Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Generations”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 523 records · Page 29Linked to original sources
PubMed2001

Reliability of functional MR imaging with word-generation tasks for mapping Broca's area.

BACKGROUND AND PURPOSE: Functional MR (fMR) imaging of word generation has been used to map Broca's area in some patients selected for craniotomy. The purpose of this study was to measure the reliability, precision, and accuracy of word-generation tasks to identify Broca's area. METHODS: The Brodmann areas activated during performance of word-generation tasks were tabulated in 34 consecutive patients referred for fMR imaging mapping of language areas. In patients performing two iterations of the letter word-generation tasks, test-retest reliability was quantified by using the concurrence ratio (CR), or the number of voxels activated by each iteration in proportion to the average number of voxels activated from both iterations of the task. Among patients who also underwent category or antonym word generation or both, the similarity of the activation from each task was assessed with the CR. In patients who underwent electrocortical stimulation (ECS) mapping of speech function during craniotomy while awake, the sites with speech function were compared with the locations of activation found during fMR imaging of word generation. RESULTS: In 31 of 34 patients, activation was identified in the inferior frontal gyri or middle frontal gyri or both in Brodmann areas 9, 44, 45, or 46, unilaterally or bilaterally, with one or more of the tasks. Activation was noted in the same gyri when the patient performed a second iteration of the letter word-generation task or second task. The CR for pixel precision in a single section averaged 49%. In patients who underwent craniotomy while awake, speech areas located with ECS coincided with areas of the brain activated during a word-generation task. CONCLUSION: fMR imaging with word-generation tasks produces technically satisfactory maps of Broca's area, which localize the area accurately and reliably.

Brain Mapping↗
PubMed2002

Decreased concentrations of heparinoids are required to inhibit thrombin generation in plasma from newborns and children compared to plasma from adults due to reduced thrombin potential.

Thrombin generation is decreased and delayed in plasma from newborns and children compared to adults. We hypothesized that lower doses of heparinoid anticoagulants are required to give similar thrombin generation in newborn (umbilical cord) and child plasmas compared to that of adults. Thrombin generation was performed in either the absence or presence of unfractionated heparin (UFH), low molecular weight heparin (LMWH) or a covalent antithrombin-heparin complex (ATH). After contact activation and recalcification of each plasma, thrombin activity was measured by periodic sub-sampling into chromogenic substrate. UFH inhibited thrombin generation to a greater extent compared to LMWH in all plasmas. Cord plasma was more sensitive to inhibition and displayed a greater difference in the effectiveness of UFH compared to LMWH than other plasmas. Lower concentrations of UFH and LMWH were required to inhibit thrombin generation in cord and child plasmas compared to adult plasma. In comparison, ATH strongly inhibited thrombin generation in all 3 plasmas. Similar peak thrombin concentrations were observed at lower ATH concentrations (0.1 U/mL) compared to either UFH (0.25 U/mL) or LMWH (0.25 U/mL). As with UFH and LMWH, cord plasma was more sensitive to inhibition by ATH than the other plasmas and lower ATH concentrations inhibited thrombin generation in cord and child plasmas compared to adult plasma. Decreased thrombin generation with heparinoids in cord and child plasmas compared to adult plasma coincided with decreased rates of prothrombin consumption and increased proportion of thrombin-alpha2-macroglobulin inhibitor complexes. In summary, lower doses of UFH, LMWH or ATH result in similar peak thrombin generation in newborn and child plasmas compared to adult plasma. Cord plasma was the most sensitive to inhibition, with ATH being more effective than UFH or LMWH.

Adolescent↗
PubMed1992

[Rearrangements of efferent activity parameters in generators of cyclic motor reactions during electric stimulation of cerebellum inputs and outputs in the cat].

