Adenosine monophosphate as a mediator of ATP effects at P1 purinoceptors

1. When perfused with a medium containing no added magnesium and 4-aminopyridine (4AP) (50 microM) hippocampal slices generated epileptiform bursts of an interictal nature. We have shown in a previous study that adenosine 5'-triphosphate (ATP) depressed epileptiform activity and that this effect was blocked by the adenosine A1 receptor antagonist cyclopentyltheophylline but was not affected by adenosine deaminase. This implied that ATP might act indirectly at P1 receptors or at a xanthine-sensitive P2 receptor. The aim of the present study was to investigate further the action of ATP on epileptiform activity. 2. ATP can be metabolized by ecto-nucleotidases to adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP) and adenosine, respectively. Each of these metabolites can activate receptors in its own right: P2 receptors for ADP and P1 receptors for AMP and adenosine. 3. We now show that both AMP and ATP (50 microM) significantly decrease epileptiform discharge rate in a rapid and reversible manner. 5'Adenylic acid deaminase (AMP deaminase, AMPase) (0.2 u ml(-1)), when perfused alone did not significantly alter the discharge rate over the 10 min superfusion period used for drug application. When perfused concurrently with AMP (50 microM), AMP deaminase prevented the depressant effect of AMP on discharge rate. 4. AMP deaminase, at a concentration of 0.2 u ml(-1) which annulled the effect of AMP (50 microM), prevented the inhibitory activity of ATP (50 microM). A higher concentration of ATP (200 microM) depressed the frequency of spontaneous bursts to approximately 30% control and this response was also prevented by AMP deaminase. 5. Superfusion of the slices with 5'-nucleotidase also prevented the inhibitory activity of ATP on epileptiform discharges. 6. The results suggest that AMP mediates the inhibitory effects of ATP on epileptiform activity, a conclusion which can explain the earlier finding that cyclopentyltheophylline but not adenosine deaminase inhibited the effect of ATP. A corollary to this is that, when examining the pharmacology of ATP, care must be taken to inactivate AMP with AMP deaminase, as well as adenosine with adenosine deaminase, before a direct action of ATP on P1 receptors can be postulated. Failure to do so may have led to erroneous conclusions in some previous studies of nucleotide activity on nucleotide receptors.     

Stress-response-dampening effects of alcohol: Attention as a mediator and moderator.

The present study sought to characterize alcohol's stress-response-dampening (SRD) effects on multiple measures of stress and whether these effects are mediated by reductions in sustained attention and, further, whether baseline levels of sustained attention moderate SRD. One hundred six men consumed either an alcohol (0.70 g/kg) or a placebo beverage prior to learning that they would deliver a self-disclosing speech. Structural equation models controlling for multiple baseline periods indicated that alcohol directly reduced self-reported anxiety and skin conductance levels in response to the stressor. Alcohol's effect on reducing heart rate response, in contrast, was indirect and mediated by effects on prestress baseline. As hypothesized, differences in sustained attention partially mediated the effects of alcohol on skin conductance (but not heart rate or self-reported anxiety) and served as a moderator of alcohol's effects on skin conductance response. Findings are discussed in terms of theoretical links among alcohol consumption, specific cognitive abilities, and stress reactivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mobility as a mediator of the effects of child maltreatment on academic performance

This study examined the role of residential and school mobility as a mediator between child maltreatment and academic outcomes. Using a sample of 711 maltreated and nonmaltreated children ranging from 5 to 15 years old matched on gender, grade, school, and socioeconomic status, path analytic techniques were employed to assess direct and indirect effects of maltreatment on recent achievement test scores, current grades, and grade repetitions. The results indicated that mobility did help account for the effects of maltreatment on each of the outcomes. For grades in English/reading, 32.7% of the effect of maltreatment was accounted for by amount of mobility, while for test scores and grade repetitions the numbers were 14.6% and 19.1%, respectively.     

