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PubMed2004

Generation and memory for contextual detail.

Generation enhances item memory but may not enhance other aspects of memory. In 12 experiments, the author investigated the effect of generation on context memory, motivated in part by the hypothesis that generation produces a trade-off in encoding item and contextual information. Participants generated some study words (e.g., hot-c__) and read others (e.g., hot-cold). Generation consistently enhanced item memory but did not enhance context memory. More specifically, generation disrupted context memory for the color of the target word but did not affect context memory for location, background color, and cue-word color. The specificity of the negative generation effect in context memory argues against a general item-context trade-off. A processing account of generation meets greater success. In addition, the results provide no evidence that generation enhances recollection of contextual details.

Cues↗

PubMed2005

A potential role for extracellular nitric oxide generation in cGMP-independent inhibition of human platelet aggregation: biochemical and pharmacological considerations.

1. Nitric oxide (NO) is a potent inhibitor of platelet activation, that inhibits the agonist-induced increase in cytosolic Ca2+ concentration through both cGMP-dependent and independent pathways. However, the NO-related (NOx) species responsible for cGMP-independent signalling in platelets is unclear. We tested the hypothesis that extracellular NO, but not NO+ or peroxynitrite, generated in the extracellular compartment is responsible for cGMP-independent inhibition of platelet activation via inhibition of Ca2+ signalling. 2. Concentration-response curves for diethylamine diazeniumdiolate (DEA/NO; a spontaneous NO generator), S-nitroso-N-valerylpenicillamine (SNVP; an S-nitrosothiol) and 3-morpholinosydnonomine (SIN-1; a peroxynitrite generator) were generated in platelet-rich plasma (PRP) and washed platelets (WP) in the presence and absence of a supramaximal concentration of the soluble guanylate cyclase inhibitor, ODQ (20 microM). All three NOx donors displayed cGMP-independent inhibition of platelet aggregation in PRP, but only DEA/NO exhibited cGMP-independent inhibition of aggregation in WP. 3. Analysis of NO generation using an isolated NO-electrode revealed that cGMP-independent effects coincided with the generation of substantial levels of extracellular NO (>40 nM) from the NOx donors. 4. Reconstitution of WP with plasma factors indicated that the copper-containing plasma protein, caeruloplasmin (CP), catalysed the release of NO from SNVP, while Cu/Zn superoxide dismutase (SOD) unmasked NO generated from SIN-1. The increased generation of extracellular NO correlated with a switch to cGMP-independent effects with both NOx donors. 5. Analysis of Fura-2 loaded WP revealed that only DEA/NO inhibited Ca2+ signalling in platelets via a cGMP-independent mechanism. However, preincubation of SNVP and SIN-1 with CP and SOD, respectively, induced cGMP-independent inhibition of intraplatelet Ca2+ trafficking by the NOx donors. 6. Taken together, our data suggest that extracellular NO (>40 nM) is required for cGMP-independent inhibition of platelet activation. Plasma constituents may play an important pharmacological role in activating cGMP-independent signalling by S-nitrosothiols or peroxynitrite generators.

Adult↗

PubMed1976

Generation of ammonia from non-urea sources in a faecal incubation system.

1. A 25% faecal suspension in sodium chloride solution, incubated anaerobically at 37 degrees C for 48 h, showed excellent survival of all the main groups of faecal bacteria. 2. All faecal incubation systems studied generated large amounts of ammonia, particularly those in which bacterial counts fell during incubation. As normal faeces contain negligible amounts of urea this ammonia must have been generated from sources other than urea. 3. Ammonia was also generated by faeces delivered by sodium chloride enema, and by ileostomy fluid, indicating that the phenomenon is not confined to distal colonic contents. 4. Ammonia generation by incubated faeces was inhibited by prior autoclaving of the sample, but not by sterilization with gamma-irradiation. 5. Generation of ammonia by incubated stool was accompanied by release of large amounts of organic anion and a fall in pH. 6. These observations are interpreted as evidence that ammonia generated within the colon in situ is not derived exclusively from urea, but also from bacterial deamination of amino acids, peptides and proteins. Simultaneously bacterial activity generates large amounts of organacid. The presence of living bacteria is not essential for ammonia generation, provided that bacterial enzymes are present. 7. Bacterial generation of organic solute in faeces which have left the body is sufficiently rapid to cast serious doubts on the validity of faecal centrifugation, or other time-consuming techniques involving lengthy handling of faeces, as methods of obtaining extracellular faecal fluid for measurements of organic constituents or ammonia.

