-specific T cell responses. To address this deficiency, an enzyme-linked immunospot (ELISPOT) assay for guinea pig interferon (IFN)-γ was developed to measure antigen/epitope-specific T cell responses to guinea pig cytomegalovirus (GPCMV) vaccines. Using splenocytes harvested from animals vaccinated with a modified vaccinia virus Ankara (MVA) vector encoding the GPCMV GP83 (homolog of human CMV pp65 [gpUL83]) protein, we were able to enumerate and map antigen-specific responses, both in vaccinated as well as GPCMV-infected animals, using a panel of GP83-specific peptides. Several potential immunodominant GP83-specific peptides were identified, including one epitope, LGIVHFFDN, that was noted in all guinea pigs that had a detectable CD8+ response to GP83. Development of a guinea pig IFN-γ ELISPOT should be useful in characterization of additional T cell-specific responses to GPCMV, as well as other pathogens. This information in turn can help focus future experimental evaluation of immunization strategies, both for GPCMV as well as for other vaccine-preventable illnesses studied in the guinea pig model. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. The Tetherin Antagonism of the Ebola Virus Glycoprotein Requires an Intact Receptor-Binding Domain and Can Be Blocked by GP1-Specific Antibodies.

    Science.gov (United States)

    Brinkmann, Constantin; Nehlmeier, Inga; Walendy-Gnirß, Kerstin; Nehls, Julia; González Hernández, Mariana; Hoffmann, Markus; Qiu, Xiangguo; Takada, Ayato; Schindler, Michael; Pöhlmann, Stefan

    2016-12-15

    The glycoprotein of Ebola virus (EBOV GP), a member of the family Filoviridae, facilitates viral entry into target cells. In addition, EBOV GP antagonizes the antiviral activity of the host cell protein tetherin, which may otherwise restrict EBOV release from infected cells. However, it is unclear how EBOV GP antagonizes tetherin, and it is unknown whether the GP of Lloviu virus (LLOV), a filovirus found in dead bats in Northern Spain, also counteracts tetherin. Here, we show that LLOV GP antagonizes tetherin, indicating that tetherin may not impede LLOV spread in human cells. Moreover, we demonstrate that appropriate processing of N-glycans in tetherin/GP-coexpressing cells is required for tetherin counteraction by EBOV GP. Furthermore, we show that an intact receptor-binding domain (RBD) in the GP1 subunit of EBOV GP is a prerequisite for tetherin counteraction. In contrast, blockade of Niemann-Pick disease type C1 (NPC1), a cellular binding partner of the RBD, did not interfere with tetherin antagonism. Finally, we provide evidence that an antibody directed against GP1, which protects mice from a lethal EBOV challenge, may block GP-dependent tetherin antagonism. Our data, in conjunction with previous reports, indicate that tetherin antagonism is conserved among the GPs of all known filoviruses and demonstrate that the GP1 subunit of EBOV GP plays a central role in tetherin antagonism. Filoviruses are reemerging pathogens that constitute a public health threat. Understanding how Ebola virus (EBOV), a highly pathogenic filovirus responsible for the 2013-2016 Ebola virus disease epidemic in western Africa, counteracts antiviral effectors of the innate immune system might help to define novel targets for antiviral intervention. Similarly, determining whether Lloviu virus (LLOV), a filovirus detected in bats in northern Spain, is inhibited by innate antiviral effectors in human cells might help to determine whether the virus constitutes a threat to humans. The

  20. The learner’s perspective in GP teaching practices with multi-level learners: a qualitative study

    Science.gov (United States)

    2014-01-01

    Background Medical students, junior hospital doctors on rotation and general practice (GP) registrars are undertaking their training in clinical general practices in increasing numbers in Australia. Some practices have four levels of learner. This study aimed to explore how multi-level teaching (also called vertical integration of GP education and training) is occurring in clinical general practice and the impact of such teaching on the learner. Methods A qualitative research methodology was used with face-to-face, semi-structured interviews of medical students, junior hospital doctors, GP registrars and GP teachers in eight training practices in the region that taught all levels of learners. Interviews were audio-recorded and transcribed. Qualitative analysis was conducted using thematic analysis techniques aided by the use of the software package N-Vivo 9. Primary themes were identified and categorised by the co-investigators. Results 52 interviews were completed and analysed. Themes were identified relating to both the practice learning environment and teaching methods used. A practice environment where there is a strong teaching culture, enjoyment of learning, and flexible learning methods, as well as learning spaces and organised teaching arrangements, all contribute to positive learning from a learners’ perspective. Learners identified a number of innovative teaching methods and viewed them as positive. These included multi-level learner group tutorials in the practice, being taught by a team of teachers, including GP registrars and other health professionals, and access to a supernumerary GP supervisor (also termed “GP consultant teacher”). Other teaching methods that were viewed positively were parallel consulting, informal learning and rural hospital context integrated learning. Conclusions Vertical integration of GP education and training generally impacted positively on all levels of learner. This research has provided further evidence about the

  1. Expression and Significance of gp96 and Immune-related Gene CTLA-4, CD8 in Lung Cancer Tissues

    Directory of Open Access Journals (Sweden)

    Haiyan ZHENG

    2010-08-01

    Full Text Available Background and objective It has been proven that gp96 plays an important role in specific cytotoxic immune response which is involved in anti-tumor effect in the body. The aim of this study is to investigate the biological significance of heat shock protein gp96 and immune-related gene CTLA-4, CD8 expressions in lung cancer tissues of different progressive stages. Methods We used Envision immunohistochemistry method to detect the levels of expression of gp96, CTLA-4, CD8 in tissue microarray, which contained 89 primary lung cancer tissues, 12 lymph node metastasis lung cancer tissues, 12 precancerous lesions and 10 normal lung tissues, and analyzed the relationship between their expressions and clinicopathological parameters. Results (1 The positive rate of gp96 in primary lung cancer was remarkably higher than that in precancerous lesion and normal lung tissue (P < 0.05. The positive rate of CTLA-4 in primary lung cancer tissue and precancerous lesion was significantly higher than that in normal lung tissue (P < 0.05. The positive rate of CD8 in primary lung cancer tissue was significantly higher than that in normal lung tissue (P < 0.05. The positive rate of gp96 in CD8-positive lymphocytes in the high expression group was less than that in the low group (P < 0.05. (2 The positive rate of gp96 was closely related to sex, differentiation and clinical stage (P < 0.05, but not to age, gross type, histological type and lymph node metastasis (P > 0.05. The positive rate of CTLA-4 was closely related to age and differentiation (P < 0.05, but not to sex, gross type, histological type, clinical stage and lymph node metastasis (P > 0.05. CD8 expression was related to clinical stage (P < 0.05, but not to sex, age, gross type, histological type, differentiation and lymph node metastasis (P > 0.05. The positive rates of gp96, CTLA-4 were higher than that of CD8 in squamous cell carcinoma and SCLC, respectively. (3 There was positive correlation between gp

  2. Computational study of HIV gp120 as a target for polyanionic entry inhibitors: Exploiting the V3 loop region.

    Directory of Open Access Journals (Sweden)

    Louis R Hollingsworth

    Full Text Available Multiple approaches are being utilized to develop therapeutics to treat HIV infection. One approach is designed to inhibit entry of HIV into host cells, with a target being the viral envelope glycoprotein, gp120. Polyanionic compounds have been shown to be effective in inhibiting HIV entry, with a mechanism involving electrostatic interactions with the V3 loop of gp120 being proposed. In this study, we applied computational methods to elucidate molecular interactions between the repeat unit of the precisely alternating polyanion, Poly(4,4'-stilbenedicarboxylate-alt-maleic acid (DCSti-alt-MA and the V3 loop of gp120 from strains of HIV against which these polyanions were previously tested (IIIb, BaL, 92UG037, JR-CSF as well as two strains for which gp120 crystal structures are available (YU2, 2B4C. Homology modeling was used to create models of the gp120 proteins. Using monomers of the gp120 protein, we applied extensive molecular dynamics simulations to obtain dominant morphologies that represent a variety of open-closed states of the V3 loop to examine the interaction of 112 ligands of the repeating units of DCSti-alt-MA docked to the V3 loop and surrounding residues. Using the distance between the V1/V2 and V3 loops of gp120 as a metric, we revealed through MD simulations that gp120 from the lab-adapted strains (BaL and IIIb, which are more susceptible to inhibition by DCSti-alt-MA, clearly transitioned to the closed state in one replicate of each simulation set, whereas none of the replicates from the Tier II strains (92UG037 and JR-CSF did so. Docking repeat unit microspecies to the gp120 protein before and after MD simulation enabled identification of residues that were key for binding. Notably, only a few residues were found to be important for docking both before and after MD simulation as a result of the conformational heterogeneity provided by the simulations. Consideration of the residues that were consistently involved in interactions

  3. HIV-1 gp120 induces NFAT nuclear translocation in resting CD4+ T-cells

    International Nuclear Information System (INIS)

    Cicala, Claudia; Arthos, James; Censoplano, Nina; Cruz, Catherine; Chung, Eva; Martinelli, Elena; Lempicki, Richard A.; Natarajan, Ven; VanRyk, Donald; Daucher, Marybeth; Fauci, Anthony S.

    2006-01-01

    The replication of human immunodeficiency virus (HIV) in CD4+ T-cells is strongly dependent upon the state of activation of infected cells. Infection of sub-optimally activated cells is believed to play a critical role in both the transmission of virus and the persistence of CD4+ T-cell reservoirs. There is accumulating evidence that HIV can modulate signal-transduction pathways in a manner that may facilitate replication in such cells. We previously demonstrated that HIV gp120 induces virus replication in resting CD4+ T cells isolated from HIV-infected individuals. Here, we show that in resting CD4+ T-cells, gp120 activates NFATs and induces their translocation into the nucleus. The HIV LTR encodes NFAT recognition sites, and NFATs may play a critical role in promoting viral replication in sub-optimally activated cells. These observations provide insight into a potential mechanism by which HIV is able to establish infection in resting cells, which may have implications for both transmission of HIV and the persistence of viral reservoirs

  4. Crystal Structure of Bacteriophage SPP1 Distal Tail Protein (gp19.1)

    Science.gov (United States)

    Veesler, David; Robin, Gautier; Lichière, Julie; Auzat, Isabelle; Tavares, Paulo; Bron, Patrick; Campanacci, Valérie; Cambillau, Christian

    2010-01-01

    Siphophage SPP1 infects the Gram-positive bacterium Bacillus subtilis using its long non-contractile tail and tail-tip. Electron microscopy (EM) previously allowed a low resolution assignment of most orf products belonging to these regions. We report here the structure of the SPP1 distal tail protein (Dit, gp19.1). The combination of x-ray crystallography, EM, and light scattering established that Dit is a back-to-back dimer of hexamers. However, Dit fitting in the virion EM maps was only possible with a hexamer located between the tail-tube and the tail-tip. Structure comparison revealed high similarity between Dit and a central component of lactophage baseplates. Sequence similarity search expanded its relatedness to several phage proteins, suggesting that Dit is a docking platform for the tail adsorption apparatus in Siphoviridae infecting Gram-positive bacteria and that its architecture is a paradigm for these hub proteins. Dit structural similarity extends also to non-contractile and contractile phage tail proteins (gpVN and XkdM) as well as to components of the bacterial type 6 secretion system, supporting an evolutionary connection between all these devices. PMID:20843802

  5. Crystal structure of an EAL domain in complex with reaction product 5'-pGpG.

    Directory of Open Access Journals (Sweden)

    Julien Robert-Paganin

    Full Text Available FimX is a large multidomain protein containing an EAL domain and involved in twitching motility in Pseudomonas aeruginosa. We present here two crystallographic structures of the EAL domain of FimX (residues 438-686: one of the apo form and the other of a complex with 5'-pGpG, the reaction product of the hydrolysis of c-di-GMP. In both crystal forms, the EAL domains form a dimer delimiting a large cavity encompassing the catalytic pockets. The ligand is trapped in this cavity by its sugar phosphate moiety. We confirmed by NMR that the guanine bases are not involved in the interaction in solution. We solved here the first structure of an EAL domain bound to the reaction product 5'-pGpG. Though isolated FimX EAL domain has a very low catalytic activity, which would not be significant compared to other catalytic EAL domains, the structure with the product of the reaction can provides some hints in the mechanism of hydrolysis of the c-di-GMP by EAL domains.