The effects of prolonged thermal

Aluminum-lithium alloys are currently being considered for applications at moderately elevated temperatures; accordingly, a study has been made on the effects of prolonged (100 and 1000 hours overaging) thermal exposure at 149 °C and 260 °C on the mechanical properties of a peakaged Al-Li-Cu-Mg-Zr alloy 8090-T8771. In the as-received T8771 temper, the alloy exhibits an excellent combination of strength (˜500 MPa) and toughness (35 MPa√m) with moderate tensile elongation (4 pct). Overaging at 149 °C results in a ˜50 pct reduction in ductility and toughness, primarily associated with the growth of equilibrium phases along grain/subgrain boundaries, resulting in formation of solute-depleted precipitate-free zones and coarsening of matrix8' andS precipitates; strength levels and fatigue-crack growth rates, however, remain largely unchanged. Thermal exposures at 260 °C, conversely, lead to dramatic reductions in strength (by ˜50 to 80 pct), toughness (by ˜30 pct) and fatigue-crack propagation resistance; crack-growth rates at all ΔK levels above ~5 MPa√m are 2 to 3 orders of magnitude faster. Microstructurally, this was associated with complete dissolution of δ′, severe coarsening ofS andT ₂ precipitates in the matrix, and formation of equilibrium Cu- and Mg-rich intermetallic phases in the matrix and along grain boundaries. The resulting lack of planar-slip deformation and low yield strength of 8090 following overaging exposures at 260 °C increase the cumulative crack-tip damage per cycle and reduce the tendency for crack-path deflection, thereby accelerating fatigue-crack growth rates. Despite this degradation in properties, the 8090-T8771 alloy has better strength retention and generally superior fatigue-crack growth properties compared to similarly overaged Al-Li-Cu-Zr 2090 and Al-Cu-Zn-Mg 7150 alloys. formerly with the University of California, formerly with the University of California,     

Peroxynitrite: a mediator of increased microvascular permeability?

1. Increased expression of inducible nitric oxide synthase (iNOS) and subsequent elevation of nitric oxide (NO) levels at inflammatory sites have led to the suggestion that peroxynitrite (the reaction product of superoxide and NO) is involved in pro-inflammatory processes. The present study has investigated the ability of peroxynitrite to induce oedema formation in the rat cutaneous microvasculature. 2. Peroxynitrite was synthesized from hydrogen peroxide and acidified nitrite. Spectrophotometry was used to measure the concentration and breakdown of peroxynitrite. It was also used to determine maximum amounts of hydrogen peroxide and sodium nitrite remaining after synthesis. 3. Oedema formation in response to intradermally (i.d.) injected peroxynitrite, hydrogen peroxide and sodium nitrite was measured by the extravascular accumulation of i.v. [125I]-albumin in the anaesthetized rat. 4. Peroxynitrite (40, 100 and 200 nmol/site) acted in a dose-dependent manner to cause a mean (+/- SEM) increase in plasma extravasation of 24 +/- 2, 55 +/- 5 and 69 +/- 6 microL, respectively (n = 4), with resulting inflammatory oedema. Peroxynitrite induced significantly larger plasma extravasation than equivalent vehicle controls at doses of 100 (P > 0.05) and 200 nmol (P > 0.001). This increased extravasation appears to be a direct microvascular response to peroxynitrite administration and not due to either a raised pH, necessary to stabilize the peroxynitrite, or contaminating concentrations of hydrogen peroxide or sodium nitrite from which peroxynitrite is formed. 5. These results suggest that peroxynitrite acts to increase microvascular permeability and oedema formation. Therefore, peroxynitrite may mediate vascular pro-inflammatory effects in addition to its direct cytotoxic activity.     

Interruption of prolonged ramipril treatment in hypertensive patients: effects on the renin-angiotensin system

The increase in renin secretion and the induction of the converting enzyme (ACE) observed during treatment by ACE inhibitors (CEIs) could result in increased angiotensin II (ang II) synthesis when the treatment is stopped. The object of this study was to compare changes in the components of the renin-angiotensin system with changes in arterial pressure in hypertensives, following the cessation of long-term ramipril treatment. Twenty hypertensives, treated for at least three months with ramipril, in monotherapy for the last three weeks, were randomly allocated to two parallel groups and received for fifteen days, on a double-bind basis, either a placebo (withdrawal group W, n = 12) or ramipril at the previous doses (treated group T, n = 8). Blood pressure was measured using four different techniques. The active renin (AR), angiotensinogen, angiotensin I (ang I), angiotensin II (ang II) and aldosterone plasma concentrations were measured, as was plasma angiotensin I converting enzyme (ACE) activity in vitro (colorimetric and fluorimetric method) and in vivo (the ang II/ang I ratio). The biological effects of cessation of long-term ramipril treatment in hypertensives were a decline in AR and angiotensin I concentrations, an increase in ACE activity and no significant changes in angiotensinogen, angiotensin II and aldosterone levels. Fifteen days after withdrawal, the different parameters of the renin-angiotensin system appear to have returned to basal value. A slow rise in blood pressure was also observed but no rebound increase was noted during the 15 days neither in angiotensin II levels nor in blood pressure. Following the cessation of prolonged ramipril treatment, in vivo converting enzyme inhibition disappears slowly, probably on account of the slow tight binding inhibitor properties of ramiprilat, the active metabolite of this CEI. The gradual decline in AF, plasma levels, together with the prolonged ACE inhibition as measured in vivo by the ang II/ang I ratio, explains the absence of a rise in ang II synthesis.     

