Search PubMed⌕ Search

Biomedical subjects

P J Noble

Publications and source records attributed to P J Noble.

16 recordsLinked to original sources
PubMed2006

Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium-calcium overload.

Late sodium current in cardiac cells is very small compared with the fast component, but as it flows throughout the action potential it may make a substantial contribution to sodium loading during each cardiac cycle. Late sodium current may contribute to triggering arrhythmia in two ways: by causing repolarisation failure (early after depolarisations); and by triggering late after depolarisations attributable to calcium oscillations in sodium-calcium overload conditions. Reduction of late sodium current would therefore be expected to have therapeutic benefits, particularly in disease states such as ischaemia in which sodium-calcium overload is a major feature.

Arrhythmias, Cardiac↗
PubMed2003

A model for human ventricular tissue.

The experimental and clinical possibilities for studying cardiac arrhythmias in human ventricular myocardium are very limited. Therefore, the use of alternative methods such as computer simulations is of great importance. In this article we introduce a mathematical model of the action potential of human ventricular cells that, while including a high level of electrophysiological detail, is computationally cost-effective enough to be applied in large-scale spatial simulations for the study of reentrant arrhythmias. The model is based on recent experimental data on most of the major ionic currents: the fast sodium, L-type calcium, transient outward, rapid and slow delayed rectifier, and inward rectifier currents. The model includes a basic calcium dynamics, allowing for the realistic modeling of calcium transients, calcium current inactivation, and the contraction staircase. We are able to reproduce human epicardial, endocardial, and M cell action potentials and show that differences can be explained by differences in the transient outward and slow delayed rectifier currents. Our model reproduces the experimentally observed data on action potential duration restitution, which is an important characteristic for reentrant arrhythmias. The conduction velocity restitution of our model is broader than in other models and agrees better with available data. Finally, we model the dynamics of spiral wave rotation in a two-dimensional sheet of human ventricular tissue and show that the spiral wave follows a complex meandering pattern and has a period of 265 ms. We conclude that the proposed model reproduces a variety of electrophysiological behaviors and provides a basis for studies of reentrant arrhythmias in human ventricular tissue.

Action Potentials↗
PubMed2003

Cold induces shifts of voltage dependence in mutant SCN4A, causing hypokalemic periodic paralysis.

BACKGROUND: The authors reported a mutation, P1158S, of the human skeletal muscle sodium channel gene (SCN4A) in a family with cold-induced hypokalemic periodic paralysis (hypoKPP) and myotonia. OBJECTIVE: To identify mechanisms of temperature dependency in this channelopathy. METHODS: Using the amphotericin B perforated patch clamp method, sodium currents were recorded at 22 and 32 degrees C from the wild-type (WT) and P1158S mutant SCN4A expressed in tsA201 cells. Computer simulation was performed, incorporating the gating parameters of the P1158S mutant SCN4A. RESULTS: P1158S mutant SCN4A exhibited hyperpolarizing shifts in voltage dependence of both activation and inactivation curves at a cold temperature and a slower rate of inactivation than the WT. Computer simulation reproduced the abnormal skeletal muscle electrical activities of both paralysis at a low potassium concentration in the cold and myotonia at a normal potassium concentration. CONCLUSIONS: Both paralysis and myotonia are attributable to the biophysical properties of the SCN4A mutation associated with hypoKPP. This is the first report of an SCN4A mutation that exhibits temperature-dependent shifts of voltage dependence in sodium channel gating.

Action Potentials↗
PubMed2002

Gastrin-cholecystokinin(B) receptor expression in AGS cells is associated with direct inhibition and indirect stimulation of cell proliferation via paracrine activation of the epidermal growth factor receptor.

BACKGROUND: Activation of the gastrin-cholecystokinin(B) (CCK(B)) receptor stimulates cell proliferation and increases production of ligands for the epidermal growth factor receptor (EGF-R). AIMS: To determine the role of gastrin-CCK(B) activation in stimulation of cell proliferation via paracrine activation of EGF-R. METHODS: AGS cells were transfected with the gastrin-CCK(B) receptor (AGS-G(R) cells) or with green fluorescent protein (AGS-GFP cells). Proliferation was determined by [(3)H] thymidine incorporation, flow cytometry, and cell counting. RESULTS: Gastrin inhibited proliferation of AGS-G(R) cells by delaying entry into S phase. However, when AGS-G(R) cells were cocultured with AGS-GFP cells, gastrin stimulated proliferation of the latter. Immunoneutralisation and pharmacological studies using metalloproteinase and kinase inhibitors indicated that the proliferative response was mediated by paracrine stimulation of EGF-R and activation of the mitogen activated protein kinase pathway through release of heparin binding EGF. CONCLUSIONS: Gastrin can directly inhibit, and indirectly stimulate, proliferation of gastric AGS cells.

Cell Division↗
PubMed2002

Stimulation of the gastrin-cholecystokinin(B) receptor promotes branching morphogenesis in gastric AGS cells.

