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At least 1,009 records · Page 56Linked to original sources
PubMed1992

Memory Formation in Day-old Chicks Requires NMDA but not Non-NMDA Glutamate Receptors.

The non-competitive N-methyl-d-aspartate (NMDA) antagonist MK-801, injected intraperitoneally at 0.1 mg/kg, at times between 1 h before and 5 min after training chicks on a one-trial passive avoidance task, resulted in amnesia for the task on test 3 or 24 h subsequently. No amnesia was apparent at 24 h if chicks were injected between 1 and 6 h after training. Amnesia did not develop immediately; it was not apparent 30 min after training in chicks injected 5 min after training. At this dose of MK-801 no other effects on motor or pecking behaviour of the birds were observed. Bilateral or unilateral intracerebral injections of 1.5 nM MK-801 5 min after training produced a similar amnesia at 3 h to that of intraperitoneally injected MK-801; no hemispheric differences were observed, presumably because of the ready diffusion of the MK-801. By contrast, intracerebral injections of the non-NMDA glutamate antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 6,7-dinitroquinoxaline-2,3-dione (DNQX) and 6,7-nitro-7-sulphamoyl-benzoquinoxaline-2,3-dione (NBQX) (0.066 microM) 5 min after training, despite producing severe if transient behavioural disturbances, were without effect on retention for the avoidance response in chicks tested 3 h subsequently. We interpret these results as pointing to a requirement for NMDA, but not kainate or quisqualate, receptor activation as an early enabling event in the biochemical cascade required for long-term memory formation for passive avoidance in the chick.

Journal Article↗
PubMed1999

Alzheimer's disease and its management in the year 2010.

By 2010 the number of cases of Alzheimer's disease and other dementias will have increased by at least 25 percent. Alzheimer's disease poses an enormous threat to health service and public health resources. Three areas that require targeted research are early detection and recognition, biological markers and diagnosis, and pharmacotherapy. Care of patients with Alzheimer's disease in managed care organizations must be improved through a combination of research, education, advocacy, and legislation. Research in the pathogenic cascade of events within the brain leading to Alzheimer's disease has advanced, and treatment targets within the steps of the process have been specified. The current drug discovery and testing infrastructure is insufficient for major advances in therapy by 2010. Strategies for achieving an optimum outcome by then include increased funding of targeted research; expansion of drug discovery and therapeutic testing efforts; increased training of basic, clinical, and translational scientists; and study of optimum health care delivery systems.

Aged↗
PubMed2004

Hypothermia induces anti-inflammatory cytokines and inhibits nitric oxide and myeloperoxidase-mediated damage in the hearts of endotoxemic rats.

STUDY OBJECTIVE: s: The impairment of cardiac contractility during endotoxemia involves induction of nitric oxide formation through a cascade of events initiated by overexpression of proinflammatory cytokines. We previously showed that hypothermia attenuates endotoxin-induced overexpression of nitric oxide in rat lungs. In the present study, we tested the hypothesis that hypothermia protects against endotoxin-induced myocardial inflammation by changing the balance of pro- and anti-inflammatory cytokines, inhibiting myeloperoxidase, an indicator of neutrophil activity, and inhibiting nitric oxide-mediated protein damage. DESIGN: Rats were randomized to treatment with either hypothermia (n = 6; 18 to 24 degrees C) or normothermia (n = 6; 36 to 38 degrees C). Endotoxin (15 mg/kg) was administered intravascularly to anesthetized animals, and heart tissue was harvested 150 min later. MEASUREMENTS AND RESULTS: Using enzyme-linked immunosorbent assays (ELISAs), we found that hypothermia induced myocardial expression of the anti-inflammatory cytokines interleukin (IL)-4 and IL-10, while decreasing concentrations of the pro-inflammatory cytokines IL-1beta and growth-related oncogene/cytokine-induced neutrophil chemoattractant (rat homolog of IL-8). Electromobility shift assay revealed that hypothermia inhibited the nuclear translocation of nuclear factor-kappaB. Reverse transcriptase-polymerase chain reaction and Western blot assays revealed that hypothermia attenuated the endotoxin-induced overexpression of both inducible nitric oxide synthase (iNOS) messenger RNA and iNOS protein, respectively. Hypothermia also attenuated nitric oxide-mediated myocardial protein damage, as determined by a nitrotyrosine ELISA. Myocardial myeloperoxidase content, an indicator of neutrophil accumulation and oxidative activity, was also inhibited by hypothermia in endotoxemic rats. CONCLUSION: These data demonstrate that hypothermia induces an anti-inflammatory cytokine profile, inhibits neutrophil aggregation, and inhibits the formation of nitric oxide during endotoxemia in the rat.