The effects of mediator rewards and suggestions upon negotiations.

Investigated the effects that 2 mediation techniques—rewarding negotiator concessions and suggesting concessions—have upon a negotiator's bargaining and outcomes. 170 male undergraduates served as the negotiator and opposing negotiator while a confederate acted as the mediator in 4 separate wage negotiations. Results show that (a) mediator rewards result in larger negotiator total concessions, more negotiator–opponent agreements, and higher joint outcomes than do no rewards; (b) mediator suggestions produce larger initial concessions than do no suggestions; and (c) mediator rewards and suggestions interact, in that each technique is more potent in the absence of the other. (12 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Metabolism and regulation of nitric oxide: a hard-to-control mediator

Although nitric oxide (NO) is implicated in numerous regulatory mechanisms, its therapeutic use remains problematic. Synthesis of this mediator of low specificity with multiple effects involves two types of enzymes (constitutive and inducible). The complexity of the corresponding regulatory mechanisms precludes control for therapeutic use. As NO interacts with numerous metabolic pathways and can also be stored, interpretation of experimental results is difficult, which hinders development of therapeutic trials. In addition, NO is a free radical and thus participates in the free radical cascade. Another difficulty in use of NO is its role in equilibrium implicating still poorly understood mediators (such as endothelin at a vascular level). The complexity of NO pathways explains why therapeutic trials of NO to date have proven unsatisfactory except for treatment of arterial pulmonary hypertension.     

Oral and systemic effects of prolonged minocycline therapy

The following case report shows the unfortunate side effects of minocycline therapy used in the management of facial acne. All three features of discoloration affecting the skin, bone and dentition were found. A 46-year-old patient presented with adult onset discoloration of the dentition following prolonged minocycline therapy. In addition, oral and cutaneous pigmentation were noted. Unfortunately, the undesirable cosmetic appearance of facial acne was exchanged for permanent discoloration of the dentition. When considering prolonged minocycline therapy, patients would benefit from dialogue between the medical and dental practitioners, so that the risk of this potential side effect can be assessed in a more informed way.     

Exercise as a mediator of psychological and nutritional effects of testosterone therapy in HIV+ men

PURPOSE: The purpose of this study was to determine whether exercise mediates the psychological and nutritional effects of testosterone therapy in men with symptomatic HIV illness, low serum testosterone, and clinical symptoms of hypogonadism. METHODS: A 12-wk open trial of biweekly intramuscular testosterone injections was conducted, with 54 men completing the trial and exercise assessments. Most (71%) men were diagnosed with AIDS; 41% had a CD4 < 50. One-third of the men were diagnosed with major depression, and nearly half had some evidence of wasting. Twenty-nine men (54%) engaged in exercise (predominantly resistance training) during the trial. Exercisers did not differ from nonexercisers on any measure of psychological well being or nutritional status at baseline. RESULTS: After 12 wk of testosterone treatment, those who exercised showed significant improvement in mood (Hamilton Rating Scale for Depression; HAM-D) and overall distress (Brief Symptom Inventory; BSI) (P < 0.000 for both), as well as a significant increase in body cell mass (P < 0.01) and lean body mass (mean increase of 2.6 kg; P < 0.000) as measured by bioelectric impedance analysis. In contrast, nonexercisers showed improvement on the HAM-D (P < 0.000), but not the BSI or measures of nutritional status. CONCLUSION: These findings indicate that exercise may be an important adjunct to testosterone therapy in the treatment of psychological distress and wasting symptoms in men with symptomatic HIV illness.     

