Biomedical subjects

K T Ng

Publications and source records attributed to K T Ng.

At least 19 recordsLinked to original sources

PubMed2006

Clinicopathological significance of homeoprotein Six1 in hepatocellular carcinoma.

Tumour recurrence and metastases of hepatocellular carcinoma (HCC) after hepatectomy are the major obstacles of long-term survival. The present study investigated the clinicopathological significance of a possible metastasis regulator Six1 in HCC patients who were undergone hepatectomy. Seventy-two pairs of RNA and 103 pairs of protein from tumour and adjacent nontumour liver tissues of HCC patients were examined. About 85 and 60% of HCC tumour tissues were found to overexpress Six1 mRNA and protein, respectively, compared with nontumour liver tissues. No Six1 protein was detected in HCC nontumour liver tissues and normal liver tissues. Increased Six1 protein expression in HCC patients was significantly correlated with pathologic tumour-node-metastasis (pTNM) stage (P=0.002), venous infiltration (P=0.004) and poor overall survival (P=0.0423). We concluded that Six1 is frequently overexpressed in HCC patients and elevated Six1 protein in HCC patients may be an indication of advanced stage and poor overall survival after hepatectomy.

Adult↗

PubMed2006

HIV-1 protein gp120 rapidly impairs memory in chicks by interrupting the glutamate-glutamine cycle.

Learning and memory impairments are frequently observed in patients suffering from AIDS Dementia Complex (ADC). These effects have been linked to the presence of gp120, an HIV viral coat glycoprotein. The present study investigated the possibility that gp120 prevents the uptake of extracellular glutamate by astrocytes, leading to an interruption of the glutamate-glutamine cycle and a subsequent impairment of memory. Ten microliters of 10nM gp120 was bilaterally injected into the region of the intermediate medial mesopallium of day-old chicks at various times before, or after, training using a single-trial passive avoidance task. Gp120 was found to significantly impair memory retention when injected 10-40 min after training. Memory impairments were evident within 5 min of gp120 administration and remained evident 24h later. Further, the amnestic effect of gp120 could be overcome with glutamine or with precursors of glutamate synthesis, but only weakly by glutamate. These results support the conclusion that the amnestic effect of gp120 is due to an impaired uptake of glutamate by astrocytes and a subsequent interruption of glutamine supply to neurones. The data indicate that the glutamate-glutamine cycle may be a useful therapeutic target in the treatment of ADC.

Amnesia↗

PubMed2006

Fat-derived hormone adiponectin combined with FTY720 significantly improves small-for-size fatty liver graft survival.

Owing to the discrepancy between organ donation and the demand for liver transplantation, expanding the liver donor pool is of vital importance. However, marginal liver grafts, such as small-for-size and/or fatty grafts, were associated with primary graft nonfunction or poor function. Therefore, novel combination therapies to rescue small-for-size fatty liver grafts should be investigated. In this study, we applied a combination therapy using a fat-derived hormone adiponectin (anti-steatosis) plus immunomodulator FTY720 (anti-inflammatory) in a rat liver transplantation model using small-for-size fatty liver grafts, and investigated the underlying protective mechanism such as anti-steatosis, intra-graft energy metabolism, hepatic microcirculatory changes, cell signaling cascades for survival, apoptosis and inflammation. The current study demonstrated that even a single treatment of adiponectin or FTY720 improved the 7-day graft survival from 0% to 62.5% (p = 0.001). The combination therapy significantly increased the 7-day graft survival rate to 100% by remarkable attenuation of graft steatosis and acute phase inflammatory response, significant activation of cell survival Akt pathway and maintenance of intra-graft adenosine triphosphate metabolism and improvement of hepatic microcirculation. In conclusion, the fat-derived hormone adiponectin combined with FTY720 might be a novel combination drug therapy for prevention of small-for-size fatty liver graft injury.