Adult↗

PubMed2002

Blockade of superoxide generation prevents high-affinity immunoglobulin E receptor-mediated release of allergic mediators by rat mast cell line and human basophils.

BACKGROUND: Previous studies have shown that rat peritoneal mast cells and mast cell model rat basophilic leukaemia (RBL-2H3) cells generate intracellular reactive oxygen species (ROS) in response to antigen challenge. However, the physiological significance of the burst of ROS is poorly understood. OBJECTIVE: The present study was undertaken to investigate the role of superoxide anion in mediator release in rat and human cell systems. METHODS: RBL-2H3 cells were directly stimulated with anti-rat FcepsilonRI alpha-subunit monoclonal antibody (mAb). For the analysis of human cell system, leucocytes were isolated by dextran sedimentation from healthy volunteers or from patients, and challenged either with anti-human FcepsilonRI mAb or with the relevant antigens. Superoxide generation was determined by chemiluminescence-based methods. The releases of histamine and leukotrienes (LT)s were determined by enzyme-linked immunosorben assay (ELISA). RESULTS: Cross-linking of FcepsilonRI on RBL-2H3 cells or on human leucocytes from healthy donors by the anti-FcepsilonRI mAb resulted in a rapid generation of superoxide anion, as determined by chemiluminescence using superoxide-specific probes. Similarly, leucocytes from patients generated superoxide anion in response to the challenge with the relevant allergen but not with the irrelevant allergen. Furthermore, diphenyleneiodonium (DPI), a well-known inhibitor of flavoenzymes suppressed the superoxide generation and the release of histamine and LTC4 induced by the anti-FcepsilonRI mAb or by allergen in parallel. CONCLUSION: These results indicate that both RBL-2H3 cells and human basophils generate superoxide anion upon FcepsilonRI cross-linking either by antibody or by allergen challenge and that blockade of the generation prevents the release of allergic mediators. The findings strongly support the role of superoxide generation in the activation of mast cells and basophils under both physiological and pathological conditions. The findings suggest that drugs regulating the superoxide generation have potential therapeutic use for allergic disorders.

Adult↗

PubMed2000

Functional and phenotypic characteristics of dendritic cells generated in human plasma supplemented medium.

One successful approach to generate dendritic cells (DC) is to cultivate peripheral blood monocytes in fetal calf serum (FCS)-containing medium in the presence of granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-4. Because the use of xenogenic proteins has to be strictly avoided for clinical applications, alternative protocols use human plasma instead of FCS. The aim of our study was to characterize DC generated in the presence of human plasma; moreover, we describe a novel protocol to generate DC directly from peripheral blood mononuclear cells (PBMC). DC generated from purified monocytes in the presence of 1% human plasma (HP-DC) and GM-CSF and IL-4 both in the allogenic mixed leukocyte reaction (MLR) and in the tetanus presentation assay were potent stimulators of T-cell proliferation. DC generated from PBMC were equally effective stimulators in the allogenic MLR as those generated from purified monocytes. When the immunophenotype of DC generated from FCS containing medium (FCS-DC) was compared to that of HP-DC, the surface expression of CD1a and CD80 was significantly lower in HP-DC. In contrast, the expression of CD83 and CD86 was significantly higher in HP-DC than in FCS-DC. The capacity of receptor mediated endocytosis and macropinocytosis was found to be significantly lower in HP-DC when compared to FCS-DC. The differences in the immunophenotype, macropinocytosis and endocytosis between the HP-DC and the FCS-DC were observed independently of the generation of the cells from PBMC or purified monocytes. Our data indicate that HP-DC are potent stimulators of T-cell proliferation and exhibit a characteristic phenotype of intermediate maturity. Moreover, DC can be directly generated from PBMC preparations.

Antigen Presentation↗

PubMed1999

Benefits and risks of third-generation oral contraceptives.

OBJECTIVE: To evaluate the risks and benefits of third-generation oral contraceptives. DATA SOURCES: A MEDLINE search was done for English language articles published from 1985 through 1998 relating to the side-effect profile of third-generation oral contraceptives or their association with cardiovascular or thromboembolic disease. All articles containing original data were included. DATA SYNTHESIS: The risk of venous thromboembolism appears to be 1.5- to 2.7-fold greater in users of third-generation, compared with second-generation, oral contraceptives. Compared with nonusers, women who use third-generation oral contraceptives may have a 4.8- to 9.4-fold greater risk of venous thromboembolism. Users of third-generation oral contraceptives do not appear to have an increased risk of myocardial infarction compared with nonusers and may have risk of myocardial infarction of 0.26 to 0.7 compared with second-generation users. Whether third-generation oral contraceptives are associated with a decreased stroke risk is still not clear. CONCLUSIONS: Although third-generation oral contraceptives most likely increase a user's risk of venous thromboembolism, their improved side-effect profile and their possible decreased association with myocardial infarction and stroke may make them a useful new class of oral contraceptives for most women except those at increased risk of venous thrombosis.