Rearrangements of the activity parameters of scratching and locomotor generators conditioned by electric stimulation of the inferior olive, nucleus reticularis lateralis as well as of the fastigial nucleus and nucleus interpositus of the cerebellum were investigated on decerebrate immobilized animals. Scratching and locomotor generators were characterized by the ability to effectively rearrange the time structure of their activity in response to certain changes in phase and amplitude characteristics of signals arriving both by the mossy and climbing inputs of the cerebellum. The flexor half-centre of the locomotor generator and aiming half-centre of the scratching generator increased both the period and intensity of their activity under influence of signals arriving to the cerebellum from the inferior olive and nucleus reticularis lateralis at the first half of the working phase of these half-centres. Stimulation of the inferior olive and nucleus reticularis lateralis during the second half of the flexor and aiming phases evoked somewhat different changes in correlation of activity for half-centres of the locomotor and scratching generators. A slight shortening of the activity period of the aiming half-centre during scratching and a decrease of the activity period of the extensor half-centre during locomotion were observed. Stimulation of the structures mentioned above during the working phase of half-centres controlling limb extensor movements evoked shortening of the extensor half-centres activity period during locomotion and exerted no effect on the scratching jerk half-centre activity period during scratching. The scratching generator, unlike the locomotor generator is characterized by a significant degree of resemblance of the rearrangement of generator efferent activity parameters evoked by electric stimulation of the cerebellum nuclei and its afferent inputs. Possible mechanisms of forming the correcting influences on scratching and locomotor generators from the cerebellum during changes in phase and amplitude characteristics of its input signals are discussed.

Afferent Pathways↗
PubMed2006

Generation of tumor-reactive effector lymphocytes using tumor RNA-introduced dendritic cells in gastric cancer patients.

Anti-tumor effector cells were generated by stimulating peripheral blood lymphocytes with cultured dendritic cells (DCs) and mRNA extracted from the gastric cancer cell line MKN45 or ascites tumor cells of gastric cancer patients. DCs were generated from an adherent fraction of peripheral blood mononuclear cells (PBMCs) in the presence of GM-CSF and IL-4. mRNA was extracted from tumor cells and subjected to T7-amplification. The DCs were electroporated (150 V/150 microF) with amplified mRNA and used after maturation with TNF-alpha to stimulate PBMCs to generate tumor RNA-introduced DC-activated killer (TRiDAK) cells. It was found that tumor RNA could efficiently be introduced into cultured DCs by electroporation (55% efficiency, 78% viability), and tumor RNA-introduced DCs could reproducibly stimulate lymphocytes to be tumor-reactive TRiDAK cells. The TRiDAK cells expressed an IFN-gamma response specific for tumor cells, but not for normal cells. Mock DCs or normal cell RNA-introduced DCs did not induce any killer cells. RNA-specific recognition of the effector cells generated was demonstrated using an amplified EGFP-mRNA system. The tumor killing activity of TRiDAK cells was inhibited not only with the anti-HLA class I antibody but also with the anti-HLA class II antibody as well as the anti-TCR antibody. TRiDAK cells reactive with autologous tumor cells could be generated in a CEA-positive gastric cancer patient with malignant ascites, in whom effector cell generation using DCs and CEA peptides had failed. These results suggest that TRiDAK cell generation is safe, feasible, and active in gastric cancer patients with malignant ascites, and is superior to other effector cell generation systems using DCs and epitope peptides. The adoptive immunotherapy of cancer using TRiDAK cells may be warranted in a clinical setting. This is the first study investigating anti-tumor effector cell generation using cultured DCs and tumor mRNA from gastric cancer cells.

Antigen-Presenting Cells↗
PubMed2005

[Caspar Friedrich Wolff (1734-1794). The concept of epigenesis and the problem of spontaneous generation].