Adiponectin↗

PubMed2006

Rapamycin attenuates liver graft injury in cirrhotic recipient--the significance of down-regulation of Rho-ROCK-VEGF pathway.

To investigate whether rapamycin could attenuate hepatic I/R injury in a cirrhotic rat liver transplantation model, we applied a rat orthotopic liver transplantation model using 100% or 50% of liver grafts and cirrhotic recipients. Rapamycin was given (0.2 mg/kg, i.v.) at 30 min before graft harvesting in the donor and 24 h before operation, 30 min before total hepatectomy and immediately after reperfusion in the recipient. Rapamycin significantly improved small-for-size graft survival from 8.3% (1/12) to 66.7% (8/12) (p = 0.027). It also increased 7-day survival rates of whole grafts (58.3%[7/12] vs. 83.3%[10/12], p = 0.371). Activation of hepatic stellate cells was mainly found in small-for-size grafts during the first 7 days after liver transplantation. Rapamycin suppressed expression of smooth muscle actin, which is a marker of hepatic stellate cell activation, especially in small-for-size grafts. Intragraft protein expression and mRNA levels of vascular endothelial growth factor (VEGF) were down-regulated by rapamycin at 48 h both in whole and small-for-size grafts. Consistently, mRNA levels and protein expression of Rho and ROCK I were decreased by rapamycin during the 48 h after liver transplantation. In conclusion, rapamycin attenuated graft injury in a cirrhotic rat liver transplantation model by suppression of hepatic stellate cell activation, related to down-regulation of Rho-ROCK-VEGF pathway.

Actins↗

PubMed2005

Noradrenaline involvement in the memory-enhancing effects of exposure to a complex rhythm stimulus following discriminated passive avoidance training in the young chick.

Previous research in our laboratory has demonstrated a significant memory-enhancing effect of exposure to a complex rhythm stimulus following weakly-reinforced passive avoidance learning in chicks. The aim of this study was to explore whether noradrenaline mediates this process. Chicks were trained on a strongly-reinforced single-trial passive avoidance task involving discrimination between two coloured beads. Intracerebral administration of the protein synthesis blocker, anisomycin, revealed that a phase of memory formation sensitive to arousal levels was extended by approximately 35 min following exposure to the complex rhythm stimulus. Administration of 2,4-dinitrophenol showed that this extension occurred during phase B of intermediate-term memory. Finally, a higher dose of the beta-adrenergic receptor antagonist, propranolol, was required to inhibit long-term memory in the presence of the auditory stimulus than in its absence. These findings suggest that the memory-enhancing effects of the complex rhythm stimulus may be mediated by noradrenaline, possibly via an increase in physiological arousal.

2,4-Dinitrophenol↗

PubMed2005

Inhibition of endogenous carbon monoxide production induces transient retention losses in the day-old chick when trained using a single trial passive avoidance learning task.

Carbon monoxide (CO) is most often thought of as an exogenous toxin rather than as a possible endogenous nootrope. However, a limited number of studies have suggested that CO is necessary in memory processing for at least some tasks. While nitric oxide (NO) and CO are known activators of guanylyl cyclase (GC), only the effect of NO on GC has been extensively investigated as a mechanism underlying memory processing. The aim of the present study was to determine if inhibition of CO production would have an effect on memory processing. Using chicks trained on a single trial passive avoidance task, inhibition of CO production using zinc (II) deuteroporphyrin IX 2,4-bis ethylene glycol (ZnBG; 5 microM) resulted in two transient retention losses occurring at around 40 and 130 min post-training. The timing of these transient retention losses was similar to those observed following inhibition of GC, using the same species and task in a previous study. This supports the notion that CO is necessary in memory processing for this task and may act through a GC-dependent mechanism. As ZnBG also directly inhibits GC or nitric oxide synthase (NOS) at high concentrations, a second experiment was carried-out to confirm the specificity of ZnBG for heme oxygenase (HO) at the concentration used. The action of ZnBG was challenged with the HO agonist hemin (100 microM) and the transient deficits were abolished. This confirmed that the action of ZnBG on memory was through a CO-related mechanism rather than directly on GC or NOS. In this way the specificity of ZnBG (5 microM) for HO could be confirmed. The results support a role for endogenous CO in memory processing, possibly through activation of GC. In addition, the transient retention losses observed following administration of ZnBG suggest that CO may be necessary for memory retrieval and not formation as previously thought.

