PubMed Health⌕ Search

Biomedical subjects

P Ting

Publications and source records attributed to P Ting.

At least 19 recordsLinked to original sources
PubMed2001

Bioartificial liver treatment prolongs survival and lowers intracranial pressure in pigs with fulminant hepatic failure.

Intracranial hypertension leading to brainstem coning is a major cause of death in fulminant hepatic failure (FHF). We have developed a bioartificial liver (BAL) utilizing plasma perfusion through a bioreactor loaded with porcine hepatocytes and a column with activated charcoal. In a Phase I clinical trial, we observed a decrease in intracranial pressure (ICP) in FHF patients. However, these patients received BAL therapy together with other measures. We therefore examined whether BAL therapy alone could prevent development of intracranial hypertension in pigs with surgically induced FHF. Pigs (40-60 kg) underwent end-to-side portacaval shunt, transection of all hepatic ligaments, and placement of slings around the hepatic artery and bile duct. After 3 days, the slings were tightened to induce liver necrosis. After 4 h, Group 1 pigs (n = 6) underwent a 6 h treatment with the BAL utilizing 10 billion cryopreserved pig hepatocytes and a charcoal column, Group 2 pigs (n = 6) with the BAL containing charcoal but no cells, and Group 3 pigs (n = 6) with the BAL containing neither cells nor charcoal. Group 1 pigs maintained a normal ICP during BAL treatment and for 14 h afterward and because of this effect they survived longer than Groups 2 and 3 animals. In contrast, Groups 2 and 3 pigs showed an early (6-8 h) rise in ICP.

Analysis of Variance↗
PubMed1999

Intracranial pressure during liver transplantation for fulminant hepatic failure.

During orthotopic liver transplantation (OLT) for fulminant hepatic failure (FHF), some patients develop cerebral injury secondary to intracranial hypertension. We monitored intracranial pressure (ICP) and cerebral perfusion pressure (CPP) before and during OLT in 12 FHF patients undergoing transplantation. All four patients who had normal ICP preoperatively maintained normal ICP/CPP throughout OLT. During OLT, four of the eight patients with pretransplant intracranial hypertension had six episodes of ICP increase. These episodes of intracranial hypertension occurred during failing liver dissection (n=3) and graft reperfusion (n=3). At the end of the anhepatic phase, the ICP was lower than the preoperative ICP in all patients, and was below 15 mmHg in all but one patient. These data suggest that in FHF patients who develop intracranial hypertension before OLT, dissection of the native liver and graft reperfusion are associated with a risk of brain injury resulting from intracranial hypertension and cerebral hypoperfusion.

Adult↗
PubMed1999

Clinical use of a bioartificial liver in the treatment of acetaminophen-induced fulminant hepatic failure.

Patients with acetaminophen-induced fulminant hepatic failure (FHF) who meet the King's College Hospital criteria have a high mortality risk (>90%) if they do not undergo liver transplantation. We have developed a treatment strategy for these patients based on the use of an extracorporeal bioartificial liver (BAL) support system. In this study, we report the results of the clinical application of BAL support in patients with acetaminophen-induced FHF. All patients were admitted to a dedicated surgical intensive care unit. They were evaluated for urgent liver transplantation and received the standard medical measures, including N-acetylcysteine administration and intracranial pressure monitoring. Moreover, they underwent daily 6-hour BAL treatments. Eight patients were treated. Three patients were bridged to liver transplantation, and five patients recovered without a transplant. All patients experienced neurological and metabolic improvement after treatments with the BAL support system. The BAL support system seems to improve the outcome of high-risk patients with acetaminophen-induced FHF, even in the absence of liver transplantation. Avoiding liver transplantation is particularly important in an era of organ shortage and high cost of transplants.

Acetaminophen↗
PubMed1997

Enhanced brain opioid receptor activity precedes blood-brain barrier disruption.

We studied the effects of transient postischemic increased opioid receptors (OPR) binding (mu, delta, kappa) on blood-brain barrier (BBB), brain water content and brain mitochondrial oxidative enzymes system. Cats were exposed to temporary middle cerebral artery occlusion (MCAO). The significant increased OPR bindings observed 10 min after the release of MCAO (ischemic rCBF = 7 +/- 1 to 11 +/- 2 ml/100 g/min) preceded the early and late BBB disruptions, brain edema and postischemic impaired mitochondrial oxidative enzymes functions. Further, the study suggests indirectly that the latter process was irreversible and hence associated with subsequent ischemic cerebral infarction. In addition, the results revealed a possible viable therapeutic window in the early postischemic recirculation period, before the onset of impaired mitochondrial oxidative function.