The link between the notion of epigenesis and that of spontaneous generation does not seem complicated when it is viewed in theoretical terms or when it is approached in a pure model form. However, once any of its particular manifestations in the history of biology is analysed, the interrelationship between the two notions ceases to be unequivocal. One example of that comes with the first fully-fledged concept of epigenesis, based on careful observation of embryonic development, presented by Caspar Friedrich Wolff in the 18th century. The process of development that an act of spontaneous generation has given rise to cannot, of course, be anything else but one of epigenesis. In this sense, epigenesis constitutes a necessary condition for spontaneous generation, but is not a sufficient condition, i.e. not every process of development through epigenesis has at its source an act of spontaneous generation. Evidence that Wolff was inclined towards the concept of spontaneous generation comes from the presence in his works of a notion described by the Latin term ortus (emergence). That notion--together with that of an organic body--is subject to detailed analysis in the current paper. If the process of spontaneous generation is understood as a process of emergence in nature of what is animate and organic, from what is inanimate and non-organic, and as a process in which living beings are not involved, but a living being is its outcome, then the notion of ortus is close in meaning to the notion of spontaneous generation. However, the deistic and theological philosophical foundation of Wolff's concept of epigenesis is in conflict with the notion of spontaneous generation. It seems that Wolff's notion of ortus can be interpreted in two ways. Firstly, it can be interpreted as as result of the theoretical extrapolation in time applied by Wolff to the usual way in which organic bodies emerge (the process is always given rise to by a nonorganic body, supplied by another organic body), all the way back to that the distant moment when the first organic body in time was to emerge; this extrapolation has been reconstructed in detail in the current paper. Secondly, the notion of ortus can be also interpreted as a special kind of heterogenesis, a process which is given rise to by an organic body, but which produces living beings that do not deserve the name of organic bodies--beings that are poorly differentiated in terms of morphology and organization, and thus devoid of distinct species membership, such as simple algae, moulds, internal parasites etc. If that is a correct interpretation, then in neither case would Wolff's ideas have anything to do with real spontaneous generation in the strict sense.

Embryology↗
PubMed1987

The effects of N-3 polyunsaturated fatty acids on the generation of platelet-activating factor-acether by human monocytes.

Human leukocytes generate platelet-activating factor (PAF-acether), a lipid mediator of inflammation, from membrane alkyl phospholipids through the release of arachidonic acid or other fatty acids at the 2-position and subsequent acetylation. Because it was previously demonstrated that fish oil fatty acids suppress human leukocyte arachidonic acid release and metabolism, separate experiments were conducted to investigate the effects of dietary fish oil supplementation and in vitro incubation with fish oil fatty acids on calcium ionophore-stimulated PAF-acether generation in human monocytes. In subjects on their regular diets, a 4-hr incubation of monocyte monolayers with an optimally effective concentration of arachidonic acid of 1 micrograms/ml resulted in a 64% increase of calcium ionophore-induced net PAF-acether generation from 7.75 +/- 0.78 ng/10(6) cells for untreated monolayers to 12.70 +/- 1.21 ng/10(6) cells (mean +/- SEM). Treatment of monolayers with eicosapentaenoic acid (EPA) at the optimal concentration of 1 micrograms/ml decreased net PAF-acether generation by 28%. However, treatment of monocyte monolayers with docosahexaenoic acid did not appreciably affect net PAF-acether generation. The changes in PAF-acether release with each fatty acid added in vitro paralleled those in total PAF-acether generation; the percentage PAF-acether release remained unaffected. Three weeks of dietary supplementation with 18 g MaxEPA daily, providing 3.2 g EPA did not affect the PAF-acether generation of calcium ionophore-stimulated human monocyte monolayers. However, 6 weeks of dietary supplementation resulted in a 47% decrease of net total PAF-acether generation and a concomitant 59% decline in net PAF-acether release; the percentage release of PAF-acether was not affected. Thus, whether added to the diet or introduced in vitro, fish oil-derived fatty acids suppress PAF-acether generation by human monocyte monolayers.

Adult↗
PubMed1986

Effectiveness of micronic aerosol generators and their aerosol characteristics.

We assessed the effectiveness of various aerosol-generating systems. Taplin's settling method and Venticis generators had a lower efficiency (37.3 +/- 3.8% and 51.8 +/- 9.6%, respectively) than the Syntevent (88.8 +/- 6.9%, p less than 0.001), Cadema (89.8 +/- 9.9%, p less than 0.001) and Mefar (85.3 +/- 19.4%, p less than 0.001) generators. The Mass Median Aerodynamic Diameter of the particles produced by the Mefar nebulizer (2.05 +/- 0.27 micron) was larger than that of any other generators (p less than 0.001). The Syntevent (0.54 +/- 0.09 micron) generator produced smaller particles than the Mefar, Taplin (0.89 +/- 0.10 micron, p less than 0.01) and Venticis (0.79 +/- 0.06 micron, p less than 0.02) generators. Particles produced by the Cadema system (0.69 +/- 0.06 micron) were smaller than those generated by the Taplin system (p less than 0.05). We conclude: that the Syntevent, Mefar and Cadema aerosol generators are more efficient than the others, and that all the generators tested except the Mefar may be used for studies that depend on the peripheral deposition of small particles within the lungs.

