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A novel retinoic acid receptor (RAR)-selective antagonist inhibits differentiation and apoptosis of HL-60 cells: implications of RARalpha-mediated signals in myeloid leukemic cells.

Retinoic acid (RA) induces HL-60 cells to differentiate terminally into mature granulocytes, which subsequently die by apoptosis. The biological effects of RA are mediated by two distinct families of transcription factors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). RARs and RXRs form heterodimers and regulate retinoid-mediated gene expression. We have recently developed a novel RAR-selective antagonist (ER27191) which prevents RAR activation by retinoids. Using this RAR-selective antagonist, and RXR and RAR agonist, we demonstrate the RAR-mediated signaling pathway is important for differentiation and apoptosis of myeloid leukemic cells. Simple activation of RXRs is not sufficient to induce apoptosis of the cells. Interestingly, the combination of the RAR-selective antagonist and 9-cis RA resulted in partial differentiation and apoptosis of HL-60 and NB4 cells, whereas the RAR antagonist completely blocked all-trans RA-induced differentiation and apoptosis of the cells. Additional experiments showed that levels of BCL-2 protein decreased during differentiation of myeloid leukemic cells. Furthermore, HL-60 cells transduced with a bcl-2 expression vector showed the same differentiation response to retinoids as did parental HL-60 cells even though apoptosis was inhibited in these bcl-2-transduced cells, suggesting that differentiation and apoptosis are regulated independently in myeloid leukemic cells.

Alitretinoin↗

A differentiation antigen expressed selectively by a proportion of human blood cells: detection with a monoclonal antibody.

A monoclonal antibody, FMC 8, has been prepared after immunization with a cell line of the non-T-non-B type acute lymphoblastic leukaemia (ALL). The antigen detected by this antibody consists of a single polypeptide chain with an apparent molecular weight of 24,000 d. The antigen is absent from T cells but appears after mitogen stimulation. It is found on the majority of normal circulating B cells but is absent in most chronic lymphocytic leukaemias. All cells of the non-T-non-B type express the antigen, whereas T-ALL cells generally do not. Granulocytes, monocytes and platelets react with the antibody, but erythrocytes do not. The wide but selective distribution of the antigen renders FMC 8 potentially useful, together with other monoclonal antibodies, in the delineation of differentiation pathways and in phenotypic analysis of leukaemia and lymphoma cells.

Animals↗

Ethanol-related traits in mice selectively bred for differential sensitivity to methamphetamine-induced activation.

Acute drug stimulation has been proposed to be an endophenotype for drug abuse. The authors previously reported the short-term selective breeding of lines of mice for low (LMACT) and high (HMACT) stimulation to methamphetamine (MA). These mice were used to examine whether common genes influence the locomotor response to MA and ethanol. Additionally, the authors tested these mice for ethanol drinking, locomotor sensitization, and clearance. LMACT mice were less stimulated by ethanol and consumed more ethanol than HMACT mice, but the lines did not differ in ethanol-induced sensitization. A small difference in ethanol clearance rate (0.1 mg/ml/h) likely had little impact on behavior. Some common genes may influence the locomotor response to MA and ethanol, as well as ethanol drinking.

Alcohol Drinking↗

gamma-Aminobutyric acid-activated chloride channels in rats selectively bred for differential acute sensitivity to alcohol.

Effects of various sedative hypnotic agents on GABA-mediated chloride flux were evaluated in whole brain membrane vesicles (microsacs) prepared from rats selectively bred for high (HAS) and low sensitivity (LAS) to an acute hypnotic dose of alcohol. The HAS rats were more sensitive to the effects of pentobarbital, phenobarbital, flunitrazepam, and ethanol on GABA-mediated chloride flux compared with the LAS rats. No differences between the lines in GABA-stimulated chloride flux were observed. Modulation of 1-[3H]-phenyl-4-butyl-2,6,7-trioxabicyclo(2.2.2)octane ([3H]-TBOB) and [3H]-diazepam binding also was measured. The lines did not differ in inhibition of [3H]-TBOB binding by pentobarbital, phenobarbital, muscimol or picrotoxin. Although the lines displayed almost identical KD and Bmax for [3H]-diazepam binding, the GABA agonist, muscimol, was a more potent stimulator of [3H]-diazepam binding in membranes prepared from HAS rats than from LAS rats. These findings are discussed in light of previous work using other selected lines.

Alcohol Drinking↗

Noradrenaline-selective versus serotonin-selective antidepressant therapy: differential effects on social functioning.

