Biomedical subjects

R J Davidson

Publications and source records attributed to R J Davidson.

At least 37 records · Page 2Linked to original sources

PubMed2000

The tyrosine kinase inhibitor STI571, like interferon-alpha, preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors from patients with chronic myeloid leukemia.

OBJECTIVE: To determine whether the compound STI571 (formerly known as CGP571418B), a selective inhibitor of the protein tyrosine kinase (PTK) activity of ABL and BCR-ABL proteins, preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors (CFU-GM) from patients with chronic myeloid leukemia while sparing normal CFU-GM and to compare responses of CML and normal cells with STI571 and IFN-alpha. MATERIALS AND METHODS: Chronic phase CML and normal CFU-GM were grown with and without STI571, IFN-alpha, or the two agents in combination. Colonies were plucked and replated in 96-well microtiter plates. Secondary colonies were scored, and the results were expressed as the area-under-the-curve (AUC) of the distribution of secondary colony numbers per primary CFU-GM. This value gives an overall measure of the replating ability or amplification of the original CFU-GM population. RESULTS: STI571 selectively inhibits the formation of granulocyte-macrophage colony-forming cells (CFU-GM) from CML patients. It also significantly inhibits the amplification of CML CFU-GM (p = 0.002) as measured by secondary colony formation after replating primary CFU-GM colonies. In contrast, amplification of normal CFU-GM was enhanced (p = 0.001) at low concentrations (0.1 microM) of STI571 with a return to baseline at 10 microM STI571. Addition of interferon (IFN)-alpha to STI571 abolished the increase in normal CFU-GM amplification seen with either agent alone. There was a highly significant correlation between the in vitro response to STI571 and the in vitro response to IFN-alpha (r = 0.74 for CML cells, and 0.77 for normal cells). CONCLUSION: We conclude that STI571, like IFN-alpha, preferentially suppresses amplification of CML CFU-GM while sparing normal CFU-GM.

Antineoplastic Agents↗

PubMed2000

Affective style, psychopathology, and resilience: brain mechanisms and plasticity.

The brain circuitry underlying emotion includes several territories of the prefrontal cortex (PFC), the amygdala, hippocampus, anterior cingulate, and related structures. In general, the PFC represents emotion in the absence of immediately present incentives and thus plays a crucial role in the anticipation of the future affective consequences of action, as well as in the persistence of emotion following the offset of an elicitor. The functions of the other structures in this circuit are also considered. Individual differences in this circuitry are reviewed, with an emphasis on asymmetries within the PFC and activation of the amygdala as 2 key components of affective style. These individual differences are related to both behavioral and biological variables associated with affective style and emotion regulation. Plasticity in this circuitry and its implications for transforming emotion and cultivating positive affect and resilience are considered.

Amygdala↗

PubMed2000

Combination of interferon alpha with either Ara-C or ATRA in vitro reduces the selective action of interferon against CML CFU-GM.

Although interferon (IFN)-alpha has no specific inhibitory effect on the plating efficiency of granulocyte-macrophage colony-forming cells (CFU-GM) from patients with chronic myeloid leukaemia (CML), it does selectively inhibit the replating ability (secondary colony formation) of CML CFU-GM. Thus, amplification of CFU-GM may be a target for IFN-alpha and other agents used in the treatment of CML. Here we examined whether cytarabine (Ara-C) or all-trans retinoic acid (ATRA) exert similar effects and whether they might in combination with IFN-alpha enhance its efficacy. We found that Ara-C preferentially inhibits the formation of CML CFU-GM compared to normal CFU-GM, but this inhibition was not increased by addition of IFN-alpha. When Ara-C was added to cultures containing IFN-alpha, the inhibition of replating by CML progenitors was abrogated. ATRA increased significantly the plating efficiency of normal CFU-GM. The addition of IFN-alpha to ATRA had no effect on CML or normal colony numbers. However, addition of ATRA to cultures containing IFN-alpha reversed the selective inhibition of CML CFU-GM replating seen in cultures containing IFN-alpha alone. In four IFN-alpha/Ara-C experiments, secondary CML patient-derived colonies were examined by fluorescence in situ hybridisation (FISH). All of them were Ph chromosome positive. No significant effects on CFU-GM production were observed when CML primitive haemopoietic progenitor cells were investigated in a delta (delta) assay. Thus we conclude that combining IFN-alpha with Ara-C or ATRA neutralises the effect of IFN-alpha on CML CFU-GM. This observation provides a rationale for treating patients with alternating courses of IFN-alpha and Ara-C or ATRA, rather than giving either of these two agents in combination with IFN-alpha.