Animals↗
PubMed2003

HSP60, Bax, and cardiac apoptosis.

HSP60 has long been known as an important chaperonin and as having key folding functions within the mitochondria. However, it has now become evident that significant amounts of HSP60 are found in extra-mitochondrial locations. This extra-mitochondrial HSP60 in the heart has key anti-apoptotic functions. Extra-mitochondrial HSP60 complexes with both bax and bak, but not with bcl-2. Reduction in HSP60 is sufficient to precipitate apoptosis. In the setting of hypoxia and reoxygenation HSP60 decreases with reoxygenation, but the apoptotic cascade has already been triggered by end-hypoxia. Redistribution of cytosolic HSP60 to the plasma membrane during hypoxia appears to contribute to the initiation of the apoptotic cascade with hypoxia and reoxygenation.

Animals↗
PubMed2004

Patterns of gene expression reveal a temporally orchestrated wound healing response in the injured spinal cord.

Spinal cord injury (SCI) induces a progressive pathophysiology affecting cell survival and neurological integrity via complex and evolving molecular cascades whose interrelationships are not fully understood. The present experiments were designed to: (1) determine potential functional interactions within transcriptional expression profiles obtained after a clinically relevant SCI and (2) test the consistency of transcript expression after SCI in two genetically and immunologically diverse rat strains characterized by differences in T cell competence and associated inflammatory responses. By interrogating Affymetrix U34A rat genome GeneChip microarrays, we defined the transcriptional expression patterns in midcervical contusion lesion sites between 1 and 90 d postinjury of athymic nude (AN) and Sprague Dawley (SD) strains. Stringent statistical analyses detected significant changes in 3638 probe sets, with 80 genes differing between the AN and SD groups. Subsequent detailed functional categorization of these transcripts unveiled an overall tissue remodeling response that was common to both strains. The functionally organized gene profiles were temporally distinct and correlated with repair indices observed microscopically and by magnetic resonance microimaging. Our molecular and anatomical observations have identified a novel, longitudinal perspective of the post-SCI response, namely, that of a highly orchestrated tissue repair and remodeling repertoire with a prominent cutaneous wound healing signature that is conserved between two widely differing rat strains. These results have significant bearing on the continuing development of cellular and pharmacological therapeutics directed at tissue rescue and neuronal regeneration in the injured spinal cord.

Algorithms↗
PubMed1999

Human atheromatous plaque extracts induce tissue factor activity (TFa) in monocytes and also express constitutive TFa.

Tissue factor activity (TFa) is a major activator of the coagulation cascade and may play a role in atheroma-induced thrombosis. Monocyte-macrophages (MO-MF) generate considerable quantities of TFa when stimulated by a variety of inducers. To test the hypothesis that MO could be induced by atheromatous plaque to generate TFa, plaque extracts obtained from patients with obstructive atheromatous disease were used. These extracts were also assayed for constitutive TFa. The constitutive activity was variable from extract to extract but could be very high, up to 250 U TFa. The TFa induced in MO could be also very high, up to 200 U (i.e. 1/5 of the TFa of full strength rabbit brain thromboplastin). These findings point to a major role for MO-MF TFa in the induction or thrombosis by atheromatous plaque.

Animals↗
PubMed1992

Effect of exogenous arachidonic acid metabolites applied on round window membrane on hearing and their levels in the perilymph.

