Triplex Operation for Children with Extrahepatic Portal Hypertension

Journal of Pediatric Surgery. Apr, 2002  |  Pubmed ID: 11912519

How to deal with the vexatious problem of esophageal and gastric varices secondary to extrahepatic portal hypertension has been discussed extensively among pediatric surgeons around the world. The aim of this study is to evaluate the effect of triplex operation (splenopneumopexy, portal azygous devascularization, and ligation of splenic artery) for children with portal hypertension in the author's hospital.

Tissue Reaction to Polypyrrole-coated Polyester Fabrics: an in Vivo Study in Rats

Tissue Engineering. Aug, 2002  |  Pubmed ID: 12202003

Electrically conductive polypyrrole is very attractive for tissue engineering because of its potential to modulate cellular activities through electrical stimulation. However, its in vivo behaviors have not been fully studied. This paper investigates the in vivo biocompatibility and biostability of PPy-coated polyester fabrics. Three PPy-coated fabrics were prepared using phosphonylation (PPy-Phos), plasma activation (PPy-Plas), and plasma activation plus heparin treatment (PPy-Plas-HE). Virgin and fluoropassivated fabrics (F-PET) were controls. The specimens were implanted subcutaneously in the back of rats for 3-90 days, then harvested and processed for enzymatic, histological, and morphological analyses. A noninvasive MRI method was used to continuously monitor the inflammation. The level of acid and alkaline phosphatase showed a similar or a less intensive cellular reaction by the PPy-coated fabrics, when compared to the controls. Histology supported the enzymatic results and showed a fast collagen infiltration at 28 days for the PPy-Phos fabric. MRI reported an overall decrease of inflammation over time, with the PPy-coated fabrics showing a similar or mild inflammation in contrast to the non-coated fabrics. PPy clusters and excessive PPy laminary coating on the PPy-Plas and PPy-Plas-HE were lost with the implantation. This experiment suggests a similar in vivo biocompatibility of the PPy-coated and noncoated polyester fabrics and the importance of achieving a thin, uniform PPy coating.

Biostability of Electrically Conductive Polyester Fabrics: an in Vitro Study

Journal of Biomedical Materials Research. Dec, 2002  |  Pubmed ID: 12221698

The biostability of a series of polypyrrole (PPy)-coated polyester fabrics was investigated in an in vitro model. PPy-coated sample fabrics were incubated in saline at 37 degrees C for 1 and 2 weeks. After each period of incubation, the surface electrical resistivity of the sample fabrics was measured to monitor the changes caused by the incubation. Redoping was then performed by immersing the sample fabrics in a 1N HCl solution at room temperature for 30 min, which was followed by another measurement of the surface resistivity. The surface morphology of the sample fabrics was observed by scanning electron microscopy. The surface chemical composition of the fabrics and the oxidation of nitrogen in PPy were measured with X-ray photoelectron spectroscopy. The surface electrical resistivity of the PPy-coated fabrics was found to increase with the progress of incubation, which was mainly caused by dedoping and uptake of oxygen. This increase was nonlinear and accelerated with time. The surface resistivity of most of the samples was retained in the range of 10(3)-10(4) Omega/square after 1 week of incubation, which was considered suitable for short-term electrical stimulation applications. Physical deterioration represented by the cracking and delamination of the PPy coating was occasionally observed on the sample fabrics showing the most significant increase of resistivity. Further improvement of the stability of conductivity is highly desirable.

Muscimol Prevents NMDA Antagonist Neurotoxicity by Activating GABAA Receptors in Several Brain Regions

