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PubMed2004

Male germ line development in Arabidopsis. duo pollen mutants reveal gametophytic regulators of generative cell cycle progression.

Male germ line development in flowering plants is initiated with the formation of the generative cell that is the progenitor of the two sperm cells. While structural features of the generative cell are well documented, genetic programs required for generative cell cycle progression are unknown. We describe two novel Arabidopsis (Arabidopsis thaliana) mutants, duo pollen1 (duo1) and duo pollen2 (duo2), in which generative cell division is blocked, resulting in the formation of bicellular pollen grains at anthesis. duo1 and duo2 map to different chromosomes and act gametophytically in a male-specific manner. Both duo mutants progress normally through the first haploid division at pollen mitosis I (PMI) but fail at distinct stages of the generative cell cycle. Mutant generative cells in duo1 pollen fail to enter mitosis at G2-M transition, whereas mutant generative cells in duo2 enter PMII but arrest at prometaphase. In wild-type plants, generative and sperm nuclei enter S phase soon after inception, implying that male gametic cells follow a simple S to M cycle. Mutant generative nuclei in duo1 complete DNA synthesis but bypass PMII and enter an endocycle during pollen maturation. However, mutant generative nuclei in duo2 arrest in prometaphase of PMII with a 2C DNA content. Our results identify two essential gametophytic loci required for progression through different phases of the generative cell cycle, providing the first evidence to our knowledge for genetic regulators of male germ line development in flowering plants.

Arabidopsis↗

PubMed1988

Arachidonic acid release is closely related to the Fc gamma receptor-mediated superoxide generation in macrophages.

Stimulation of macrophages with IgG2 immune complexes induced dose-dependently the O2- generation and the release of arachidonic acid and its metabolites. This Fc gamma R-mediated O2- generation was inhibited by a phospholipase A2 inhibitor, 4-p-bromophenacyl bromide (4-pBPB), in parallel to the dose-dependent inhibition of arachidonic acid release. The main arachidonic acid metabolites released were shown to be prostaglandin E2 and thromboxane B2 and blocking of the production of these metabolites by indomethacin did not inhibit the O2- generation. Inhibition of the Fc gamma R-mediated O2- generation and the arachidonic acid release by the C-kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), was less intense than by 4-pBPB. These results support the previously proposed hypothesis that arachidonic acid acts as an intracellular activator of the Fc gamma R-mediated O2- generation in macrophages. Although the C-kinase activation may also contribute to the activation of the O2--generating system, arachidonic acid release appears to play a major role in Fc gamma R-mediated O2- generation. In contrast, activation of C-kinase seems to be contributing mainly in the induction of both the arachidonic acid release and O2- generation by 12-o-tetradecanoylphorbol 13-acetate (TPA). Furthermore, suboptimal concentrations of TPA and arachidonate were found to act synergistically to stimulate O2- generation and the inhibition study suggested a positive synergism between C-kinase and arachidonic acid release to induce O2- generation. This synergistic action may have general importance in receptor-mediated O2- generation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1995

An analysis of the growth of the retinal cell population in embryonic chicks yielding proliferative ratios, numbers of proliferative and non-proliferative cells and cell-cycle times for successive generations of cell cycles.

Growth curves of the retinal cell population of embryonic chicks were fitted by a branching-process model of cell population growth, thereby estimating the proliferative ratios and mean cell-cycle times of the generations of cell cycles that underlie retinal growth. The proliferative ratio determines the proportion of cells that divides in the next generation, so the numbers of proliferative and non-proliferative cells in each generation of cell cycles were obtained. The mean cell-cycle times determine the times over which the generations are extant. Assuming growth starts from one cell in generation 0, the proliferative cells reach 3.6 x 10(6) and the non-proliferative cells reach 1.1 x 10(6) by generation 23. The next four generations increase the proliferative cell numbers to 13.9 x 10(6) and produce 20.1 x 10(6) non-proliferative cells. In the next five generations in the end phase of growth, non-proliferative cells are produced in large numbers at an average of 13.9 x 10(6) cells per generation as the retinal lineages are completed. The retinal cell population reaches a maximum estimated here at 98.2 x 10(6) cells. The mean cell-cycle time estimates range between 6.8 and 10.1 h in generations before the end phase of growth and between 10.6 and 17.2 h in generations in the end phase. The retinal cell population growth is limited by the depletion of the proliferative cell population that the production of non-proliferative cells entails. The proliferative ratios and the cell-cycle-time distribution parameters are the likely determinants of retinal growth rates. The results are discussed in relation to other results of spatial and temporal patterns of the cessation of cell cycling in the embryonic chick retina.