The outcome of antidepressant therapy in terms of social functioning was evaluated in a randomized, placebo-controlled, double-blind study comparing the selective noradrenaline reuptake inhibitor (NARI), reboxetine, with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Of the 381 patients with major depression participating in the study, 302 patients were assessed using the new self-rating Social Adaptation Self-evaluation Scale (SASS). Mean SASS total score at last assessment was superior (p < 0.05) to placebo for both reboxetine and fluoxetine. Moreover, reboxetine was superior (p < 0.05) to fluoxetine. Evaluation of the sensitivity to change in individual items by point-biserial correlation analysis showed a significant correlation between improvement in item score and reboxetine treatment in all but one item for the reboxetine-placebo comparison. In the fluoxetine-placebo comparison, a significant correlation was evident for only 12 of the 21 items. Direct comparison of reboxetine with fluoxetine revealed a significant correlation between change in item score and treatment for nine items, in favour of reboxetine. The association was maximal for six items, mainly related to negative self-perception and to active social behaviour. In the subset of patients in remission at last assessment (n = 91), the mean SASS total score for reboxetine was superior to that of both fluoxetine and placebo (p < 0.05). Point-biserial correlation analysis revealed that most items sensitive to change under active treatment in the total population did so with reboxetine (17 items) or fluoxetine (nine items) in patients in remission. In the reboxetine-fluoxetine comparison, 14 items showed a significant association with reboxetine treatment. In conclusion, while social motivation and behaviour in depression are significantly affected by both noradrenergic and serotonergic antidepressant treatment, noradrenergic therapy seems particularly effective in improving negative self-perception and motivation towards action, resulting in a better quality of remission in terms of social functioning.

Adolescent↗

Ethanol withdrawal and proclivity are inversely related in rats selectively bred for differential saccharin intake.

Withdrawal severity and voluntary alcohol consumption are inversely related in rats and mice. The present study demonstrated this empirical relation and extended it in two ways. First, the rats were selectively bred for low (LoS) and high (HiS) saccharin intake, a phenotype that correlates positively with ethanol intake and inversely with emotional reactivity. Withdrawal has not yet been studied in these rats. Second, proclivity to consume ethanol was measured as conditioned preference for an ethanol-paired flavor. After 2 weeks of forced exposure to ethanol and a period of abstinence, LoS rats showed elevated acoustic startle; HiS rats did not (Exp. 1). When ethanol- and no-ethanol solutions were available freely during conditioning, both LoS and HiS rats preferred a flavor paired with 4% ethanol, but only HiS rats preferred a flavor paired with 10% ethanol (Exp. 2A); when exposure to the two solutions was controlled, all groups except LoS males preferred flavors paired with 4% or 10% ethanol (Exp. 2B). Thus, as predicted, withdrawal was more severe in the line with less ethanol proclivity (LoS). These results implicate basic associative and affective processes in individual differences in patterns of alcohol use.

Acoustic Stimulation↗

Differential cardioprotection with selective inhibitors of adenosine metabolism and transport: role of purine release in ischemic and reperfusion injury.

In a previous report, we have demonstrated that simultaneous inhibition of nucleoside transport and adenosine deaminase accumulates endogenous adenosine and protects the myocardium against stunning. The differential cardioprotective effects of erythro-9(2-hydroxy-3-nonyl)-adenine (EHNA), a potent inhibitor of adenosine deamination but not transport, and p-nitrobenzylthioinosine (NBMPR), a selective blocker of adenosine and inosine transport, are not known. Thirty-seven anaesthetized adult dogs were instrumented to monitor left ventricular performance using sonomicrometery. Dogs were randomly assigned into four groups. The control group (n = 8) received only the vehicle solution. Treated groups received saline containing 100 microM EHNA (EHNA-group, n = 7), 25 microM NBMPR (NBMPR-group, n = 7), or a combination of 100 microM EHNA and 25 microM NBMPR (EHNA/NBMPR-group, n = 10). Hearts were subjected to 30 min of normothermic global ischaemia and 60 min of reperfusion while on bypass. Adenine nucleotides, nucleosides, oxypurines and NAD+ were determined in extracts of transmural myocardial biopsies using HPLC. TTC staining revealed the absence of necrosis in this model. Drug administration did not affect myocardial ATP metabolism and cardiac function in the normal myocardium. Ischemia caused about 50% ATP depletion and accumulation of nucleosides. The ratio between adenosine/inosine at the end of ischemia was 1:10, 1:1, 1:1 and 10:1 in the control, EHNA-, NBMPR- and EHNA/NBMPR-group, respectively. Upon reperfusion, both nucleosides washed out from the myocardium in the control and EHNA-group while retained in the myocardium in the NBMPR and EHNA/NBMPR groups. Ventricular dysfunction 'stunning' persisted in the control group (52%) and in the EHNA-treated group (32%) after 30 min of reperfusion. Significant improvement of function was observed in the EHNA group only after 60 min of reperfusion. LV function recovered in the NBMPR- and EHNA/NBMPR-treated groups during reperfusion. ATP recovery occurred only when animals were pretreated with the combination of EHNA/NBMPR and remained depressed in the control group and EHNA and NBMPR-treated groups. At post mortem, TTC staining revealed the absence of myocardial necrosis. Superior myocardial protection was observed with inhibition of nucleoside transport by NBMPR alone or in combination with inhibition of adenosine deaminase by EHNA. Selective blockade of nucleoside transport by NBMPR is more cardioprotective than inhibition of adenosine deaminase alone in attenuating myocardial stunning. It is not known why EHNA partially inhibit adenosine deaminase, in vivo.