  6. Development of GP and GEP models to estimate an environmental issue induced by blasting operation.

    Science.gov (United States)

    Faradonbeh, Roohollah Shirani; Hasanipanah, Mahdi; Amnieh, Hassan Bakhshandeh; Armaghani, Danial Jahed; Monjezi, Masoud

    2018-05-21

    Air overpressure (AOp) is one of the most adverse effects induced by blasting in the surface mines and civil projects. So, proper evaluation and estimation of the AOp is important for minimizing the environmental problems resulting from blasting. The main aim of this study is to estimate AOp produced by blasting operation in Miduk copper mine, Iran, developing two artificial intelligence models, i.e., genetic programming (GP) and gene expression programming (GEP). Then, the accuracy of the GP and GEP models has been compared to multiple linear regression (MLR) and three empirical models. For this purpose, 92 blasting events were investigated, and subsequently, the AOp values were carefully measured. Moreover, in each operation, the values of maximum charge per delay and distance from blast points, as two effective parameters on the AOp, were measured. After predicting by the predictive models, their performance prediction was checked in terms of variance account for (VAF), coefficient of determination (CoD), and root mean square error (RMSE). Finally, it was found that the GEP with VAF of 94.12%, CoD of 0.941, and RMSE of 0.06 is a more precise model than other predictive models for the AOp prediction in the Miduk copper mine, and it can be introduced as a new powerful tool for estimating the AOp resulting from blasting.

  7. Crystal structure of an EAL domain in complex with reaction product 5'-pGpG.

    Science.gov (United States)

    Robert-Paganin, Julien; Nonin-Lecomte, Sylvie; Réty, Stéphane

    2012-01-01

    FimX is a large multidomain protein containing an EAL domain and involved in twitching motility in Pseudomonas aeruginosa. We present here two crystallographic structures of the EAL domain of FimX (residues 438-686): one of the apo form and the other of a complex with 5'-pGpG, the reaction product of the hydrolysis of c-di-GMP. In both crystal forms, the EAL domains form a dimer delimiting a large cavity encompassing the catalytic pockets. The ligand is trapped in this cavity by its sugar phosphate moiety. We confirmed by NMR that the guanine bases are not involved in the interaction in solution. We solved here the first structure of an EAL domain bound to the reaction product 5'-pGpG. Though isolated FimX EAL domain has a very low catalytic activity, which would not be significant compared to other catalytic EAL domains, the structure with the product of the reaction can provides some hints in the mechanism of hydrolysis of the c-di-GMP by EAL domains.

  8. Development of the gas puff charge exchange recombination spectroscopy (GP-CXRS) technique for ion measurements in the plasma edge

    International Nuclear Information System (INIS)

    Churchill, R. M.; Theiler, C.; Lipschultz, B.; Dux, R.; Pütterich, T.; Viezzer, E.

    2013-01-01

    A novel charge-exchange recombination spectroscopy (CXRS) diagnostic method is presented, which uses a simple thermal gas puff for its donor neutral source, instead of the typical high-energy neutral beam. This diagnostic, named gas puff CXRS (GP-CXRS), is used to measure ion density, velocity, and temperature in the tokamak edge/pedestal region with excellent signal-background ratios, and has a number of advantages to conventional beam-based CXRS systems. Here we develop the physics basis for GP-CXRS, including the neutral transport, the charge-exchange process at low energies, and effects of energy-dependent rate coefficients on the measurements. The GP-CXRS hardware setup is described on two separate tokamaks, Alcator C-Mod and ASDEX Upgrade. Measured spectra and profiles are also presented. Profile comparisons of GP-CXRS and a beam based CXRS system show good agreement. Emphasis is given throughout to describing guiding principles for users interested in applying the GP-CXRS diagnostic technique

  9. Development of the gas puff charge exchange recombination spectroscopy (GP-CXRS) technique for ion measurements in the plasma edge

    Energy Technology Data Exchange (ETDEWEB)

    Churchill, R. M.; Theiler, C.; Lipschultz, B. [MIT Plasma Science and Fusion Center, Cambridge, Massachusetts 02139 (United States); Dux, R.; Pütterich, T.; Viezzer, E. [Max-Planck-Institut für Plasmaphysik, EURATOM Association, Boltzmannstrasse 2, D-85748 Garching (Germany); Collaboration: Alcator C-Mod Team; ASDEX Upgrade Team

    2013-09-15

    A novel charge-exchange recombination spectroscopy (CXRS) diagnostic method is presented, which uses a simple thermal gas puff for its donor neutral source, instead of the typical high-energy neutral beam. This diagnostic, named gas puff CXRS (GP-CXRS), is used to measure ion density, velocity, and temperature in the tokamak edge/pedestal region with excellent signal-background ratios, and has a number of advantages to conventional beam-based CXRS systems. Here we develop the physics basis for GP-CXRS, including the neutral transport, the charge-exchange process at low energies, and effects of energy-dependent rate coefficients on the measurements. The GP-CXRS hardware setup is described on two separate tokamaks, Alcator C-Mod and ASDEX Upgrade. Measured spectra and profiles are also presented. Profile comparisons of GP-CXRS and a beam based CXRS system show good agreement. Emphasis is given throughout to describing guiding principles for users interested in applying the GP-CXRS diagnostic technique.

  10. Studies on adsorptions of metallic ions in water by zirconium glyphosate (ZrGP): Behaviors and mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Jia Yunjie; Zhang Yuejuan [State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Box. 98, No.15, Beisanhuan donglu, Beijing 100029 (China); Wang Runwei [State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, Jilin University, Changchun 130012 (China); Fan Faying [State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Box. 98, No.15, Beisanhuan donglu, Beijing 100029 (China); Xu Qinghong, E-mail: xuqh@mail.buct.edu.cn [State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Box. 98, No.15, Beisanhuan donglu, Beijing 100029 (China)

    2012-01-15

    A new adsorbent named zirconium glyphosate [Zr(O{sub 3}PCH{sub 2}NHCH{sub 2}COOH){sub 2}{center_dot}0.5H{sub 2}O, denoted as ZrGP] and its selective adsorptions to Pb{sup 2+}, Cd{sup 2+}, Mg{sup 2+} and Ca{sup 2+} ions in water were reported in this paper. Compared to other zirconium adsorbents, such as zirconium phosphate [Zr(HPO{sub 4}){sub 2}], ZrGP exhibited highly selective adsorption to Pb{sup 2+} in solution which contained Pb{sup 2+}, Cd{sup 2+}, Mg{sup 2+} and Ca{sup 2+} ions. The loaded ZrGP with metallic ions can be efficaciously regenerated by aqueous solution of HCl (1.0 M) without any noticeable capacity loss, and almost all of it can be reused and recycled. The memory effect on structural regeneration of ZrGP was also found when Mg{sup 2+} and Ca{sup 2+} were adsorbed. To be specific, the structure of ZrGP was destroyed due to adsorbing these two ions, but it could be regenerated after the loaded materials were dipped in HCl solution (1.0 M) for several minutes to remove metallic ions.

  11. Studies on adsorptions of metallic ions in water by zirconium glyphosate (ZrGP): Behaviors and mechanisms

    International Nuclear Information System (INIS)

    Jia Yunjie; Zhang Yuejuan; Wang Runwei; Fan Faying; Xu Qinghong

    2012-01-01

    A new adsorbent named zirconium glyphosate [Zr(O 3 PCH 2 NHCH 2 COOH) 2 ·0.5H 2 O, denoted as ZrGP] and its selective adsorptions to Pb 2+ , Cd 2+ , Mg 2+ and Ca 2+ ions in water were reported in this paper. Compared to other zirconium adsorbents, such as zirconium phosphate [Zr(HPO 4 ) 2 ], ZrGP exhibited highly selective adsorption to Pb 2+ in solution which contained Pb 2+ , Cd 2+ , Mg 2+ and Ca 2+ ions. The loaded ZrGP with metallic ions can be efficaciously regenerated by aqueous solution of HCl (1.0 M) without any noticeable capacity loss, and almost all of it can be reused and recycled. The memory effect on structural regeneration of ZrGP was also found when Mg 2+ and Ca 2+ were adsorbed. To be specific, the structure of ZrGP was destroyed due to adsorbing these two ions, but it could be regenerated after the loaded materials were dipped in HCl solution (1.0 M) for several minutes to remove metallic ions.

  12. Mimicking protein-protein interactions through peptide-peptide interactions: HIV-1 gp120 and CXCR4

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    Andrea eGross

    2013-09-01

    Full Text Available We have recently designed a soluble synthetic peptide that functionally mimics the HIV-1 coreceptor CXCR4, which is a chemokine receptor that belongs to the family of seven-transmembrane GPCRs. This CXCR4 mimetic peptide, termed CX4-M1, presents the three extracellular loops (ECLs of the receptor. In binding assays involving recombinant proteins, as well as in cellular infection assays, CX4-M1 was found to selectively recognize gp120 from HIV-1 strains that use CXCR4 for cell entry (X4 tropic HIV-1. Furthermore, anti-HIV-1 antibodies modulate this interaction in a molecular mechanism related to that of their impact on the gp120-CXCR4 interaction. We could now show that the selectivity of CX4-M1 pertains not only to gp120 from X4 tropic HIV-1, but also to synthetic peptides presenting the V3 loops of these gp120 proteins. The V3 loop is thought to be an essential part of the coreceptor binding site of gp120 that contacts the second ECL of the coreceptor. We were able to experimentally confirm this notion in binding assays using substitution analogs of CX4-M1 and the V3 loop peptides, respectively, as well as in cellular infection assays. These results indicate that interactions of the HIV-1 Env with coreceptors can be mimicked by synthetic peptides, which may be useful to explore these interactions at the molecular level in more detail.

