Biomedical subjects

P Tandon

Publications and source records attributed to P Tandon.

At least 19 recordsLinked to original sources

PubMed1999

Monte Carlo Simulation of Particle Aggregation and Simultaneous Restructuring.

Ultrafine ("nano"-) particles produced from highly supersaturated vapors or liquids often undergo rapid coagulation and slow interspherule coalescence. Resulting "aggregates" typically contain hundreds of small spherules bound together in tenuous structures characterized by mass fractal dimensions much less than 3. Such aggregates have large and relatively accessible initial surface area but are metastable with respect to more compact configurations, especially in high temperature environments (e.g., flames). Subject to deliberately idealized "uncoupled" rate laws for coagulation and coalescence, we illustrate the power of Monte Carlo simulation methods to obtain the self-preserving joint distribution function (with respect to both particle size and surface area) of populations of coagulating fractal aggregates in the continuum regime, simultaneously undergoing finite-rate restructuring (e.g., via surface-energy-driven viscous flow). Unconditional distributions with respect to either particle volume or area are also obtained from the Monte Carlo simulations. These are conveniently quantified by fitting them to log-normal distributions and we report the sensitivity of the associated spreads to characteristic fusion/coagulation time ratio, chi, and particle fractal dimension, Df, here prespecified. We also calculate and report selected "mixed" moments of the joint pdf with respect to particle volume and surface area needed for engineering calculations of deposition or diffusion-controlled vapor scavenging, as well as the important ratio of actual mean area to that area corresponding to the mean particle volume in the aerosol population. This work sets the stage for tractable simulations of particle dynamics in more complex coagulating systems requiring multi-internal (state-) variables for their more realistic and self-consistent description. Copyright 1999 Academic Press.

Journal Article↗

PubMed1998

Synaptic reorganization following kainic acid-induced seizures during development.

Prolonged seizures in the adult brain causes neuronal loss in the hippocampus and aberrant growth (sprouting) of granule cell axons (mossy fibers) in the supragranular zone of the fascia dentata and stratum infrapyramidale of CA3. There is considerable evidence that these changes in neuronal growth following seizures are age related, with younger animals having fewer reactive changes following prolonged seizures than older animals. However, there is little information available regarding the age at which seizures in the developing brain result in alterations in axonal growth and synapse formation. In this study, we evaluated the effects of kainic acid (KA)-induced seizures during development on synaptic reorganization using the expression of growth-associated protein-43 (GAP-43), a marker for synaptogenesis and Timm stain which detects the presence of zinc in granule cell axons. Age specific doses of KA were used to induce seizures of similar intensity at various ages (postnatal days (P) 12, 21, 25, 35, 45, 60) in Sprague-Dawley rats. Up to the age of P25, there were no differences in either Timm or GAP-43 staining between animals with KA seizures and controls. In P25 and older KA-treated rats, Timm staining was found in the supragranular layer of the dentate gyrus. This staining increased with age at the time of KA injection. Seizures in adult (P60), but not younger rats also resulted in increased staining in the suprapyramidal layer of the CA3 subfields. Changes in GAP-43 were delayed compared to the Timm staining with no differences between KA-treated animals and controls until P35 when a band of GAP-43 immunostaining appeared in the supragranular inner molecular layer, progressively increasing in intensity and thickness with time. This study demonstrates that seizure-induced reactive synaptogenesis is age-related. Since both Timm and GAP-43 reflect different aspects of reactive synaptogenesis, used in combination these methods provide useful information about the structural changes following seizures during development.

Aging↗

PubMed1998

Kinetics of beta2-integrin and L-selectin bonding during neutrophil aggregation in shear flow.