Animals↗

PubMed2004

Inhibition of short-term memory formation in the chick by blockade of extracellular glutamate uptake.

Injection of monosodium glutamate (40nmol/hemisphere) into the intermediate hyperstriatum ventrale of the day-old chick inhibits the formation of short-term memory for a single trial learning that discriminates between colours of beads. These experiments showed that an excess of glutamate close to learning could be damaging to memory. In the present experiments we have blocked the normal reuptake of glutamate and suggest that glutamate release plays a role in normal learning. Removal of glutamate, released from presynaptic neurones during learning, is achieved by various neuronal and astrocytic glutamate transporters. By blocking the primarily astrocytic removal of glutamate by the injection of L-aspartic acid beta-hydroxamate, we effectively increased extrasynaptic levels of glutamate and inhibited short-term memory in a similar manner to central injection of 40nmol glutamate per hemisphere. These experiments suggest that glutamate release within 2.5min of the learning experience is an important feature of short-term memory formation.

Animals↗

PubMed2003

Three-dimensional pseudospectral modelling of cardiac propagation in an inhomogeneous anisotropic tissue.

Various investigators have used the monodomain model to study cardiac propagation behaviour. In many cases, the governing non-linear parabolic equation is solved using the finite-difference method. An adequate discretisation of cardiac tissue with realistic dimensions, however, often leads to a large model size that is computationally demanding. Recently, it has been demonstrated, for a two-dimensional homogeneous monodomain, that the Chebyshev pseudospectral method can offer higher computational efficiency than the finite-difference technique. Here, an extension of the pseudospectral approach to a three-dimensional inhomogeneous case with fibre rotation is presented. The unknown transmembrane potential is expanded in terms of Chebyshev polynomial trial functions, and the monodomain equation is enforced at the Gauss-Lobatto node points. The forward Euler technique is used to advance the solution in time. Numerical results are presented that demonstrate that the Chebyshev pseudospectral method offered an even larger improvement in computational performance over the finite-difference method in the three-dimensional case. Specifically, the pseudospectral method allowed the number of nodes to be reduced by approximately 85 times, while the same solution accuracy was maintained. Depending on the model size, simulations were performed with approximately 18-41 times less memory and approximately 99-169 times less CPU time.

Algorithms↗

PubMed2002

Inhibition of guanylate cyclase and protein kinase G impairs retention for the passive avoidance task in the day-old chick.

Nitric oxide (NO) is a highly labile chemical messenger which has previously been implicated in memory processes in a variety of learning paradigms and species. However, there is only limited evidence to suggest which enzymes are acted upon by NO during the formation of memory. The present study investigates the role of guanylate cyclase (GC) and protein kinase G (PKG) in a form of passive avoidance learning known to be dependent on nitric oxide activity. It was determined that in vivo pharmacological inhibition of GC using either 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one or 6-anilino-5,8-quinolinedione resulted in two transitory memory retention deficits centred around 40 and 120 min posttraining, respectively. In contrast, inhibition of PKG with N-[2-(methylamino)ehtyl]-5-isoquinoline-sulfornamide hydrochloride (H-8) resulted in a single temporary retention loss centered at 120 min posttraining. These temporary retention losses appear to be specific to memory since they were dose-dependent and could not be explained by nonspecific performance effects. Further, these results suggest that these agents inhibit memory retrieval rather than formation, since memory is subsequently available. The current findings indicate that guanylyl cyclase mediates two memory retrieval processes, the latter of which appears to be PKG-dependent. In contrast, since inhibition of NO results in a permanent retention loss, it is suggested that NO is required for memory formation through GC-independent processes.