  13. P-gp expression levels in the erythrocytes of brown trout: a new tool for aquatic sentinel biomarker development.

    Science.gov (United States)

    Valton, Emeline; Wawrzyniak, Ivan; Amblard, Christian; Combourieu, Bruno; Bayle, Marie-Laure; Desmolles, François; Kwiatkowski, Fabrice; Penault-Llorca, Frédérique; Bamdad, Mahchid

    2017-09-01

    P-glycoprotein (P-gp) is a ubiquitous membrane detoxification pump involved in cellular defence against xenobiotics. Blood is a hub for the trade and transport of physiological molecules and xenobiotics. Our recent studies have highlighted the expression of a 140-kDa P-gp in brown trout erythrocytes in primary cell culture and its dose-dependent response to Benzo[a]pyrene pollutant. The purpose of this study was focused on using P-gp expression in brown trout erythrocytes as a biomarker for detecting the degree of river pollution. abcb1 gene and P-gp expression level were analysed by reverse transcriptase-PCR and Western blot, in the erythrocytes of brown trouts. The latter were collected in upstream and downstream of four rivers in which 17 polycyclic aromatic hydrocarbons and 348 varieties of pesticides micro-residues were analysed by liquid chromatography and mass spectrometry. The abcb1 gene and the 140-kDa P-gp were not expressed in trout erythrocytes from uncontaminated river. In contrast, they are clearly expressed in contaminated rivers, in correlation with the river pollution degree and the nature of the pollutants. This biological tool may offer considerable advantages since it provides an effective response to the increasing need for an early biomarker.

  14. Upregulations of Clcn3 and P-Gp Provoked by Lens Osmotic Expansion in Rat Galactosemic Cataract

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    Lixia Ji

    2017-01-01

    Full Text Available Objective. Lens osmotic expansion, provoked by overactivated aldose reductase (AR, is the most essential event of sugar cataract. Chloride channel 3 (Clcn3 is a volume-sensitive channel, mainly participating in the regulation of cell fundamental volume, and P-glycoprotein (P-gp acts as its modulator. We aim to study whether P-gp and Clcn3 are involved in lens osmotic expansion of galactosemic cataract. Methods and Results. In vitro, lens epithelial cells (LECs were primarily cultured in gradient galactose medium (10–60 mM, more and more vacuoles appeared in LEC cytoplasm, and mRNA and protein levels of AR, P-gp, and Clcn3 were synchronously upregulated along with the increase of galactose concentration. In vivo, we focused on the early stage of rat galactosemic cataract, amount of vacuoles arose from equatorial area and scattered to the whole anterior capsule of lenses from the 3rd day to the 9th day, and mRNA and protein levels of P-gp and Clcn3 reached the peak around the 9th or 12th day. Conclusion. Galactosemia caused the osmotic stress in lenses; it also markedly leads to the upregulations of AR, P-gp, and Clcn3 in LECs, together resulting in obvious osmotic expansion in vitro and in vivo.

  15. Human immunodeficiency virus envelope protein Gp120 induces proliferation but not apoptosis in osteoblasts at physiologic concentrations.

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    Nathan W Cummins

    Full Text Available Patients with HIV infection have decreased numbers of osteoblasts, decreased bone mineral density and increased risk of fracture compared to uninfected patients; however, the molecular mechanisms behind these associations remain unclear. We questioned whether Gp120, a component of the envelope protein of HIV capable of inducing apoptosis in many cell types, is able to induce cell death in bone-forming osteoblasts. We show that treatment of immortalized osteoblast-like cells and primary human osteoblasts with exogenous Gp120 in vitro at physiologic concentrations does not result in apoptosis. Instead, in the osteoblast-like U2OS cell line, cells expressing CXCR4, a receptor for Gp120, had increased proliferation when treated with Gp120 compared to control (P<0.05, which was inhibited by pretreatment with a CXCR4 inhibitor and a G-protein inhibitor. This suggests that Gp120 is not an inducer of apoptosis in human osteoblasts and likely does not directly contribute to osteoporosis in infected patients by this mechanism.

  16. The major surface glycoprotein (gp63) from Leishmania major and Leishmania donovani cleaves CD4 molecules on human T cells

    DEFF Research Database (Denmark)

    Hey, A S; Theander, T G; Hviid, L

    1994-01-01

    The effect of Leishmania major and L. donovani surface protease gp63 on surface markers on human T cells was studied using fluorescence-activated flow cytometry. Purified gp63 (63,000 m.w. glycoprotein) at concentrations above 10 micrograms/ml completely inhibited binding of six different anti-CD4......-expression of CD4, reaching 50% of the initial level after 72 h of incubation in medium. Preincubation of cells with live promastigotes showed an inhibitory effect on CD4 comparable to that seen with purified gp63. The binding of Abs directed against other surface markers present on human T-cells--CD2, CD3, CD5......, CD8, CD11A, CD25, CD45RO, CD45RA, CD58, TCR-alpha, TCR-gamma, and HLA DQ--was not inhibited by gp63. These data suggest that gp63, both in its purified form and in the form anchored to the parasite membrane, cleaves CD4 on human T cells. The cleavage of CD4 by the protease might play a role...

  17. Anti-coagulation effect of Fc fragment against anti-β2-GP1 antibodies in mouse models with APS.

    Science.gov (United States)

    Xie, Weidong; Zhang, Yaou; Bu, Cunya; Sun, Shijing; Hu, Shaoliang; Cai, Guoping

    2011-01-01

    Anti-beta (2)-glycoprotein I (anti-β2-GP1) is one of the important pathogenesis factors responsible for thrombosis formation in patients with antiphospholipid syndrome (APS). Administration of intravenous immunoglobulin (IVIg) is a common method used to inhibit the abnormal antibody levels and decrease the mortality of APS in emergency situations. We hypothesize that the Fc fragment of IgG is the molecular structure responsible for these effects. The present study investigates the beneficial effects of both recombinant and natural human Fc fragments of heterogeneous IgG against human anti-β2-GP1 antibodies in mouse models with APS. Results showed that both recombinant and natural human Fc fragments moderately but significantly decreased the levels of serum anti-β2-GP1 antibodies and had anti-coagulation effects in human β2-GP1-immunized mice. Furthermore, both recombinant and natural human Fc fragments inhibited thrombosis formation and decreased mortality in mouse models infused intravenously with human anti-β2GP1 antibodies from patients with APS. Findings suggest that the Fc fragment might be one of the active structural units of heterogeneous IgG. Thus, recombinant human Fc fragment administration may be a useful treatment for individuals with APS. Copyright © 2010 Elsevier B.V. All rights reserved.

  18. General Practitioner (GP) trainees' experience of a '1-h protected supervision model' given during psychiatry placements in the United Kingdom.

    Science.gov (United States)

    Thomas, Gareth; McNeill, Helen

    2018-01-05

    Background A '1-hour protected supervision model' is well established for Psychiatry trainees. This model is also extended to GP trainees who are on placement in psychiatry. To explore the experiences of the '1-hour protected supervision model' for GP trainees in psychiatry placements in the UK. Methods Using a mixed methods approach, an anonymous online questionnaire was sent to GP trainees in the North West of England who had completed a placement in Psychiatry between February and August 2015. Results Discussing clinical cases whilst using the e-portfolio was the most useful learning event in this model. Patient care can potentially improve if a positive relationship develops between trainee/supervisor, which is impacted by the knowledge of this model at the start of the placement. Trainees found that clinical pressures were impacting on the occurrence of supervision. Conclusion The model works best when both GP trainees and their supervisors understand the model. The most frequently used and educationally beneficial aspect for GP trainees in psychiatry is the exploration of clinical cases using the learning portfolio as an educational tool. For effective delivery of this model of supervision, organisations must reflect on the balance between service delivery and allowing the supervisor and trainee adequate time for it to occur.

  19. GP-9s are ubiquitous proteins unlikely involved in olfactory mediation of social organization in the red imported fire ant, Solenopsis invicta.

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    Walter S Leal

    Full Text Available The red imported fire ant (RIFA, Solenopsis invicta, is an invasive species, accidentally introduced in the United States that can cause painful (sometimes life-threatening stings to human, pets, and livestock. Their colonies have two social forms: monogyne and polygyne that have a single and multiple functional queens, respectively. A major gene (Gp-9, identified as a putative pheromone-binding protein on the basis of a modest amino acid sequence identity, has been suggested to influence the expression of colony social organization. Monogyne queens are reported to possess only the GP-9B alleles, whereas polygyne queens possess both GP-9B and GP-9b. Thus, both social forms are reported to express GP-9B, with GP-9b being a marker expressed in polygynes but it is absent in monogynes. Here, we report two types of polygyne colonies, one that does not express GP-9b (monogyne-like and the other expressing both proteins, GP-9B and GP-9b. Given their expression pattern, GP-9s are hemolymph proteins, which are more likely to be involved in the transport of lipids and small ligands within the homocoel. GP-9B existed in two forms, one of them is phosphorylated. The helical-rich content of the protein resembles the secondary structures of a beetle hemolymph protein and moth pheromone-binding proteins. An olfactory role is unlikely given the lack of specific expression in the sensillar lymph. In marked contrast to GP-9s, a chemosensory protein, SinvCSP, is demonstrated to be specifically expressed in the antennae. Within the antennae, expression of SinvCSP is restricted to the last two segments, which are known to house olfactory sensilla.

  20. Immunization With Fc-Based Recombinant Epstein–Barr Virus gp350 Elicits Potent Neutralizing Humoral Immune Response in a BALB/c Mice Model

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    Bingchun Zhao

    2018-05-01

    Full Text Available Epstein–Barr virus (EBV was the first human virus proved to be closely associated with tumor development, such as lymphoma, nasopharyngeal carcinoma, and EBV-associated gastric carcinoma. Despite many efforts to develop prophylactic vaccines against EBV infection and diseases, no candidates have succeeded in effectively blocking EBV infection in clinical trials. Previous investigations showed that EBV gp350 plays a pivotal role in the infection of B-lymphocytes. Nevertheless, using monomeric gp350 proteins as antigens has not been effective in preventing infection. Multimeric forms of the antigen are more potently immunogenic than monomers; however, the multimerization elements used in previous constructs are not approved for human clinical trials. To prepare a much-needed EBV prophylactic vaccine that is potent, safe, and applicable, we constructed an Fc-based form of gp350 to serve as a dimeric antigen. Here, we show that the Fc-based gp350 antigen exhibits dramatically enhanced immunogenicity compared with wild-type gp350 protein. The complete or partial gp350 ectodomain was fused with the mouse IgG2a Fc domain. Fusion with the Fc domain did not impair gp350 folding, binding to a conformation-dependent neutralizing antibody (nAb and binding to its receptor by enzyme-linked immunosorbent assay and surface plasmon resonance. Specific antibody titers against gp350 were notably enhanced by immunization with gp350-Fc dimers compared with gp350 monomers. Furthermore, immunization with gp350-Fc fusion proteins elicited potent nAbs against EBV. Our data strongly suggest that an EBV gp350 vaccine based on Fc fusion proteins may be an efficient candidate to prevent EBV infection in clinical applications.

  1. Proteomic plasma membrane profiling reveals an essential role for gp96 in the cell surface expression of LDLR family members, including the LDL receptor and LRP6.