Activated neutrophils aggregate in a shear field via bonding of L-selectin to P-selectin glycoprotein ligand-1 (PSGL-1) followed by a more stable bonding of LFA-1 (CD11a/CD18) to intercellular adhesion molecule 3 (ICAM-3) and Mac-1 (CD11b/CD18) to an unknown counter receptor. Assuming that the Mac-1 counter receptor is ICAM-3-like in strength and number, rate processes were deconvoluted from neutrophil homoaggregation data for shear rates (G) of 100-3000 s-1 with a two-body hydrodynamic collision model (. Biophys. J. 73:2819-2835). For integrin-mediated aggregation (characteristic bond strength of 5 microdynes) in the absence of L-selectin contributions, an average forward rate of kf = 1.57 x 10(-12) cm2/s predicted the measured efficiencies for G = 100-800 s-1. For a selectin bond formation rate constant equal to the integrin bond formation rate constant, the colloidal stability of unactivated neutrophils was satisfied for a reverse rate of the L-selectin-PGSL bond corresponding to an average bond half-life of 10 ms at a characteristic bond strength of 1 microdyne. Colliding neutrophils initially bridged by at least one L-selectin-PSGL-1 bond were calculated to rotate from 8 to 50 times at G = 400 to 3000 s-1, respectively, before obtaining mechanical stability in sheared fluid of either 0.75 or 1.75 cP viscosity. Thus for G > 400 s-1, the interaction time needed for the rotating aggregates to become stable was relatively constant at 52.5 +/- 8.5 ms, largely independent of shear rate or shear stress. Aggregation data and the colloidal stability criterion can provide a consistent set of forward and reverse rate constants and characteristic bond strengths for a known time-dependent stoichiometry of receptors on cells interacting in a shear flow field.

Biophysical Phenomena↗

PubMed1998

Comparison of valproate and phenobarbital treatment after status epilepticus in rats.

OBJECTIVE: To investigate the long-term effects of two widely used antiepileptic medications, valproate and phenobarbital, on learning and behavior in the kainic acid (KA) model of epilepsy. BACKGROUND: Prior clinical and animal studies have demonstrated that phenobarbital administered during development may result in subsequent cognitive impairment. It is unclear whether these adverse effects of phenobarbital extend to other antiepileptic drugs. METHODS: A convulsant dose of KA was administered to rats on postnatal day (P) 35. From P36-75 rats received daily injections of phenobarbital (PH), valproate (VPA), or saline and spontaneous seizure frequency was monitored with video recordings. After tapering of the drugs, the rats were tested in the water maze (a measure of visuospatial memory) and handling test (a measure of emotionality). Brains were then analyzed for histologic lesions. RESULTS: KA caused status epilepticus in all the rats. In the PH- and saline-treated groups, there was impaired learning in the water maze, increased emotionality, recurrent seizures, and histologic lesions in the hippocampal areas CA3, CA1, and dentate hilus. However, VPA-treated rats had no spontaneous seizures, abnormalities in handling, or deficits in visuospatial learning, and had fewer histologic lesions than animals receiving KA alone. CONCLUSIONS: The long-term consequences of AED treatment during development are related to the drug used. VPA treatment after KA-induced status epilepticus prevents many of the neurologic sequelae typically seen after KA.

Animals↗

PubMed1997

Seizure-induced glutamate release in mature and immature animals: an in vivo microdialysis study.

A glutamate biosensor was used to measure extracellular glutamate concentrations in the hippocampus of mature and immature animals. Significant elevations of extracellular glutamate were observed following seizures induced by either kainic acid or pilocarpine. The degree of glutamate increase following seizures was similar in both mature and immature animals. These results suggest that excitotoxicity may play a role in seizure-induced brain damage in the adult brain. In the immature brain, however, no brain damage is seen after seizures, suggesting that glutamate release may not cause as significant excitotoxic damage early in development.

Aging↗

PubMed1997

Hydrodynamic effects and receptor interactions of platelets and their aggregates in linear shear flow.