Cell Division↗

PubMed2000

Contact-mediated inhibition of human haematopoietic progenitor cell proliferation may be conferred by stem cell antigen, CD34.

INTRODUCTION: The function of CD34, a transmembrane sialomucin expressed by human haematopoietic progenitor cells, is poorly understood. Its structure suggests it may act as a cell adhesion and signalling molecule. MATERIALS AND METHODS: KGIa cells and primary CD34-positive marrow cells were tested for their ability to aggregate in the presence of the anti-CD34 antibody QBEND10; CFU-GM colonies were grown using standard methods and tested for their content of colony-forming cells by replating; 'haematons' were isolated from marrow by filtration; the phosphorylation of CD34 was investigated by immunoprecipitation and Western blotting DISCUSSION: CD34-positive cells in human bone marrow, like KG1a cells, aggregate when incubated with QBEND10. Staining aggregates with anti-CD34-FITC revealed that aggregation involved co-localisation of CD34 at intercellular binding sites. We examined myeloid colonies (CFU-GM) grown from normal human bone marrow cells, and multicellular aggregates ('haematons') separated from freshly aspirated marrow by filtration, and found CD34-positive cells bound together with co-localisation of the CD34 at the binding sites. This finding shows that CD34-positive cell-cell adhesion occurs physiologically in vitro and in vivo. QBEND10-induced aggregation of KG1a and CD34-positive cells was enhanced by staurosporine (a protein kinase C inhibitor) and inhibited by genistein (a protein tyrosine kinase inhibitor). Moreover, aggregated cells had increased phosphorylation of tyrosine on CD34 and translocation of protein kinase C (PKC) to the cytoplasm, compared with non-aggregated cells. We used the ability of primary colonies to produce secondary colonies on replating as a functional parameter and found that the replating ability of the colonies was increased by treatment with genistein (P=0.003). In addition, the ability of individual samples of primary CD34-positive cells to undergo QBEND10-induced aggregation and the ability of CD34-positive cell-derived colonies to produce secondary clones on replating were inversely related (r=0.86). CONCLUSION: Our results suggest that homotypic aggregation of haematopoietic progenitor cells may be an important mechanism for preventing inappropriate proliferation in vivo. Thus, regulation of expression of the CD34 molecule may play an important role in maintaining the normal level of haematopoietic activity by contact-mediated inhibition of progenitor cell proliferation.

Antibodies, Monoclonal↗

PubMed2000

Exploring Hindu Indian emotion expressions: evidence for accurate recognition by Americans and Indians.

Subjects were presented with videotaped expressions of 10 classic Hindu emotions. The 10 emotions were (in rough translation from Sanskrit) anger, disgust, fear, heroism, humor-amusement, love, peace, sadness, shame-embarrassment, and wonder. These emotions (except for shame) and their portrayal were described about 2,000 years ago in the Natyasastra, and are enacted in the contemporary Hindu classical dance. The expressions are dynamic and include both the face and the body, especially the hands. Three different expressive versions of each emotion were presented, along with 15 neutral expressions. American and Indian college students responded to each of these 45 expressions using either a fixed-response format (10 emotion names and "neutral/no emotion") or a totally free response format. Participants from both countries were quite accurate in identifying emotions correctly using both fixed-choice (65% correct, expected value of 9%) and free-response (61% correct, expected value close to zero) methods.

Adolescent↗

PubMed2000

Fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae: contributions of type II topoisomerase mutations and efflux to levels of resistance.