    Science.gov (United States)

    Weekes, Michael P; Antrobus, Robin; Talbot, Suzanne; Hör, Simon; Simecek, Nikol; Smith, Duncan L; Bloor, Stuart; Randow, Felix; Lehner, Paul J

    2012-03-02

    The endoplasmic reticulum chaperone gp96 is required for the cell surface expression of a narrow range of proteins, including toll-like receptors (TLRs) and integrins. To identify a more comprehensive repertoire of proteins whose cell surface expression is dependent on gp96, we developed plasma membrane profiling (PMP), a technique that combines SILAC labeling with selective cell surface aminooxy-biotinylation. This approach allowed us to compare the relative abundance of plasma membrane (PM) proteins on gp96-deficient versus gp96-reconstituted murine pre-B cells. Analysis of unfractionated tryptic peptides initially identified 113 PM proteins, which extended to 706 PM proteins using peptide prefractionation. We confirmed a requirement for gp96 in the cell surface expression of certain TLRs and integrins and found a marked decrease in cell surface expression of four members of the extended LDL receptor family (LDLR, LRP6, Sorl1 and LRP8) in the absence of gp96. Other novel gp96 client proteins included CD180/Ly86, important in the B-cell response to lipopolysaccharide. We highlight common structural motifs in these client proteins that may be recognized by gp96, including the beta-propeller and leucine-rich repeat. This study therefore identifies the extended LDL receptor family as an important new family of proteins whose cell surface expression is regulated by gp96.

  2. Investigation of the function of the putative self-association site of Epstein-Barr virus (EBV) glycoprotein 42 (gp42)

    International Nuclear Information System (INIS)

    Rowe, Cynthia L.; Matsuura, Hisae; Jardetzky, Theodore S.; Longnecker, Richard

    2011-01-01

    The Epstein-Barr virus (EBV) glycoprotein 42 (gp42) is a type II membrane protein essential for entry into B cells but inhibits entry into epithelial cells. X-ray crystallography suggests that gp42 may form dimers when bound to human leukocyte antigen (HLA) class II receptor (Mullen et al., 2002) or multimerize when not bound to HLA class II (Kirschner et al., 2009). We investigated this self-association of gp42 using several different approaches. We generated soluble mutants of gp42 containing mutations within the self-association site and found that these mutants have a defect in fusion. The gp42 mutants bound to gH/gL and HLA class II, but were unable to bind wild-type gp42 or a cleavage mutant of gp42. Using purified gp42, gH/gL, and HLA, we found these proteins associate 1:1:1 by gel filtration suggesting that gp42 dimerization or multimerization does not occur or is a transient event undetectable by our methods.

  3. A Critical View on In Vitro Analysis of P-glycoprotein (P-gp) Transport Kinetics

    DEFF Research Database (Denmark)

    Saaby, Lasse; Brodin, Birger

    2017-01-01

    Transport proteins expressed in the different barriers of the human body can have great implications on absorption, distribution, and excretion of drug compounds. Inhibition or saturation of a transporter can potentially alter these absorbtion, distribution, metabolism and elimination properties...... and thereby also the pharmacokinetic profile and bioavailability of drug compounds. P-glycoprotein (P-gp, ABCB1) is an efflux transporter which is present in most of the barriers of the body, including the small intestine, the blood-brain barrier, the liver, and the kidney. In all these tissues, P-gp may...... mediate efflux of drug compounds and may also be a potential site for drug-drug interactions. Consequently, there is a need to be able to predict the saturation and inhibition of P-gp and other transporters in vivo. For this purpose, Michaelis-Menten steady-state analysis has been applied to estimate...

  4. Differences in cell morphometry, cell wall topography and gp70 expression correlate with the virulence of Sporothrix brasiliensis clinical isolates.

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    Rafaela A Castro

    Full Text Available Sporotrichosis is a chronic infectious disease affecting both humans and animals. For many years, this subcutaneous mycosis had been attributed to a single etiological agent; however, it is now known that this taxon consists of a complex of at least four pathogenic species, including Sporothrix schenckii and Sporothrix brasiliensis. Gp70 was previously shown to be an important antigen and adhesin expressed on the fungal cell surface and may have a key role in immunomodulation and host response. The aim of this work was to study the virulence, morphometry, cell surface topology and gp70 expression of clinical isolates of S. brasiliensis compared with two reference strains of S. schenckii. Several clinical isolates related to severe human cases or associated with the Brazilian zoonotic outbreak of sporotrichosis were genotyped and clustered as S. brasiliensis. Interestingly, in a murine subcutaneous model of sporotrichosis, these isolates showed a higher virulence profile compared with S. schenckii. A single S. brasiliensis isolate from an HIV-positive patient not only showed lower virulence but also presented differences in cell morphometry, cell wall topography and abundant gp70 expression compared with the virulent isolates. In contrast, the highly virulent S. brasiliensis isolates showed reduced levels of cell wall gp70. These observations were confirmed by the topographical location of the gp70 antigen using immunoelectromicroscopy in both species. In addition, the gp70 molecule was sequenced and identified using mass spectrometry, and the sequenced peptides were aligned into predicted proteins using Blastp with the S. schenckii and S. brasiliensis genomes.

  5. Cloning and Characterization of the Genes Encoding the Murine Homologues of the Human Melanoma Antigens MART1 and gp100

    Science.gov (United States)

    Zhai, Yifan; Yang, James C.; Spiess, Paul; Nishimura, Michael I.; Overwijk, Willem W.; Roberts, Bruce; Restifo, Nicholas P.; Rosenberg, Steven A.

    2008-01-01

    The recent identification of genes encoding melanoma-associated antigens has opened new possibilities for the development of cancer vaccines designed to cause the rejection of established tumors. To develop a syngeneic animal model for evaluating antigen-specific vaccines in cancer therapy, the murine homologues of the human melanoma antigens MART1 and gp 100, which were specifically recognized by tumor-infiltrating lymphocytes from patients with melanoma, were cloned and sequenced from a murine B16 melanoma cDNA library. The open reading frames of murine MART1 and gp 100 encode proteins of 113- and 626-amino acids with 68.8 and 77% identity to the respective human proteins. Comparison of the DNA sequences of the murine MART1 genes, derived from normal melanocytes, the immortalized nontumorgenic melanocyte line Melan-a and the B16 melanoma, showed all to be identical. Northern and Western blot analyses confirmed that both genes encoded products that were melanocyte lineage proteins. Mice immunized with murine MART1 or gp 100 using recombinant vaccinia virus failed to produce any detectable T-cell responses or protective immunity against B16 melanoma. In contrast, immunization of mice with human gp 100 using recombinant adenoviruses elicited T cells specific for hgp100, but these T cells also cross reacted with B16 tumor in vitro and induced significant but weak protection against B16 challenge. Immunization with human and mouse gp100 together [adenovirus type 2 (Ad2)-hep100 plus recombinant vaccinia virus (rVV)-mgp100], or immunization with human gp100 (Ad2-hgp100) and boosting with heterologous vector (rVV-hgp100 or rVV-mgp100) or homologous vector (Ad2-hgp100), did not significantly enhance the protective response against B16 melanoma. These results may suggest that immunization with heterologous tumor antigen, rather than self, may be more effective as an immunotherapeutic reagent in designing antigen-specific cancer vaccines. PMID:9101410

  6. Potentiating Effects of MPL on DSPC Bearing Cationic Liposomes Promote Recombinant GP63 Vaccine Efficacy: High Immunogenicity and Protection

    Science.gov (United States)

    Mazumder, Saumyabrata; Maji, Mithun; Ali, Nahid

    2011-01-01

    Background Vaccines that activate strong specific Th1-predominant immune responses are critically needed for many intracellular pathogens, including Leishmania. The requirement for sustained and efficient vaccination against leishmaniasis is to formulate the best combination of immunopotentiating adjuvant with the stable antigen (Ag) delivery system. The aim of the present study is to evaluate the effectiveness of an immunomodulator on liposomal Ag through subcutaneous (s.c.) route of immunization, and its usefulness during prime/boost against visceral leishmaniasis (VL) in BALB/c mice. Methodology/Principal Findings Towards this goal, we formulated recombinant GP63 (rGP63)-based vaccines either with monophosphoryl lipid A-trehalose dicorynomycolate (MPL-TDM) or entrapped within cationic liposomes or both. Combinatorial administration of liposomes with MPL-TDM during prime confers activation of dendritic cells, and induces an early robust T cell response. To investigate whether the combined formulation is required for optimum immune response during boost as well, we chose to evaluate the vaccine efficacy in mice primed with combined adjuvant system followed by boosting with either rGP63 alone, in association with MPL-TDM, liposomes or both. We provide evidences that the presence of either liposomal rGP63 or combined formulations during boost is necessary for effective Th1 immune responses (IFN-γ, IL-12, NO) before challenge infection. However, boosting with MPL-TDM in conjugation with liposomal rGP63 resulted in a greater number of IFN-γ producing effector T cells, significantly higher levels of splenocyte proliferation, and Th1 responses compared to mice boosted with liposomal rGP63, after virulent Leishmania donovani (L. donovani) challenge. Moreover, combined formulations offered superior protection against intracellular amastigote replication in macrophages in vitro, and hepatic and splenic parasite load in vivo. Conclusion Our results define the

  7. Identification of a human protein-derived HIV-1 fusion inhibitor targeting the gp41 fusion core structure.

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    Lijun Chao

    Full Text Available The HIV-1 envelope glycoprotein (Env gp41 plays a crucial role in the viral fusion process. The peptides derived from the C-terminal heptad repeat (CHR of gp41 are potent HIV fusion inhibitors. However, the activity of these anti-HIV-1 peptides in vivo may be attenuated by their induction of anti-gp41 antibodies. Thus, it is essential to identify antiviral peptides or proteins with low, or no, immunogenicity to humans. Here, we found that the C-terminal fragment (aa 462-521 of the human POB1 (the partner of RalBP1, designated C60, is an HIV-1 fusion inhibitor. It bound to N36, the peptide derived from the N-terminal heptad repeat (NHR of gp41, and to the six-helix bundle (6-HB formed by N36 and C34, a CHR-peptide, but it did not bind to C34. Unlike the CHR-peptides, C60 did not block gp41 6-HB formation. Rather, results suggest that C60 inhibits HIV-1 fusion by binding to the 6-HB, in particular, the residues in the gp41 NHR domain that are exposed on the surface of 6-HB. Since 6-HB plays a crucial role in the late stage of fusion between the viral envelope and endosomal membrane during the endocytic process of HIV-1, C60 may serve as a host restriction factor to suppress HIV-1 entry into CD4+ T lymphocytes. Taken together, it can be concluded from these results that C60 can be used as a lead for the development of anti-HIV-1 therapeutics or microbicides for the treatment and prevention of HIV-1 infection, as well as a molecular probe to study the fusogenic mechanism of HIV-1.