Animals↗

PubMed2004

Continuities in antisocial behavior and parenting across three generations.

BACKGROUND: Accumulating evidence indicates that there are intergenerational continuities in antisocial behavior, and that parenting patterns play a role in these continuities. Very few studies, however, enable assessment across two generations of children at comparable ages, employing independent reporters and comparable measurements. The present study addresses the extent to which antisocial behavior in parents predicts antisocial behavior in children in two successive generations; the degree to which a man's childhood antisocial behavior predicts antisocial behavior in his own children; the extent to which parenting problems are related to child antisocial behavior similarly in two successive generations; and the extent to which intergenerational continuities in antisocial behavior are mediated by parenting variables. METHODS: Questions are addressed with prospective longitudinal data from the Cambridge Study in Delinquent Development (CSDD). The CSDD includes data on 411 Inner London males (Generation 2, or G2), their female partners, their parents (G1) and their children (G3). At time 1, when G2 were aged 8-10, data on G2 child conduct problems and G1 parenting and convictions were available. At time 2 when G2 males were aged 32, data were available on the parenting of 178 G2 fathers with G3 children aged 3-15, and on their G3 children's behavior. Time 1 data come predominantly from G1 mothers, whereas time 2 data come predominantly from G2 fathers. RESULTS: Between generations, antisocial G1 mothers and fathers predicted conduct problems in G2 and G3 children, but G2 child conduct problems did not predict G3 child conduct problems. Within generations, G2 child conduct problems predicted G2 adult antisocial behavior and antisocial partnerships, which in turn predicted G3 conduct problems. Parental conflict and authoritarian parenting were similarly related to early childhood conduct problems in two successive generations. There was relatively little continuity between G1 and G2 parenting except that G2 males who were poorly supervised by their parents were themselves poor supervisors as fathers. Both G1 and G2 generations displayed assortative mating, with antisocial males tending to partner antisocial female peers. CONCLUSIONS: There are between-generation and within-generation continuities in antisocial behavior, although assessment of such continuities is complicated by inevitable design and measurement limitations. Parenting partly mediated the impact of parental antisocial behavior on child antisocial behavior in two successive generations, but the relation between antisocial parents and antisocial children is not fully mediated by parenting variables.

Adolescent↗

PubMed1996

Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. Transnational Research Group on Oral Contraceptives and the Health of Young Women.

OBJECTIVE: To test whether use of combined oral contraceptives containing third generation progestogens is associated with altered risk of venous thromboembolism. DESIGN: Matched case-control study. SETTING: 10 centres in Germany and United Kingdom. SUBJECTS: Cases were 471 women aged 16-44 who had a venous thromboembolism. Controls were 1772 women (at least 3 controls per case) unaffected by venous thromboembolism who were matched with corresponding case for age and for hospital or community setting. MAIN OUTCOME MEASURES: Odds ratios derived with stratified analyses and unconditional logistic regression to adjust for potential confounding variables. RESULTS: Odds ratios (95% confidence intervals) for venous thromboembolism were: for any oral contraceptives versus no use, 4.0 (3.1 to 5.3); for second generation products (low dose ethinyl-oestradiol, no gestodene or desogestrel) versus no use, 3.2 (2.3 to 4.3); for third generation products (low dose ethinyloestradiol, gestodene or desogestrel) versus no use, 4.8 (3.4 to 6.7); for third generation products versus second generation products, 1.5 (1.1 to 2.1); for products containing gestodene versus second generation products, 1.5 (1.0 to 2.2); and for products containing desogestrel versus second generation products, 1.5 (1.1 to 2.2). Probability of death due to venous thromboembolism for women using third generation products is about 20 per million users per year, for women using second generation products it is about 14 per million users per year, and for non-users it is five per million per year. CONCLUSIONS: Risk of venous thromboembolism was slightly increased in users of third generation oral contraceptives compared with users of second generation products.

Adolescent↗

PubMed1997

Mortality from venous thromboembolism among young women in Europe: no evidence for any effect of third generation oral contraceptives.