Amphetamine-induced hyperfunction of the dopaminergic system and delta sleep-inducing peptide]

The experimental study carried out on white rats, which was introduced of sodium nitrate at a dose of 9,6 g/kg of their mass. It is followed by the development of considerable disturbances of energy metabolism in liver. It has been shown the depression and the uncoupling of oxidation and phosphorylation, decrease of energy quotient in hepatic tissues. The results obtained permit supposing the significant role of nitric oxide (NO) in liver as a factor resulting in decrease of energy potential. The research has stated that the use of hyperbaric oxygenation (HBO) prevents difficult disturbances of energy metabolism in liver of white rats. The results permit supposing that the effect HBO is connected with the decrease of the speed of reduction of nitrate-ions to more toxic products of their biotransformation.     

Quetiapine produces a prolonged reversal of the sensorimotor gating-disruptive effects of basolateral amygdala lesions in rats.

Prepulse inhibition (PPI) of startle is impaired in schizophrenia and in rats after manipulations of limbic cortical and subcortical regions. The atypical antipsychotic quetiapine was used to reverse PPI deficits after basolateral amygdala (BLA) lesions in rats. BLA quinolinic acid lesions significantly disrupted PPI 1 week postsurgery. Tests with quetiapine (0 vs 7.5 mg/kg) in a within-subject design 2-3 weeks postsurgery revealed a normalization of PPI. Carry-over effects lasted up to 3 weeks, with a return of lesion-induced deficits by Week 5 postsurgery. This dose of quetiapine also blocked the PPI-disruptive effects of phencyclidine. PPI deficits after BLA lesions are reversed by quetiapine, in a manner that is sustained beyond its acute pharmacological effects and which may be mediated downstream from the BLA. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Some effects of prolonged experience in communication nets.

Comcon (all can communicate to each), star (all communicate to one) and slash (each can communicate to several, but not to all) communication nets were studied with respect to their effects on group behavior when groups were required to operate in the same net over a period of several days. While the comcon groups developed predominantly an "each-to-all" organization, and the star a "central" organization, the slash appeared to be completely disorganized. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cancer: a response to prolonged tissue necrosis

We report the first case published in Spain of a palliative anatomic correction associated with aortic arch repair in a neonate with (S,D,L)-transposition of the great arteries, multiple ventricular septal defects, and severe hypoplasia of the right ventricle with subaortic obstruction and hypoplasic aortic arch with coarctation. A one stage palliative surgery on cardiopulmonary bypass was performed with reconstruction of the aortic arch and an arterial switch procedure which obtained a satisfactory result. The principle of this operation is to switch the subaortic obstruction into a subpulmonary obstruction and reconstruct a large natural aortic root from the principal ventricle. The right ventricle-pulmonary artery continuity may promote growth of the right ventricle with the possibility of a future biventricular repair. We conclude that this operation, when used by surgical teams experienced with arterial switch surgery, is the best treatment for the complex newborn group with single ventricles or severe ventricular disbalance, ventriculoarterial discordance and stablished subaortic stenosis.     

Adenosine A1 receptor stimulation antagonizes the negative inotropic effects of the PKC activator dioctanoylglycerol

It has been suggested that adenosine cardioprotection occurs via adenosine A1 receptor-mediated activation of protein kinase C (PKC). However, adenosine has well-known vasodilatory effects in the myocardium, whereas PKC is a vasoconstrictor. This study examined whether adenosine A1 receptor activation alters the effects of the PKC activator. 1,2-dioctanoyl-s,n-glycerol (DOG) in isolated perfused rat hearts (left-ventricular developed pressure) and rat ventricular myocytes ([Ca2+]i and cell shortening). Exposure to DOG decreased left-ventricular developed pressure by 30%, an effect that was completely reversible. Pretreatment of isolated hearts with either the PKC inhibitor chelerythrine or the adenosine A1 agonist 2-chloro-N6-cyclo-cyclo-isolated pentlyadenosine (CCPA) attenuated the negative inotropic effects of DOG. In the isolated myocytes, DOG decreased [Ca2+]i and cell shortening by 25 and 28%, respectively, effects that were attenuated by both chelerythrine and CCPA. The CCPA attenuation of the DOG-induced decrease in [Ca2+]i and cell shortening was blocked by pretreating the myocytes with the adenosine A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). These results indicate that in rat ventricular myocardium, adenosine A1 receptor activation attenuates the apparent PKC-dependent negative inotropic effects of DOG via preservation of [Ca2+]i levels.     

