[The man behind the syndrome: George Hoyt Whipple. He was the first one to theorize on infectious causes of a rare systemic disease].
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Aged↗
Biomedical subjects
M Carlsson
Publications and source records attributed to M Carlsson.
Interleukin 4 strongly augments or inhibits DNA synthesis and differentiation of B-type chronic lymphocytic leukemia cells depending on the co-stimulatory activation and progression signals.
This study describes the opposing effects that interleukin (IL) 4 exerts on the B cell stimulatory factor (BSF-MP6) and IL 2-dependent proliferation and differentiation of cells of one selected B-type chronic lymphocytic leukemia cell clone (I83), which depend on the nature of the activation inducer. In I83 cells activated by a 1-h pulse of 12-O-tetradecanoylphorbol 13-acetate, the BSF-MP6-dependent DNA synthesis was strongly enhanced by 50-100 U/ml of recombinant IL 4. Recombinant IL 2 stimulation was necessary only when a suboptimal dose of BSF-MP6 was used. The differentiation was also markedly enhanced by IL 4 as measured by quantitation of IgM secretion both at the population (enzyme-linked immunosorbent assay analyses of the supernatant) and single-cell level (enzyme-linked immunospot technique), by morphological examination of the maturation stage and flow cytometric analysis of differentiation-associated surface antigens (CD11c, FMC7, PCA-1 and CD38). No Ig isotype switch was found. In contrast, DNA synthesis and differentiation of I83 cells, activated by Staphylococcus aureus Cowan strain I (SAC) and co-stimulated with BSF-MP6 plus IL 2, were strongly inhibited by IL 4, both when it was added simultaneously with SAC or after 2 days of SAC exposure. Analysis of the cell-cycle progression of SAC and BSF-MP6 plus IL 2 and IL 4-stimulated cells by acridine orange staining and fluorescence-activated cell sorter (FACS) analysis demonstrated an arrest of a minor cell population in G0 and a block of the transition of G1 cells to S phase. Neither the enhancing nor the inhibitory effect of IL 4 on the proliferation and differentiation of I83 cells was an indirect effect via IL 4-induced activation of contaminating T cells, monocytes or natural killer cells, as shown by experiments where these cell types were depleted by FACS sorting. Furthermore the expression of CD23 and CD25 was not inhibited by IL 4. The results thus demonstrate contrasting biological effects of IL 4 on clonal leukemic B cells depending on the nature of the activation and progression stimuli. This adds to the emerging picture of a very complex cytokine and cell-to-cell contact-mediated regulation of the activation and subsequent growth and/or differentiation of human B cells.
Antigens, Differentiation, B-Lymphocyte↗
The partial dopamine receptor agonists (--)-3-PPP and transdihydrolisuride enhance prolactin secretion in female but not in male rats.
The effects exerted by the partial dopamine (DA) receptor agonists (--)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(--)-3-PPP] and transdihydrolisuride (TDHL) on prolactin secretion were compared in male and female rats. Both agents were found to increase prolactin release more than tenfold in female rats. In male rats, in contrast, (--)-3-PPP and TDHL were either without effect or decreased prolactin secretion. It is suggested that this sexually differentiated prolactin response to partial DA agonists reflects a lower responsiveness of lactotroph DA receptors in female than in male rats.
Animals↗
Effects of mild stress on adrenal and heart catecholamines in male and female rats.
The present study was undertaken with the aim of evaluating the sensitivity and convenience of a stress model reflecting sympatho-adrenal activation. Rats of both sexes were subjected to mild stress, consisting of four body temperature recordings, and investigated with regard to adrenal and heart catecholamine levels. Adrenal dopamine (DA) levels were considered to reflect medullary synthesis activity and heart adrenaline (A) concentrations were presumed to reflect A released from the adrenals. Expressed in relation to heart weight, adrenal catecholamine levels were about 50% higher in female rats. Following stress, adrenal DA levels were enhanced in both male and female rats; the magnitude of the stress response appeared similar in the two sexes. Concentrations of A in the hearts of unstressed animals were about 85% higher in females than in males but rose to a similar extent in male and female rats following stress. On the other hand, the stress-induced alterations in heart DA and NA concentrations, reflecting sympathetic activity, were gender-dependent. The advantages of the present model in relation to other techniques for measuring sympatho-adrenal activation in response to mild stress are discussed.