Animals↗
PubMed1994

Neuro-pathophysio-biochemical profiles of neonatal asphyxia.

Neurological and neuroelectrophysio-biochemical profiles were evaluated in newborn lambs exposed to severe temporary asphyxia. Isoelectric EEG, marked disturbances of phosphorus magnetic resonance spectrum (31P-MRS), and significant brain intracellular acidosis (pHi) were noted during asphyxia. Following resuscitation, the presence of early postasphyxic blood-brain-barrier (BBB) opening was associated with a marked transient increase in intracranial pressure (ICP), a 50% neonatal mortality and a 67% incidence of severe asphyxic encephalopathy. In contrast, those lambs exposed to the same magnitude of asphyxia, but without early BBB opening experienced neither death nor severe neurological deficits. Further, these lambs showed a rapid progressive normalization of the 31P-MRS and pHi, despite, the lack of EEG recovery in the first hour following resuscitation. Thus, the present study depicts that the early postasphyxic BBB disruption following temporary neonatal asphyxia is associated with poor prognosis.

Acid-Base Equilibrium↗
PubMed1994

Endogenous opioid system activity following temporary focal cerebral ischemia.

We studied changes in opioid receptors (mu, delta, kappa) concentrations during temporary middle cerebral artery occlusion (MCAO) in cats by sequential displacement of unselective opioid antagonist, [3H]-diprenorphine with highly selective ligands for mu, delta and kappa, subsites. Following threshold cerebral ischemia (rCBF < 10 ml/100 g/min) there was a 2 to 3 fold increase in the 3 opioid receptor subtype concentrations at 10 min following the release of MCAO. Further, 56% of the cats depicted early postischemic hyperemia BBB opening, at 1 h and 3 h following the release of occlusion, with significant subsequent progression of brain edema. We believe that the enhanced brain opioid activity may be relevant to the neuronal damage caused by the early postischemic BBB opening.

Animals↗
PubMed1994

The effects of naloxone on the post-asphyxic cerebral pathophysiology of newborn lambs.

Both early post-ischaemic blood-brain barrier disruption and enhanced brain endogenous opioid system activity have been implicated in the pathogeneses of ischaemic neuronal damage; however, their roles in neonatal asphyxia have not been evaluated. Under alpha-Chloralose anaesthesia, 17 newborn lambs were asphyxiated until their mean arterial pressures were < or = 25 mmHg. They were then immediately resuscitated, and assigned to two groups. Group I, but not group II lambs received IV bolus of 10 mg kg-1 Naloxone within 5 min of resuscitation. The infusion was continued at the same dose hourly until sacrificed 24 h post-asphyxia. Arterial pH/gases, intracranial/arterial pressures, and rectal temperature were monitored. Neurological examinations were performed on both groups prior to sacrifice, and the blood-brain barrier integrity was assessed by Evans blue. Despite aggressive resuscitation, 5 lambs died during asphyxia, but 12 survived and were assigned according to the protocol. There were no significant group differences in the magnitude of asphyxia, arterial and intracranial pressures. However, blood-brain barrier disruption was observed in 5 out of 6 untreated, and in only 1 of the 6 lambs treated with Naloxone (p < 0.05). Severe neurological abnormalities were observed in 75% of lambs with disrupted, but in none of the animals with intact blood-brain barrier (p < 0.05). Our study suggests that post-asphyxia blood-brain barrier disruption is causally related to poor neurological outcome, and that Naloxone prevents both the disruption, and the neurological dysfunction among those survivors with intact blood-brain barrier.

Animals↗
PubMed1991

Murine and human T-lymphocyte GATA-3 factors mediate transcription through a cis-regulatory element within the human T-cell receptor delta gene enhancer.