Epithelial organization is maintained by cell proliferation, migration, and differentiation. In the case of the gastric epithelium, at least some of these events are regulated by the hormone gastrin. In addition, gastric epithelial cells are organized into characteristic tubular structures (the gastric glands), but the cellular mechanisms regulating the organization of tubular structures (sometimes called branching morphogenesis) are uncertain. In the present study, we examined the role of the gastrin-cholecystokinin(B) receptor in promoting branching morphogenesis of gastric epithelial cells. When gastric cancer AGS-G(R) cells were cultured on plastic, gastrin and PMA stimulated cell adhesion, formation of lamellipodia, and extension of long processes in part by activation of protein kinase C (PKC) and phosphatidylinositol (PI)-3 kinase. Branching morphogenesis was not observed in these circumstances. However, when cells were cultured on artificial basement membrane, the same stimuli increased the formation of organized multicellular arrays, exhibiting branching morphogenesis. These effects were reversed by inhibitors of PKC but not of PI-3 kinase. We conclude that, in the presence of basement membrane, activation of PKC by gastrin stimulates branching morphogenesis.

Basement Membrane↗
PubMed2001

Modelling of Ca2+-activated chloride current in tracheal smooth muscle cells.

Stimulation of airway myocytes by contractile agents such as acetylcholine (ACh) activates a Ca2+-activated Cl- current (I(ClCa)) which may play a key role in calcium homeostasis of airway myocytes and hence in airway reactivity. The aim of the present study was to model I(ClCa) in airway smooth muscle cells using a computerised model previously designed for simulation of cardiac myocyte functioning. Modelling was based on a simple resistor-battery permeation model combined with multiple binding site activation by calcium. In order to validate the model, a combination of equations, used to mimic [Ca2+]i response to ACh stimulation, were incorporated into the model. The results indicate that the model developed in this article accounts for experimental recordings and electrophysiological characteristics of this current in airway smooth muscle cells, with parameter values consistent with those calculated from experimental data. Such a model may thus be used to predict I(ClCa) functioning, though additional experimental data from airway myocytes would be useful to more accurately determine some parameter values of the model.

Acetylcholine↗
PubMed2000

Facilitation of the L-type calcium current in rabbit sino-atrial cells: effect on cardiac automaticity.

OBJECTIVE: The L-type Ca(2+) current (I(Ca,L)) contributes to the generation and modulation of the pacemaker action potential (AP). We investigated facilitation of I(Ca,L) in sino-atrial cells. METHODS: Facilitation was studied in regularly-beating cells isolated enzymatically from young albino rabbits (0.8-1 kg). We used the whole-cell patch-clamp technique to vary the frequency of the test depolarizations evoked at -10 mV or the conditioning diastolic membrane potential prior to the test pulse. RESULTS: High frequencies (range 0.2-3.5 Hz) slowed the decay kinetics of I(Ca,L) evoked from a holding potential (HP) of -80 mV in 68% of cells resulting in a larger Ca(2+) influx during the test pulse. The amount of facilitation increased progressively between 0.2 and 3.0 Hz. When the frequency was changed from 0.1 to 1 Hz, the averaged increase in the time integral of I(Ca,L) was 27+/-7% (n=22). Application of conditioning voltages between -80 and -50 mV induced similar facilitation of I(Ca,L) in 73% of cells. The maximal increase of Ca(2+) entry occurred between -60 and -50 mV, and was on average 38+/-14% for conditioning prepulses of 5 s in duration (n=15). Numerical simulations of the pacemaker activity showed that facilitation of I(Ca,L) promotes stability of sino-atrial rate by enhancing Ca(2+) entry, thus establishing a negative feedback control against excessive heart rate slowing. CONCLUSION: Facilitation of I(Ca,L) is present in rabbit sino-atrial cells. The underlying mechanism reflects modulation of I(Ca,L) decay kinetics by diastolic membrane potential and frequency of depolarization. This phenomenon may provide an important regulatory mechanism of sino-atrial automaticity.

Animals↗
PubMed1998

Silent orbitocranial penetration by a pencil.

OBJECTIVE: To emphasise the value of computed tomography even in the absence of symptoms in a case of penetrating injury of the upper eyelid. METHODS: Case report. RESULTS: Although clinically asymptomatic, penetration of upper eyelid was associated with intracranial penetration that left a track in the brain parenchyma. CONCLUSIONS: Computed tomography of orbit and brain is an important investigation, even in seemingly trivial eyelid injury, to reveal the full extent of the damage.

Brain Injuries↗
PubMed1997

Regulated expression of GATA-6 transcription factor in gastric endocrine cells.