Adrenal Glands↗
Dramatic synergism between MK-801 and clonidine with respect to locomotor stimulatory effect in monoamine-depleted mice.
The present study corroborates previous findings showing that the selective, non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)-cyclohepten-5,10-imi ne] produces a dose-dependent increase in locomotion in mice pretreated with a combination of the monoamine-depleter reserpine and the catecholamine synthesis inhibitor alpha-methyl-para-tyrosine. Moreover, the present investigation demonstrates a synergistic interaction between MK-801 and the alpha-adrenergic agonist clonidine in monoamine-depleted mice: MK-801 in a dose of 1 mg/kg and clonidine in a dose of 2 mg/kg hardly affected locomotion when given separately, but when the two drugs were combined a dramatic enhancement of motor activity was observed. This effect was effectively antagonized by the alpha 2-adrenergic blockers idazoxan and yohimbine, as well as by the "atypical" neuroleptic clozapine. Likewise, a clear-cut synergism was observed when a low dose of the dopamine receptor agonist apomorphine (0.1 mg/kg), which did not per se affect motor activity, was combined with MK-801 (1.5 mg/kg); however, the synergism between apomorphine and MK-801 was less dramatic than that observed between MK-801 and clonidine. The results may have important neuropsychiatric implications related to, e.g. the treatment of Parkinson's disease and the pathogenesis of schizophrenia.
Animals↗
The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice.
It was shown in the present study that the selective non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imin e] caused a pronounced and dose-dependent increase in locomotion in mice pretreated with a combination of reserpine and alpha-methyl-para-tyrosine. Haloperidol pretreatment did not antagonize the MK-801-induced stimulation of locomotion. The findings are discussed in relation to the concept of a corticostriatothalamocortical negative feedback loop serving to protect the cortex from an overload of information and hyperarousal. Such a feedback loop would encompass i.a. corticostriatal glutamatergic neurons and it would be modulated by mesencephalostriatal dopaminergic neurons.
Animals↗
Marked locomotor stimulation in monoamine-depleted mice following treatment with atropine in combination with clonidine.
The present study demonstrates that the muscarinic antagonist atropine and the alpha-adrenergic agonist clonidine, though ineffective when administered separately, produced a pronounced locomotor stimulation in monoamine-depleted mice when combined. The atropine + clonidine-induced locomotor stimulation was counteracted by both the alpha 2-adrenoceptor antagonist idazoxan and the acetylcholinesterase inhibitor physostigmine. Thus, it is clear that simultaneous manipulations with cholinergic and adrenergic systems are as effective in restoring locomotion in monoamine-depleted mice as increasing central dopaminergic tone. This finding may have implications for the treatment of a movement disorder like Parkinson's disease.
Animals↗
The enhanced responsiveness of hypophyseal DA receptors in female rats induced by repeated reserpine treatment is not due to decreased oestrogen secretion.
In a previous study we have demonstrated that repeated reserpine treatment markedly enhances the intrinsic activity of the partial dopamine (DA) agonist (-)-3-PPP (preclamol) on pituitary DA receptors in female rats. This effect was attributed to the DA-depleting action of reserpine. However, since reserpine may also decrease oestrogen secretion, and since this hormone is known to affect dopaminergic transmission, experiments with ovariectomized, oestrogen-replaced female rats were undertaken. Ovariectomized rats were administered a depot preparation of oestradiol valerate in a dose that, according to literature data, yields physiological or slightly supraphysiological plasma concentrations of oestrogen. In spite of this treatment, repeated reserpine administration was found to substantially increase the intrinsic activity of (-)-3-PPP, as well as that of the partial DA agonist TDHL (terguride), on female pituitary DA receptors. It was concluded that repeated reserpine treatment increases pituitary DA receptor responsiveness in female rats by depleting DA, rather than by decreasing oestrogen secretion.