Aerosols↗
PubMed1985

Interleukin generation in experimental colon cancer of rats: effects of tumor growth and tumor therapy.

The capacity of inbred W/Fu rats bearing syngeneic colon carcinomas to generate interleukin(s) (IL) was studied during primary tumor growth, after tumor resection, and during postresection immunotherapy. During local tumor growth, there was a significant decrease in the capacity of the host's adherent mononuclear cells to generate IL-1 and of peripheral blood mononuclear cells to generate IL-2 (16.6 and 23%, respectively, when compared to control animals; P less than .01). The presence of regional metastases or large primary tumor burden resulted in a further sharp fall in IL generation (0.9 and 10% for IL-1 and IL-2, respectively, when compared to control animals; P less than .01). With the use of three different doses of tumor inoculum, inhibition of IL generation was shown to occur when tumors were barely palpable. Decrease in IL correlated with tumor growth and not with the initial number of tumor cells injected. Tumor resection resulted in a rise in IL-2 generation from 36 to 64% of control animals' levels. Postresection immunotherapy with the use of an active specific immunization protocol successfully modulated IL-2 production to normal in animals protected from tumor recurrence. Animals that developed recurrent tumors despite immunization exhibited a continued inability to generate IL (mean values of IL-2 production compared to controls: 184% in animals free of recurrence after immunotherapy, 1% in animals developing recurrent tumors after immunotherapy; P less than .01). These results suggested that alterations in IL generation may lead to immune unresponsiveness during tumor growth. Active specific immunotherapy protecting animals from recurrence after primary tumor resection may be predicated on the successful modulation of IL level generation by host immunocytes.

Adenocarcinoma↗
PubMed1985

The effect of isosorbide dinitrate and isosorbide-5-mononitrate on prostacyclin (PGI2) and thromboxane A2 (TXA2) generation in rat and human arteries.

The mechanism by which nitrates produce relaxation of the vascular smooth muscle and anti-aggregatory effect on platelets has not been understood. Several reports have suggested that vasoactive prostaglandin generation may account for part of the pharmacological action of nitroglycerin. However, few studies have been reported that isosorbide dinitrate or its main metabolite, isosorbide-5-mononitrate, directly stimulates prostacyclin (PGI2) generation in blood vessels. We examined the effect of ISDN and 5-ISMN on PGI2 and thromboxane A2 (TXA2) generation in rat thoracic aorta and human thoracic aorta and coronary artery. The stimulation of PGI2 generation was dependent on the concentration of ISDN and the maximum PGI2 generation was effected by ISDN 5.0 ng/ml in both rat and human vessels. The ratio of peak to basal PGI2 generation was about 1.6 with rat thoracic aorta and about 1.6 with human thoracic aorta and about 1.3 with human coronary artery. On the other hand, TXA2 generation showed a smaller increase than that of PGI2 with ISDN used in the therapeutic dose range and 5-ISMN did not significantly affect PGI2 or TXA2 generation. Previous studies of the effect of cyclooxygenase inhibitor, for example indomethacin, on the vasodilating response to nitrates have given conflicting results. It is believed, however, that ISDN is partially, not wholly, associated with the hemodynamic and platelet antiaggregation effects due to vascular PGI2 generation, which may play a beneficial role in inhibiting coronary vasospasm during anginal attacks.

Aged↗
PubMed1985

Studies of the earliest generated cells of the cat's visual cortex: cogeneration of subplate and marginal zones.