Brain Research. Dec, 2003  |  Pubmed ID: 14642834

N-Methyl-D-aspartate (NMDA) glutamate receptor antagonists are being developed as therapeutic agents for several clinical conditions. However, the ability of these agents to produce neurotoxicity and psychosis can compromise their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state may play a role in neurodegenerative and psychotic disorders. A better understanding of the mechanism underlying these adverse effects should allow for the safer use of these agents and might clarify mechanisms underlying certain clinical disorders. NRHypo neurotoxicity is mediated by a complex disinhibition mechanism in which NMDA antagonists abolish GABAergic inhibition, resulting in the simultaneous excessive release of acetylcholine and glutamate onto the vulnerable retrosplenial cortex (RSC) neurons. Systemically administered GABAergic agents are potent protectors against NRHypo neurotoxicity. To determine where in brain GABAergic agents could be acting to protect against NRHypo neurotoxicity, we injected the GABAergic agonist, muscimol, into different brain regions of rats treated systemically with a neurotoxic dose of the potent NMDA antagonist, MK-801. We report that muscimol injections into the anterior thalamus or diagonal band of Broca provide substantial protection, suggesting that disinhibition of neurons in these regions underlies NRHypo neurotoxicity. Muscimol injections into the RSC also provide substantial protection possibly by directly inhibiting the vulnerable RSC neuron. Injections of muscimol into other areas known to project to the RSC (ventral orbital cortex, anterior cingulate cortex and subiculum) provide only minimal protection. We conclude that GABAergic agents prevent NRHypo neurotoxicity mainly by activating GABA receptors in the anterior thalamus, diagonal band of Broca and RSC.

In the Adult CNS, Ethanol Prevents Rather Than Produces NMDA Antagonist-induced Neurotoxicity

Brain Research. Nov, 2004  |  Pubmed ID: 15518643

Single doses of an NMDA antagonist cause an adult or a prepubertal form of neurodegeneration, depending on the age of the animal. Single doses of ethanol (EtOH) by blocking NMDA receptors produce apoptotic neurodegeneration in young animals. This capability could account, in part, for the ability of EtOH to produce the fetal alcohol syndrome. We investigated whether EtOH could produce NMDA antagonist-induced neurotoxicity (NAN), a different neurotoxicity that is seen only in adult animals. In spite of producing blood EtOH levels (30 to 600 mg/dl) known to block NMDA receptors, EtOH was unable to produce neurotoxicity in the adult central nervous system (CNS). Moreover, EtOH in a dose-dependent fashion (ED(50)=138 mg/dl) prevented the selective and powerful NMDA antagonist, MK-801, from producing NAN in adult animals, suggesting that activity at another site might be negating the neurotoxic effect of EtOH's inherent NMDA antagonistic activity. Because GABA(A) agonism and non-NMDA glutamate antagonism, properties which EtOH possesses, can prevent NAN, we proceeded to study whether GABA(A) antagonists (or agents capable of reversing EtOH's GABAergic effects) and non-NMDA agonists could reverse EtOH's protective effect. Bicuculline, Ro15-4513, finasteride, kainic acid or AMPA, alone or in combination, did not significantly reverse EtOH's protective effect. Given that EtOH has effects on a wide range of ion channels and receptors, determining the precise mechanism of EtOH's protective effect will take additional effort. The inability of EtOH to acutely produce NAN in the adult CNS indicates that, in contrast to fetuses, brief exposure of the adult CNS to EtOH is non-toxic for neurons.

[Determination of Transition Metals in Environmental Water Samples by Low Pressure Ion Chromatography]

Se Pu = Chinese Journal of Chromatography / Zhongguo Hua Xue Hui. Sep, 2004  |  Pubmed ID: 15706958

Action Potential Fidelity During Normal and Epileptiform Activity in Paired Soma-axon Recordings from Rat Hippocampus

The Journal of Physiology. Jul, 2005  |  Pubmed ID: 15890699

Although action potential initiation and propagation are fundamental to nervous system function, there are few direct electrophysiological observations of propagating action potentials in small unmyelinated fibres, such as the axons within mammalian hippocampus. To circumvent limitations of previous studies that relied on extracellular stimulation, we performed dual recordings: whole-cell recordings from hippocampal CA3 pyramidal cell somas and extracellular recordings from their axons, up to 800 micro m away. During brief spike trains under normal conditions, axonal spikes were more resistant to amplitude reduction than somatic spikes. Axonal amplitude depression was greatest at the axon initial segment < 150 microm from the soma, and initiation occurred approximately 75 microm from the soma. Although prior studies, which failed to verify spike initiation, suggested substantial axonal depression during seizure-associated extracellular K+([K+]o) rises, we found that 8 mm [K+]o caused relatively small decreases in axonal spike amplitude during brief spike trains. However, during sustained, epileptiform spiking induced in 8 mm [K+]o, axonal waveforms decreased significantly in peak amplitude. During epileptiform spiking, bursts of two or more action potentials > 20 Hz failed to propagate in most cases. In normal [K+]o at 25 and 32 degrees C, spiking superimposed on sustained somatic depolarization, but not spiking alone, produced similar axonal changes as the epileptiform activity. These results highlight the likely importance of steady-state inactivation of axonal channels in maintaining action potential fidelity. Such changes in axonal propagation properties could encode information and/or serve as an endogenous brake on seizure propagation.