Animals↗
Interleukin-2 and a T cell hybridoma (MP6) derived B cell-stimulatory factor act synergistically to induce proliferation and differentiation of human B-chronic lymphocytic leukemia cells.
In this paper we communicate that cells of a selected B-CLL clone (I83), after 2 days of Staphylococcus aureus Cowan strain 1 (SAC) activation, respond to recombinant IL-2 (rIL-2) and a B cell stimulatory factor (BSF-MP6) and act in strong synergism with induction of simultaneous high-rate proliferation and differentiation. None of the factors alone or other lymphokines (IFN-gamma, TNF-alpha, 12 kDa BCGF, IL-1, IL-4, IL-5, IL-6) induced significant DNA synthesis in SAC-activated cells. However, low levels of IgM were produced by cells stimulated by SAC + rIL-2. The SAC activation was followed by an increase in IL-2 receptor (IL-2R; CD25) expression, and the proliferation induced by BSF-MP6 + rIL-2 could be blocked in a dose-dependent manner by alpha-CD25 antibody. Furthermore, flow cytometric cell cycle studies showed that SAC and BSF-MP6 + rIL-2 stimulated cells underwent a complete transition through the cell cycle to become arrested in G1. The induced proliferation by BSF-MP6 + rIL-2 was dependent on serum but independent of the 2.8% of CD4, CD8, CD14, and CD16 positive cells contaminating the I83 cell population. Previously, we reported that I83 cells activated by 12-O-tetradecanoylphorbol-13-acetate (TPA) were induced to differentiation only but that the addition of BSF-MP6 induced DNA synthesis concomitantly with the differentiation. This paper demonstrates that physiological stimuli can induce both high-rate proliferation and differentiation in a B-CLL clone in vitro. It also suggests that the low proliferation and the differentiation block in vivo, characteristic of most B-CLLs, may reflect a subnormal response of B-CLL cells to growth and differentiation factors, or a dysfunction in the factor production by the patients' T cells.
Cell Cycle↗
Differentiation associated c-myc expression in phorbol ester and lymphokine stimulated B-type chronic lymphocytic leukemia cells.
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Cell Differentiation↗
In vivo evidence for a greater brain tryptophan hydroxylase capacity in female than in male rats.
Previous studies have revealed that brain levels of tryptophan, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) are moderately higher in female than in male rats. Since tryptophan hydroxylase is only about half saturated with substrate, the greater availability of precursor in female rats might contribute to their higher 5-hydroxyindole levels. The present investigation was aimed at clarifying whether there is a sex difference in central tryptophan hydroxylase capacity. Hence, both sexes received a high dose of L-tryptophan (400 mg/kg), which resulted in a tenfold increase in brain tryptophan concentrations and presumably a virtual saturation of tryptophan hydroxylase. Following such treatment, 5-hydroxytryptophan (5-HTP) levels, measured after L-amino acid decarboxylase inhibition, were compared in males and females. Both in saline- and L-tryptophan-treated rats, 5-HTP levels were generally higher in females. In another group of animals, receiving 400 mg/kg of L-tryptophan as sole treatment, 5-HT and 5-HIAA concentrations were measured. As in the case of 5-HTP, the higher 5-HT and 5-HIAA levels observed in females persisted after L-tryptophan treatment. The present data suggest that brain tryptophan hydroxylase activity is greater in females; this sex difference probably contributes to the higher 5-HT and 5-HIAA levels in females.
5-Hydroxytryptophan↗
The intrinsic activity of (-)-3-PPP (preclamol) on pituitary DA receptors in female rats is enhanced following chronic DA depletion.