The earliest generated cells of the cat's telencephalon that may play a role in the formation of the primary visual cortex are the subject of this study. Using [3H]thymidine autoradiography, we have found that these cells are generated between embryonic day 24 (E24) and E30 (gestation is 65 days) and that they are present in very low numbers in the white matter of the adult brain. These cells are rarely labeled by injections made after E30, when the cells destined for the cortical layers are generated. Examination of the labeling pattern in the fetal brain 10 days or more after administration of [3H]thymidine between E24 and E30 revealed a bistratified distribution of these early generated cells. Labeled cells were found in large numbers in two embryonic zones flanking the developing cortical plate: above in the marginal zone and below in the subplate. (Some if not all of the marginal zone cells constitute the population of Cajal-Retzius cells of the cat's telencephalon.). These experiments indicate that cells of the subplate and marginal zones are cogenerated in time during the days just preceding the genesis of the cortical plate. We also examined the distribution of the early generated cells shortly after their genesis--on E30, a time when cells of the cortical plate are just being generated at the ventricular zone. In this case, the labeling pattern at the occipital pole was not bistratified. Rather, labeled cells were situated within a single zone extending from the pial surface inward to the border of the ventricular zone. This finding indicates that the cells of the subplate and marginal zones are generated as a contiguous population that is subsequently split apart by the insertion of cells forming the cortical plate. A comparison between the number of early generated cells found in fetal and newborn brains with that found in adult brains suggests that these cells are generated initially in substantial numbers but then largely disappear during early postnatal life, since injections of [3H]thymidine between E24 and E30 yielded large numbers of labeled cells in the white matter and layer 1 at birth, but very few at 2 months postnatal. This significant loss contrasted with the results from injections made just a few days later (E33) that resulted in large numbers of labeled cells in cortical layer 6 not only at birth but also in adulthood.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Suppression of lipopolysaccharide-induced tumor necrosis factor-alpha generation from human peripheral blood monocytes by inhibitors of phosphodiesterase 4: interaction with stimulants of adenylyl cyclase.

We assessed the role of cyclic nucleotides in modulating lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) generation in human peripheral blood monocytes. Exposure of monocytes to LPS (3 ng/ml) evoked a delayed, time-dependent generation of TNF-alpha that reached a maximum level 5-6 hr after LPS challenge and remained constant for up to 24 hr. This effect was concentration dependent and resulted in a 20-40-fold increase in the release of TNF-alpha that was sensitive to actinomycin D and cycloheximide. Treatment of monocytes with agents reputed to activate the cAMP/cAMP-dependent protein kinase (PKA) cascade in general inhibited LPS-induced TNF-alpha generation. Thus, the beta 2-adrenoceptor agonists albuterol and procaterol partially (approximately 40%) suppressed TNF-alpha generation in a propranolol-sensitive manner. Furthermore, 8-bromo-cAMP, cholera toxin, prostaglandin E2, and a number of drugs (i.e., rolipram (ZK 62711), denbufylline (BRL 30892), Ro 20-1724, benafentrine (AH 21-132), that inhibit the phosphodiesterase (PDE) 4 isoenzyme family abolished cytokine generation. In contrast, forskolin, inhibitors of PDE3 and PDE5, and activators of soluble and particulate guanylyl cyclase were essentially inactive. Interestingly, rolipram failed to potentiate the inhibitory effect of albuterol on LPS-induced TNF-alpha biosynthesis but, paradoxically, synergized with albuterol in the generation of cAMP and in the activation of PKA. When PGE2 was used to activate adenylyl cyclase, however, rolipram potentiated cAMP accumulation, PKA activation, and inhibition of TNF-alpha generation. In contrast, forskolin did not increase the cAMP content of monocytes in the absence or presence of rolipram. Collectively, these data suggest that LPS-induced TNF-alpha generation by human peripheral blood monocytes is due to increased transcription and subsequent translation of the TNF-alpha gene and that these effects are suppressed by a range of agents that activate the cAMP/PKA cascade. However, the failure of rolipram to potentiate the inhibitory effect of albuterol and procaterol on TNF-alpha generation suggests that beta 2-adrenoceptor agonists may affect gene expression and/or post-transcriptional regulatory processes by, at least in part, a cAMP-independent mechanism(s).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Generation of masticatory rhythm in the brainstem.