A family of transcriptional activators has recently been identified in chickens; these transcriptional activators recognize a common consensus motif (WGATAR) through a conserved C4 zinc finger DNA-binding domain. One of the members of this multigene family, cGATA-3, is most abundantly expressed in the T-lymphocyte cell lineage. Analysis of human and murine GATA-3 factors shows a striking degree of amino acid sequence identity and similar patterns of tissue specificity of expression in these three organisms. The murine and human factors are abundantly expressed in a variety of human and murine T-cell lines and can activate transcription through a tissue-specific GATA-binding site identified within the human T-cell receptor delta gene enhancer. We infer that the murine and human GATA-3 proteins play a central and highly conserved role in vertebrate T-cell-specific transcriptional regulation.

Amino Acid Sequence↗
PubMed1990

Modulation of the cytotoxic mechanism of 6-thioguanine by 4-amino-5-imidazolecarboxamide.

Previous evidence has indicated that either purine starvation or incorporation into DNA may be the dominant biochemical effect of the antileukemic agent 6-thioguanine (TG), depending on exposure conditions. Furthermore, it has been suggested that the paradoxical decrease in TG-induced cytotoxicity at high drug concentrations may be due to an antagonistic interaction between these two mechanisms, in which purine starvation inhibits DNA synthesis and, therefore, incorporation of TG into DNA. In this report we test the hypothesis that by concurrent treatment of L1210 cells with TG and the purine precursor 4-amino-5-imidazolecarboxamide (AIC) it is possible to alleviate DNA synthesis inhibition caused by high concentrations of TG, thus enhancing TG incorporation into DNA and TG-induced cell kill. Both the cytotoxic and cytokinetic results presented support this hypothesis. However, gross incorporation of TG into DNA was not increased by AIC under conditions in which a significant enhancement of cytotoxicity (i.e., 1 log) was observed. These findings suggest that the potentiating effect of AIC may be most prominent on the subpopulation of cells that are resistant to treatment with TG alone, and they demonstrate that the cytotoxic effects of TG treatments are more accurately reflected by observing specific cytokinetic changes (delayed late S/G2 arrest) than by measuring the average extent of TG incorporation into DNA within a given population. Finally, we propose that it may be possible to select conditions for administration of TG that favor one or the other cytotoxic mechanism, depending on whether the clinical objective is induction of remission (where rapid cell lysis due to purine starvation would be desired) or eradication of subclinical disease during remission (where proliferation-dependent cytotoxicity due to DNA incorporation should be more effective.

Aminoimidazole Carboxamide↗
PubMed1990

Indomethacin attenuates early postischemic vasogenic edema and cerebral injury.

Inhibition of cyclooxygenase products by IND given during and after temporary MCAO produced a marked reduction in the incidence of early postischemic BBB opening to albumin, despite the presence of reactive hyperemia. This beneficial effect might be due to direct prevention of endothelial cell damage by inhibition of prostaglandin synthesis. Reduction was insignificant in postischemic brain edema: however, the intensity of postischemic neuronal damage was reduced by IND.

Animals↗
PubMed1989

Prediction of thioguanine-induced cytotoxicity by dual-parameter flow cytometric analysis.

A method is presented for the quantitative analysis of delayed cytokinetic effects resulting from the treatment of L1210 cells with 6-thioguanine (TG). By using dual-parameter (DNA/protein) flow cytometry, we could observe the accumulation of late S/G2/M cells with abnormally high green fluorescence (i.e., protein content), indicative of unbalanced growth. The use of mitotic cells from a pseudotetraploid line (HT29) as external markers for both red and green fluorescence facilitated highly reproducible measurement of the mean green fluorescence (GFLmean) of the arrested late S/G2/M population. We found that the dose dependence of the observed GFLmean values followed the same unusual biphasic pattern as did cytotoxicity in this cell line, indicating that this parameter might be a suitable means of predicting TG-induced toxicity in vivo. We propose that the low background expected for this kind of measurement would make it particularly appropriate for the analysis of clinical specimens (e.g., mononuclear bone marrow cells) from leukemic patients receiving thiopurines, to monitor (and, hopefully, predict) their response to treatment.

Algorithms↗
PubMed1986

Brain metabolic correlates of hypoxic-ischemic cerebral necrosis in mid-gestational sheep fetuses: significance of hypotension.