Adenine↗

Use of cell differentiation effectors to select a human B lymphoblastoid cell line enriched in C3b receptors.

A study was undertaken to establish conditions of growth to increase C3b receptor synthesis on a human B lymphoblastoid cell line (Raji) by use of cell differentiation effectors. It appears that whereas two polar compounds HMBA (2mM) and Me2SO(2%) have no or little effect, 5 BrdU (30microM) and db cAMP (5 x10(-4) M) are able to increase in 48 h and 36 h respectively the synthesis of C3b receptor on Raji cell surface. These two compounds help to select a variant in which 100% of cells have C3b receptors with a high density of receptors per cell. The mechanism of BrdU action on the regulation of C3b receptor synthesis is discussed.

Acetamides↗

Arousal as an explanation for differences in rats selectively bred for differential alcohol sensitivity.

A common error made by behavior genetics researchers is breeding two lines for differences in central arousal rather than for a specific behavioral feature. Two lines of rats (Riley, Freed, & Lester, 1976) were selectively bred for locomotor impairment in response to a subhypnotic dose (1.5 g/kg) of ethanol. These lines (designated "most affected" and "least affected") were compared in a variety of tests and showed differences in a number of phenotypic traits in addition to locomotor impairment to ethanol. The published findings have been interpreted in light of a hypothesis suggesting adventitiously selected differences in central arousal between the two lines. This interpretation showed that their usefulness as animal models of alcoholism is seriously compromised.

Alcoholism↗

Lung and chest wall mechanics during differential ventilation with selective PEEP.

Eight patients free from cardio-pulmonary disease and with a mean age of 46 years were studied during general anaesthesia in the lateral position. Measurements of hemithoracic mechanics were made during four different modes of ventilation: 1. Conventional ventilation (free distribution of ventilation) with no positive end-expiratory pressure (PEEP) (CV), 2. differential ventilation (50% of ventilation to each lung) with no PEEP (DV:0), and 3 and 4. DV with selective PEEP of 0.8 and 1.6 kPa, respectively, to the dependent lung only (DV:8, DV:16). During CV, 60% of ventilation was distributed to the non-dependent lung. Non-dependent hemithoracic compliance was 64% greater and inspiratory resistance 39% lower than those of the dependent hemithorax. No significant differences between the two hemithoraces were noted during DV:0, but on application of selective PEEP the compliance of the dependent hemithorax increased and its resistance decreased. With DV:16, the compliances of the two hemithoraces were essentially equal, as were their resistances. Selective PEEP caused a larger volume increase in the dependent lung than general PEEP. Selective PEEP reduced the volume of the non-dependent lung but only by 1/3 of the simultaneous increase in that of the dependent lung. Oesophageal pressure increased only slightly on selective inflation of the dependent lung, and remained negative within the 21 volume range studied. It is suggested that the altered mechanics of the dependent lung during selective PEEP result in a more even distribution of the inspired gas within that lung.

Adult↗

Differential impairments of selective attention due to frequency and duration of cannabis use.

The evidence for long-term cognitive impairments associated with chronic use of cannabis has been inconclusive. We report the results of a brain event-related potential (ERP) study of selective attention in long-term cannabis users in the unintoxicated state. Two ERP measures known to reflect distinct components of attention were found to be affected differentially by duration and frequency of cannabis use. The ability to focus attention and filter out irrelevant information, measured by frontal processing negativity to irrelevant stimuli, was impaired progressively with the number of years of use but was unrelated to frequency of use. The speed of information processing, measured by the latency of parietal P300, was delayed significantly with increasing frequency of use but was unaffected by duration of use. The results suggest that a chronic buildup of cannabinoids produces both short- and long-term cognitive impairments.