STUDY OBJECTIVE: To investigate whether there has been an increase of venous thromboembolism (VTE) mortality in European countries, concurrent with the replacement of second generation by third generation combined oral contraceptives (COCs). Such an increase has been predicted, and reportedly detected, because published studies have detected an increased incidence of VTE associated with third generation rather than second generation COC use. DESIGN: Data were collected on population and annual VTE mortality in women 15-34 and 35-49 years old, and on second and third generation COC sales, from 1981 to 1994 in 13 European countries. Data from the seven most populous countries were analysed by linear regression of annual VTE mortality, in the 15-34 and 15-49 age groups, with respect to calculated total and third generation COC use rates, and the regression coefficients used to estimate mortality differences between second generation users and non-users and between third and second generation users, respectively. MAIN RESULTS: The estimated mortality differences in all seven countries had confidence intervals wide enough to contain both zero and the excess mortalities expected from the results of published studies. This was true both for the mortality difference between third and second generation COC users and for that between second generation users and COC non-users. CONCLUSIONS: Mortality differences of the size expected from the published studies cannot be measured using annual national VTE mortality and COC sales data alone, because of residual interannual variation in VTE mortality, and possibly confounding between rising third generation market share and total COC use.

Adolescent↗

PubMed1988

A new local feedback model of the saccadic burst generator.

1. To accommodate the finding that the superior colliculus is an important input to the brain stem pathways that generate saccades (the saccadic burst generator), a new model of the burst generator is proposed. Unlike the model of Robinson (61) from which it was derived, the model attempts to match a neural replica of change in eye position, which is the output of the burst generator, to a neural replica of change in target position, which is the output of the colliculus and the input to the model. 2. The elements of the model correspond to neurons known or thought to be associated with the actual primate saccadic burst generator and are mostly connected together in accord with the results of anatomical and physiological experiments. 3. The model was simulated on a digital computer to compare its behavior with that of the actual burst generator under normal and experimental conditions. Simulated peak burst frequency and saccade duration matched that obtained from monkey excitatory burst neurons and inhibitory burst neurons for saccades up to 15 degrees but did not match at larger sizes; stimulation of the omnipause neurons caused an interruption of the saccade, and the saccade resumed at the end of stimulation as in actual data; the model can generate the abnormally long-duration saccades seen under decreased alertness or various pathologies by changing the burst generator inputs and without having to change any properties of the neurons themselves or their connections; a simulated horizontal and vertical burst generator pair connected only through the omnipause neurons can generate realistic oblique saccades. 4. The implications of the model for higher-order control of the saccadic burst generator are discussed.

Efferent Pathways↗

PubMedDate not supplied

G proteins and phospholipase C mediate thrombin-induced generation of plasminogen activator inhibitor-1 from vascular smooth muscle cells.

The present study investigated transcellular signalling mechanism involved in thrombin-induced production of plasminogen activator inhibitor-1 (PAI-1) in cultured vascular baboon aortic smooth muscle cells (BASMC). Treatments with thrombin dose-dependently increased the steady state levels of PAI-1 mRNA and the generation of PAI-1 antigen from BASMC. Thrombin receptor-activating peptide mimicked the effect of thrombin on the generation of PAI-1. Sodium fluoride (1 mM) stimulated PAI-1 generation from BASMC. Pertussis toxin dose-dependently suppressed thrombin-induced increase of PAI-1 generation. Treatment with 5 mM neomycin, 10 microM U73122 or 1 microM calphostin C blocked thrombin-induced PAI-1 generation. Phorbol myristate acetate at 10 nM for 3 h strongly stimulated the generation of PAI-1 from BASMC. Forskolin (100 microM) or 8-bromo-cAMP (100 microM) suppressed thrombin-induced PAI-1 generation. The responses of quiescent BASMC to thrombin or the inhibitors on PAI-1 generation were comparable to that of growing cells. The results of the present study suggest that pertussis toxin-sensitive G proteins and a phospholipase C are involved in thrombin-induced generation of PAI-1 in BASMC, which may transmit signals from occupied thrombin receptor to protein kinase C and thereby increase the generation of PAI-1. Elevated levels of intracellular cAMP may negatively regulate the generation of PAI-1 from vascular SMC.

Animals↗

PubMed2004

Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies.