We have modeled platelet aggregation in a linear shear flow by accounting for two body collision hydrodynamics, platelet activation and receptor biology. Considering platelets and their aggregates as unequal-sized spheres with DLVO interactions (psi(platelet) = -15 mV, Hamaker constant = 10(-19) J), detailed hydrodynamics provided the flow field around the colliding platelets. Trajectory calculations were performed to obtain the far upstream cross-sectional area and the particle flux through this area provided the collision frequency. Only a fraction of platelets brought together by a shearing fluid flow were held together if successfully bound by fibrinogen cross-bridging GPIIb/IIIa receptors on the platelet surfaces. This fraction was calculated by modeling receptor-mediated aggregation using the formalism of Bell (Bell, G. I. 1979. A theoretical model for adhesion between cells mediated by multivalent ligands. Cell Biophys. 1:133-147) where the forward rate of bond formation dictated aggregation during collision and was estimated from the diffusional limited rate of lateral association of receptors multiplied by an effectiveness factor, eta, to give an apparent rate. For a value of eta = 0.0178, we calculated the overall efficiency (including both receptor binding and hydrodynamics effects) for equal-sized platelets with 50,000 receptors/platelet to be 0.206 for G = 41.9 s(-1), 0.05 for G = 335 s(-1), and 0.0086 for G = 1920 s(-1), values which are in agreement with efficiencies determined from initial platelet singlet consumption rates in flow through a tube. From our analysis, we predict that bond formation proceeds at a rate of approximately 0.1925 bonds/microm2 per ms, which is approximately 50-fold slower than the diffusion limited rate of association. This value of eta is also consistent with a colloidal stability of unactivated platelets at low shear rates. Fibrinogen was calculated to mediate aggregation quite efficiently at low shear rates but not at high shear rates. Although secondary collisions (an orbitlike trajectory) form only a small fraction of the total number of collisions, they become important at high shear rates (>750 s(-1)), as these are the only collisions that provide enough time to result in successful aggregate formation mediated by fibrinogen. The overall method provides a hydrodynamic and receptor correction of the Smoluchowski collision kernel and gives a first estimate of eta for the fibrinogen-GPIIb/IIIa cross-bridging of platelets. We also predict that secondary collisions extend the shear rate range at which fibrinogen can mediate successful aggregation.

Adenosine Diphosphate↗

PubMed1997

Acute effects of MK801 on kainic acid-induced seizures in neonatal rats.

Kainic acid (KA) causes behavioral and electrographic status epilepticus (SE) in rats of all ages. In adult rats, the noncompetitive N-methyl-D-aspartate (NMDA) channel blocker MK801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine ) is anticonvulsant against KA-induced seizures: it reduces their severity and protects against neuronal damage, although it may worsen electrographic seizures. Here we examined the effects of MK801 on KA seizures in the immature brain. Neonatal rats (P11-P12) were pretreated with MK801 (0.01, 0.1, 0.5 or 1.0 mg/kg, i.p.) or saline twenty minutes prior to KA (2 mg/kg, i.p.). Clinical seizure behavior was monitored for > 6 hrs, and in some rats the EEG was monitored with an intrahippocampal or intracortical electrode. MK801 caused immobility alternating with hyperactivity, ataxia, scratching and sometimes alternate limb cycling, which correlated with the appearance of spikes on the EEG. Compared to KA alone or KA preceded by 0.01 mg/kg MK801, the higher doses of MK801 (0.1, 0.5 and 1.0 mg/kg) significantly lowered the latency to electrographic seizures (P < 0.001), ictal scratching (P < 0.0001), and status epilepticus (P < 0.0001). MK801 pretreatment did not lower significantly the death rate due to KA seizures. No histologic damage was seen after MK801, KA or both agents together. These results suggest that MK801 exacerbates KA-induced seizures in the neonatal brain, and may even cause ictal behavioral and electrographic manifestations by itself. The findings point to an age-dependency of NMDA antagonist action, and suggest caution in considering the use of NMDA antagonists in neonates.

Animals↗

PubMed1997

Multiple kainic acid seizures in the immature and adult brain: ictal manifestations and long-term effects on learning and memory.

PURPOSE: While there is increasing evidence that the adverse effects of prolonged seizures are less pronounced in the immature than in the mature brain, there have been few investigations of the long-term effects of recurrent seizures during development. This study examined the effects of multiple administrations of the convulsant kainic acid (KA) on seizure characteristics and spatial learning as a function of brain development. METHODS: To determine the long-term effects of serial KA seizures during ontogeny, saline or convulsant doses of KA were given intraperitoneally 4 times, at 2-day intervals. Immature rats were given KA on P20, P22, P24 and P26; adult rats got KA on P60, P62, P64 and P66. Ictal characteristics and EEGs were recorded. To examine the effects of multiple KA seizures on the retention of spatial learning, water maze testing was performed before (immature group: from P16-19, adult group: from P56-P59) and after (immature: from P60-P63, adult: from P100-P103) KA injections. Finally, histology was performed to compare KA-induced damage at each age. RESULTS: In immature animals, serial KA administration resulted in seizures with a progressively longer onset latency and decreased severity. In contrast, KA serially administered to adult rats caused severe seizures after each of the 4 injections. In immature rats, epileptiform EEG changes were most prominent after the first KA injection, whereas in adults, prolonged paroxysmal EEG patterns were seen after all 4 KA injections. Before KA, both rat pups and adults acquired place learning in the water maze. One month after the final KA injection, there was no deficit in spatial learning retention in the immature group, whereas the adult group had profound impairment compared to age-matched, saline-injected controls. Histology revealed no lesions in immature rats treated multiple times with KA but profound cell loss in hippocampal fields CA4, CA3 and CA1 in rats treated serially with KA as adults. CONCLUSIONS: Previous studies have shown that a single KA injection causes prolonged status epilepticus (which persists for several hours), leading to severe histologic and behavioral sequelae in adult rats but not in pups. Our study extends those findings, demonstrating that immature rats are spared the cognitive and pathological sequelae of multiple injections of convulsant doses of KA as well.