Aminoquinolines↗

PubMed2001

Concentration-dependent effects of protein phosphatase (PP) inhibitors implicate PP1 and PP2A in different stages of memory formation.

Numerous studies have demonstrated roles for protein phosphorylation and for specific kinases in memory formation; however, a role for specific protein phosphatases has not been established. Previous studies using pharmacobehavioral methods to implicate protein phosphatase activity in memory formation have been unable to discriminate between protein phosphatases 1 (PP1) and 2A (PP2A), as available cell-permeable agents generally inhibit both enzyme classes. To address this difficulty the present study exploited differences in the potency of the selective phosphatase inhibitor, okadaic acid, toward PP1 and PP2A. Within the context of a temporally precise animal model of memory, developed using the day-old chick (Gallus domesticus), acute administration of various concentrations of okadaic acid was found to disrupt two temporally distinct stages of memory formation. When administered bilaterally into an area of the chick brain implicated in memory formation, concentrations of okadaic acid known to selectively inhibit PP2A in vitro disrupted memory from 50 min posttraining. Higher concentrations, reported to inhibit both PP2A and PP1 in vitro, produced significant retention deficits from 20 min posttraining. Identical temporally specific effects were also obtained by varying the concentration and time of administration of calyculin A, a phosphatase inhibitor with equal potency toward both enzyme classes. Hence, different phosphatase enzymes may contribute to different stages of the enzymatic cascade believed to underlie memory formation.

Animals↗

PubMed2001

Calibrated single-plunge bipolar electrode array for mapping myocardial vector fields in three dimensions during high-voltage transthoracic defibrillation.

Mapping of the myocardial scalar electric potential during defibrillation is normally performed with unipolar electrodes connected to voltage dividers and a global potential reference. Unfortunately, vector potential gradients that are calculated from these data tend to exhibit a high sensitivity to measurement errors. This paper presents a calibrated single-plunge bipolar electrode array (EA) that avoids the error sensitivity of unipolar electrodes. The EA is triaxial, uses a local potential reference, and simultaneously measures all three components of the myocardial electric field vector. An electrode spacing of approximately 500 microm allows the EA to be direct-coupled to high-input-impedance, isolated, differential amplifiers and eliminates the need for voltage dividers. Calibration is performed with an electrolytic tank in which an accurately measured, uniform electric field is produced. For each EA, unique calibration matrices are determined which transform potential difference readings from the EA to orthogonal components of the electric field vector. Elements of the matrices are evaluated by least squares multiple regression analysis of data recorded during rotation of the electric field. The design of the electrolytic tank and electrode holder allows the electric field vector to be rotated globally with respect to the electrode axes. The calibration technique corrects for both field perturbation by the plunge electrode body and deviations from orthogonality of the electrode axes. A unique feature of this technique is that it eliminates the need for mechanical measurement of the electrode spacing. During calibration, only angular settings and voltages are recorded. For this study, ten EAs were calibrated and their root-mean-square (rms) errors evaluated. The mean of the vector magnitude rms errors over the set of ten EAs was 0.40% and the standard deviation 0.07%. Calibrated EAs were also tested for multisite mapping in four dogs during high-voltage transthoracic shocks.

Animals↗

PubMed2000

Two-dimensional Chebyshev pseudospectral modelling of cardiac propagation.