OBJECTIVE: Based on lower rates of acute extrapyramidal side effects associated with second-generation antipsychotics, compared to first-generation antipsychotics, and based on preliminary data, second-generation antipsychotics are expected to cause less tardive dyskinesia than first-generation antipsychotics. This hypothesis was examined in a systematic review of studies involving open or controlled treatment with any second-generation antipsychotic. METHOD: Studies of treatment with second-generation antipsychotics lasting > or =1 year and reporting on new cases of tardive dyskinesia or dyskinesia were systematically reviewed. RESULTS: In 11 studies, 2,769 patients received treatment with risperidone (five studies, N=1,235), olanzapine (two studies, N=610), quetiapine (two studies, N=386), amisulpride (one study, N=331), or ziprasidone (one study, N=207) for a weighted mean and median duration of 263 and 306 days, respectively. Study designs were double blind and randomized (N=3); open-label extensions of double-blind, randomized trials (N=4); and open label (N=4). Of the four trials that had a comparator (all involving adults with schizophrenia spectrum disorders), three used haloperidol (N=408) and one used placebo (N=71). Studied populations included children (N=77), adults (N=1,419), adults and elderly persons (N=794), and exclusively patients age 54 years or older (N=479). The weighted mean annual incidence of tardive dyskinesia for second-generation antipsychotics was 0% in the children, 0.8% (range=0.0%-1.5%) in the adults, 6.8% in the mixed adult and elderly population, and 5.3% (range=0.0%-13.4%) in the patients age 54 years and older, compared to 5.4% (range=4.1%-7.4%) in adults treated with haloperidol. CONCLUSIONS: Results from 11 long-term studies support the idea that second-generation antipsychotics have a reduced risk for tardive dyskinesia, compared to first-generation antipsychotics, although the doses of haloperidol used in the comparator studies were relatively high. More carefully designed studies, ideally lasting beyond 1 year and comparing the effects of different second-generation antipsychotics in patients who have never taken first-generation antipsychotics, are needed to estimate the true risk. It would not appear premature for clinicians to consider these findings in making long-term treatment decisions.

Adolescent↗

PubMed2000

Testing memory for self-generated items in dementia: method makes a difference.

OBJECTIVE: To learn how pAD (probable Alzheimer's disease), PD+ ("Parkinson's Plus" syndrome), and control subjects remember internally generated material under different conditions. BACKGROUND: "Self-discovered," or internally generated knowledge, prized by educators and therapists, can bring about considerable behavioral change. Both parietal-temporal-limbic (pAD) and frontal-subcortical dementia (e.g. PD+) cause dysmemory, but may cause different internal-external memory bias. pAD subjects, confusing internal and external information (confabulation) and reporting internal information during memory testing (intrusions), may be biased to remember internal material. PD+ subjects, impaired at generative tests, may be externally biased. METHODS: Ten pAD, 5 PD+, and 10 control subjects generated words in a category without instruction to remember (INR), and took a list-learning test of incidental memory for internally and externally generated words. To test how INR influences memory, subjects then generated and attempted to recall four more words. RESULTS: All three subject groups remembered more internally generated than externally provided words without INR. Recall versus recognition of internally generated words differed by group, with PD+ subjects showing greatest improvement with recognition. The pAD subjects performed worse with INR than without INR, had the most intrusion errors, and, rather than demonstrating a release from proactive inhibition, recalled fewer words outside the category. Groups differed in overall recall/recognition improvement (p = 0.015). CONCLUSIONS: Aged subjects preferentially retained internally generated material. However, among demented subjects, memory for internally generated words was influenced by the testing method used. PD+ subjects have poor internal recall, but excellent internal recognition. In pAD, memory for internally generated words may exceed external memory, but only when subjects are not explicitly trying to remember.

Aged↗

PubMed2005

Regulation of H2O2 generation in thyroid cells does not involve Rac1 activation.