Our previous studies revealed that treatment with sodium salicylate or indomethacin caused hearing loss, a decrease in prostaglandin (PG) levels, and an increase in leukotriene (LT) levels of the arachidonic acid (AA) cascade in the perilymph. We suspected that decreased PG-levels and/or elevated LT-levels in the inner ear may be responsible for the salicylate ototoxicity. In order to test this hypothesis, effects of exogenous treatments with PGs, PG-analog, LTs, and other lipoxygenase products on hearing and levels of AA metabolites in the perilymph were studied in chinchillas. Cyclooxygenase products, PGI2, 6-keto-PGF1 alpha, Iloprost (PGI2 analog), PGE2, and LTB4, LTC4, and 15-hydroxyeicosatetraenoic acid (15-HETE) in the lipoxygenase products in the dose of 150 ng were applied on the round window membrane (RWM); cochlear function tested by auditory brainstem response (ABR) and samples of perilymph were collected at 0.5, 1, 2, and 4 hours after the application. Samples of perilymph were assayed for all spectra of AA metabolites by high performance liquid chromatography (HPLC) and radioimmunoassay (RIA). PG-treated animals developed minimal or no hearing loss. LT-treated animals exhibited hearing loss of 20 to 40 dB, peaking at one hour after the treatment. Elevated levels of arachidonic acid metabolites were measured in the perilymph of the ears treated with respective AA metabolites, with peak levels at one hour from the application. The findings of this study indicate that hearing loss can be induced by altered levels of PGs or LTs in the perilymph. This is another strong evidence that salicylate induced ototoxicity can be mediated by abnormal arachidonic acid metabolism in the inner ear.

Animals↗
PubMed2006

Levalbuterol aerosol delivery with a nonelectrostatic versus a nonconducting valved holding chamber.

BACKGROUND: Hydrofluoroalkane-propelled levalbuterol (Xopenex) aerosol is a recently approved formulation for delivery via metered-dose inhaler for the treatment or prevention of bronchospasm in adults, adolescents, and children > or = 4 years of age who have reversible obstructive airway disease. Valved holding chambers (VHCs) made from conventional polymers are susceptible to accumulation of electrostatic charge, which can be minimized by prewashing with ionic detergent, but it may be desirable to be able to use the product straight from the package, without pretreatment, especially during an exacerbation. METHODS: We studied the performance of the AeroChamber Plus and AeroChamber Max VHCs in delivering hydrofluoroalkane-propelled levalbuterol. Both VHCs were prewashed, rinsed, and drip-dried before testing. The AeroChamber Max is manufactured from charge-dissipative material and was therefore also evaluated without prewashing. Aerosol samples were collected at 28.3 L/min with an Andersen 8-stage cascade impactor, per the procedure specified in Chapter 601 of the United States Pharmacopeia. RESULTS: The mean +/- SD fine-particle mass (mass of aerosol particles < 4.7 microm aerodynamic diameter) values were 33.5 +/- 1.4 microg and 36.3 +/- 1.1 microg with the AeroChamber Max, without and with wash/rinse pretreatment, respectively, and 28.5 +/- 2.4 microg with the prewashed AeroChamber Plus. CONCLUSIONS: We think the small differences we observed are unlikely to be of clinical importance, given the inter-patient variability seen with inhaled drug delivery. The performance of the AeroChamber Max was substantially comparable whether or not it was prewashed.

Aerosol Propellants↗
PubMed1988

Fibrinolytic agents and their effects on the haemostatic system.

Fibrinolytic agents used in intravenous thrombolytic therapy of myocardial infarction also exert, at effective dosages, significant side effects on the haemostatic system outside the direct resolution of the target thrombus. The side effects of the agents streptokinase and anisyolated plasminogen-streptokinase activator complex are larger than the side effects of the more fibrin-specific agents tissue-type plasminogen activator and pro-urokinase. An important difference between the two groups of compounds is that the major plasmin inhibitor alpha 2-antiplasmin is completely exhausted for the first two agents, but only in part of the cases for the fibrin-specific agents. The effects on various factors in the fibrinolytic cascade on the plasminogen activator, plasminogen-plasmin and fibrinogen-fibrin levels are reviewed concisely.