Physiological Activity Depresses Synaptic Function Through an Effect on Vesicle Priming

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Jun, 2006  |  Pubmed ID: 16775150

Neurons engage compensatory, homeostatic synaptic changes to maintain their overall firing rate. We examined the induction and expression of a persistent presynaptic adaptation. We explored the effect of mild extracellular potassium elevation to increase hippocampal pyramidal neuron spiking over a physiological range. With several days of mild depolarization, glutamate release adapted, as revealed by an increased mismatch between the number of active, FM1-43-positive, glutamatergic synapses and the total number of synapses defined by vesicular glutamate transporter-1 antibody staining. Surprisingly, the adaptation of glutamate terminals was all-or-none; recycling vesicle pool size at remaining active synapses was not significantly altered by the adaptation. Tetrodotoxin (TTX), but not postsynaptic receptor blockade, reversed depolarization-induced adaptation, and TTX added to normal incubation medium increased the number of active synapses, suggesting that normal spiking activity sustains a steady-state percentage of inactive terminals. Chronic mild depolarization depressed EPSCs and decreased the size of the readily releasable pool of vesicles (RRP). Several hours of 10 Hz electrical stimulation also depressed the RRP size, confirming that spiking alone induces adaptation and that strong stimulation induces more rapid presynaptic adaptation. Despite the importance of RRP alteration to the adaptation, ultrastructural experiments revealed no changes in docked or total synaptic vesicle numbers. Furthermore, alpha-latrotoxin induced vesicle release at adapted synapses, consistent with the idea that adaptation resulted from changes in vesicle priming. These results show that glutamatergic neurotransmission persistently adapts to changes in electrical activity over a wide physiological range.

Topotecan in Combination with Cisplatin for the Treatment of Stage IVB, Recurrent, or Persistent Cervical Cancer

Oncology (Williston Park, N.Y.). Oct, 2006  |  Pubmed ID: 17112001

Topotecan, a camptothecin analog previously approved for the treatment of ovarian cancer and small-cell lung cancer, was granted regular approval by the US Food and Drug Administration (FDA) on June 14, 2006, for use in combination with cisplatin to treat women with stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The purpose of this summary is to review the database supporting this approval.

Vesicle Pool Heterogeneity at Hippocampal Glutamate and GABA Synapses

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Sep, 2007  |  Pubmed ID: 17855599

Glutamate and GABA are the major fast excitatory and inhibitory neurotransmitters, respectively, in the CNS. Although glutamate and GABA have clearly distinct postsynaptic actions, we are just beginning to appreciate that presynaptic differences between glutamatergic and GABAergic neurons may contribute to distinct functions of these transmitter systems. We therefore probed possible differences between the functional synaptic vesicle populations of glutamatergic and GABAergic neurons. We examined superecliptic synaptopHluorin (SpH) fluorescence during 20 Hz electrical stimulation in transfected hippocampal neurons and identified the phenotype of SpH-fluorescent synapses with post hoc immunostaining. With 200 stimuli (10 s), individual glutamate synapses displayed considerably more variability in peak SpH fluorescence than GABA synapses, without a strong difference in the mean SpH fluorescence increase. This spatial heterogeneity could not be accounted for by differences in endocytosis, which was nearly constant over these short time periods across glutamate and GABA synapses. Instead, variability in vesicle exocytosis correlated with variability in total vesicle staining and in measures of the total recycling pool size. Differences were also evident using FM1-43 [N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide] uptake. These data support the idea that the population of glutamate synapses exhibits more heterogeneity in release properties than the population of GABA synapses, possibly correlated with glutamatergic synaptic malleability.