OBJECTIVES: The H2O2 generating system of the thyrocyte and the O2- generating system of macrophages and leukocytes present numerous functional analogies. The main constituent enzymes belong to the NADPH oxidase (NOX) family (Duox/ThOX for the thyroid and NOX2 /gp91phox for the leukocytes and macrophages), and in both cell types, H2O2 generation is activated by the intracellular generation of Ca2+ and diacylglycerol signals. Nevertheless, although the controls involved in these two systems are similar, their mechanisms are different. The main factors controlling O2- production by NOX2 are the cytosolic proteins p67phox and p47phox, and Rac, a small GTP-binding protein. We have previously reported that there is no expression of p67phox and p47phox in thyrocytes. Here, we investigated whether Rac1 is an actor in the thyroid H2O2-generating system. DESIGN AND METHODS: Ionomycin- and carbamylcholine-stimulated H2O2 generation was measured in dog thyroid cells pretreated with the Clostridium difficile toxin B, which inhibits Rac proteins. Activation of Rac1 was measured in response to agents stimulating H2O2 production, using the CRIB domain of PAK1 as a probe in a glutathione S-transferase (GST) pull-down assay. RESULTS: Among the various agents inducing H2O2 generation in dog thyrocytes, carbamylcholine is the only one which activates Rac1, whereas phorbol ester and calcium increase alone have no effect, and cAMP inactivates it. Moreover, whereas toxin B inhibits the stimulation of O2- generation by phorbol ester in leukocytes, it does not inhibit H2O2 generation induced by carbamylcholine and ionomycin in dog thyrocytes. CONCLUSIONS: Unlike in leukocytes, Rac proteins do not play a role in H2O2 generation in thyroid cells. A different regulatory cascade for the control of H2O2 generation remains to be defined.

Actins↗

PubMed2006

Adolescent participation in preventive health behaviors, physical activity, and nutrition: differences across immigrant generations for Asians and Latinos compared with Whites.

OBJECTIVES: We investigated preventive health behaviors (bicycle helmet, seat belt, and sunscreen use), physical activity, television viewing or video game playing, and nutrition (fruit, vegetable, milk, and soda consumption) among Asian and Latino adolescents living in the United States; assessed trends across generations (first-, second-, and third-generation immigrants or later); and compared each generation with White adolescents. METHODS: We used data from 5801 adolescents aged 12 to 17 years in the representative 2001 California Health Interview Survey. RESULTS: In multivariate analysis, first-generation Asians measured worse than Whites for preventive health behaviors (lower participation), physical activity (less activity), and television viewing or video game playing (more hours), but improved across generations. For these same behaviors, Latinos were similar to or worse than Whites, and generally showed no improvement across generations. First-generation Asians and Latinos had healthier diets than Whites (higher fruit and vegetable consumption, lower soda consumption). With succeeding generations, Asians' fruit, vegetable, and soda consumption remained stable, but Latinos' fruit and vegetable consumption decreased and their soda consumption increased, so that by the third generation Latinos' nutrition was poorer than Whites'. CONCLUSIONS: For the health behaviors we examined, Asian adolescents' health behaviors either improved with each generation or remained better than that of Whites. Latino adolescents demonstrated generally worse preventive health behaviors than did Whites and, in the case of nutrition, a worsening across generations. Targeted interventions may be needed to address behavioral disparities.

Acculturation↗

PubMed2000

Generativity in midlife and young adults: links to agency, communion and subjective well-being.

Three questions stimulated by Erik Erikson's theory of generativity were addressed: 1) Is generativity associated with greater subjective well-being? 2) Are agency and communion additive or interactive predictors of generativity? 3) Does generativity play a distinct role during the midlife period? Among ninety-eight midlife adults, generativity was positively related to positive affectivity, satisfaction with life, and work satisfaction. Generativity was independently predicted by agentic (masculine) and communal (feminine) traits. Among fifty-eight young adults, generativity predicted positive affect at home. Generativity was independently predicted by agentic (power) and communal (love) interpersonal orientations. Using event-contingent recording of agentic and communal behavior at work, agency was a stronger predictor of generativity for young adult men, and communion was a stronger predictor for young adult women. The studies demonstrate that generativity has similar relations to agency and communion in young and midlife adults; however, generativity may be a stronger predictor of subjective well-being in midlife adults.

Adaptation, Psychological↗

PubMed2001

Generation of reactive oxygen species by equine spermatozoa.