Blood Coagulation Tests↗
PubMedDate not supplied

Generalized eigenvector algorithm for nonlinear system identification with non-white inputs.

Traditional methods for nonlinear system identification require a white, Gaussian, test input, a restriction that has limited their usability in many fields. In this study, we address the problem of identifying the dynamics of a nonlinear system when the input is highly colored-a restriction commonly encountered in the study of physiological systems. An extension of the parallel cascade method is developed that is optimal in a constrained minimum mean squared error sense and exactly corrects for the distortion induced by the non-white input spectrum. However, this correction is a deconvolution, which may become extremely ill-conditioned if the input spectrum departs significantly from whiteness; to confront this, we develop a low-rank projection operation that stabilizes the deconvolution. The overall algorithm is robust and places few requirements on the nature of the test input. Practical application of this new method is demonstrated by using it to identify a known analog nonlinear system from experimental data.

Algorithms↗
PubMed2002

Alteration in intracellular calcium homeostasis reduces motor neuronal viability expressing mutated Cu/Zn superoxide dismutase through a nitric oxide/guanylyl cyclase cGMP cascade.

Missense mutations in the human Cu/Zn superoxide dismutase gene (SOD-1) cause many cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS). The accumulation of intracellular calcium is one of the primary mechanisms of motor neuronal degeneration associated with mutations in SOD-1. In order to investigate the effect of various calcium modulators and the SOD-1 mutation on neuronal death, we tested motoneuron-neuroblastoma hybrid (VSC 4.1) cells constitutively expressing human SOD-1 gene with mutations (A4V, G93A) or wild-type. These cells were treated with endogenous calcium releaser (ryanodine, thapsigargin, cyclic ADP-ribose) or calcium mobilizer through cell membrane (4-bromo-calcium ionophore A23187). In particular, calcium ionophore reduced survival in the cells expressing mutant SOD-1. Cell death was associated with increased nitric oxide (NO) generation. This toxicity was attenuated when a nitric oxide synthase (NOS) inhibitor was added. Exogenous NOadministration (S-nitrosoglutathione) also induced cell death. The NO-dependent guanylyl cyclase-cGMP cascade inhibitor protected the mutant cells from the toxic effects of calcium ionophore. Our data suggests that motoneuron degeneration with the SOD-1 mutation may be mediated by calcium dysregulation, particularly by the exogenous calcium influx. This process induces oxidative stress generation that results in motor neuronal death through the guanylyl cyclase-cGMP dependent cascade.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Identifying hypocoagulable states with a modified global assay of overall haemostasis potential in plasma.

To test the sensitivity of the global assay of overall haemostasis potential (OHP) in detecting hypocoagulation, the OHP was assayed in plasma containing exogenous thrombin (0.04 IU/ml), tissue-plasminogen activator (330 ng/ml), Ca and a platelet reagent. Commercial plasmas with factor II, V, VIII, IX, X, XI, XII or VII deficiency were mixed with normal plasma in different proportions to imitate different severities. Samples from patients with haemophilia and factor XII deficiency were also examined. No clot was found in the absence of factor II/factor X, indicating that the tiny dose of thrombin worked solely as a trigger for the intrinsic pathway activation. Changed levels of the investigated coagulants, apart from factor XII, influenced the outcome. OHPs were decreased in patients with haemophilia but were unchanged or even increased in those with factor XII deficiency. This modified OHP method may therefore be useful for estimating the bleeding tendency in haemophilic patients and to find suitable doses and intervals for prophylactic treatment. It may also be of use in investigations of the effect of antifibrinolytic drugs as well as for identifying a thrombotic tendency in patients with factor XII deficiency. For detection of other coagulation factor deficiencies, our investigations with the commercial plasmas suggest that the OHP assay is also valuable, especially when the intrinsic pathway of the coagulation cascade is impaired.

Blood Coagulation↗
PubMed1999

Prospective follow-up of intellectual development in children with a recent onset of epilepsy.