We report on amino acid substitutions in the quinolone resistance-determining region of type II topisomerases and the prevalence of reserpine-inhibited efflux for 70 clinical isolates of S. pneumoniae for which the ciprofloxacin MIC is >/=4 microgram/ml and 28 isolates for which the ciprofloxacin MIC is </=2 microgram/ml. The amino acid substitutions in ParC conferring low-level resistance (MICs, 4 to 8 microgram/ml) included Phe, Tyr, and Ala for Ser-79; Asn, Ala, Gly, Tyr, and Val for Asp-83; Asn for Asp-78; and Pro for Ala-115. Isolates with intermediate-level (MICs, 16 to 32 microgram/ml) and high-level (MICs, 64 microgram/ml) resistance harbored substitutions of Phe and Tyr for Ser-79 or Asn and Ala for Asp-83 in ParC and an additional substitution in GyrA which included either Glu-85-Lys (Gly) or Ser-81-Phe (Tyr). Glu-85-Lys was found exclusively in isolates with high-level resistance. Efflux contributed primarily to low-level resistance in isolates with or without an amino acid substitution in ParC. The impact of amino acid substitutions in ParE was minimal, and no substitutions in GyrB were identified.

Amino Acid Substitution↗

PubMed2000

Temporal stability of the emotion-modulated startle response.

In the present study, we examined the stability of one measure of emotion, the emotion-modulated acoustic startle response, in an undergraduate sample. Using the acoustic startle paradigm on two different occasions, we measured stability of affective modulation of the startle response during and following the presentation of pictures selected to be of positive, negative, or neutral emotional valence. The two assessments were separated by 4 weeks. Two groups of subjects were compared: one group that viewed the same pictures at each assessment and a second group that viewed different pictures at the second assessment. We found that viewing different pictures at two assessments separated by 4 weeks yielded moderate stability of the emotion modulation of startle magnitude, whereas subjects who viewed the same pictures at both assessments showed poor stability. Furthermore, this difference was due to the stability of responses to high versus low arousal pictures, not to differences in valence.

Adolescent↗

PubMed2000

Suppression and enhancement of emotional responses to unpleasant pictures.

Despite the prominence of emotional dysfunction in psychopathology, relatively few experiments have explicitly studied emotion regulation in adults. The present study examined one type of emotion regulation: voluntary regulation of short-term emotional responses to unpleasant visual stimuli. In a sample of 48 college students, both eyeblink startle magnitude and corrugator activity were sensitive to experimental manipulation. Instructions to suppress negative emotion led to both smaller startle eyeblinks and decreased corrugator activity. Instructions to enhance negative emotion led to larger startle eyeblinks and increased corrugator activity. Several advantages of this experimental manipulation are discussed, including the use of both a suppress and an enhance emotion condition, independent measurement of initial emotion elicitation and subsequent regulation of that emotion, the use of a completely within-subjects design, and the use of naturalistic emotion regulation strategies.

Adult↗

PubMed1999

Thalamic metabolic rate predicts EEG alpha power in healthy control subjects but not in depressed patients.

BACKGROUND: EEG alpha power has been demonstrated to be inversely related to mental activity and has subsequently been used as an indirect measure of brain activation. The hypothesis that the thalamus serves as a neuronal oscillator of alpha rhythms has been supported by studies in animals, but only minimally by studies in humans. METHODS: In the current study, PET-derived measures of regional glucose metabolism, EEG, and structural MRI were obtained from each participant to assess the relation between thalamic metabolic activity and alpha power in depressed patients and healthy controls. The thalamus was identified and drawn on each subject's MRI. The MRI was then co-registered to the corresponding PET scan and metabolic activity from the thalamus extracted. Thalamic activity was then correlated with a 30-min aggregated average of alpha EEG power. RESULTS: Robust inverse correlations were observed in the control data, indicating that greater thalamic metabolism is correlated with decreased alpha power. No relation was found in the depressed patient data. CONCLUSIONS: The results are discussed in the context of a possible abnormality in thalamocortical circuitry associated with depression.

Adult↗

PubMed1999

Individual differences in prefrontal activation asymmetry predict natural killer cell activity at rest and in response to challenge.

Reliable individual differences in electrophysiological measures of prefrontal activation asymmetry exist and predict dispositional mood and other psychological and biological indices of affective style. Subjects with greater relative right-sided activation report more dispositional negative affect and react with greater intensity to negative emotional challenges than their left-activated counterparts. We previously established that such individual differences in measures of prefrontal activation asymmetry were related to basal NK function, with left-activated subjects exhibiting higher levels of NK function than right-activated subjects. The present study was designed to replicate and extend these earlier findings. Subjects were tested in five experimental sessions over the course of 1 year. During the first two sessions, baseline measures of brain electrical activity were obtained to derive indices of asymmetric activation. During sessions 3 and 4, blood samples were taken during a nonstressful period in the semester and then 24 h prior to the subjects' most important final examination. During session 5, subjects were presented with positive and negative film clips 30 min in duration. Blood samples were obtained before and after the film clips. Subjects with greater relative right-sided activation at baseline showed lower levels of basal NK function. They also showed a greater decrease in NK function during the final exam period compared to the baseline period. Subjects with greater relative left-sided activation showed a larger increase in NK function from before to after the positive film clip. These findings indicate that individual differences in electrophysiological measures of asymmetric prefrontal activation account for a significant portion of variance in both basal levels of, and change in NK function.