Animals↗

PubMed1997

Ketogenic diet: effects on expression of kindled seizures and behavior in adult rats.

PURPOSE: Despite use of the ketogenic diet (KD) for >75 years its effectiveness or mechanism of action has been examined in few animal studies. Using the kindling model of epilepsy, we tested the anticonvulsant effectiveness and behavioral consequences of an experimental KD in adult rats. METHODS: Rats fully kindled from the amygdala were divided into KD-fed or standard rat diet-fed groups; diet treatment continued for 5 weeks. The KD approximated at 4:1 ("classic") ketogenic diet and consisted (by weight) of 70% fat, 14% protein, no carbohydrate, and appropriate vitamins, minerals and fiber; 92% of energy provided was contributed by fat and 8% was contributed by protein. Afterdischarge threshold and duration (ADT, ADD) and stage 5 seizure threshold and duration (ST, SD) were assessed weekly for 5 weeks. During week 3, learning and memory were tested by the water maze and the behavioral response to a novel environment was assessed by the open field test. RESULTS: Rats receiving the KD became ketonemic and had weight gains similar to those of control rats. As compared with rats receiving a standard diet, those fed the KD had an elevated ADT and ST for the first 2 weeks of treatment. The control and KD-fed groups did not differ with regard to ADD or SD at any time during the study, and both groups performed similarly in the water maze and open field test. CONCLUSIONS: In the kindling model, the KD afforded transient protection against the focal generation of kindled seizures but not seizure spread. Rats that received the KD did not perform differently from control-fed rats on spatial learning or exploratory behavior tasks. Our results provide a promising model for study of the anticonvulsant mechanisms of ketosis.

Animals↗

PubMed1997

Out of hours cross-cover between oral and maxillofacial surgery and ear, nose and throat surgery.

Emergency cross-cover between two specialties, oral and maxillofacial surgery and ear, nose and throat surgery, has been introduced and run successfully in York District Hospital for the last 18 months in order to reduce the working hours of junior doctors, as recommended by the New Deal. During this trial period of out of normal hours cross-cover in a two-tier system, we have found that the new arrangement has increased our shared knowledge, understanding and practical experience of both specialties as well as satisfying the service needs with no significant clinical problems arising.

Education, Medical, Graduate↗

PubMed1996

Age-dependent effects of glutamate toxicity in the hippocampus.

While prolonged seizures can cause brain damage at any age, the extent of brain damage following prolonged seizures is highly age-dependent. Seizures in the immature brain are followed by far less histological damage than seizures of similar duration and intensity in mature animals. The reasons for this age-related phenomenon are unclear. Seizure-induced cell death may be due to the neurotoxic effects of excessive glutamate release, we tested the hypothesis that the immature brain is less vulnerable to glutamate-induced neurotoxicity than the mature brain. We administered equal amounts of glutamate (0.5 mumol in 1.0 microliter) unilaterally into the CA1 subfield of the hippocampus of rats at postnatal (P) days 10, 20, 30, and 60. Equal volumes of saline were injected in the contralateral hippocampus. Rats were killed 7 days later and their brains were examined for hippocampal cell loss. The size of the resultant hippocampal lesion was highly age-dependent. Minimal cell loss was noted in the P10 rats, lesions in the P20 rats were smaller than those at P30 and P60, which were similar in extent. This study demonstrates that the extent of glutamate neurotoxicity in the hippocampus is highly age-dependent, with immature hippocampi relatively resistant to glutamate-induced cell death.