  8. Structural improvement of unliganded simian immunodeficiency virus gp120 core by normal-mode-based X-ray crystallographic refinement

    International Nuclear Information System (INIS)

    Chen, Xiaorui; Lu, Mingyang; Poon, Billy K.; Wang, Qinghua; Ma, Jianpeng

    2009-01-01

    The structural model of the unliganded and fully glycosylated simian immunodeficiency virus gp120 core determined to 4.0 Å resolution was substantially improved using a recently developed normal-mode-based anisotropic B-factor refinement method. The envelope protein gp120/gp41 of simian and human immunodeficiency viruses plays a critical role in viral entry into host cells. However, the extraordinarily high structural flexibility and heavy glycosylation of the protein have presented enormous difficulties in the pursuit of high-resolution structural investigation of some of its conformational states. An unliganded and fully glycosylated gp120 core structure was recently determined to 4.0 Å resolution. The rather low data-to-parameter ratio limited refinement efforts in the original structure determination. In this work, refinement of this gp120 core structure was carried out using a normal-mode-based refinement method that has been shown in previous studies to be effective in improving models of a supramolecular complex at 3.42 Å resolution and of a membrane protein at 3.2 Å resolution. By using only the first four nonzero lowest-frequency normal modes to construct the anisotropic thermal parameters, combined with manual adjustments and standard positional refinement using REFMAC5, the structural model of the gp120 core was significantly improved in many aspects, including substantial decreases in R factors, better fitting of several flexible regions in electron-density maps, the addition of five new sugar rings at four glycan chains and an excellent correlation of the B-factor distribution with known structural flexibility. These results further underscore the effectiveness of this normal-mode-based method in improving models of protein and nonprotein components in low-resolution X-ray structures

  9. Designing and overproducing a tandem epitope of gp350/220 that shows a potential to become an EBV vaccine

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    Widodo

    2018-03-01

    Full Text Available Background: Epstein-Barr virus (EBV can cause cancer in people from around the world. There is no EBV vaccine available for use on a global scale. However, emerging evidence suggests that the epitope on the gp350/220 capsid protein may be developed into an EBV vaccine. Nevertheless, the production of small, single epitope is challenging of stability issues and possible alteration of peptide structure. In this study, a tandem epitope was developed consisting of three single epitopes, aimed to improve stability, antigenicity and preserve epitope structure. Materials and methods: A tandem epitope was designed using bioinformatics based on the epitope structure of the gp350/220 protein. The tandem epitope structure was analyzed using a protein folding method with Abalone software, which was further refined via YASARA force field and molecular repairing using a FoldX method. Immunogenicity was examined with Epitopia software, whereas allergen properties were tested using AlgPred. The pattern of the tandem epitope binding with anti-gp350/220 antibodies was performed using Z-dock and snugDock. The tandem epitope was then overproduced in E. coli strain BL21 as a host cell. Result: Our model demonstrated a successfully designed and overproduced tandem epitope. The tandem epitope demonstrated a similar structure compared with the epitope of whole protein gp350/220. Our epitope also demonstrated non-allergen and antigenicity properties, and possessed antibody binding patterns consistent with whole protein gp350/220. Conclusion and recommendation: These data suggest a novel tandem epitope composed of three similar epitopes demonstrates antigenicity, structure, and binding properties consistent with whole protein gp350/220. We also demonstrate successful production of the tandem epitope using E. coli strain BL21 as a host. Future in vivo experimental animal research is necessary to test the ability of this tandem epitope to stimulate antibody production

  10. Applying the Trigger Review Method after a brief educational intervention: potential for teaching and improving safety in GP specialty training?

    Science.gov (United States)

    McKay, John; de Wet, Carl; Kelly, Moya; Bowie, Paul

    2013-08-30

    The Trigger Review Method (TRM) is a structured approach to screening clinical records for undetected patient safety incidents (PSIs) and identifying learning and improvement opportunities. In Scotland, TRM participation can inform GP appraisal and has been included as a core component of the national primary care patient safety programme that was launched in March 2013. However, the clinical workforce needs up-skilled and the potential of TRM in GP training has yet to be tested. Current TRM training utilizes a workplace face-to-face session by a GP expert, which is not feasible. A less costly, more sustainable educational intervention is necessary to build capability at scale. We aimed to determine the feasibility and impact of TRM and a related training intervention in GP training. We recruited 25 west of Scotland GP trainees to attend a 2-hour TRM workshop. Trainees then applied TRM to 25 clinical records and returned findings within 4-weeks. A follow-up feedback workshop was held. 21/25 trainees (84%) completed the task. 520 records yielded 80 undetected PSIs (15.4%). 36/80 were judged potentially preventable (45%) with 35/80 classified as causing moderate to severe harm (44%). Trainees described a range of potential learning and improvement plans. Training was positively received and appeared to be successful given these findings. TRM was valued as a safety improvement tool by most participants. This small study provides further evidence of TRM utility and how to teach it pragmatically. TRM is of potential value in GP patient safety curriculum delivery and preparing trainees for future safety improvement expectations.

  11. [Evaluation of special GP-centered health care contracts in Germany by the participating GPs. present situation and future perspectives].

    Science.gov (United States)

    Klingenberg, Anja; Broge, Björn; Herholz, Harald; Szecsenyi, Joachim; Ose, Dominik

    2010-02-01

    In 2004, German statutory health care funds were given the possibility to offer their insured a special general practitioner-( GP-)centered health care contract (HZV), since 2007 they are obliged to do so. The aim of these contracts is to strengthen the role of the GP as a coordinator in the health care system. Until now, the evidence regarding the GPs' view on these contracts is poor. A written survey was conducted in Hesse in order to learn how the participating GPs evaluate the regional HZV. In Apri 2008, a questionnaire was developed, tested and mailed to 2,815 GPs who were participating in the GP-centered health care contract at that time. All analyses where conducted with SPSS (version 15.0). A total of 686 questionnaires were returned (response rate 24.4%). Altogether, the GPs' feedback ranged from great approval to clear disapproval of the contract. However, 70.0% of the survey's participants evaluated the HZV in general to be positive, 60.1% felt it strengthens their role as a GP. Quality circles on good prescribing and GP-specific education, obligatory parts of the HZV, were evaluated to be especially positive (70.3% and 69.4%, respectively). Positive effects were also seen concerning coordination of care (53.3%) and cooperation with patients (36.3%). Improvements concerning cooperation with specialists and hospitals were reported less often (24.9% and 13.0%, respectively). Workload because of additional administration for the HZV was criticized. In future, special GP-centered health care contracts should focus on improvement of cooperation between GPs and other caregivers. Workload for additional administration should be reduced.

  12. Human CNS cultures exposed to HIV-1 gp120 reproduce dendritic injuries of HIV-1-associated dementia

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    Hammond Robert R

    2004-05-01

    Full Text Available Abstract HIV-1-associated dementia remains a common subacute to chronic central nervous system degeneration in adult and pediatric HIV-1 infected populations. A number of viral and host factors have been implicated including the HIV-1 120 kDa envelope glycoprotein (gp120. In human post-mortem studies using confocal scanning laser microscopy for microtubule-associated protein 2 and synaptophysin, neuronal dendritic pathology correlated with dementia. In the present study, primary human CNS cultures exposed to HIV-1 gp120 at 4 weeks in vitro suffered gliosis and dendritic damage analogous to that described in association with HIV-1-associated dementia.

  13. Marburg Virus Glycoprotein GP2: pH-Dependent Stability of the Ectodomain α-Helical Bundle†

    Science.gov (United States)

    Harrison, Joseph S.; Koellhoffer, Jayne F.; Chandran, Kartik; Lai, Jonathan R.

    2012-01-01

    Marburg virus (MARV) and Ebola virus (EBOV) constitute the family Filoviridae of enveloped viruses (filoviruses) that cause severe hemorrhagic fever. Infection by MARV is required for fusion between the host cell and viral membranes, a process that is mediated by the two subunits of the envelope glycoprotein GP1 (surface subunit) and GP2 (transmembrane subunit). Upon viral attachment and uptake, it is believed that the MARV viral fusion machinery is triggered by host factors and environmental conditions found in the endosome. Next, conformational rearrangements in the GP2 ectodomain result in the formation of a highly stable six-helix bundle; this refolding event provides the energetic driving force for membrane fusion. Both GP1 and GP2 from EBOV have been extensively studied, but there is little information available for the MARV glycoproteins. Here we have expressed two variants of the MARV GP2 ectodomain in Escherichia coli and analyzed their biophysical properties. Circular dichroism indicates that the MARV GP2 ectodomain adopts an α-helical conformation, and one variant sediments as a trimer by equilibrium analytical ultracentrifugation. Denaturation studies indicate the α-helical structure is highly stable at pH 5.3 (unfolding energy, ΔGunf H2O, of 33.4 ± 2.5 kcal/mol and melting temperature, Tm, of 75.3 ± 2.1 °C for one variant). Furthermore, we found the α-helical stability to be strongly dependent on pH with higher stability under lower pH conditions (Tm values ranging from ~92 °C at pH 4.0 to ~38 °C at pH 8.0). Mutational analysis suggests two glutamic acid residues (E579 and E580) are partially responsible for this pH-dependent behavior. Based on these results, we hypothesize that pH-dependent folding stability of the MARV GP2 ectodomain provides a mechanism to control conformational preferences such that the six-helix bundle ‘post-fusion’ state is preferred under conditions of appropriately matured endosomes. PMID:22369502

  14. Immunization with Hexon modified adenoviral vectors integrated with gp83 epitope provides protection against Trypanosoma cruzi infection.

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    Anitra L Farrow

    2014-08-01

    Full Text Available Trypanosoma cruzi is the causative agent of Chagas disease. Chagas disease is an endemic infection that affects over 8 million people throughout Latin America and now has become a global challenge. The current pharmacological treatment of patients is unsuccessful in most cases, highly toxic, and no vaccines are available. The results of inadequate treatment could lead to heart failure resulting in death. Therefore, a vaccine that elicits neutralizing antibodies mediated by cell-mediated immune responses and protection against Chagas disease is necessary.The "antigen capsid-incorporation" strategy is based upon the display of the T. cruzi epitope as an integral component of the adenovirus' capsid rather than an encoded transgene. This strategy is predicted to induce a robust humoral immune response to the presented antigen, similar to the response provoked by native Ad capsid proteins. The antigen chosen was T. cruzi gp83, a ligand that is used by T. cruzi to attach to host cells to initiate infection. The gp83 epitope, recognized by the neutralizing MAb 4A4, along with His6 were incorporated into the Ad serotype 5 (Ad5 vector to generate the vector Ad5-HVR1-gp83-18 (Ad5-gp83. This vector was evaluated by molecular and immunological analyses. Vectors were injected to elicit immune responses against gp83 in mouse models. Our findings indicate that mice immunized with the vector Ad5-gp83 and challenged with a lethal dose of T. cruzi trypomastigotes confer strong immunoprotection with significant reduction in parasitemia levels, increased survival rate and induction of neutralizing antibodies.This data demonstrates that immunization with adenovirus containing capsid-incorporated T. cruzi antigen elicits a significant anti-gp83-specific response in two different mouse models, and protection against T. cruzi infection by eliciting neutralizing antibodies mediated by cell-mediated immune responses, as evidenced by the production of several Ig isotypes