Adolescent↗

PubMed1999

Regional brain function, emotion and disorders of emotion.

Significant progress has been made in our understanding of the neural substrates of emotion and its disorders. Neuroimaging methods have been used to characterize the circuitry underlying disorders of emotion. Particular emphasis has been placed on the prefrontal cortex, anterior cingulate, parietal cortex, and the amygdala as critical components of the circuitry that may be dysfunctional in both depression and anxiety.

Affective Symptoms↗

PubMed1999

Manipulating smoking motivation: impact on an electrophysiological index of approach motivation.

A chief goal of this research was to determine whether stimuli and events known to enhance smoking motivation also influence a physiological variable with the potential to index approach motivation. Asymmetry of electroencephalographic (EEG) activity across the frontal regions of the 2 hemispheres (left minus right hemisphere activation) was used to index approach motivation. In theory, if EEG asymmetry sensitively indexes approach dispositions, it should be influenced by manipulations known to affect smoking motivation, that is, exposure to smoking cues and tobacco deprivation. Seventy-two smokers participated in this research and were selectively exposed to a smoking-anticipation condition (cigarettes plus expectation of imminent smoking) following either 24 hr of tobacco withdrawal or ad libitum smoking. Results indicated that EEG asymmetry was increased by smoking anticipation and that smoking itself reduced EEG asymmetry. Results also suggested that smoking anticipation increased overall (bihemispheric) EEG activation. Results were interpreted in terms of major theories of drug motivation.

Adult↗

PubMed1999

Optimal timing for processing and cryopreservation of umbilical cord haematopoietic stem cells for clinical transplantation.

Some of the factors that may influence the number and quality of cord blood haematopoietic progenitor cells available for transplantation have been investigated including site of collection, delayed processing after collection and cryopreservation protocol. We used the granulocyte-macrophage progenitor (CFU-GM) and erythroid burst-forming unit (BFU-E) assays to quantify progenitors. The capacity of CFU-GM to produce secondary colonies was used as a measure of progenitor cell quality. We found that: (1) there were no significant differences in total nucleated cells (TNC), mononuclear cells (MNC), CFU-GM or BFU-E numbers in paired specimens from the umbilical vein or veins at the base of the placenta. The potential of the CFU-GM to produce secondary colonies from the two sites was similar; (2) storing cord blood at room temperature or at 4 degrees C resulted in a significant reduction in progenitor cell numbers beyond 9 h; and (3) cryopreservation following either controlled rate freezing or passive cooling reduced MNC numbers, viability and CFU-GM survival insignificantly but the potential of CFU-GM to produce secondary colonies was significantly reduced post cryopreservation (P = 0.04). We conclude that the yield of CB progenitor cells is not affected by the site of collection, but is adversely affected by delays between collection and cryopreservation. Furthermore, cryopreservation reduced the CFU-GM potential to produce secondary colonies. Measures of progenitor cell quality as well as quantity may be relevant to assessing CB blood collections.

Blood Specimen Collection↗

PubMed1999

Cell biology of CML cells.

At the cellular level, expansion of haemopoiesis in chronic myeloid leukaemia (CML) must involve some imbalance in cell production along the myeloid maturation pathway. The relevant kinetic parameters are cell loss by apoptosis and differentiation and cell gain by proliferation (self-renewal). In spite of the predominance of the BCR-ABL-positive leukaemic cells, some BCR-ABL-negative, presumably normal, progenitor cells remain for long periods in chronic phase CML. Thus, understanding the kinetics of CML and normal progenitor cells may lead to therapeutic strategies capable of reducing malignant cell growth and reactivating normal haemopoiesis.

Antineoplastic Agents↗

PubMed1999

Evidence for a continuous decline in haemopoietic cell function from birth: application to evaluating bone marrow failure in children.