The present investigation was aimed at comparing the influence of the partial dopamine (DA) receptor agonist (-)-3-PPP (preclamol) on prolactin release in acutely hyperprolactinemic but otherwise intact female rats and female rats subjected to chronic DA depletion. One group of animals received daily vehicle injections (controls) and another group daily reserpine (1 mg/kg) injections for a period of seven days. On the eighth day all animals were administered 10 mg/kg of reserpine in order to eliminate endogenous DA and elevate serum prolactin levels. In the control group (-)-3-PPP lowered serum prolactin levels only moderately. In contrast, in the chronically reserpinized female rats, a pronounced reduction of prolactin secretion was observed. It is suggested that this increase in intrinsic activity of (-)-3-PPP following chronic DA depletion reflects an enhanced responsiveness of hypophyseal DA receptors, possibly due to conformational changes in the receptor molecules. Our observations lend further support to the hypothesis that an inverse relationship exists between the intrinsic activity of a mixed agonist/antagonist and the degree of previous receptor occupancy.
Animals↗
A regional study of sex differences in rat brain serotonin.
1. Male and female rats were compared with respect to serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) levels in five brain regions (brainstem, hypothalamus/preoptic area, corpora striata, limbic forebrain and cortex). Brain 5-HT synthesis rate was also studied in the two sexes. 2. There were no consistent gender differences in the dopaminergic system. 3. In contrast, the serotonergic system was more expressed in females: 5-HT levels were significantly higher in females than in males in the brainstem and limbic forebrain and tended to be so in the cortex. 5-HIAA levels were significantly higher in females in all five brain regions. The 5-HIAA/5-HT ratios were significantly higher in females in the hypothalamus/preoptic area and limbic forebrain and tended to be so in the striatum and cortex. Tryptophan concentrations were significantly higher in females in the brainstem, striatum and cortex. In no brain region were 5-HT, 5-HIAA or tryptophan levels higher in males. Following L-amino acid decarboxylase inhibition 5-hydroxytryptophan (5-HTP) accumulation was more pronounced in the female rat brain. 4. Taken together these results suggest that the brain 5-HT system has a higher potential in female than in male rats. This sex difference is not restricted to a specific region but seems to exist generally in the brain.
3,4-Dihydroxyphenylacetic Acid↗
Femininity, masculinity, and psychological androgyny in nurses.
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Female↗
Induction of IgM secretion by chronic B-lymphocytic leukaemia cells in serum-free medium: effects of interferon-alpha, -gamma and phorbol ester.
Serum-free culture conditions would be preferable when studying the cellular and molecular regulation of B lymphocyte activation, proliferation and differentiation. We describe here the morphological and functional differentiation of chronic B-lymphocytic leukaemia (B-CLL) cells from 10 patients cultured in serum-free medium. When exposed to the phorbol ester TPA, cells from 8/10 cases expressed blastoid morphology and secreted significant levels of monoclonal IgM. The addition of 0.5% newborn calf serum to the serum-free medium increased both the spontaneous and TPA-induced IgM secretion of B-CLL cells by a factor of 6 and 7, respectively. Compared with TPA, significant but lower levels of IgM secretion and morphological differentiation were observed with native purified leucocyte interferon-alpha (IFN-alpha) (6/8 patients), some batches of recombinant IFN-alpha 2 (5/8 patients) and recombinant IFN-gamma (4/8 patients) in a dose-dependent and specific manner. Preactivation of B-CLL cells with TPA or anti-mu antibody was not necessary for the IFN-induced functional maturation. Significant DNA synthesis was not observed with any of the inducers used. These studies show that B-CLL cells can be induced to differentiate under serum-free conditions in response to physiological and non-physiological ligands.
Aged↗
Cell cycle progression of B-chronic lymphocytic leukemia cells induced to differentiate by TPA.