  15. HIV gp120 binds to mannose receptor on vaginal epithelial cells and induces production of matrix metalloproteinases.

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    Sashaina E Fanibunda

    Full Text Available BACKGROUND: During sexual transmission of HIV in women, the virus breaches the multi-layered CD4 negative stratified squamous epithelial barrier of the vagina, to infect the sub-epithelial CD4 positive immune cells. However the mechanisms by which HIV gains entry into the sub-epithelial zone is hitherto unknown. We have previously reported human mannose receptor (hMR as a CD4 independent receptor playing a role in HIV transmission on human spermatozoa. The current study was undertaken to investigate the expression of hMR in vaginal epithelial cells, its HIV gp120 binding potential, affinity constants and the induction of matrix metalloproteinases (MMPs downstream of HIV gp120 binding to hMR. PRINCIPAL FINDINGS: Human vaginal epithelial cells and the immortalized vaginal epithelial cell line Vk2/E6E7 were used in this study. hMR mRNA and protein were expressed in vaginal epithelial cells and cell line, with a molecular weight of 155 kDa. HIV gp120 bound to vaginal proteins with high affinity, (Kd = 1.2±0.2 nM for vaginal cells, 1.4±0.2 nM for cell line and the hMR antagonist mannan dose dependently inhibited this binding. Both HIV gp120 binding and hMR exhibited identical patterns of localization in the epithelial cells by immunofluorescence. HIV gp120 bound to immunopurified hMR and affinity constants were 2.9±0.4 nM and 3.2±0.6 nM for vaginal cells and Vk2/E6E7 cell line respectively. HIV gp120 induced an increase in MMP-9 mRNA expression and activity by zymography, which could be inhibited by an anti-hMR antibody. CONCLUSION: hMR expressed by vaginal epithelial cells has high affinity for HIV gp120 and this binding induces production of MMPs. We propose that the induction of MMPs in response to HIV gp120 may lead to degradation of tight junction proteins and the extracellular matrix proteins in the vaginal epithelium and basement membrane, leading to weakening of the epithelial barrier; thereby facilitating transport of HIV across the

  16. Access to and utilisation of GP services among Burmese migrants in London: a cross-sectional descriptive study.

    Science.gov (United States)

    Aung, Nyein Chan; Rechel, Bernd; Odermatt, Peter

    2010-10-12

    An estimated 10,000 Burmese migrants are currently living in London. No studies have been conducted on their access to health services. Furthermore, most studies on migrants in the United Kingdom (UK) have been conducted at the point of service provision, carrying the risk of selection bias. Our cross-sectional study explored access to and utilisation of General Practice (GP) services by Burmese migrants residing in London. We used a mixed-method approach: a quantitative survey using self-administered questionnaires was complemented by qualitative in-depth interviews for developing the questionnaire and triangulating the findings of the survey. Overall, 137 questionnaires were received (a response rate of 57%) and 11 in-depth interviews conducted. The main outcome variables of the study included GP registration, barriers towards registration, GP consultations, barriers towards consultations, and knowledge on entitlements to health care. Quantitative data were analysed using descriptive statistics, association tests, and a multivariate analysis using logistic regression. The qualitative information was analysed using content analysis. The respondents were young, of roughly equal gender (51.5% female), well educated, and had a fair level of knowledge on health services in the UK. Although the GP registration rate was relatively high (80%, 109 out of 136), GP service utilisation during the last episode of illness, at 56.8% (54 out of 95), was low. The statistical analysis showed that age being younger than 35 years, lacking prior overseas experience, having an unstable immigration status, having a shorter duration of stay, and resorting to self-medication were the main barriers hindering Burmese migrants from accessing primary health care services. These findings were corroborated by the in-depth interviews. Our study found that having formal access to primary health care was not sufficient to ensure GP registration and health care utilisation. Some respondents faced

  17. Access to and utilisation of GP services among Burmese migrants in London: a cross-sectional descriptive study

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    Rechel Bernd

    2010-10-01

    Full Text Available Abstract Background An estimated 10,000 Burmese migrants are currently living in London. No studies have been conducted on their access to health services. Furthermore, most studies on migrants in the United Kingdom (UK have been conducted at the point of service provision, carrying the risk of selection bias. Our cross-sectional study explored access to and utilisation of General Practice (GP services by Burmese migrants residing in London. Methods We used a mixed-method approach: a quantitative survey using self-administered questionnaires was complemented by qualitative in-depth interviews for developing the questionnaire and triangulating the findings of the survey. Overall, 137 questionnaires were received (a response rate of 57% and 11 in-depth interviews conducted. The main outcome variables of the study included GP registration, barriers towards registration, GP consultations, barriers towards consultations, and knowledge on entitlements to health care. Quantitative data were analysed using descriptive statistics, association tests, and a multivariate analysis using logistic regression. The qualitative information was analysed using content analysis. Results The respondents were young, of roughly equal gender (51.5% female, well educated, and had a fair level of knowledge on health services in the UK. Although the GP registration rate was relatively high (80%, 109 out of 136, GP service utilisation during the last episode of illness, at 56.8% (54 out of 95, was low. The statistical analysis showed that age being younger than 35 years, lacking prior overseas experience, having an unstable immigration status, having a shorter duration of stay, and resorting to self-medication were the main barriers hindering Burmese migrants from accessing primary health care services. These findings were corroborated by the in-depth interviews. Conclusions Our study found that having formal access to primary health care was not sufficient to ensure GP

  18. Intrinsic acid-base properties of a hexa-2'-deoxynucleoside pentaphosphate, d(ApGpGpCpCpT): neighboring effects and isomeric equilibria.

    Science.gov (United States)

    Domínguez-Martín, Alicia; Johannsen, Silke; Sigel, Astrid; Operschall, Bert P; Song, Bin; Sigel, Helmut; Okruszek, Andrzej; González-Pérez, Josefa María; Niclós-Gutiérrez, Juan; Sigel, Roland K O

    2013-06-17

    The intrinsic acid-base properties of the hexa-2'-deoxynucleoside pentaphosphate, d(ApGpGpCpCpT) [=(A1∙G2∙G3∙C4∙C5∙T6)=(HNPP)⁵⁻] have been determined by ¹H NMR shift experiments. The pKa values of the individual sites of the adenosine (A), guanosine (G), cytidine (C), and thymidine (T) residues were measured in water under single-strand conditions (i.e., 10% D₂O, 47 °C, I=0.1 M, NaClO₄). These results quantify the release of H⁺ from the two (N7)H⁺ (G∙G), the two (N3)H⁺ (C∙C), and the (N1)H⁺ (A) units, as well as from the two (N1)H (G∙G) and the (N3)H (T) sites. Based on measurements with 2'-deoxynucleosides at 25 °C and 47 °C, they were transferred to pKa values valid in water at 25 °C and I=0.1 M. Intramolecular stacks between the nucleobases A1 and G2 as well as most likely also between G2 and G3 are formed. For HNPP three pKa clusters occur, that is those encompassing the pKa values of 2.44, 2.97, and 3.71 of G2(N7)H⁺, G3(N7)H⁺, and A1(N1)H⁺, respectively, with overlapping buffer regions. The tautomer populations were estimated, giving for the release of a single proton from five-fold protonated H₅(HNPP)(±) , the tautomers (G2)N7, (G3)N7, and (A1)N1 with formation degrees of about 74, 22, and 4%, respectively. Tautomer distributions reveal pathways for proton-donating as well as for proton-accepting reactions both being expected to be fast and to occur practically at no "cost". The eight pKa values for H₅(HNPP)(±) are compared with data for nucleosides and nucleotides, revealing that the nucleoside residues are in part affected very differently by their neighbors. In addition, the intrinsic acidity constants for the RNA derivative r(A1∙G2∙G3∙C4∙C5∙U6), where U=uridine, were calculated. Finally, the effect of metal ions on the pKa values of nucleobase sites is briefly discussed because in this way deprotonation reactions can easily be shifted to the physiological pH range. Copyright © 2013 WILEY

  19. Molecular characterization of Cryptosporidium parvum and Cryptosporidium hominis GP60 subtypes worldwide

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    Catalina Avendaño V

    2017-09-01

    Full Text Available Cryptosporidium is a zoonotic parasite very important in animal health as well as in public health. It is because this is one of the main causes of diarrhea in children, calves, lambs and other variety of youth mammalians in a lot of countries. The globalization has enabled the exchange of biological material in different regions worldwide, encouraging the spread of diseases and exposure to these biological agents to different environmental conditions, inducing adaptation through genetic changes. Based in the polymorphism of the gene for GP60, this review intended to present the distribution of Cryptosporidium parvum and Cryptosporidium hominis in humans and calves worldwide. The subtype that affects cattle more frequently corresponds to IIaA15G2R; while the subtype most frequently isolated from human samples is IaA19G2.

  20. Evidence for CNO processed material in the accretion disk of GP Comae

    International Nuclear Information System (INIS)

    Marsh, T.R.; Horne, K.; Rosen, S.

    1991-01-01

    NIR spectroscopic observations of GP Com are reported. Data obtained using the 2.5-m Isaac Newton Telescope and the 4.2-m William Herschel Telescope at La Palma during April and June 1988 and with the 5-m Hale reflector at Palomar Observatory during January 1983 are presented in tables and sample spectra and discussed in detail. Number ratios H/He less than 0.00001, N/O = about 50, and N/C greater than 100 are calculated under the assumption of a uniform optically thin slab of gas in LTE. From the N overabundance it is inferred that the material observed is being extracted by Roche-lobe overflow from the secondary's H-exhausted core, at a time after most C and O have been converted to N in the CNO cycle. 33 refs

  1. Derivative Trade Optimizing Model Utilizing GP Based on Behavioral Finance Theory

    Science.gov (United States)

    Matsumura, Koki; Kawamoto, Masaru

    This paper proposed a new technique which makes the strategy trees for the derivative (option) trading investment decision based on the behavioral finance theory and optimizes it using evolutionary computation, in order to achieve high profitability. The strategy tree uses a technical analysis based on a statistical, experienced technique for the investment decision. The trading model is represented by various technical indexes, and the strategy tree is optimized by the genetic programming(GP) which is one of the evolutionary computations. Moreover, this paper proposed a method using the prospect theory based on the behavioral finance theory to set psychological bias for profit and deficit and attempted to select the appropriate strike price of option for the higher investment efficiency. As a result, this technique produced a good result and found the effectiveness of this trading model by the optimized dealings strategy.

  2. Direct demonstration of the lectin activity of gp90MEL, a lymphocyte homing receptor

    Science.gov (United States)

    1990-01-01

    Considerable evidence implicates gp90MEL as a lymphocyte homing receptor mediating lymphocyte attachment to high endothelial venules of lymph nodes in mouse. The protein appears to function as a calcium- dependent, lectin-like receptor as inferred primarily by the ability of specific carbohydrates to block its function and by the presence of a calcium-type lectin domain in its primary sequence. An ELISA assay is described which provides the first demonstration that the isolated protein has lectin activity and allows a further definition of its carbohydrate specificity. In addition to the monosaccharides mannose-6- phosphate and fructose-1-phosphate, ligand activity is shown for the sulfated glycolipid, sulfatide, and for two sulfated fucose-containing polysaccharides (fucoidin and egg jelly coat) from nonmammalian sources. PMID:2202735

  3. Elimination of ion losses in the EhGP-10-1 charge-exchange accelerator

    International Nuclear Information System (INIS)

    Fridrikh, M.