Contraceptives, Oral↗

PubMed1992

Experimental examination of factors that affect dust generation by using Heubach and MRI testers.

Four factors that affect dust generation were investigated--type of test material, particle size distribution of the test material, moisture content of the test material, and apparatus used to generate dust. Dust generated from silicon carbide and aluminum oxide was measured by using MRI and Heubach dustiness testers modified to allow the measurement of dust particle size distribution with an Andersen impactor. The two materials investigated generated similar dusts. The size distribution of the test material slightly influenced the amount but strongly influenced the size distribution of the dust generated. Increased moisture content decreased the amount of dust generated; moisture content had little influence on dust size distribution. The two testers generated different amounts of dust; however, the dust particle size distributions generated were similar. These results help explain factors that affect dust generation and the relative importance of alternative methods for dust control.

Aluminum Oxide↗

PubMed2004

Hand-assisted laparoscopic devices: the second generation.

BACKGROUND AND PURPOSE: Hand-assisted laparoscopic (HAL) nephrectomy is an increasingly popular surgical modality. Within the last year, three newly designed second-generation hand-assist devices have emerged with the intention to improve efficacy and ease of use. We prospectively evaluated and compared these with each other and with the first-generation devices. MATERIALS AND METHODS: A total of 130 urologists performed two HAL nephrectomies in a porcine laboratory using two different hand devices at an American Urological Association-sponsored learning course. Sixty-three urologists utilized the second-generation devices (Gelport, Omniport, LapDisc), while 67 urologists used the first-generation devices (Handport, Intromit, PneumoSleeve). Each surgeon completed a 12-question survey evaluating the devices. RESULTS: Evaluation of the second-generation devices revealed that Gelport was statistically significantly superior in all parameters to the Omniport and in 5 of 10 parameters to the LapDisc. Comparison of the first- and second-generation devices revealed that only the Gelport achieved a significant increase in all ratings. Among the first-generation devices, no device scored better than 8.27 of 10 in any category. Analysis of the second-generation devices demonstrated that the Gelport scored a rating above 8.25 in all parameters with an overall satisfaction score of 8.59. Both the Omniport and the LapDisc attained ratings comparable to those of the first-generation devices. CONCLUSION: The HAL procedure relies heavily on devices that allow the hand to be introduced into the laparoscopic environment. The Gelport, when evaluated in a porcine model by training laparoscopic urologists, appears to be significantly better than other devices available to date. Further testing with larger cohorts and human clinical trials are required to confirm these findings.

Animals↗

PubMed2006

Association of first- and second-generation air bags with front occupant death in car crashes: a matched cohort study.

First-generation air bags entail a decreased risk of death for most front seat occupants in car crashes but an increased risk for children. Second-generation air bags were developed to reduce the risks for children, despite the possibility of decreasing protection for others. Using a matched cohort design, the authors estimated risk ratios for death for use of each generation of air bag versus no air bag, adjusted for seat position, restraint use, sex, age, and all vehicle and crash characteristics, among 128,208 automobile occupants involved in fatal crashes on US roadways during 1990-2002. The authors then compared adjusted risk ratios (aRRs) between the two generations of air bags. Among front seat occupants, the aRR for death with a first-generation air bag was 0.90 (95% confidence interval (CI): 0.86, 0.94); the aRR with a second-generation air bag was 0.89 (95% CI: 0.79, 1.00) (p = 0.83 for comparison of aRRs). Among children under age 6 years, the aRR with a first-generation air bag was 1.66 (95% CI: 1.20, 2.30), while the aRR with a second-generation air bag was 1.10 (95% CI: 0.63, 1.93) (p = 0.20 for comparison of aRRs). The differences in aRRs between first- and second-generation air bags among other subgroups were small and not statistically significant.

Accidents, Traffic↗

PubMed2004

Strategies for precise quantification of transgene expression levels over several generations in rice.