BACKGROUND & AIMS: GATA transcription factors may regulate gene expression in developing tissues, including gut epithelium. In the stomach, their expression has been linked to regulation of proton pump genes. However, GATA consensus sequences also occur in the promoter of the histidine decarboxylase gene, located in enterochrommafin-like cells. The aim of this study was to determine if GATA factors are located in gastric endocrine cells and to examine their expression during development and in response to changes in the gastric luminal environment. METHODS: Polymerase chain reaction cloning, Northern blot, and gel shift assays were used to examine GATA expression in gastric endocrine cells; changes in GATA messenger RNA during development and in response to fasting, feeding, and gastric achlorhydria were determined by Northern blot. RESULTS: GATA-6 was expressed strongly in rodent gastric endocrine cell fractions, in a human ECL cell tumor, and in an endocrine cell line (STC-1) derived from gut epithelium; proteins from STC-1 cells bound specifically to GATA consensus sequences in the human histidine decarboxylase promoter. GATA messenger RNA abundance was up-regulated during terminal differentiation of the rat stomach and on feeding after a fast. CONCLUSIONS: The GATA-6 transcription factor is expressed in gastric endocrine cells and is a potential regulator of gastric differentiation and of genes involved in the response to feeding.

Achlorhydria↗
PubMed1995

Expression of immediate early genes in rat gastric myenteric neurones: a physiological response to feeding.

1. Expression of the immediate early genes c-fos, c-jun and c-myc in rat stomach in response to feeding and gastric distension was examined by Northern blot analysis and in situ hybridization. 2. Refeeding of fasted rats induced a transient increase in c-fos mRNA abundance in gastric corpus and antrum that was sixfold within 15 min and declined within 4 h. The response was not mediated by gastrinergic or muscarinic cholinergic mechanisms; it was reduced but not abolished by hexamethonium. No changes in expression of c-jun, c-myc or the constitutively expressed protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were observed. 3. In conscious rats prepared with a gastric fistula, gastric distension with nutritive and non-nutritive solutions at a physiological pressure for 30 min induced expression of c-fos, c-jun and c-myc, but not GAPDH. 4. Messenger RNA encoding c-fos was localized by in situ hybridization to gastric myenteric neurones of animals that underwent gastric distension, but not of undistended controls. 5. The results suggest that expression of c-fos in gastric myenteric neurones is an early response to the physiological stretching of the stomach wall that accompanies feeding. With supraphysiological distension, other immediate early genes may be recruited.

Animals↗
PubMed1993

Identification of the GABAA receptor alpha 3 subunit in the IMR-32 neuroblastoma cell line.

A previous report has described the presence of t-[35S]-butylbicyclophosphorothionate binding sites and GABA-gated Cl- flux in the human neuroblastoma IMR-32 cell line. We now report the further characterisation of this binding site and, even more important, the identification of the GABAA receptor alpha 3 sub-unit expressed in these cells. Cell membranes prepared from IMR-32 cells were screened by immunoblotting for reactivity with various GABAA receptor alpha subunit-specific antibodies. Of these, only anti-Cys alpha 3 454-467 antibodies recognised specifically and in a dose-dependent manner an immunoreactive band. This M(r) 58,000 immunoreactive species and the N-deglycosylated derivatives were both coincident with the respective homologues found in both calf cerebral cortex membranes and purified receptor preparations. This is the first report of the identification of a specific GABAA receptor subunit expressed in a human cell line, and it therefore provides a convenient model for the study of receptor structure and regulation.

Animals↗
PubMed1991

HIV infection.

Explore the source record for details and available documents.

HIV Infections↗
PubMedDate not supplied

Alloreactivity. I. Effects of age and thymic hormone treatment on cell-mediated immunity in C57B1/6NNia mice.

C57B1/6NNia mice 1, 12, and 24 months old showed loss of cellular-mediated cytotoxicity with aging. Treatment of the three age groups with different thymic hormone preparations effected their cellular mediated cytotoxicity differently. When cytotoxicity of the thymic hormone treated groups was compared to that of the physiological saline treated group, 1-month-old mice treated with serum thymic factor (FTS) at 1 microgram/mouse and 10 ng/mouse had significantly higher activity, and lower to similar activities at 12 and 24 months; TP5 (active fragment of thymopoietin) at 1 microgram and 10 ng caused significantly higher activity in 1-month-old mice, and lower to higher and significantly lower to similar activity at 12 and 24 months, respectively; TM4 (an analogue of TP5) at 1 ng showed significantly depressed activity in 1-month-old mice, and significantly enhanced activity in 12- and 24-month-old mice; thymosin at 10 micrograms and 1 microgram had slightly lower, but not significant, depression at 1 month, similar activities at 12 months and significantly depressed to higher activity at 24 months. Unimmunized control mice showed significant protection in the 12-month-old mice in comparison to 1- and 24-month-old mice. Different hormone preparations showed age- and dose-dependent effects on the ability of spleen cells to kill P815 mastocytoma. Partial restoration of cytotoxicity was observed in 24-month-old mice treated with FTS, TP5 and thymosin fraction V.

Aging↗