    1986-01-01

    To improve the ion transit factor in the EhGP-10-1 charge-exchange accelerator the injector ion-optical properties are studied. The injector operates at constant high voltage U a -23 kV. Using an immersion lens the negative ion energy before entering the accelerating tube is increased up to energy proportional to the conductor voltage. A single electrostatic lens provides a cross-over in the vicinity of immersion lens. By reducing the electric field gradient at the accelerating tube inlet, optimizing input electrode voltage and shifting the single lens by 0.26 m towards the accelerating tube inlet almost full beam transit is attained at all conductor voltages

  4. No impact on P-gp level in radio-resistant Mcf-7 cells

    International Nuclear Information System (INIS)

    Madhu, L.N.; Rao, Shama; Sarojini, B.K.

    2016-01-01

    Cancer has become the leading cause of human death worldwide. One possible cause for therapeutic failure is that residual tumor cells are reminiscent of stem cells, which ultimately give rise to secondary tumors or distant metastasis. The property of resistance to radiation therapy or chemotherapy might be the major clinical criterion to characterize 'cancer stem cells (CSCs)'. In the process of radiotherapy, the radiosensitive cancer will become a radioresistant one. Such radio-resistance cells might also show the characters of multi drug resistance (MRD) properties which may affect the chemotherapy process. The present study was carried out to know the expression level of P-gp, a MRD protein in radioresistance breast cancer cells. The study conducted by exposing the MCF-7 cells to 4Gy of gamma radiation

  5. Payment mechanism and GP self-selection: capitation versus fee for service.

    Science.gov (United States)

    Allard, Marie; Jelovac, Izabela; Léger, Pierre-Thomas

    2014-06-01

    This paper analyzes the consequences of allowing gatekeeping general practitioners (GPs) to select their payment mechanism. We model GPs' behavior under the most common payment schemes (capitation and fee for service) and when GPs can select one among them. Our analysis considers GP heterogeneity in terms of both ability and concern for their patients' health. We show that when the costs of wasteful referrals to costly specialized care are relatively high, fee for service payments are optimal to maximize the expected patients' health net of treatment costs. Conversely, when the losses associated with failed referrals of severely ill patients are relatively high, we show that either GPs' self-selection of a payment form or capitation is optimal. Last, we extend our analysis to endogenous effort and to competition among GPs. In both cases, we show that self-selection is never optimal.

  6. Functional, non-clonal IgMa-restricted B cell receptor interactions with the HIV-1 envelope gp41 membrane proximal external region.

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    Laurent Verkoczy

    Full Text Available The membrane proximal external region (MPER of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specific broadly neutralizing antibodies like 2F5 and 4E10 is due to structural constraints with the gp41 MPER, or alternatively, if gp41 MPER epitope-specific B cells are lost to immunological tolerance. An equally important question is how B cells interact with, and respond to, the gp41 MPER epitope, including whether they engage this epitope in a non-canonical manner i.e., by non-paratopic recognition via B cell receptors (BCR. To begin understanding how B cells engage the gp41 MPER, we characterized B cell-gp41 MPER interactions in BALB/c and C57BL/6 mice. Surprisingly, we found that a significant (approximately 7% fraction of splenic B cells from BALB/c, but not C57BL/6 mice, bound the gp41 MPER via their BCRs. This strain-specific binding was concentrated in IgM(hi subsets, including marginal zone and peritoneal B1 B cells, and correlated with enriched fractions (approximately 15% of gp41 MPER-specific IgM secreted by in vitro-activated splenic B cells. Analysis of Igh(a (BALB/c and Igh(b (C57BL/6 congenic mice demonstrated that gp41 MPER binding was controlled by determinants of the Igh(a locus. Mapping of MPER gp41 interactions with IgM(a identified MPER residues distinct from those to which mAb 2F5 binds and demonstrated the requirement of Fc C(H regions. Importantly, gp41 MPER ligation produced detectable BCR-proximal signaling events, suggesting that interactions between gp41 MPER and IgM(a determinants may elicit partial B cell activation. These data suggest that low avidity, non-paratopic interactions between the gp41 MPER and membrane Ig on naïve B cells may interfere with or divert bnAb responses.

  7. Fitting the elementary rate constants of the P-gp transporter network in the hMDR1-MDCK confluent cell monolayer using a particle swarm algorithm.

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    Deep Agnani

    Full Text Available P-glycoprotein, a human multidrug resistance transporter, has been extensively studied due to its importance to human health and disease. In order to understand transport kinetics via P-gp, confluent cell monolayers overexpressing P-gp are widely used. The purpose of this study is to obtain the mass action elementary rate constants for P-gp's transport and to functionally characterize members of P-gp's network, i.e., other transporters that transport P-gp substrates in hMDR1-MDCKII confluent cell monolayers and are essential to the net substrate flux. Transport of a range of concentrations of amprenavir, loperamide, quinidine and digoxin across the confluent monolayer of cells was measured in both directions, apical to basolateral and basolateral to apical. We developed a global optimization algorithm using the Particle Swarm method that can simultaneously fit all datasets to yield accurate and exhaustive fits of these elementary rate constants. The statistical sensitivity of the fitted values was determined by using 24 identical replicate fits, yielding simple averages and standard deviations for all of the kinetic parameters, including the efflux active P-gp surface density. Digoxin required additional basolateral and apical transporters, while loperamide required just a basolateral tranporter. The data were better fit by assuming bidirectional transporters, rather than active importers, suggesting that they are not MRP or active OATP transporters. The P-gp efflux rate constants for quinidine and digoxin were about 3-fold smaller than reported ATP hydrolysis rate constants from P-gp proteoliposomes. This suggests a roughly 3∶1 stoichiometry between ATP hydrolysis and P-gp transport for these two drugs. The fitted values of the elementary rate constants for these P-gp substrates support the hypotheses that the selective pressures on P-gp are to maintain a broad substrate range and to keep xenobiotics out of the cytosol, but not out of the

  8. Fangchinoline inhibits human immunodeficiency virus type 1 replication by interfering with gp160 proteolytic processing.

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    Zhitao Wan

    Full Text Available The introduction of highly active antiretroviral therapy has led to a significant reduction in the morbidity and mortality of acquired immunodeficiency syndrome patients. However, the emergence of drug resistance has resulted in the failure of treatments in large numbers of patients and thus necessitates the development of new classes of anti-HIV drugs. In this study, more than 200 plant-derived small-molecule compounds were evaluated in a cell-based HIV-1 antiviral screen, resulting in the identification of a novel HIV-1 inhibitor (fangchinoline. Fangchinoline, a bisbenzylisoquinoline alkaloid isolated from Radix Stephaniae tetrandrae, exhibited antiviral activity against HIV-1 laboratory strains NL4-3, LAI and BaL in MT-4 and PM1 cells with a 50% effective concentration ranging from 0.8 to 1.7 µM. Mechanism-of-action studies showed that fangchinoline did not exhibit measurable antiviral activity in TZM-b1 cells but did inhibit the production of infectious virions in HIV-1 cDNA transfected 293T cells, which suggests that the compound targets a late event in infection cycle. Furthermore, the antiviral effect of fangchinoline seems to be HIV-1 envelope-dependent, as the production of infectious HIV-1 particles packaged with a heterologous envelope, the vesicular stomatitis virus G glycoprotein, was unaffected by fangchinoline. Western blot analysis of HIV envelope proteins expressed in transfected 293T cells and in isolated virions showed that fangchinoline inhibited HIV-1 gp160 processing, resulting in reduced envelope glycoprotein incorporation into nascent virions. Collectively, our results demonstrate that fangchinoline inhibits HIV-1 replication by interfering with gp160 proteolytic processing. Fangchinoline may serve as a starting point for developing a new HIV-1 therapeutic approach.

  9. Work-family balance by women GP specialist trainees in Slovenia: a qualitative study.

    Science.gov (United States)

    Petek, Davorina; Gajsek, Tadeja; Petek Ster, Marija

    2016-01-28

    Women physicians face many challenges while balancing their many roles: doctor, specialist trainee, mother and partner. The most opportune biological time for a woman to start a family coincides with a great deal of demands and requirements at work. In this study we explored the options and capabilities of women GP specialist trainees in coordinating their family and career. This is a phenomenological qualitative research. Ten GP specialist trainees from urban and rural areas were chosen by the purposive sampling technique, and semi-structured in-depth interviews were conducted, recorded, transcribed and analysed by using thematic analysis process. Open coding and the book of codes were formed. Finally, we performed the process of code reduction by identifying the themes, which were compared, interpreted and organised in the highest analytical units--categories. One hundred fifty-five codes were identified in the analysis, which were grouped together into eleven themes. The identified themes are: types, causes and consequences of burdens, work as pleasure and positive attitude toward self, priorities, planning and help, and understanding of superiors, disburdening and changing in specialisation. The themes were grouped into four large categories: burdens, empowerment, coordination and needs for improvement. Women specialist trainees encounter intense burdens at work and home due to numerous demands and requirements during their specialisation training. In addition, there is also the issue of the work-family conflict. There are many consequences regarding burden and strain; however, burnout stands out the most. In contrast, reconciliation of work and family life and needs can be successful. The key element is empowerment of women doctors. The foremost necessary systemic solution is the reinforcement of general practitioners in primary health care and their understanding of the specialisation training scheme with more flexible possibilities for time adaptations of

  10. GP obstetricians' views of the model of maternity care in New Zealand.

    Science.gov (United States)

    Miller, Dawn L; Mason, Zara; Jaye, Chrystal

    2013-02-01

    The Lead Maternity Carer (LMC) model of maternity care, and independent midwifery practice, was introduced to New Zealand in the 1990s. The LMC midwife or general practitioner obstetrician (GPO) has clinical and budgetary responsibility for women's primary maternity care. To determine views of practising GPOs and former GPOs about the LMC model of care, its impact on maternity care in general practice, and future of maternity care in general practice. 10 GPOs and 13 former GPOs were interviewed: one focus group (n = 3), 20 semi-structured interviews. The qualitative data analysis program ATLAS.ti assisted thematic analysis. Participants thought the LMC model isolates the LMC - particularly concerning during intrapartum care, in rural practice, and covering 24-hour call; Is not compatible with or adequately funded for GP participation; Excludes the GP from caring for their pregnant patients. Participants would like a flexible, locally adaptable, adequately funded maternity model, supporting shared care. Some thought work-life balance and low GPO numbers could deter future GPs from maternity practice. Others felt with political will, support of universities, and Royal New Zealand College of General Practice and Royal Australian and New Zealand College of Obstetrics and Gynaecology, GPs could become more involved in maternity care again. Participants thought the LMC model isolates maternity practitioners, is incompatible with general practice and causes loss of continuity of general practice care. They support provision of maternity care in general practice; however, for more GPs to become involved, the LMC model needs review. © 2013 The Authors ANZJOG © 2012 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

  11. GP views on strategies to cope with increasing workload: a qualitative interview study.

    Science.gov (United States)

    Fisher, Rebecca Fr; Croxson, Caroline Hd; Ashdown, Helen F; Hobbs, Fd Richard

    2017-02-01

    The existence of a crisis in primary care in the UK is in little doubt. GP morale and job satisfaction are low, and workload is increasing. In this challenging context, finding ways for GPs to manage that workload is imperative. To explore what existing or potential strategies are described by GPs for dealing with their workload, and their views on the relative merits of each. Semi-structured, qualitative interviews with GPs working within NHS England. All GPs working within NHS England were eligible. Of those who responded to advertisements, a maximum-variation sample was selected and interviewed until data saturation was reached. Data were analysed thematically. Responses were received from 171 GPs, and, from these, 34 were included in the study. Four main themes emerged for workload management: patient-level, GP-level, practice-level, and systems-level strategies. A need for patients to take greater responsibility for self-management was clear, but many felt that GPs should not be responsible for this education. Increased delegation of tasks was felt to be key to managing workload, with innovative use of allied healthcare professionals and extended roles for non-clinical staff suggested. Telephone triage was a commonly used tool for managing workload, although not all participants found this helpful. This in-depth qualitative study demonstrates an encouraging resilience among GPs. They are proactively trying to manage workload, often using innovative local strategies. GPs do not feel that they can do this alone, however, and called repeatedly for increased recruitment and more investment in primary care. © British Journal of General Practice 2017.