Adolescent↗

Selective criteria for differential diagnosis of infants with symptoms of congenital heart disease.

147 case records of infants referred to the Brompton Hospital in the first year of life with a provisional diagnosis of congenital heart disease were examined. Statistical analyses were performed to evaluate selective criteria for the allocation of these infants into a group with lung disease, or into 1 of 5 major haemodynamic groups--namely, acyanotic, complete transposition of the great arteries, pulmonary outflow tract obstruction, common mixing situations, or hypoplastic left heart syndrome. Arterial PO2 in high oxygen concentration, cardiothoracic ratio, and pulmonary vascular markings on the admission chest x-ray; respiratory rate; P-wave morphology, the electrical sign of the T-wave in lead V4R, and the presence or absence of Q-waves in leads V4R and v6 on the electrocardiogram were significant. A decision tree for the differential diagnosis of infants with suspected congenital heart disease into 5 haemodynamic groups and a group with lung disease is presented, and its predictive value is assessed.

Analysis of Variance↗

Differential ventilation and selective positive end-expiratory pressure: effects on patients with acute bilateral lung disease.

Eleven patients with acute respiratory failure due to diffuse, bilateral lung disease were treated according to a new ventilation concept. The patients were intubated with a double-lumen catheter and positioned in the lateral decubital posture. With two synchronized ventilators, each lung received half of the tidal volume (VT), in accordance with its presumed perfusion (differential ventilation--DV), and the end-expiratory pressure was increased locally in the dependent lung (selective PEEP). DV with and without selective PEEP was compared with conventional ventilation with free distribution of VT, with and without PEEP applied to both lungs. The major findings were that DV with a selective PEEP of 12 cmH2O to the dependent lung decreased venous admixture by 38% (P less than 0.01) in comparison with conventional ventilation with no PEEP. Furthermore, it was found that selective PEEP, in contrast to general PEEP, had no deleterious effect on cardiac output. Consequently, DV with selective PEEP increased arterial oxygen tension by 23% (P less than 0.05) compared with general PEEP and by 46% (P less than 0.001) in comparison with conventional ventilation with no PEEP.

Acute Disease↗

ICMSF methods studies. IX. The influence of selective enrichment broths, differential planting media, and incubation temperatues on the detection of Salmonella in dried foods and feed ingredients.

Ninety-eight dried foods and feed ingredients were analyzed for Salmonella using tetrathionate brilliant green (T) and selenite cystine (S) broths incubated at 35 and 43 degrees C. The four enrichment cultures for each sample were subcultured in duplicate onto brilliant green (BG) , Salmonella--Shigella (SS), and bismuth sulfite (BS) agars, one plate of each being incubated at 35 degrees C, the other at 43 degrees C. Salmonellae were isolated from 44 of the 98 samples. Differences in the Salmonella recovery rates from the four selective enrichment conditions were not significant. However, there was a trend toward a higher proportion of Salmonella colonies on the selective media when the enrichment broths were incubated at 43 degrees C, although the differences were significantly only with BG and SS subcultured from T. While the four enrichment systems were not significantly different, the trend toward a higher proportion of Salmonella colonies on the differential media subcultured from 43 degrees C enrichment broths indicates an advantage to incubation at the elevated temperature. Incubation of selective agars at 35 degrees C was best because at 43 degrees C Salmonella recovery was significantly reduced. Detection of salmonellae on BS was significantly better than on BG or SS.

Agar↗

Selection bias from differential residential mobility as an explanation for associations of wire codes with childhood cancer.

Several studies of childhood cancer, especially leukemia, in residential areas have reported an association with wire configuration codes. These codes were suggested to be surrogates of electromagnetic field exposure. However, the selection criteria used in several of the studies caused the case and control populations to be non-comparable, especially with respect to residential mobility. Specifically, controls were required to be residentially stable but cases were not. Thus, an artificial association between residential mobility and cancer was created by the subject selection procedure. The present study of 5721 residences in Columbus, Ohio was conducted to learn if bias due to differences in residential mobility, rather than electromagnetic fields, could explain the reported association between wire configuration codes and childhood cancer. It was found that the proportion of homes classified as "high" wire code in the non-stable population was 31% greater than the corresponding proportion in the stable population. This finding shows that high wire codes are associated with homes in which the residents are mobile and low wire codes are associated with homes occupied by stable residents. Thus, as a consequence of this association between residential mobility and high wire codes, studies that created an artificial association between residential mobility and childhood cancer will also produce a false association between high wire codes and cancer.

Case-Control Studies↗