In this study the intellectual development of children with a recent onset of epilepsy was compared to that of children without epilepsy. Eleven children aged 7-15 years and with mean duration of epilepsy of 2 years and 38 children without epilepsy performed three times the dutch Wechsler intelligence scale for children-revised and the Beery developmental test for visuo-motor integration. The children with epilepsy did show a significantly less gain in FSIQ score over the 11 years of follow-up. Performance intelligence scores and Beery standardized scores showed a trend towards this effect. Findings partly support the hypothesized cascadic model of deterioration, in which children with epilepsy are supposed to show a process of mental deterioration shortly after the onset of epilepsy. The lack of evidence of an absolute mental deterioration are discussed in terms of methodology, mental age and premorbid intelligence level.

Adolescent↗
PubMed1996

Factors influencing fetal macrophage development: I. Reactions of the tumor necrosis factor-alpha cascade and their inhibitors.

BACKGROUND: When fetal rat lungs are explanted to organ culture, precursor angular cells soon convert to nascent macrophages that multiply rapidly as they mature into efficient phagocytes. The present study examines the influence of proinflammatory early cytokines of the tumor necrosis factor-alpha (TNF alpha) cascade on this initial expression of the macrophage phenotype. METHODS: Fourteen- and 15-day fetal rat lungs were grown for varying periods on an agar-solidified medium with and without test factors added singly or in combination. Growth of the macrophage population was followed daily by light microscopy and quantified by measuring the area of coronas formed as cells emerged from explants. RESULTS: TNF alpha interleukin-1 beta (IL-1 beta) stimulated growth of the macrophage population, as had macrophage- and granulocyte-macrophage colony-stimulating factors (M- and GM-CSFs) in prior studies. Inhibition was obtained by exposure to IL-1 receptor antagonist and antibodies neutralizing the CSFs. Only the effects of TNF alpha were sufficiently delayed to discount possible influence on conversion and growth of nascent macrophages. Two transcription blockers, dexamethasone and pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor NF-kappa B, both profoundly suppressed macrophage growth without preventing conversion of precursors. Effects of dexamethasone were significantly ameliorated by IL-1 beta alone and combined with GM-CSF; those of PDTC were mitigated by M-CSF and a combination of IL-1 beta and TNF alpha but not by GM-CSF. CONCLUSIONS: IL-1 beta, M-CSF, and GM-CSF all promote growth of the young macrophage population. TNF alpha is effective only later on, likely because early-stage cells lack its receptors which normally use intracellular signalling pathways similar to those for IL-1. The severity of PDTC inhibition to population growth indicates that NF-kappa B is important for transmitting proliferative signals in these cells.

Animals↗
PubMed1994

The stable prostacyclin analogue Cicaprost inhibits metastasis to lungs and lymph nodes in the 13762NF MTLn3 rat mammary carcinoma.

Prostacyclin and its stable analogues have been shown to interfere specifically with certain steps of the metastatic cascade. The antimetastatic activity of the stable prostacyclin analogue Cicaprost (Schering AG) on haematogenous metastasis in a series of tumours in rats and mice has been well established. In order to test the effect of Cicaprost on lymphogenous metastasis we chose the metastatic cell clone MTLn3 derived from the 13762NF rat mammary carcinoma. The effect of Cicaprost on prevention of lung metastasis, lymph node metastasis and primary tumour growth was investigated. Cicaprost given in daily doses of 0.01, 0.03 and 0.1 mg/kg orally, reduced the number of lung metastases in a dose-dependent manner. Whereas the median number of lung metastases in the controls was greater than 1000, Cicaprost at a dose of 0.1 mg/kg reduced the number of lung metastases to between 11 and 100. The weight of the ipsilateral axillary lymph nodes was diminished by Cicaprost to 30-50% of controls. Moreover, metastasis to the contralateral axillary lymph node was completely inhibited by Cicaprost at all three doses tested. Cicaprost did not influence the growth rate of the MTLn3 cell clone implanted into the mammary fat pad or the weight of the primary tumour at the end of treatment. In conclusion, in addition to its dose-dependent effect on haematogenous metastasis, Cicaprost strongly inhibits lymph node metastasis.