  12. Training in hospitals: what do GP specialist trainees think of workplace-based assessments?

    Science.gov (United States)

    Sabey, Abigail; Harris, Michael

    2011-03-01

    Workplace-based assessment (WBPA) was introduced in 2007 as a new approach to monitoring competence of GP specialist trainees (GPSTs). It includes a raft of assessments carried out in the workplace to assess what a trainee actually does in clinical practice. The assessment tools used are adapted from other contexts of doctors' training but little is known about how they function in day-to-day practice within GP training or how valid and useful they are found to be by trainees. To establish how the new system of WPBA is working in day-to-day practice for GPSTs in hospital posts. A mixed methods design including quantitative and qualitative phases of data collection. Two training locations within Severn Deanery. A questionnaire was completed by 52 GPSTs (67% response rate) currently in hospital posts. Twenty-two took part in focus groups and semi-structured interviews to explore key findings from the questionnaire in greater depth. There is value in the face-to-face contact between trainees and senior doctors. However, quality and depth of feedback are not consistent and there is evidence of poor use of the tools, reducing the value of the assessments. The system is further undermined by a clear perception of bias and lack of honesty in judgements which limit the scope for assessment to lead to learning. Overall, these weaknesses may impair the validity and usefulness of the system and its potential to improve the performance of doctors. General practice trainees in this study have a low opinion of how WPBA assessments function in the hospital setting. Changes are needed to optimise the potential of WPBA to improve the performance of doctors in training and to increase its credibility.

  13. Binding of recombinant HIV coat protein gp120 to human monocytes

    International Nuclear Information System (INIS)

    Finbloom, D.S.; Hoover, D.L.; Meltzer, M.S.

    1991-01-01

    Inasmuch as the exact level of CD4 Ag expression on macrophages is controversial and because HIV may interact with macrophages in a manner different from that on T cells, we analyzed the binding of gp120 to freshly isolated and cultured monocytes. rgp120 was iodinated using the lactoperoxidase method to a sp. act. of 600 Ci/mmol. Highly purified monocytes (greater than 90%) were isolated from the leukapheresed blood of normal volunteers by Ficoll-Hypaque sedimentation followed by countercurrent centrifugal elutriation and cultured 7 days in DMEM supplemented with 1000 U/ml macrophage CSF in 10% human serum. Whereas MOLT/4 cells consistently bound freshly prepared 125I-rgp120 at 80% specificity with 5100 +/- 700 mol/cell, MCSF cultured monocytes bound rgp120 at only 0 to 20% specificity and 420 +/- 200 mol/cell. Most of the radioactivity bound by these cells could not be blocked by the addition of unlabeled rgp120. In contrast, the U937 myeloid cell line bound rgp120 with 50% specificity and about 2500 mol/cell. Whereas the antibody OKT4a (anti-CD4) blocked 80% of the binding on MOLT/4 cells and 50% on U937 cells, binding was only inhibited on the average of 6% on cultured monocytes. When soluble rCD4 was used as an inhibitor, binding to MOLT/4 cells was blocked by 80%. In contrast, binding to cultured monocytes was inhibited by 28%. HIV infectivity was blocked by similar concentrations of OKT4a. These observations suggest that although most binding of gp120 to cultured monocytes is not to the CD4 determinant, several hundred molecules do bind to a CD4-like molecule which promotes virus entry and replication

  14. Gadolinium deposition in the brain: association with various GBCAs using a generalized additive model

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Sohi; Lee, Ho-Joon; Han, Kyunghwa; Park, Yae-Won; Choi, Yoon Seong; Ahn, Sung Soo; Kim, Jinna; Lee, Seung-Koo [Yonsei University College of Medicine, Department of Radiology, Severance Hospital, Research Institute of Radiological Science, Seoul (Korea, Republic of)

    2017-08-15

    To determine the relationship between the number of administrations of various gadolinium-based contrast agents (GBCAs) and increased T1 signal intensity in the globus pallidus (GP) and dentate nucleus (DN). This retrospective study included 122 patients who underwent double-dose GBCA-enhanced magnetic resonance imaging. Two radiologists calculated GP-to-thalamus (TH) signal intensity ratio, DN-to-pons signal intensity ratio and relative change (R{sub change}) between the baseline and final examinations. Interobserver agreement was evaluated. The relationships between R{sub change} and several factors, including number of each GBCA administrations, were analysed using a generalized additive model. Six patients (4.9%) received linear GBCAs (mean 20.8 number of administration; range 15-30), 44 patients (36.1%) received macrocyclic GBCAs (mean 26.1; range 14-51) and 72 patients (59.0%) received both types of GBCAs (mean 31.5; range 12-65). Interobserver agreement was almost perfect (0.99; 95% CI: 0.99-0.99). R{sub change} (DN:pons) was associated with gadodiamide (p = 0.006) and gadopentetate dimeglumine (p < 0.001), but not with other GBCAs. R{sub change} (GP:TH) was not associated with GBCA administration. Previous administration of linear agents gadoiamide and gadopentetate dimeglumine is associated with increased T1 signal intensity in the DN, whereas macrocyclic GBCAs do not show an association. (orig.)

  15. Optogenetic Activation of the Sensorimotor Cortex Reveals "Local Inhibitory and Global Excitatory" Inputs to the Basal Ganglia.

    Science.gov (United States)

    Ozaki, Mitsunori; Sano, Hiromi; Sato, Shigeki; Ogura, Mitsuhiro; Mushiake, Hajime; Chiken, Satomi; Nakao, Naoyuki; Nambu, Atsushi

    2017-12-01

    To understand how information from different cortical areas is integrated and processed through the cortico-basal ganglia pathways, we used optogenetics to systematically stimulate the sensorimotor cortex and examined basal ganglia activity. We utilized Thy1-ChR2-YFP transgenic mice, in which channelrhodopsin 2 is robustly expressed in layer V pyramidal neurons. We applied light spots to the sensorimotor cortex in a grid pattern and examined neuronal responses in the globus pallidus (GP) and entopeduncular nucleus (EPN), which are the relay and output nuclei of the basal ganglia, respectively. Light stimulation typically induced a triphasic response composed of early excitation, inhibition, and late excitation in GP/EPN neurons. Other response patterns lacking 1 or 2 of the components were also observed. The distribution of the cortical sites whose stimulation induced a triphasic response was confined, whereas stimulation of the large surrounding areas induced early and late excitation without inhibition. Our results suggest that cortical inputs to the GP/EPN are organized in a "local inhibitory and global excitatory" manner. Such organization seems to be the neuronal basis for information processing through the cortico-basal ganglia pathways, that is, releasing and terminating necessary information at an appropriate timing, while simultaneously suppressing other unnecessary information. © The Author 2017. Published by Oxford University Press.

  16. Study of MRI characteristics of newborn bilirubin encephalopathy

    International Nuclear Information System (INIS)

    Wu Wulin; Wang Xiaoyi; Liao Weihua; Liu Fan; Zhang Ping

    2008-01-01

    Objective: To explore routine magnetic resonance imaging characteristics of newborn bilirubin encephalopathy (NBE). Methods: MRI features and clinical data of 17 patients with Newborn bilirubin encephalopathy were retrospectively analyzed, globus pallidus (GP)and subthalamic signal intensity was evaluated. The increase of GP signal intensity and serum total bilirubin peak value were analyzed using pearson correlation analysis. Serum total bilirubin peak value between patients with high signal in the subthalamic nuclei on T 1 WI and patients without high signal in the subthalamic nuclei were compared statistically. Results: The main MRI presentation in the NBE group was abnormally increased signal intensity in the GP on T 1 WI, which was not apparent on T 2 WI. One patient showed abnormal high signal intensity in the posteromedial part of GP. Nine patients had high signal in the subthalamic nuclei on T 1 WI and normal signal on T 2 WI. Four patients showed high signal in the brainstem with sparing of dorsal pontine. The increase in value of GP signal intensity was 249.0-423.8 in 12 patients and their serum total bilirubin peak values were 366.0-983.3 μmol/L. A positive correlation was found between increase of GP signal intensity and serum total bilirubin peak value. The serum total bilirubin level of abnormal subthalamic group and normal subthalamic group were 660.7±192.4 μmol/L and 513.3±107.51 μmol/L respectively. The difference between the two groups was not statistically significant (t=1.914, P>0.05). Conclusion: The routine MRI has some characteristics and is useful in the diagnosis of newborn bilirubin encephalopathy. (authors)

  17. The process behind the expression of mdr-1/P-gp and mrp/MRP in human leukemia/lymphoma.

    Science.gov (United States)

    Hirose, Masao

    2009-04-01

    There is a controversy over the link between phenotypes of multidrug resistance (MDR) and clinical outcome in leukemia/lymphoma patients. This may be because the process behind the induction and loss of expression of genotypes and phenotypes by which MDR develops and the role of MDR in fresh cells of human leukemia/lymphoma are not clearly defined. P-glycoprotein (P-gp) increased and decreased along with mdr-1 expression in three cell lines out of five vincristine (VCR)-resistant cell lines. MRP appeared with increased mrp expression in the other two cell lines. After the drug was removed from the culture system, mdr-1/P-gp changed in parallel with the level of VCR resistance, although mrp and MRP did not. It was concluded that P-gp is directly derived from mdr-1 and that mdr-1/P-gp supports the VCR-resistance but mrp/MRP is not directly linked to the VCR-resistance. These results should contribute to a better understanding of MDR phenomenon in cancer.

  18. A monocyte chemotaxis inhibiting factor in serum of HIV infected men shares epitopes with the HIV transmembrane protein gp41

    NARCIS (Netherlands)

    Tas, M.; Drexhage, H. A.; Goudsmit, J.

    1988-01-01

    This report describes that gp41, the transmembranous envelope protein of HIV, is able to inhibit monocyte chemotaxis (measured as FMLP-induced polarization). To study the presence of such immunosuppressive HIV env proteins in the circulation of HIV-infected men, fractions were prepared from serum

  19. Salivary agglutinin, which binds Streptococcus mutans and Helicobacter pylori, is the lung scavenger receptor cysteine-rich protein gp-340.

    Science.gov (United States)

    Prakobphol, A; Xu, F; Hoang, V M; Larsson, T; Bergstrom, J; Johansson, I; Frängsmyr, L; Holmskov, U; Leffler, H; Nilsson, C; Borén, T; Wright, J R; Strömberg, N; Fisher, S J

    2000-12-22

    Salivary agglutinin is a high molecular mass component of human saliva that binds Streptococcus mut