Mid-gestational sheep fetuses exposed to marked hypoxia for 2 h remain brain intact if MABP is maintained above 30 mm Hg. On the other hand, similarly hypoxic fetuses, if they experience reductions in MABP below 30 mm Hg, develop foci of necrosis that predominantly affect hemispheric white matter and neostriatum. Cortex damage is more restricted and is usually associated with more massive underlying white matter damage. The present study examines the brain metabolic basis for the important role of hypotension in brain injury development in marked hypoxia. Sheep fetuses rendered hypoxic by respiring their ewes with 11% oxygen (fetal PaO2 = 8-12 mm Hg) in which MABP was maintained above 30 mm Hg showed increases in brain lactic acid concentrations to 7-13 mumol/g but unaltered energy charge. In contrast, fetuses that sustained MABP reductions below 30 mm Hg showed increases in lactic acid concentrations in vulnerable structures to 16-24 mumol/g accompanied by marked decreases in energy charge. The vulnerable structures also showed reductions in fructose concentrations but a variable behavior of other brain metabolites including phosphocreatine, glycogen, and glucose. Thus, the present findings suggest a relation between hypotension during marked hypoxia, low energy charge, lactic acid accumulation in brain at high concentrations, and fetal brain injury. The ewes of hypoxic hypotensive fetuses received pentobarbital at lower doses than did those of fetuses that maintained blood pressure. This suggests that pentobarbital plays an important role in protecting the fetal brain from asphyxia by extending the hypoxic fetus's ability to maintain blood pressure in addition to reducing its brain metabolism.

Animals↗
PubMed1986

Influence of blood-brain barrier opening to proteins on development of post-ischaemic brain injury.

The effect of the BBB opening to proteins on development of post-ischaemic brain injury was assessed in 32 cats subjected to one hour MCA occlusion. The CBF was measured by hydrogen clearance from electrodes inserted in the caudate and the cerebral cortex within the MCA territory. In 16 animals, a prevention of subsequent reactive hyperaemia was attempted by hypovolaemia, produced by withdrawal of blood just before the release of MCA occlusion. The hypovolaemia was successful in prevention of post-ischaemic hyperaemia in five out of eight cats sacrificed at 3 h and in six out of eight animals killed after 3 and 14 days. In cats sacrificed 3 h after release of MCA occlusion, ischaemic sites, associated with reactive hyperaemia, showed evidence of BBB breakdown to proteins and significantly more severe oedema than at the ischaemic sites without reactive hyperaemia, which otherwise failed to reveal leakage of EB tracer. In the cats sacrificed at 3 and 14 days, the ischaemic sites which showed reactive hyperaemia after release of MCA occlusion, revealed much more severe ischaemic brain tissue injury than was observed at the sites without reactive hyperaemia, which also did not show any EB leakage. The present study indicates that reactive hyperaemia, which follows release of major cerebral artery occlusion, may play a significant role in the breakdown of the BBB to proteins, and in increasing the severity of post-ischaemic oedema and of ischaemic brain tissue injury.

Animals↗
PubMed1985

The biphasic opening of the blood-brain barrier to proteins following temporary middle cerebral artery occlusion.

The behavior of the blood-brain barrier (BBB) was studied in cats following release after 1-h middle cerebral artery (MCA) occlusion. The regional cerebral blood flow (rCBF) was determined by hydrogen clearance method in the caudate nucleus and the cerebral cortex. The BBB was assayed with Evans blue (EB) tracer and by immunohistochemical peroxidase-antiperoxidase (PAP) method. Following release of MCA occlusion, there were two openings of the BBB, separated by a refractory period. The first opening, occurred shortly after recirculation; this was associated with rCBF below 15 ml/100 g/min during the ischemic period and a pronounced reactive hyperemia promptly following release of MCA occlusion. A refractory period of the BBB was indicated by the absence of EB leakage in cats injected with the tracer 30 min before killing at 3 h after recirculation, although the rCBF values in these animals were even lower (6 +/- 1 ml/100 g/min) during occlusion, and all of them showed a pronounced hyperemia after recirculation. The occurrence of the previous BBB opening in these animals was confirmed by the PAP staining. The second opening of the BBB was observed at 5 and 72 h after recirculation in cats which were injected with EB 30 min before killing, and which showed rCBF below 15 ml/100 g/min during occlusion, followed by a pronounced reactive hyperemia. No EB extravasations were observed at any time in cats in which the rCBF during occlusion was above 15 ml/100 g/min and which failed to show a marked reactive hyperemia.

Animals↗