Animals↗
PubMed2006

Cell biology of pancreatic proteases.

More than 100 years ago it was proposed that pancreatitis essentially is a disease in which the pancreas undergoes autodigestion by its own prematurely activated digestive enzymes. Why and how digestive zymogens autoactivate within the pancreas early in the disease process has been a matter of controversy and debate. Some of the mechanisms that are considered to be involved indigestive protease activation are inherited and as of recently can be tested for clinically. Here we review the most recent progress in elucidating the mechanisms involved in the onset of pancreatitis. We specifically focus on serine and cysteine proteases in the autodigestive cascade that precedes acinar cell injury and the biochemical processes involved in their activation.

Animals↗
PubMedDate not supplied

Evidence for the involvement of cyclooxygenase activity in the development of cocaine sensitization.

Phospholipase A2 (PLA(2)) activation generates the release of arachidonic acid (AA) and platelet-activating factor (PAF), two compounds which may be involved in neuroplasticity. In previous studies, we found that PLA(2) activation is involved in the development of stimulant sensitization. In the present study, we have examined the roles of AA and PAF in the development of stimulant sensitization using agonists and antagonists selective for PAF receptors or the induction of various AA cascade-mediated eicosanoids. Sprague-Dawley rats were treated for 5 days with cocaine (30 mg/kg) or D-amphetamine (1 mg/kg) preceded 15 min earlier by various antagonists, and then tested following a 10-day withdrawal period for cocaine (15 mg/kg) or D-amphetamine (0.5 mg/kg)-induced locomotion. Consistent with our earlier work, pretreatment with the PLA(2) inhibitor quinacrine (25 mg/kg) blocked the development of cocaine and amphetamine sensitization. The lipoxygenase (LOX) inhibitors nordihydroguaiaretic acid (NDGA) (5-10 mg/kg) and MK-886 (1 mg/kg) had no effect on cocaine sensitization. The PAF receptor antagonist WEB 2086 (5-10 mg/kg) reduced the development of cocaine sensitization. The cyclooxygenase (COX) inhibitors indomethacin (1-2 mg/kg), piroxicam (0.5-1 mg/kg), 6-methoxy-2-napthylacetic acid (6-MNA; 0.5-1 mg/kg), and NS-398 (0.5-1 mg/kg) blocked the development of cocaine sensitization. The COX inhibitors indomethacin (2 mg/kg) and 6-MNA (1 mg/kg) also reduced the development of amphetamine sensitization. Rats were administered bilateral intraventral tegmental area (VTA) injections of D-amphetamine (5 microg/side) or saline coadministered with indomethacin (0.5 microg/side) or vehicle three times over 5 days and were then tested after a 10-day withdrawal for D-amphetamine (0.5 mg/kg ip)-induced locomotion. Intra-VTA amphetamine induced a robust form of amphetamine sensitization, which was blocked by coadministration of indomethacin. Unilateral intra-VTA injections of PAF (1 microg) did not significantly alter cocaine (15 mg/kg ip)-induced locomotion when tested after a 3-day withdrawal. These findings suggest that COX, and possibly PAF, activity is involved in the development of stimulant sensitization. Neuroanatomical studies demonstrate that this may occur at the level of the VTA.

Amphetamine↗
PubMed1985

An investigation of the alarm response in Bufo boreas and Rana cascadae tadpoles.

Tadpoles of the western toad (Bufo boreas) and of the Cascades frog (Rana cascadae) show an alarm reaction to an extract containing chemical cues from damaged conspecifics. The mean time spent by individual B. boreas tadpoles in the half of the test tank to which the extract solution was added was significantly lower than expected by chance. Activity was also significantly greater in Bufo extract tests than in control tests. Tadpoles did not avoid an extract of another tadpole species (Hyla regilla). Rana cascadae tadpoles did not avoid areas containing Rana extract but did significantly increase their level of activity in response to the extract. These results suggest that the R. cascadae tadpole alarm reaction exists but differs from the B. boreas reaction.

Animals↗