Variation in transgene expression levels can result from uncontrolled differences in experimental protocols. Studies conducted over generations could, by their design, generate additional unwanted variation. To study sources of spurious variation, transgene expression levels were quantified over five homozygous generations in two independent transgenic rice lines created by particle bombardment. Both lines contained the same gus expression unit and had been shown to exhibit stable inheritance of transgene structure and expression. All plants were cultured and sampled using previously developed standardized protocols. Plants representative of each generation (T2, T3, T4, T5, T6) were grown either all together or across several different growth periods. GUS activity in plants from different generations was quantified either in the same assay or over multiple independent assays. Strategies in which plants were grown and phenotyped independently, significantly increased (up to 3-fold) extraneous variation in transgene expression level quantification, thus reducing the precision of molecular genetic studies and generating artefactual results in transgenic studies conducted over generations. Identification of sources of unwanted variation and quantification of their effect allowed the development of new strategies designed to control spurious variation. Growth and phenotyping of all plants from all generations together, using standard operating procedures (SOP), led to a reduction in extraneous variation associated with transgene expression level quantification. Adoption of such strategies is key to improving the reproducibility of transgenic studies conducted over generations.

Gene Expression Regulation, Plant↗

PubMed1998

Forty generations of bidirectional selection for mating frequency in male Japanese quail.

A bidirectional replicated selection experiment for high (H1 and H2) or low (L1 and L2) cumulative number of complete matings (CNCM) in male Japanese quail was conducted for 40 generations. In the S32 generation, a subline was taken from each selected line and selection was relaxed. In the randombred control line (C), CNCM and unselected traits changed significantly over generations. Means of the selected lines were adjusted each generation for deviations from the control means. After 40 generations of selection, there was a 21-fold difference in CNCM (59.4 vs 2.8) between Lines H1 and L1. Whereas means increased and variation decreased in the high lines, means decreased and variation increased in the low lines. Regressions of mean CNCM on generation of Lines H1, H2, L1, and L2 were 1.15 +/- 0.08, 0.61 +/- 0.08, -0.26 +/- 0.04, and -0.34 +/- 0.03, respectively. Although responses to selection were observed throughout the 40 generations in Line H1, the low lines appeared to have reached a limit to selection after the S30 generation. Relaxed lines provided supporting evidence for this conclusion. Mean CNCM decreased in the relaxed high lines to that of the control, whereas the low relaxed lines remained at the same level as their corresponding selected lines. Line H2 went into extinction in the 37th generation as a result of reduced fitness. Realized heritabilities of CNCM were 0.09, 0.07, 0.06, and -0.15 in Lines H1, H2, L1, and L2, respectively. As correlated responses to the selection, male quail in the high lines were heavier, exhibited greater relative aggressiveness, and had larger cloacal glands than those of the control and low lines.

Animals↗

PubMed2004

Neurotoxic lesions of phasic pontine-wave generator cells impair retention of 2-way active avoidance memory.

STUDY OBJECTIVES: The aim of this study was to test the hypothesis that the activation of pontine (P)-wave generator is critical for the posttraining rapid eye movement (REM) sleep-dependent memory processing. DESIGN: Ibotenic acid was microinjected (0.5 microg in 0.05 microL) into the functionally identified P-wave generator in order to destroy the cell bodies and thus to study the effects of their destruction upon waking-sleep states, P-waves, and 2-way active avoidance memory. SETTING: Sleep research laboratory at Boston University School of Medicine. PARTICIPANTS: Adult male Sprague-Dawley rats (N = 27). INTERVENTIONS: Chronically implanted for recording polygraphic signs of sleep and bilateral guide tubes for the local microinjections into the P-wave generator. MEASUREMENTS AND RESULTS: The ibotenic acid produced a small spherical area (< or = 0.35 mm in diameter) of nerve cell loss centered on the P-wave generator. Bilateral lesioning of the P-wave generator decreased P-waves during REM sleep by > 95% without significantly changing the amounts of time spent in wake, slow-wave sleep, or REM sleep. In these P-wave generator-lesioned rats, acquisition of avoidance learning and posttraining wake-sleep changes were identical to those of the sham-lesioned rats. However, in the test trials, after 6 hours of undisturbed sleep-wake, P-wave generator-lesioned rats had no retention of avoidance memory. CONCLUSIONS: These findings, for the first time, provide direct evidence that P-wave-generating cells are critical for normal REM sleep-dependent memory processing. This evidence supports our hypothesis that the P-wave generator in the brainstem may act as an on switch to provide activating input to forebrain structures for sleep-dependent memory processing.