There are considerable differences in haemopoietic activity between young children and adults on the one hand, and between adults and the elderly on the other. A fundamental unanswered question is whether these differences relate to discrete stages or are part of a continuous process. We have sought to define aspects of the haematological ageing process, and have found that results from children with bone marrow failure syndromes differ from age-matched reference values. Haemopoietic cells were obtained from umbilical cord blood, from blood and bone marrow of healthy individuals and from the blood of young patients with bone marrow failure syndromes. Clonogenic myeloid progenitors (CFU-GM) were grown in semi-solid medium to measure their frequency; the proliferative capacity of myeloid progenitors was measured by replating colonies and observing secondary colony formation. We found that the frequency of CFU-GM in normal marrow increased and their proliferative capacity decreased exponentially with age. The proliferative capacity of CFU-GM in normal blood also decreased exponentially with age. This relationship extrapolated back to the levels of proliferation measured for cord blood CFU-GM (age = 0). The proliferative capacities of CFU-GM from children with bone marrow failure syndromes were severely reduced compared with age-matched reference values. These results indicate that a decline in haemopoietic progenitor cell function begins at birth and continues throughout life. This decline may occur prematurely in childhood marrow failure syndromes with a predisposition to leukaemia.

Adolescent↗

PubMed1999

EEG alpha power and alpha power asymmetry in sleep and wakefulness.

Asymmetry of waking electroencephalography (EEG) alpha power in frontal regions has been correlated with waking emotional reactivity and the emotional content of dream reports. Little is known regarding alpha asymmetry during sleep. The present study was performed to compare alpha power and alpha power asymmetry in various brain regions across states of sleep and wakefulness. Waking and sleep EEG were recorded in a group of patients undergoing polysomnographic evaluation for possible sleep disorders. Alpha EEG asymmetry in frontal and temporal regions was significantly correlated in waking versus sleep, particularly during rapid eye movement (REM) sleep. These results suggest that patterns of frontal alpha asymmetry are stable across sleep and waking and may be related to emotional reactivity during dreaming. During sleep, alpha power was highest during slow-wave sleep and lowest during REM sleep. Implications of these data for understanding the functional significance of alpha power during waking and sleeping are considered.

Adult↗

PubMed1998

Metabolic rate in the right amygdala predicts negative affect in depressed patients.

The role of the amygdala in major depression was investigated. Resting regional cerebral metabolic rate (rCMRglu) was measured with [18F]fluorodeoxyglucose positron emission tomography (PET) in two samples of subjects using two different PET cameras. The samples consisted of 10 and 17 medication-free depressives and 11 and 13 controls, respectively. Using coregistration of PET and magnetic resonance images, regions were individually delineated for the amygdala and thalamus, the latter of which was used as a control region. Within the depressed groups, right amygdalar rCMRglu was positively correlated with negative affect. Thalamic rCMRglu was not related to negative affect, and amygdalar rCMRglu accounted for a significant portion of variance in depressives' negative affect scores over and above the contribution of thalamic rCMRglu.

Amygdala↗

PubMed1998

Treatment with interferon-alpha preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors (CFU-GM) from patients with chronic myeloid leukemia but spares normal CFU-GM.

The biological target for interferon (IFN)-alpha in chronic myeloid leukemia (CML) is unknown, but one possibility is that amplification of granulocyte-macrophage colony-forming cells (CFU-GM) is reduced. Replating CFU-GM colonies and observing secondary colony formation provides a measure of CFU-GM amplification. Amplification of CML, but not normal, CFU-GM in vitro was significantly inhibited by IFN-alpha (P = 0.02). In 5 out of 15 CML cases studied by fluorescence in situ hybridization, in vitro treatment with IFN-alpha increased the proportion of CFU-GM, which lacked BCR-ABL. The ability of patients' CFU-GM to amplify, and suppression of this ability by IFN-alpha, predicted responsiveness to IFN-alpha therapy in 86% of cases. Investigation of patients on treatment with IFN-alpha showed a threefold reduction in CFU-GM amplification in responders (P = 0.03) but no significant change in nonresponders (P = 0.8). We conclude that IFN-alpha preferentially suppresses amplification of CML CFU-GM to varying degrees. The differing in vitro sensitivities to IFN-alpha and growth kinetics of individual patients' cells could help differentiate those who will or will not benefit from treatment with IFN-alpha.

Antineoplastic Agents↗