Mastication is a typical rhythmical behavior in mammals. Like respiration, it is now generally accepted that the motor command for the basic pattern of rhythmical oral-facial movements is generated by a neuronal population in the brainstem (central pattern generator, CPG). The central pattern generation of rhythmical masticatory movements can be divided into three processes: (1) generation of the masticatory rhythm, (2) generation of a pattern of activities of the jaw, tongue and facial muscles, and (3) coordination of the activities of these muscles. There are several lines of evidence that the masticatory CPG is functionally subdivided into two neuronal groups: one for generation of the masticatory rhythm, giving the timing signal for rhythmical alternation of jaw closing and jaw opening (central rhythm generator, CRG), and the other for generation of the spatiotemporal pattern of activities of the jaw, tongue and facial muscles. This review will deal, first of all, with the localization of the CRG for rhythmical masticatory jaw movements, sources for its activation, and the premotor neurons mediating its output to the trigeminal motoneurons. Next, we will discuss the neurochemical basis for rhythmical trigeminal motoneurons activity as well as central masticatory rhythm generation. Finally, our recent attempt at induction of neural activities reflecting sucking movements (fictive sucking) in an in vitro preparation is presented.

Animals↗
PubMed1993

CD28 ligation by monoclonal antibodies or B7/BB1 provides an accessory signal for the cyclosporin A-resistant generation of cytotoxic T cell activity.

Ligation of the T cell membrane Ag CD28 with mAb 9.3 or with its natural ligand B7/BB1 on accessory cells has been shown to provide a helper signal for stimulation through the TCR/CD3 complex. The present study was undertaken to investigate whether CD28 could function as an accessory signal receptor in the generation and effector phase of CTL activity. Purified resting human T cells were activated for 3 to 4 days with immobilized anti-CD3 mAb as the primary stimulus, and CTL activity was then measured by an anti-CD3-redirected 4-hr 51Cr release assay on Fc gamma R-bearing P815 target cells. When the concentration of immobilized anti-CD3 mAb as the primary signal for CTL generation was below threshold, CTL activity could be generated by addition of mAb 9.3 to the cultures. At optimal concentrations of immobilized anti-CD3, the addition of anti-CD28 did not further enhance the generation of CTL activity, but under these conditions generation of CTL activity was almost completely resistant to cyclosporin A (CsA) as a result of CsA-resistant IL-2 production. When 3T6 mouse fibroblasts, transfected with Fc gamma RII and B7, were used as accessory cells, anti-CD3 and B7 were also found to generate cytotoxic activity. Cytotoxic T cell generation under these conditions could be blocked by anti-B7 mAb, but was totally resistant to CsA. CTL activity could be generated by CD3 and CD28 ligation in both CD4(+) and CD8(+) subpopulations. Finally, we found that the activity of CTL lines (isolated from ascitic fluid of a patient with ovarian carcinoma and cultured in IL-2) was higher on B7-transfected targets than on the B7(-) targets. We conclude that CD28 ligation provides a major accessory signal for the CsA-resistant generation of CTL activity and that CD28-B7 interaction also enhances cytotoxic effector functions of CTL. These findings might have important implications for immunotherapeutic interventions.

Abatacept↗
PubMed1993

IL-3 alters free arachidonic acid generation in C5a-stimulated human basophils.

IL-3 is known to enhance the secretion of several mediators from human basophils activated by receptor-mediated stimuli. IL-3 can cause a qualitative change in the mediator release pattern for C5a-mediated stimulation; without IL-3, C5a causes no leukotriene release whereas in the presence of IL-3, significant leukotriene occurs. This study examines the influence of a 15-min pretreatment of basophils with IL-3 (10 ng/ml) on several signal transduction events. Basophils stimulated with C5a typically displayed only a transient cytosolic Ca2+ response [Ca2+]i, attributed to the release of intracellular calcium stores. IL-3 had sporadic, statistically nonsignificant, effects on the peak of this initial response as well as inconsistent effects on the generation of a second phase in the [Ca2+]i response (i.e., that which is caused by the influx of extracellular Ca2+). IL-3 also had no effect on resting [Ca2+]i levels. Challenge of basophils in the presence of EGTA had little effect on the amount of leukotrienes generated. This maneuver did not influence the initial transient elevation of [Ca2+]i. Although basophil leukotriene release is usually slow, after exposure to IL-3 it was found that leukotriene release occurred rapidly, during the brief window of time (0 to 45 s) in which the [Ca2+]i transient occurred. These results suggested that the generation of AA was accelerated by pretreatment with IL-3. Subsequent mass measurements of free AA by gas chromatography-mass spectroscopy showed: 1) IL-3 itself caused no free AA generation; 2) without IL-3, C5a stimulated little or no free AA generation; and 3) in the presence of IL-3, C5a generated substantial levels of free AA at an accelerated rate. A similar acceleration in the rate of free AA generation, without any apparent increase in the amount, occurred in IL-3-primed basophils stimulated with FMLP. Additional studies showed that IL-3 had no effects on whole cell ATP levels and that the kinase inhibitor, staurosporine, did not inhibit the ability of IL-3 to cause enhanced responses to C5a. We conclude that the primary effect of a short period of pretreatment with IL-3 is to couple the generation of free AA to C5a-mediated stimulation in particular and to accelerate its generation after other stimuli. Enhancements of the [Ca2+]i response, while sporadic and at best modest, may have some influence on enhanced mediator release but did not clearly explain the functional effects of IL-3.