Animals↗

PubMed1993

Multiple generational bovine embryo cloning.

Repeated cycles (multiple generations) of nuclear transfer procedures have the potential of producing a large number of identical offspring from the micromanipulation of one mammalian embryo. This paper outlines the differences in nuclear transfer procedure efficiencies and developmental rates for the various stages and generations of embryos. We report the production of 54 genetically identical embryos that developed to the morula stage from one parent embryo. When a limited number of nuclear transfer embryos (clones) were transferred to recipient females, first, second, and third generation calves were born. Clones cultured for 5 days in the sheep oviduct had a greater number of cells (28.1 +/- 1.7) than clones cultured for 4 days (17.8 +/- 1.7). However, fusion rates were lower for Day 5 clones (Day 5, 57% vs. Day 4, 68%; p < 0.001) used as donors for the next generation of cloning. Different generations of clones also varied in fusion rates. Fusion rates generally declined with each additional generation and ranged from 66% for the parent-donor embryos to 52% for second generation donors (p < 0.01). Developmental rates were highest for first and third generation donors (20% and 19%) and lowest for second generation donors (10%; p < 0.001). Further understanding of the factors that are conducive to high developmental rates and nuclear reprogramming may make it possible to produce an unlimited number of genetically identical animals.

Animals↗

PubMed1995

Inhibition of extrinsic and intrinsic thrombin generation by a novel synthetic thrombin inhibitor (Ro 46-6240), recombinant hirudin and heparin in human plasma.

To further define the anticoagulant activity of Ro 46-6240, a novel, synthetic, thrombin inhibitor, we compared its effect on extrinsic and intrinsic thrombin generation in human platelet-poor plasma with that of recombinant hirudin and standard heparin. The time course of thrombin generation was followed with a chromogenic substrate assay. The total amount of active thrombin formed was quantified by calculating the area under the thrombin generation curve. Ro 46-6240 and r-hirudin delayed thrombin formation in a concentration-dependent manner in both activation systems whereas heparin showed this effect only in the intrinsic system. Heparin was the most potent inhibitor of extrinsic and intrinsic thrombin generation with IC50 values of 20 and 27 nM, respectively. Ro 46-6240 was nearly as potent as r-hirudin for inhibiting extrinsic thrombin generation (IC50 418 vs 229 nM) and intrinsic thrombin generation (IC50 463 vs 343 nM) despite a much lower affinity of Ro 46-6240 for thrombin (Ki apparent: 0.3 nM) in a purified buffer system. The similar potency of the small active-site thrombin inhibitor compared to the larger hirudin may be explained by different kinetic mechanisms for inhibition of thrombin and by a higher accessibility to the phospholipid surface where thrombin generation takes place. In conclusion, our results show that a specific small thrombin inhibitor efficiently inhibits and delays thrombin generation in human coagulating plasma. This reduced thrombin generation might be caused by inhibition of thrombin-mediated feedback reactions during blood coagulation.

Antithrombins↗

PubMed1987

Effects of angiotensin I converting enzyme (ACE)-related substances on prostacyclin generation and ACE activity of human vascular endothelial cells and rat aortic rings.

The effects of angiotensin I (ANG I) converting enzyme (ACE)-related substances on prostacyclin (PGI2) generation were investigated using cultured human vascular endothelial cells (EC) and rat aortic rings. ANG I or bradykinin (BK) increased while captopril decreased PGI2 generation and ACE activity of EC, whereas ANG II was without effect. The enhancement of PGI2 generation induced by ANG I or BK was not affected by the pretreatment with captopril. In rat aortic rings, ANG I, ANG II, and BK enhanced whereas captopril (10(-3) M) attenuated PGI2 generation. Mechanical stimulation of aortic rings stimulated PGI2 generation. These results suggest that (a) the conversion of ANG I to ANG II did not enhance PGI2 generation in EC; (b) the ANG II stimulated PGI2 generation of aortic rings was partially derived by mechanical stimulation of EC, probably originating from the contraction of smooth muscle cells by ANG II; (c) captopril directly inhibited PGI2 generation; and (d) in EC, the stimulation of PGI2 generation by ANG I or BK is probably regulated by an activating effect on ACE as an autoregulatory mechanism.

Animals↗

PubMed1998

Influence of muscle morphometry and moment arms on the moment-generating capacity of human neck muscles.