The cell cycle transition and differentiation-associated surface antigen expression was studied in a clone of B cell chronic lymphocytic leukemia (B-CLL) with phenotypic properties similar to those of resting B lymphocytes. Differentiation was induced with TPA (12-O-tetradecanoyl-phorbol-13-acetate) and defined and quantitated by morphological and functional markers. Changes in the cell cycle position were determined by flow cytometry of acridine orange-stained cells. The uninduced B-CLL cells represented a homogeneous population with the same cell cycle position (GO) as resting normal peripheral blood lymphocytes. After five days of TPA stimulation, 56% of the B-CLL cells were found in G1A, 9% in G1B, and 3% in the S + G2/M phase, of which 2% was accounted to proliferating T cells. The cell cycle transition of the differentiating B-CLL cells was also examined using cell cycle-associated surface antigens as markers. HLA-DR and CD23 antigens were present already on noninduced cells. The former had a high constant expression, while the amount of CD23 increased upon induction. The 4F2 antigen was absent on noninduced cells but present on 86% of the induced cells. HH1 (CD37) was expressed by the majority of the cells before TPA treatment and decreased to almost undetectable levels within 24 hours. Two antigens related to late stages of the cell cycle, the interleukin 2 (IL 2; CD25) and the transferrin receptor, were present on about 20% of the induced cells. Experiments with enriched T cells showed that T but not B cells incorporated 3H-thymidine. Taken together these results and previous work on the induction of the protooncogene c-myc and c-fos suggest that this B-CLL clone represents GO cells that undergo differentiation without concomitant proliferation when exposed to TPA.
Antibodies, Monoclonal↗
Phorbol ester and B cell-stimulatory factor synergize to induce B-chronic lymphocytic leukemia cells to simultaneous immunoglobulin secretion and DNA synthesis.
This paper discusses the response of two B cell-type chronic lymphocytic leukemia (B-CLL) clones, 173 and 183, to the phorbol ester TPA combined with a B cell-stimulatory factor (BSF) derived from a T helper cell hybridoma (MP6). Previous studies with 173 and 183 cells have consistently shown that TPA alone induces differentiation but no proliferation. However, when the two clones were exposed to TPA plus BSF-MP6, not only differentiation but also DNA synthesis was observed. Compared with TPA exposure alone, the fraction of cells with induced lymphoblastoid-plasmacytoid morphology increased and Ig secretion was enhanced. By a 1-hr TPA pulse followed by BSF-MP6, the DNA synthesis was further augmented, but less maturation was observed. T cell and monocyte removal, using cell sorting, showed that the DNA synthesis induced was independent of these cell types, also under serum-free conditions. Quantitation of several cell cycle-associated surface Ags showed that the 4F2, Ba, Bac-1, and cD23 Ags increased while the CD37 decreased in expression upon addition of BSF-MP6. We conclude that B-CLLs are inducible by TPA and BSF-MP6 not only to differentiation, but also to DNA synthesis even under serum-free conditions in vitro. The results furthermore suggest that the very low proliferation activity in B-CLL tumors in vivo may reflect a relative deficiency of proper growth and differentiation factors or a subnormal response of B-CLL cells to such factors.
Antigens, Differentiation, B-Lymphocyte↗
Chronic B-lymphocytic leukemia--expression of B cell activation markers in relation to activity of the disease.
Two-color FACS analysis was used to study phenotypic subset and activation markers on circulating B (tumor) cells of 21 patients with chronic B-lymphocytic leukemia (B-CLL). Patients with clinically active (progressive) disease differed from patients with stable disease: B cells from the former patient category showed a significantly increased expression of the activation antigen 1D11 and FN99(CD9), and a decreased expression of the FN1 B subset marker. No clinical associations were observed using the CD23, CD25, 4F2, Ba, Bac-1 or FN50 markers. Functional studies showed that the B cells from both clinical categories of patients responded equally well with DNA synthesis when optimally triggered and supplied with T cell factors. However, B-CLL cells from patients with progressive disease secreted significantly higher levels of IgM in response to phorbol ester. The present experiments thus show that differences exist in the activation of B-CLL cells in vivo and that these patterns are correlated with disease activity. Further, the maximal in vitro proliferative capacity of individual tumor cells is similar, whereas differences in accessory T cell functions may exist between patients.
Antigens, Differentiation, B-Lymphocyte↗