Arachidonic Acid↗
PubMed1995

Effects of heparin and hirudin on thrombin generation and platelet aggregation after intrinsic activation of platelet rich plasma.

The effects of unfractionated heparin (UH) and recombinant hirudin (rH) on prothrombin activation, free thrombin generation, and platelet aggregation induced by endogenously generated thrombin after intrinsic activation of platelet rich plasma were compared. Free thrombin generation and platelet aggregation were assessed simultaneously by delaying fibrinogen polymerisation with GPRP. UH more effectively inhibited prothrombin activation and free thrombin generation than rH. Increasing concentrations of rH had hardly any effect on the peak amount of free thrombin, while in the presence of 400 nM UH only traces of free thrombin were detected. Comparison of TAT and THC (thrombin-hirudin complex) generated until the onset of platelet aggregation on a molar basis showed that much more thrombin was inactivated in the presence of rH than in plasma containing UH. The explosive generation of free thrombin in hirudinized plasmas was accompanied by a markedly steeper aggregation curve as compared to heparinized plasmas. The generation of thromboxane B2 was markedly delayed in the presence of UH but not influenced in the presence of rH. Our results suggest that UH is more effective than rH in inhibiting prothrombin activation after intrinsic activation of platelet rich plasma, while rH prevents clotting more by direct inactivation of already generated thrombin. The inability of even high concentrations of rH to prevent the explosive generation of free thrombin might contribute to the observed inefficiency of rH to inhibit platelet aggregation.

Blood Platelets↗
PubMed1977

[Generators of pathologically enhanced excitation as determinant structures in the spinal cord].

Using tetanus toxin as a tool to disturb the inhibition, enhanced excitation generators were created in the anterior horns of lumbar segments of the left and right sides of albino rat spinal cord. The generators worked at different regimens: the "left-side" generator originating under conditions of a more prolonged toxin action, on being activated by trigger stimulation, produced first tonic and then intermittent activity or periodic spontaneous discharges; the "right-side" generator produced only tonic activity. After the inhibition of one of the generators by glycine the other continued working in its regimen. Activation of one of the generators was followed by inhibition of the effect of the other. In case of separate activation of one of the generators all pools of the spinal and supraspinal motor neurons reproduced the activity pattern of the generator working at that moment. Thus, the latter played the role of the hyperactive structure determining the system behaviour, i.e. the determinant. The evidence obtained is analyzed from the point of view of the general concept on the role of the determinant structures in the nervous system activity and the theory of generator mechanisms of the neuropathological syndromes characterized by the system hyperactivity.

Animals↗
PubMed1997

Distinct immunological states in murine cutaneous leishmaniasis by immunising with different amounts of antigen: the generation of beneficial, potentially harmful, harmful and potentially extremely harmful states.