STUDY DESIGN: The function of neck muscles was quantified by incorporating experimentally measured morphometric parameters into a three-dimensional biomechanical model. OBJECTIVE: To analyze how muscle morphometry and moment arms influence moment-generating capacity of human neck muscles in physiologic ranges of motion. SUMMARY OF BACKGROUND DATA: Previous biomechanical analyses of the head-neck system have used simplified representations of the musculoskeletal anatomy. The force- and moment-generating properties of individual neck muscles have not been reported. METHODS: A computer graphics model was developed that incorporates detailed neck muscle morphometric data into a model of cervical musculoskeletal anatomy and intervertebral kinematics. Moment arms and force-generating capacity of neck muscles were calculated for a range of head positions. RESULTS: With the head in the upright neutral position, the muscles with the largest moment arms and moment-generating capacities are sternocleidomastoid in flexion and lateral bending, semispinalis capitis and splenius capitis in extension, and trapezius in axial rotation. The moment arms of certain neck muscles (e.g., rectus capitis posterior major in axial rotation) change considerably in the physiologic range of motion. Most neck muscles maintain at least 80% of their peak force-generating capacity throughout the range of motion; however, the force-generating capacities of muscles with large moment arms and/or short fascicles (e.g., splenius capitis) vary substantially with head posture. CONCLUSION: These results quantify the contributions of individual neck muscles to moment-generating capacity and demonstrate that variations in force-generating capacity and moment arm throughout the range of motion can alter muscle moment-generating capacities.

Biomechanical Phenomena↗

PubMed2001

Oxygen radical generation by emigrated, intra-abdominal, and circulating PMNLs during human secondary peritonitis.

The purpose of the study was to characterize oxygen radical generation by emigrated, intraabdominal and circulating polymorphonuclear leukocytes (ePMNLs and cPMNLs) during peritonitis, as well as to assess any differences between oxygen radical production in patients with low Mannheim peritonitis index (MPI < 26, group 1) or high Mannheim peritonitis index (MPI > or = 26, group 2). Lucigenin-enhanced chemiluminescence was used to determine spontaneous and stimulated (FMLP, PMA, and A23 187) oxygen radical generation by ePMNLs and cPMNLs. In group 1 spontaneous and stimulated oxygen radical generation by emigrated PMNLs was markedly enhanced compared to circulating PMNLs (e.g., spontaneous oxygen radical generation: 30.3 +/- 11.8 cpm/cPMNLs versus 107 +/- 46 cpm/ePMNLs, P < 0.05) . In group 2 oxygen radical generation by cPMNLs markedly increased within 48 h after diagnosis of peritonitis and surgery, contrary to radical generation by ePMNLs (e.g., A23 187-stimulated oxygen radical generation 993.7 +/- 350 cpm/cPMNLs versus 285.6 +/- 77 cpm/ePMNLs, P < 0.05. In conclusion, cPMNLs and ePMNLs exhibit marked polymorphism in their capacity to generate oxygen radicals in response to secondary peritonitis. Severe peritonitis (MPI - 26) was associated with a strong increase in oxygen radical generation by cPMNLs without a parallel activity being manifest by ePMNLs.

Abdomen↗

PubMed1979

Organization of haemopoietic stem cells: the generation-age hypothesis.

This paper proposes that the previous division history of each stem cell is one determinant of the functional organization of the haemopoietic stem cell population. Stem cells from a lineage of stem cells which have generated many stem cells (older stem cells) are used in the animal to form blood before stem cells which have generated few stem cells (younger stem cells). The stem cell generating capacity of a lineage of stem cells is finite. After a given number of generations a stem cell is lost to the stem cell compartment by forming two committed precursors of the cell lines. Its part in blood formation is taken by the next oldest stem cell. We have called this proposal the generation-age hypothesis. Experimental evidence in support of the proposal is presented. We stripped away older stem cells from normal bone marrow and 13 day foetal liver with phase-specific drugs and revealed a younger population of stem cells whose capacity for stem cell generation was three- to four-fold greater than that of the average normal, untreated population. We aged normal stem cells by continuous irradiation and serial retransplantation and found that their stem cell generative capacity had declined eight-fold. We measured the stem cell generative capacity of stem cells in the bloodstream. It was a half to a quarter that of normal bone marrow stem cells and we found a subpopulation of circulating stem cells whose capacity for stem cell generation was an eighth to a fortieth that of normal femoral stem cells. This subpopulation was identified by its failure to express the brain-associated antigen which was present on 75% of normal femoral stem cells but was not found on their progeny, the committed precursors of granulocytes.

Animals↗