OBJECTIVE: To characterize generation of reactive oxygen species (ROS) by equine spermatozoa. SAMPLE POPULATION: Multiple semen samples collected from 9 stallions. PROCEDURE: Equine spermatozoa were separated from seminal plasma on a discontinuous polyvinylpyrrolidone (PVP)-coated silica gradient and resuspended in a modified Tyrode albumin-lactate-pyruvate medium. Amount of hydrogen peroxide (H2O2) generated was assayed by use of a 1-step fluorometric assay, using 10-acetyl-3,7-dihydroxyphenoxazine as a probe for detection of H2O2 in a microplate assay format. Concentration of H2O2 was determined by use of a fluorescence microplate reader. RESULTS: Amount of H2O2 generated increased significantly with time and spermatozoa concentration for live and flash-frozen spermatozoa, and amount of H2O2 generated was significantly greater for flash-frozen than for live spermatozoa. Addition of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) significantly increased generation of H2O2 by live and flash-frozen spermatozoa. Addition of a calcium ionophore also significantly increased the amount of H2O2 generated by live spermatozoa but did not have an effect on amount of H2O2 generated by flash-frozen spermatozoa. Abnormal equine spermatozoa generated significantly greater amounts of H2O2 than did normal spermatozoa. CONCLUSIONS AND CLINICAL RELEVANCE: Equine spermatozoa generate ROS in vitro, possibly via a NADPH-oxidase reaction. Spermatozoa damaged during flash-freezing or morphologically abnormal spermatozoa generated significantly greater amounts of ROS than did live or morphologically normal spermatozoa. Damaged and abnormal spermatozoa generate greater amounts of ROS that may contribute to reduced fertility or problems related to semen preservation.

Animals↗

PubMedDate not supplied

Recent oral contraceptive use patterns in four European countries: evidence for selective prescribing of oral contraceptives containing third-generation progestogens.

A survey among oral contraceptive (OC) prescribers in the United Kingdom, Germany, Sweden and the Netherlands was performed to investigate OC prescription patterns before and after recent publicity in the media about studies reporting a higher risk of venous thromboembolism with OCs containing third-generation progestogens as compared to OCs containing second-generation progestogens. Before this publicity, most physicians prescribed third-generation OCs as their first-choice formulations for normal healthy women as well as for young girls (< 20 years) and older fertile women (30-35 years). In women presenting with cardiovascular risk factors, third-generation progestogens (desogestrel, gestodene) were considered safer and were five times more often prescribed than second-generation preparations (71% versus 14%). Most prescribers considered ethinylestradiol to be the most important component in relation to the risk of venous thromboembolism (71%), myocardial infarction (66%) and stroke (67%). In addition, for women presenting with cardiovascular risk factors, OC preparations containing 20 or 30 micrograms ethinylestradiol were considered safer than preparations containing 35 or 50 micrograms ethinylestradiol. Although the vast majority of prescribers (78%) stated that their attitudes towards safety of third-generation OCs had not changed since the recent publicity and the regulatory actions in some countries, 56% had changed their prescribing practice, largely due to patient concern about the safety of third-generation OCs. The results from this survey strongly suggest that, prior to the recent publicity, most prescribers considered third-generation OCs to be safer than second-generation preparations. Because of this perceived better safety profile, physicians have selectively been prescribing third-generation OCs to women at increased risk of cardiovascular disease. This pattern of selective OC prescribing may have seriously biased the results of the recently published studies on OCs and venous thromboembolism in favor of second-generation OCs.

Adult↗

PubMed1991

Generating makes words memorable, but so does effective reading.

In many experiments, memorial benefits have been found when subjects generate items from fragments rather than read items in their complete forms. Does generation cause this difference, or are subjects disposed to adopt different strategies when generating as opposed to reading? If generating causes the difference, items processed in the same way apart from a generative stage should therefore benefit from that generative stage. Our experiments did result in benefits for generating as opposed to reading, but only when the readers processed the words poorly--by pronouncing them. When the readers processed the items well, by imagining them, generating was no better than reading. A new generation effect was found in metamemory. Subjects thought they would remember more generated items than read items; however, the act of making the prediction entailed meaningful processing, and the generated items were not actually remembered better than the read ones.

Adult↗

PubMed1999

The levels of factor XIIa generated in human plasma on an electronegative surface are insensitive to wide variation in the concentration of FXII, prekallikrein, high molecular weight kininogen or FXI.