Sprycel for Chronic Myeloid Leukemia and Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia Resistant to or Intolerant of Imatinib Mesylate

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Jan, 2008  |  Pubmed ID: 18223208

On June 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) with resistance or intolerance to prior therapy including imatinib. This summary reviews the database supporting this approval.

[Clinical Analysis of Primary Nasal Cavity-nasal Sinuses T/NK Cell Lymphoma]

Lin Chuang Er Bi Yan Hou Tou Jing Wai Ke Za Zhi = Journal of Clinical Otorhinolaryngology, Head, and Neck Surgery. Mar, 2008  |  Pubmed ID: 18476612

To investigate the clinical feature, diagnosis, treatment and prognosis of primary nasal cavity-nasal sinuses T/NK cell lymphoma.

A Specific Role for Ca2+-dependent Adenylyl Cyclases in Recovery from Adaptive Presynaptic Silencing

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. May, 2008  |  Pubmed ID: 18480272

Glutamate generates fast postsynaptic depolarization throughout the CNS. The positive-feedback nature of glutamate signaling likely necessitates flexible adaptive mechanisms that help prevent runaway excitation. We have previously explored presynaptic adaptive silencing, a form of synaptic plasticity produced by ongoing neuronal activity and by strong depolarization. Unsilencing mechanisms that maintain active synapses and restore normal function after adaptation are also important, but mechanisms underlying such presynaptic reactivation remain unexplored. Here we investigate the involvement of the cAMP pathway in the basal balance between silenced and active synapses, as well as the recovery of baseline function after depolarization-induced presynaptic silencing. Activation of the cAMP pathway activates synapses that are silent at rest, and pharmacological inhibition of cAMP signaling silences basally active synapses. Adenylyl cyclase (AC) 1 and AC8, the major Ca2+-sensitive AC isoforms, are not crucial for the baseline balance between silent and active synapses. In cells from mice doubly deficient in AC1 and AC8, the baseline percentage of active synapses was only modestly reduced compared with wild-type synapses, and forskolin unsilencing was similar in the two genotypes. Nevertheless, after strong presynaptic silencing, recovery of normal function was strongly inhibited in AC1/AC8-deficient synapses. The entire recovery phenotype of the double null was reproduced in AC8-deficient but not AC1-deficient cells. We conclude that, under normal conditions, redundant cyclase activity maintains the balance between presynaptically silent and active synapses, but AC8 plays a particularly important role in rapidly resetting the balance of active to silent synapses after adaptation to strong activity.

Ixabepilone in Combination with Capecitabine and As Monotherapy for Treatment of Advanced Breast Cancer Refractory to Previous Chemotherapies

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Jul, 2008  |  Pubmed ID: 18628451

To describe the considerations leading to marketing approval of ixabepilone in combination with capecitabine and as monotherapy for the treatment of advanced breast cancer that is refractory to other chemotherapies.

Tasigna for Chronic and Accelerated Phase Philadelphia Chromosome--positive Chronic Myelogenous Leukemia Resistant to or Intolerant of Imatinib

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Sep, 2008  |  Pubmed ID: 18765523

This Food and Drug Administration (FDA) approval report describes the data and analyses leading to the approval by the FDA of nilotinib (Tasigna, AMN-107; Novartis Pharmaceuticals Corporation), an inhibitor of Bcr-Abl tyrosine kinase, for the treatment of chronic-phase (CP) and accelerated-phase (AP) chronic myelogenous leukemia (CML) resistant to or intolerant of imatinib.

Adenylyl Cyclases 1 and 8 Initiate a Presynaptic Homeostatic Response to Ethanol Treatment

PloS One. 2009  |  Pubmed ID: 19479030

Although ethanol exerts widespread action in the brain, only recently has progress been made in understanding the specific events occurring at the synapse during ethanol exposure. Mice deficient in the calcium-stimulated adenylyl cyclases, AC1 and AC8 (DKO), demonstrate increased sedation duration and impaired phosphorylation by protein kinase A (PKA) following acute ethanol treatment. While not direct targets for ethanol, we hypothesize that these cyclases initiate a homeostatic presynaptic response by PKA to reactivate neurons from ethanol-mediated inhibition.