Bidomain or monodomain modelling has been used widely to study various issues related to action potential propagation in cardiac tissue. In most of these previous studies, the finite difference method is used to solve the partial differential equations associated with the model. Though the finite difference approach has provided useful insight in many cases, adequate discretisation of cardiac tissue with realistic dimensions often requires a large number of nodes, making the numerical solution process difficult or impossible with available computer resources. Here, a Chebyshev pseudospectral method is presented that allows a significant reduction in the number of nodes required for a given solution accuracy. The new method is used to solve the governing nonlinear partial differential equation for the monodomain model representing a two-dimensional homogeneous sheet of cardiac tissue. The unknown transmembrane potential is expanded in terms of Chebyshev polynomial trial functions and the equation is enforced at the Gauss-Lobatto grid points. Spatial derivatives are obtained using the fast Fourier transform and the solution is advanced in time using an explicit technique. Numerical results indicate that the pseudospectral approach allows the number of nodes to be reduced by a factor of sixteen, while still maintaining the same error performance. This makes it possible to perform simulations with the same accuracy using about twelve times less CPU time and memory.

Action Potentials↗

PubMed2000

Modification of a weak learning experience by memory retrieval in the day-old chick.

Activation of memory retrieval after weak learning (WL), during either the short- or intermediate-term stages of memory in day-old chickens, resulted in the strengthening of the memory to levels normally associated with strong learning. Administration of the calcium channel antagonist lanthanum chloride, the glutamate receptor agonist monosodium glutamate, or the N-methyl-D-aspartate glutamatergic receptor antagonist AP5 prevented strengthening of a WL memory by reminder-activated memory retrieval. The results of this study are discussed in light of our recent findings suggesting two phases of memory retrieval in the day-old chick. The results are consistent with the proposition that a memory undergoing the processes of formation may be modified to include information gleaned at the time of memory retrieval and that a second phase of memory retrieval may be responsible for such modification.

2-Amino-5-phosphonovalerate↗

PubMed1999

Changes in phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in processing of short-term and long-term memories after passive avoidance learning.

Characteristic autophosphorylation of calcium/ calmodulin-dependent protein kinase II (CaMKII) and its consequences have made this kinase an interesting target in studying the molecular pathway for important neuronal functions including learning and memory formation. In this article, we use immunoprecipitation and immunoblotting methods to detect changes in phosphorylation of CaMKII during memory formation in 1-day-old chicks trained in a single trial passive avoidance task. A 60-kDa protein has been immunoprecipitated from the chick brain with an anti-rabbit CaMKII antibody. This protein shows strong and specific immunoactivities with antibodies against the calmodulin binding site of CaMKII, and the N and C terminals of beta-CaMKII. Commercially available anti-phosphoserine and anti-phosphothreonine antibodies are shown to sensitively detect phosphorylation of purified CaMKII. The basal phosphorylation of CaMKII from the intermediate medial hyperstriatum ventrale (IMHV) and lobus parolfactorius (LPO) regions of the chick brain is shown to be largely right hemisphere-lateralized. When chicks are subjected to a passive avoidance training experience, a specific increase in CaMKII phosphorylation is induced in the IMHV and LPO of the left hemisphere from those chicks whose memory for the training experience is successfully retrieved. While this specific increase in CaMKII phosphorylation is seen in both the left IMHV and left LPO in short-term memory, it is detectable only in the left LPO associated with long-term memory retrieval. The present results provide evidence that in vivo changes in phosphorylation of CaMKII are associated specifically with processing of distinct memory stages, which take place in specific brain regions.

3T3 Cells↗

PubMed1999

Cognitive and behavioral outcome following mild traumatic head injury in children.

OBJECTIVES: To investigate outcome in children with mild traumatic head injury (THI) at 1 week and 3 months postinjury and to identify factors associated with persisting problems. DESIGN: Postconcussional symptomatology, behavior ratings, and neuropsychological test performance were examined at 1 week and 3 months postinjury. SETTING: Participants were recruited from successive presentations to emergency departments of two major hospitals. PARTICIPANTS: 130 Children with mild THI were compared with 96 children having other minor injuries as controls. RESULTS: Children with mild THI experienced headaches, dizziness, and fatigue but exhibited no cognitive impairments, relative to controls, at 1 week postinjury. By 3 months, symptoms had resolved. However, 17% of children showed significant ongoing problems. They were more likely to have a history of previous head injury, learning difficulties, neurological or psychiatric problems, or family stressors. CONCLUSIONS: Persisting problems following mild head injury in children are more common in those with previous head injury, preexisting learning difficulties, or neurological, psychiatric, or family problems. These "at-risk" children should be identified in the emergency department and monitored.