The contribution of the various components of the contact system in the generation of factor XIIa (FXIIa) and of kallikrein (KRN) on an electronegative surface and the release of the generated enzymes to the bulk phase was examined in mixtures of normal human plasma and plasmas congenitally deficient in these components. The incubation of normal human plasma in the presence of sulphatide vesicles (40 microM) resulted in a fast generation of amidolytic activities due to FXIIa and to KRN followed by slower first-order inactivation rates of FXIIa (k'FXIIa) and of KRN (k'KRN) due to the presence of esterase inhibitors. Variation of the levels of factor XII (FXII), over a wide range, showed little effect on levels of FXIIa and of KRN but no activities were detected in 100% FXII-deficient plasma. The variation of prekallikrein (PKRN) concentration showed little effect on the generation of FXIIa but the generation of KRN declined linearly with the decrease in the level of PKRN. No activities were detected on treatment of PKRN-deficient plasma. The variation in the concentration of high molecular weight kininogen (HK) showed effects on FXIIa and KRN that were qualitatively similar to those seen on variation of PKRN but 100% HK-deficient plasma generated considerable activities of both FXIIa and KRN. The variation in the concentration of factor XI (FXI) showed no effect on the generation of FXIIa, whereas KRN levels increased linearly with the contribution of FXI-deficient in normal plasma. The present results suggest that the contiguous binding of FXIIa, FXII, PKRN-HK and FXI-HK onto the electronegative surface induces a rapid generation of FXIIa and KRN. The bound PKRN-HK complex prevents the release of generated FXIIa and therefore further binding and activation of FXII from the bulk phase. Consequently, the turnover of FXII is independent of its levels in the bulk phase and is rather related to the concentration of contact surface. The generated KRN is also protected by HK. However, since the enzyme responsible for the activation of PKRN-HK is FXIIa, the levels of generated KRN are positively related to the concentration of substrate.

Animals↗

PubMed1999

"Normal" thrombin generation.

We have investigated the influence of alterations in plasma coagulation factor levels between 50% and 150% of their mean values for prothrombin, factor X, factor XI, factor IX, factor VII, factor VIII, factor V, protein C, protein S, antithrombin III (AT-III), and tissue factor pathway inhibitor (TFPI) as well as combinations of extremes, eg, 50% anticoagulants and 150% procoagulants or 50% procoagulants and 150% anticoagulants in a synthetic "plasma" system. The reaction systems were constructed in vitro using purified, natural, and recombinant proteins and synthetic phospholipid vesicles or platelets with the reactions initiated by recombinant tissue factor (TF)-factor VIIa complex (5 pmol/L). To investigate the influence of the protein C system, soluble thrombomodulin (Tm) was also added to the reaction mixture. For the most extreme situations in which the essential plasma procoagulants (prothrombin, and factors X, IX, V, and VIII) and the stoichiometric anticoagulants (AT-III and TFPI) were collectively and inversely altered by 50%, a 28-fold difference in the total available thrombin generated was observed. Variations of most of these proteins 50% above and below the "normal" range, with the remainder at 100%, had only modest influences on the peak and total levels of thrombin generated. The dominant factors influencing thrombin generation were prothrombin and AT-III. When these 2 components were held at 100% and all other plasma procoagulants were reduced to 50%, there was a 60% reduction in the available thrombin generated. No increase in the thrombin generated was observed when the 150% level of all plasma procoagulants other than prothrombin was evaluated. When only prothrombin was raised to 150%, and all other factors were maintained at 100%, the thrombin generated increased by 71% to 121%. When AT-III was at 50% and all other constituents were at 100%, thrombin production was increased by 104% to 196%. The additions of protein C and protein S over the 50% to 150% ranges with Tm at 0.1 nmol/L concentration had limited influence on thrombin generation. Individual variations in factors VII, XI, and X concentrations had little effect on the duration of the initiation phase, the peak thrombin level achieved, or the available thrombin generated. Paradoxically, increases in factor IX concentration to 150% led to lowered thrombin generation, while decreases to 50% led to enhanced thrombin generation, most likely a consequence of factor IX as a competitive substrate with factor X for factor VIIa-TF. Reductions in factor V or factor VIII concentration led to prolongations of the initiation phase, while the reduction of TFPI to 50% led to shortening of this phase. However, none of these alterations led to significant changes in the available thrombin generated. Based on these data, one might surmise that increases in prothrombin and reductions in AT-III, within the normal range, would be potential risk factors for thrombosis and that algorithms that combine normal factor levels may be required to develop predictive tests for thrombosis.

Anticoagulants↗