Infection of BALB/c mice with a standard and substantial number of Leishmania major parasites results in progressive disease, following the induction of a parasite-specific Th2 response. These mice have been designated as "susceptible" on this basis. We show that distinct types of immune response can be generated in "susceptible" BALB/c mice depending upon the number of parasites employed for infection, and that the pathophysiological consequences of such distinct responses are dramatically different. Infection with very low numbers of parasites results in the exclusive induction of a cell-mediated, Th1 response, and the generation of resistance to the standard and substantial challenge. Spleen cells from such resistant mice can confer resistance upon normal mice when transferred to them, but these spleen cells do not contain T cells expressing DTH or Th1 effector cells that produce IFN gamma on short term culture (48 hrs) with parasite antigen. The immune response in this case appears to result in the virtual elimination of parasites from the lymph node draining the site of infection and, by implication, from the infected mouse. We suggest that such elimination results in the absence of antigen stimulation and hence of effector T cells, and that "memory Th1 cells" are responsible for the capacity of spleen cells to confer resistance on normal mice. We predict such mice will not suffer parasitemia upon immune suppression, i.e. are not susceptible to reactivation disease. This is the "beneficial state". In contrast to this infection with a very low number of parasites infection with a low number usually results in one of two states: (i) The generation of a response with a very small Th2 component, production of a small amount of antibody, chronic parasitemia and hence chronic generation of parasite-specific effector Th1/Th2 cells, or (ii) The generation of a response with a greater Th2 component, the production of more antibody, the formation of a frank lesion, and the long term generation of a stable, mixed Th1/Th2 response. We refer to the latter state as borderline leishmaniasis in analogy with borderline leprosy. Parasites can be recovered from the draining lymph node in both these cases many months after infection. We therefore believe that mice infected with a low number of parasites, that harbour a chronic subclinical infection, will suffer reactivation disease upon immune suppression, and we consequently designate the state generated as potentially harmful. We consider mice with borderline disease to be in a harmful state. Mice immunised with high doses of parasite antigen produce in the long term Th2 responses, whereas those immunised with lower doses produce Th1 responses. Mice immunised to produce a Th2 response were subsequently infected with a very low number of parasites that is normally contained. The generation of a Th2 response results in the generation of a Th2 imprint, such that the response to the low dose infection is modulated from a Th1 to a Th2 mode, resulting in progressive disease. We argue that immunisation/vaccination, resulting in a state that deviates the protective response to a non-protective mode, may result in epidemics. Such a state has the potential for being extremely harmful.

Animals↗
PubMedDate not supplied

The effect of dialysate glucose on phagocyte superoxide generation in CAPD patients.

OBJECTIVE: In the present study, we investigated the influence of dialysate glucose on superoxide (O2-) generation by peripheral and peritoneal phagocytes in continuous ambulatory peritoneal dialysis (CAPD) patients. DESIGN: Peripheral polymorphonuclear leukocytes (PMNL) and mononuclear leukocytes (MNL), and peritoneal cells were isolated from peripheral blood and peritoneal effluents, respectively, and their oxidative metabolism was assessed by measuring O2- generation after stimulation with a soluble stimulant [phorbol myristate acetate (PMA), 1 mg/mL, Sigma Chemical, St. Louis, MO, U.S.A.] using the chemiluminescence method. Dialysate glucose effect on O2- generation was also studied in vitro by exposing peripheral PMNL and MNL from healthy controls to peritoneal dialysis fluid (PDF) containing glucose or amino acids at a neutral pH for different time periods. RESULTS: The amount of O2- generation by both peripheral and peritoneal phagocytes in CAPD patients was significantly higher than that in the control, and the response was greater in patients who were dialyzed with high glucose dialysate than those using low glucose dialysate. In an in vitro study, all incubated cells, except the control, showed suppression of O2- generation in the early dwell time (2 hr), and subsequently showed increased responses (peaking at 6 hr), although lower in degree than those observed in vivo. In contrast, amino acid-based PDF exhibited no such effect on O2- generation at identical pH with similar or lower osmolality. Furthermore, the respective increased or decreased oxidative responses with the increased or decreased PDF glucose concentrations in the same patient confirmed the positive effect of PDF glucose on phagocyte O2- generation. CONCLUSION: It is suggested that increased O2- generation by peritoneal and circulating phagocytes in CAPD patients is at least partly due to the enhancement of hexose monophosphate shunt activity by increasing glucose metabolism in phagocytes, and the increased O2- generation might be involved in long-term complications of CAPD. Therefore, a suitable alternative osmotic agent is needed to provide a more physiological environment to minimize the adverse effects of glucose on cell functions.

Adult↗