Adolescent↗

PubMed1998

Peptidyl-prolyl-cis/trans-isomerase activity may be necessary for memory formation.

At present, evidence for a plethora of physiological roles for the different classes of peptidyl-prolyl-cis/trans-isomerases (PPIases, EC 5.2.1.8) is emerging. Cyclosporin A (CyA) has been previously reported to disrupt memory formation in a temporally specific manner, when administered intracranially to day-old chicks trained on a single-trial, passive-avoidance task [Bennett, P.C., Zhao, W., Lawen, A. and Ng, K.T. (1996) Brain Res. 730, 107-1171. CyA is known to inhibit both the PPIase activity of cyclophilin and, indirectly, the protein phosphatase activity of calcineurin. Therefore to begin to distinguish between these two functions we studied the effects on memory formation of three non-immunosuppressive CyA analogues, in order to study the involvement of cyclophilins. These drugs retain the capacity to bind to and inhibit the PPIase activity of cyclophilin, but do not bind in the complex with cyclophilin to calcineurin and, therefore, do not inhibit its phosphatase activity. All three drugs exert effects on memory formation comparable to those induced by CyA, significantly inhibiting memory formation when injected intracranially (50 fmol per hemisphere) immediately following training. Brain extracts from chicks treated with [MeVal4]CyA show a strong inhibition of cyclophilin activity. These data show a requirement for the PPIase activity of a cyclophilin for successful memory formation and constitute the first set of data establishing a physiological role for a cyclophilin.

Animals↗

PubMed1998

Further support for nitric oxide-dependent memory processing in the day-old chick.

There is considerable evidence that nitric oxide activity is essential for memory formation, particularly from studies using inhibitors of nitric oxide synthase. The particular stage of memory formation requiring nitric oxide activity has not, however, been systematically investigated. In the current experiments, day-old black Australorp-white Leghorn chicks were trained on a passive avoidance task. Intracranial injections of the nitric oxide synthase inhibitor, l-NG-nitroarginine methylester (0.5 mM), were found to inhibit memory formation shortly after training, when injected pre- or posttraining. This effect was replicated with a second inhibitor, l-NG-nitroarginine (1 mM), and counteracted by the NO donor, sodium nitroprusside (150 microM). These findings provide covergent evidence that nitric oxide activity plays a critical role in the consolidation of memory in the day-old chick.

Animals↗

PubMed1998

A new three-dimensional finite-difference bidomain formulation for inhomogeneous anisotropic cardiac tissues.

Bidomain modeling of cardiac tissues provides important information about various complex cardiac activities. The cardiac tissue consists of interconnected cells which form fiber-like structures. The fibers are arranged in different orientations within discrete layers or sheets in the tissue, i.e., the fibers within the tissue are rotated. From a mathematical point of view, this rotation corresponds to a general anisotropy in the tissue's conductivity tensors. Since the rotation angle is different at each point, the anisotropic conductivities also vary spatially. Thus, the cardiac tissue should be viewed as an inhomogeneous anisotropic structure. In most of the previous bidomain studies, the fiber rotation has not been considered, i.e., the tissue has been modeled as a homogeneous orthotropic medium. In this paper, we describe a new finite-difference bidomain formulation which accounts for the fiber rotation in the cardiac tissue and hence allows a more realistic modeling of the cardiac tissue. The formulation has been implemented on the data-parallel CM-5 which provides the computational power and the memory required for solving large bidomain problems. Details of the numerical formulation are presented together with its validation by comparing numerical and analytical results. Some computational performance results are also shown. In addition, an application of this new formulation to provide activation patterns within a tissue slab with a realistic fiber rotation is demonstrated.

Algorithms↗