Aging↗

PubMed1996

Long-term effects of excitatory amino acid antagonists NBQX and MK-801 on the developing brain.

Because of the critical role of excitatory amino acids (EAAs) in epileptogenesis and seizure-induced brain damage, EAA antagonists are now being considered as a possible therapy for seizures. However, during development EAAs play a pivotal role in learning, memory, and brain plasticity. To evaluate the long-term effects of a short course of EAA antagonists on the developing brain, a non-NMDA antagonist, NBQX, or a NMDA antagonist, MK-801, were administered over 7 days by osmotic pumps stereotaxically implanted into the lateral ventricles of normal 10 day old rats. Alternatively, 10 and 20 day old rats received a 7 day course of intraperitoneal (i.p.) NBQX. One month later, the NBQX-, MK-801-treated rats, and controls underwent a series of behavioral studies: handling test, open field, and Morris water maze. Flurothyl inhalation was used to test seizure susceptibility in all groups. Although all of the rats treated with NBQX via osmotic pumps has spontaneous seizure, rats surviving infusion of EAAs had no deficits in learning, memory, or behavior and did not differ from controls in seizure susceptibility with flurothyl. In the developing animal, a short-term course of EAA antagonists leads to no long-term adverse effects on behavior or seizure susceptibility.

Animals↗

PubMed1996

Recurrent seizures in immature rats: effect on auditory and visual discrimination.

The effect of recurrent seizures in developing rats on subsequent long-term behavior was studied. Fifteen day old rats received a convulsant dosage of flurothyl three times daily for five consecutive days. When the rats were fully mature, they underwent behavioral testing using the water maze and auditory quality or location discrimination. With serial flurothyl administration seizure duration increased progressively but latency to seizure onset did not change. Compared to controls, flurothyl-treated rats had impaired performance in the water maze and on auditory location, but not on quality discrimination. Histological examination showed no gross cell loss in the hippocampus. This study demonstrates that serial seizures in the developing brain cause detrimental effects on visual and auditory spatial learning.

Animals↗

PubMed1994

Fenthion produces a persistent decrease in muscarinic receptor function in the adult rat retina.

Several reports have suggested that exposure to organophosphate pesticides damages the visual system. The prolonged effects of an acute dose of fenthion (dimethyl 3-methyl-4-methylthiophenyl phosphorothionate) were studied on the cholinergic system of the rat retina. Fenthion was administered in a single dose of 0 or 100 mg/kg (sc, in corn oil) to adult, male, Long-Evans rats. The animals were killed 4, 14, or 56 days after treatment and cholinesterase (ChE) activity as well as muscarinic receptor (mChR) function measured in the retina and frontal cortex. Fenthion produced 89% inhibition of ChE activity in both tissues at 4 days, and, although there was recovery, slight (15%) inhibition of the enzyme activity was still observed at 56 days in both tissues. A long-lasting decrease in carbachol-stimulated inositolphosphate (IP) release was observed following fenthion treatment in the retina: IP release was depressed at 4 days and this depression persisted up to 56 days after dosing. The density of mChR in the retina as well as in the cortex was decreased by 14-20% at 4 days and returned to control levels by 56 days. Fenthion had no effect on the metabolism of phospholipids in the retina following intraocular injections of labeled precursors [3H]myo-inositol, [methyl-14C]choline, or [2-3H]glycerol 4 days after fenthion treatment. These prolonged effects of fenthion on mChR function (signal transduction) appear to be specific to the retina as the cortex showed no change in receptor-stimulated IP release even in the presence of significant mChR down-regulation and ChE inhibition. This dose of fenthion did not produce overt morphological changes in the retina or in the cortex, as observed with light microscopy, although an increase in glial fibrillary acidic protein immunoreactivity (GFAP IR) extending from the internal limiting membrane to the external limiting membrane of the retina was noted. This increase in GFAP IR was observed at 14 days and persisted as long as 56 days post-treatment in the retina, but was not noted in the cortex at any of the time points studied. Thus, this long-lasting perturbation in the retinal cholinergic second messenger system induced by fenthion may occur independently of depressed ChE activity and down-regulation of mChR.