A Role for the Ubiquitin-proteasome System in Activity-dependent Presynaptic Silencing

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Feb, 2010  |  Pubmed ID: 20130189

Chronic changes in electrical excitability profoundly affect synaptic transmission throughout the lifetime of a neuron. We have previously explored persistent presynaptic silencing, a form of synaptic depression at glutamate synapses produced by ongoing neuronal activity and by strong depolarization. Here we investigate the involvement of the ubiquitin-proteasome system (UPS) in the modulation of presynaptic function. We found that proteasome inhibition prevented the induction of persistent presynaptic silencing. Specifically, application of the proteasome inhibitor MG-132 (carbobenzoxy-L-leucyl-L-leucyl-L-leucinal) prevented decreases in the size of the readily releasable pool of vesicles and in the percentage of active synapses. Presynaptic silencing was accompanied by decreases in levels of the priming proteins Munc13-1 and Rim1. Importantly, overexpression of Rim1alpha prevented the induction of persistent presynaptic silencing. Furthermore, strong depolarization itself increased proteasome enzymatic activity measured in cell lysates. These results suggest that modulation of the UPS by electrical activity contributes to persistent presynaptic silencing by promoting the degradation of key presynaptic proteins.

Rapid Activation of Dormant Presynaptic Terminals by Phorbol Esters

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Jul, 2010  |  Pubmed ID: 20668189

Presynaptic stimulation stochastically recruits transmission according to the release probability (P(r)) of synapses. The majority of central synapses have relatively low P(r), which includes synapses that are completely quiescent presynaptically. The presence of presynaptically dormant versus active terminals presumably increases synaptic malleability when conditions demand synaptic strengthening or weakening, perhaps by triggering second messenger signals. However, whether modulator-mediated potentiation involves recruitment of transmission from dormant terminals remains unclear. Here, by combining electrophysiological and fluorescence imaging approaches, we uncovered rapid presynaptic awakening by select synaptic modulators. A phorbol ester phorbol 12,13-dibutyrate (PDBu) (a diacylglycerol analog), but not forskolin (an adenylyl cyclase activator) or elevated extracellular calcium, recruited neurotransmission from presynaptically dormant synapses. This effect was not dependent on protein kinase C activation. After PDBu-induced awakening, these previously dormant terminals had a synaptic P(r) spectrum similar to basally active synapses naive to PDBu treatment. Dormant terminals did not seem to have properties of nascent or immature synapses, judged by NR2B NMDAR (NMDA receptor) receptor subunit contribution after PDBu-stimulated awakening. Strikingly, synapses rendered inactive by prolonged depolarization, unlike basally dormant synapses, were not awakened by PDBu. These results suggest that the initial release competence of synapses can dictate the acute response to second messenger modulation, and the results suggest multiple pathways to presynaptic dormancy and awakening.

Presynaptic Silencing is an Endogenous Neuroprotectant During Excitotoxic Insults

Neurobiology of Disease. Aug, 2011  |  Pubmed ID: 21605675

Glutamate release is a root cause of acute and delayed neuronal damage in response to hypoxic/ischemic insults. Nevertheless, therapeutics that target the postsynaptic compartment have been disappointing clinically. Here we explored whether presynaptic silencing (muting) of glutamatergic terminals is sufficient to reduce excitotoxic damage resulting from hypoxia and oxygen/glucose deprivation. Our evidence suggests that strong depolarization, previously shown to mute glutamate synapses, protects neurons by a presynaptic mechanism that is sensitive to inhibition of the proteasome. Postsynaptic Ca2+ rises in response to glutamate application and toxicity in response to exogenous glutamate treatment were unaffected by depolarization preconditioning. These features strongly suggest that reduced glutamate release explains preconditioning protection. We addressed whether hypoxic depolarization itself induces presynaptic silencing, thereby participating in the damage threshold for hypoxic insult. Indeed, we found that the hypoxic insult increased the percentage of mute glutamate synapses in a proteasome-dependent manner. Furthermore, proteasome inhibition exacerbated neuronal loss to mild hypoxia and prevented hypoxia-induced muting. In total our results suggest that presynaptic silencing is an endogenous neuroprotective mechanism that could be exploited to reduce damage from insults involving excess synaptic glutamate release.