Coping as a mediator of emotion.

There is widespread conviction among health care professionals that coping affects emotion. Yet theory and research have traditionally emphasized the effects of emotion on coping. The present research addresses this imbalance by evaluating the extent to which coping mediated emotions during stressful encounters in two Caucasian, community-residing samples. Subjects' recently experienced stressful encounters, the ways they coped with the demands of those encounters, and the emotions they experienced during two stages of those encounters were assessed repeatedly. The extent to which eight forms of coping mediated each of four sets of emotions was evaluated with a series of hierarchical regression analyses (of residuals). Coping was associated with changes in all four sets of emotions, with some forms of coping associated with increases in positive emotions and other forms associated with increases in negative emotions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

c-Myc is a major mediator of the synergistic growth inhibitory effects of retinoic acid and interferon in breast cancer cells

The molecular signaling events involved in the inhibition of breast cancer cell growth by retinoic acid and interferon-alpha were investigated. All-trans-retinoic acid and interferon-alpha acted synergistically to inhibit growth of both the estrogen receptor-positive breast cancer cell line MCF-7 and the estrogen receptor-negative line BT-20. In MCF-7 cells, all-trans-retinoic acid potentiated the effects of interferon-alpha by up-regulating the expression of the RNA-dependent protein kinase (PKR). Consequently, the synergism between all-trans-retinoic acid and interferon-alpha down-regulated the expression of c-Myc, but not its functional partner, Max. Transfection of MCF-7 cells with a dominant-negative mutant of PKR relieved c-Myc down-regulation and cell growth inhibition, indicating that PKR is directly involved in c-Myc down-regulation and that c-Myc down-regulation is responsible for the inhibition of cell growth. Corresponding with c-Myc down-regulation, c-Myc.Max heterodimers bound to their consensus DNA sequence were undetectable in cells treated with all-trans-retinoic acid and interferon-alpha, indicating diminished c-Myc functionality. When c-Myc was overexpressed ectopically via a c-Myc expression vector, MCF-7 cells became resistant to growth inhibition by all-trans-retinoic acid plus interferon-alpha. These experiments define the following pathway as a major pathway in the synergistic growth inhibition of MCF-7 cells by all-trans-retinoic acid plus interferon-alpha: all-trans-retinoic acid + interferon-alpha --> upward arrow double-stranded RNA-dependent protein kinase --> downward arrow c-Myc --> cell growth inhibition.     

The prolonged hematologic effects of a single injection of PEG-rHuMGDF in normal and thrombocytopenic mice

A single injection of > or =10 microg/kg PEG-rHuMGDF in mice causes a dose-dependent increase in circulating platelets beginning on day 3 and peaking on days 5-6. The mean platelet volume and platelet distribution width at doses > or =100 microg/kg initially increase in a dose-dependent fashion and later decrease. However, the mean platelet volume does not change when platelets are incubated with PEG-rHuMGDF in vitro. The number of marrow megakaryocytes increases in a dose-dependent fashion as early as day 1 and peaks on day 3. Marrow megakaryocyte colony-forming units (CFU-Meg) do not increase on days 1-3 at a dose of 100 microg/kg (a dose that increases platelet numbers two- to threefold and may be clinically relevant), but the relative frequency of high ploidy megakaryocytes and the proportion of large marrow megakaryocytes (29-50 microm in diameter) increases. After a dose of 1,000 microg/kg the percentage of megakaryocytes in mitosis peaks at 24-48 hours and the percentage of megakaryocytes incorporating BrdU is maximal at 48 hours, the relatively delayed peak of BrdU incorporation most likely representing endomitosis. The relative frequency of type II and III megakaryocytes peaks on days 3 and 4, respectively. Pharmacokinetic analysis of PEG-rHuMGDF shows peak serum concentrations at 2-4 hours and a terminal half-life of 11.4+/-2.5 hours. A single injection of PEG-rHuMGDF ameliorates carboplatin-induced megakaryocytopenia and thrombocytopenia in a dose-response dependent fashion. In conclusion, a single injection of PEG-rHuMGDF increases megakaryocyte and platelet production in normal and myelo-suppressed mice.