Animals↗

PubMed1994

Compensatory changes in the hippocampus following intradentate infusion of colchicine.

Direct infusion of colchicine into the dentate gyrus of the hippocampus kills granule cells and elicits behavioral, neurochemical and neuroanatomical changes. Colchicine-treated rats are less sensitive to the behavioral effects of cholinergic muscarinic receptor antagonists and more sensitive to cholinergic agonists. These behavioral changes are associated with time- and dose-dependent alterations in the cholinergic signal transduction mechanism. Carbachol-stimulated turnover of phosphoinositides is increased in the hippocampus of colchicine-treated rats; similar changes are not observed in the cortex or striatum of colchicine-treated animals. Intradentate colchicine produces a significant increase in choline- acetyltransferase activity and staining for acetylcholinesterase activity in the hippocampus, suggesting reactive synaptogenesis of cholinergic fibers. Other studies have shown that the integrity of the septohippocampal pathway is necessary for these colchicine-induced compensatory changes to occur. It is suggested that the mechanism for these neurochemical changes in colchicine-treated animals may be occurring via alterations in negative feedback control of receptor-G-protein-mediated phosphoinositide hydrolysis.

Animals↗

PubMed1994

Dynamics of Met5- and Leu5-enkephalin and their receptor binding activity in relation to morphine.

A complete normal coordinate analysis of Met5- and Leu5-enkephalins using Wilson's GF matrix method and Urey Bradley force field has been carried out to understand the dynamical behaviour of enkephalins. In addition, the charge distributions on different atoms of the two enkephalins and morphine using CNDO/2 method are also reported. The similarity in the charge distribution on the part of these two molecules is indicative of the possible interactions at the same receptor site as that of morphine and its derivatives. Apart from the topographical features and charge distribution, binding onto receptor site is not a static but a dynamic process and low frequency modes must play an important role in the recognition process. The significance of the out-of-plane amide VII band and other skeletal modes as characteristic of conformational states of Met5- and Leu5-enkephalins are discussed.

Enkephalin, Leucine↗

PubMed1993

Operations on gliomas involving speech centres.

One hundred patients with gliomas of the dominant hemisphere, who survived for more than one year after operation, have been analysed. In all of them radical tumour removal had been attempted. Already preoperatively 58 of them had signs of speech deficit. Postoperatively 65% improved and only 15% deteriorated with regard to their speech function. Therefore it seems not to be justified to deny operative tumour removal to patients with gliomas located within or near the speech areas.

Adult↗

PubMed1993

Locally synthesized phosphatidylcholine, but not protein, undergoes rapid retrograde axonal transport in the rat sciatic nerve.

Retrograde axonal transport of phosphatidylcholine in the sciatic nerve has been demonstrated only after injection of lipid precursors into the cell body region. We now report, however, that after microinjection (1 microliter) of [methyl-3H]choline chloride into the rat sciatic nerve (35-40 mm distal to the L4 and L5 dorsal root ganglia), time-dependent accumulation of 3H-labeled material occurred in dorsal root ganglia ipsilateral, but not contralateral, to the injection site. The level of radioactivity in the ipsilateral dorsal root ganglia was minimal at 2 h after isotope injection but was significantly increased at 7, 24, 48, and 72 h after intraneural isotope injection (n = 3-8 per time point); at these time points, all of the radiolabel in the chloroform/methanol extract of the ipsilateral dorsal root ganglia was present in phosphatidylcholine. The radioactivity in the water-soluble fraction did not show a time-dependent accumulation in the ipsilateral dorsal root ganglia as compared with the contralateral DRGs, ruling out transport or diffusion of precursor molecules. In addition, colchicine injection into the sciatic nerve proximal to the isotope injection site prevented the accumulation of radiolabel in the ipsilateral dorsal root ganglia. Therefore, this time-dependent accumulation of radiolabeled phosphatidylcholine in the ipsilateral dorsal root ganglia is most likely due to retrograde axonal transport of locally synthesized phospholipid material. Moreover, 24 h after injection of both [3H]choline and [35S]-methionine into the sciatic nerve, the ipsilateral/contralateral ratio of radiolabel was 11.7 for 3H but only 1.1 for 35S, indicating that only locally synthesized choline phospholipids, but not protein, were retrogradely transported.

Animals↗