Peripheral blood mononuclear cells: a model for the human vitamin D endocrine system in health and disease.
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Calcitriol↗
Biomedical subjects
R Koren
Publications and source records attributed to R Koren.
The effect of growth hormone supplementation on in vitro fertilization outcome: a prospective randomized placebo-controlled double-blind study.
OBJECTIVE: To determine the effect of growth hormone (GH) supplementation to a long gonadotropin-releasing hormone agonist (GnRH-a)/human menopausal gonadotropin (hMG) treatment protocol, on ovarian response, embryo quality, and clinical outcome in in vitro fertilization (IVF). DESIGN: Growth hormone or placebo were administered in a prospective randomized double-blind manner. PATIENTS: Forty-two normal ovulatory, women who were 38 years of age or less with mechanical factor infertility and a normal male factor were selected for this study. INTERVENTIONS: Gonadotropin-releasing hormone agonist, 0.5 mg/d, was initiated in the midluteal phase of the preceding cycle and continued until the day of human chorionic gonadotropin (hCG) administration. Ovulation induction with hMG was started 14 days after pituitary down regulation (17 beta-estradiol [E2] serum level less than 30 pg/mL). Growth hormone (12 IU/d) or placebo were administered on days 1, 3, 5, and 7 of hMG treatment. RESULTS: Breaking the code at the completion of the study revealed that 20 women received GH and 22 placebo. The age and duration of infertility did not differ between the two groups. Follicular phase duration, hMG ampules used, serum E2, and number of follicles (greater than or equal to 14 mm) on day of hCG as well as number of oocytes and embryos achieved were similar in both groups. Embryo morphology and rate of cleavage were also similar. Insulin-like growth factor-I (IGF-I) serum levels did not change after pituitary down regulation and increased significantly both after GH/hMG and placebo/hMG ovulation induction treatment. Clinical pregnancy rate (PR) per embryo transfer and implantation rate were 40% versus 32% and 17.9% versus 11.3% in the GH and placebo groups, respectively, and were not statistically different. CONCLUSIONS: In normo-ovulatory women undergoing ovulation induction for IVF, GH supplementation to hMG after GnRH-a pituitary down regulation does not seem to augment ovarian response or improve embryo quality. The effect of this regimen on actual PRs and implantation rates needs further clarification.
Adult↗
Erythrocytes from patients with low serum concentrations of IGF-I have an increase in receptor sites for IGF-I.
The binding characteristics of insulin-like growth factor I on erythrocytes were studied in 11 patients with long-term IGF-I deprivation and low serum IGF-I levels. Six patients had Laron type dwarfism and 5 idiopathic isolated growth hormone deficiency, with a mean (+/- SEM) serum IGF-I level of 6.01 +/- 1.01 nmol/l as compared with that in 25 normal controls of 26.35 +/- 2.73 nmol/l (p = 0.00001). The mean (+/- SEM) [125I]IGF-I specific binding at a concentration of 4 x 10(12) cell/l was 12.11 +/- 1.29% for the patient group compared with 8.75 +/- 0.62% for the controls (p = 0.005). Scatchard analysis showed a curvilinear plot. Using a non-linear curve fit, the mean (+/- SEM) number of high-affinity receptor sites per cell was found to be 7.34 +/- 1.80 in the IGF-I-deprived patients and 2.84 +/- 0.29 in the controls (p = 0.0005). The mean +/- SEM dissociation constant was found to be 0.33 +/- 0.10 nmol/l for the patients and 0.26 +/- 0.08 nmol/l for the controls (NS). This study has demonstrated that the low serum concentration of IGF-I in Laron type dwarfism and isolated growth hormone deficiency is associated with an increase in receptor sites for IGF-I on the erythrocytes. The application of this property as a diagnostic acid remains to be established.
Adolescent↗
[Treatment of diaphyseal fractures of the lower extremity with sliding plates].
This paper reports on the clinical application modified sliding plates in osteosynthesis of the long bones of the lower extremity especially of the femur. This method allows early weight bearing after operation. Early consolidation after fractures was noticed.
Adolescent↗
1,25-Dihydroxyvitamin D3 potentiates the decreased response of lymphocytes from atopic subjects to agents that increase intracellular cyclic adenosine monophosphate.
The inhibitory effect of prostaglandin E2, histamine, isobutylmethylxanthine, and 1,25-dihydroxyvitamin D3 (1,25-[OH]2D3) on the mitogenic stimulation of peripheral blood lymphocytes from normal and atopic subjects was studied. We found that lymphocytes from atopic patients were less susceptible to inhibition by the three agents that elevate intracellular cyclic adenosine monophosphate (cAMP) concentrations and by the active metabolite of vitamin D (inhibition of 27%, 14%, 12%, and 36% for the atopic patients as compared with 40%, 20%, 22%, and 46% for the normal donors, by the four agents, respectively; p less than 0.02). The inhibitory effect of the cAMP-elevating agents was potentiated by the addition of 1,25-(OH)2D3 to the lymphocyte cultures. The potentiation was more pronounced on lymphocytes from the atopic donors, increasing their responsiveness to levels comparable to levels of lymphocytes from normal donors. The synthetic corticosteroid, dexamethasone, had a similar potentiating effect on the inhibitory action of prostaglandin E2. In view of the beneficial action of beta-agonists, phosphodiesterase inhibitors, and corticosteroids in the treatment of allergy, the potentiating effect of 1,25-(OH)2D3 on the action of cAMP-elevating agents may be of therapeutic interest.
1-Methyl-3-isobutylxanthine↗
1,25-dihydroxyvitamin D3 and agents that increase intracellular adenosine 3',5'-monophosphate synergistically inhibit the mitogenic stimulation of human lymphocytes.
1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3], like the immune response modulators prostaglandin E2 (PGE2) and histamine, inhibits mitogen-induced proliferation of human peripheral blood mononuclear cells. 1,25-(OH)2D3 acts synergistically with PGE2 and histamine to inhibit lymphocyte mitogenesis. This is apparent at a wide concentration range of 1,25-(OH)2D3 (3 X 10(-11)-10(-8) mol/L). Cholera toxin, forskolin, and isobutylmethylxanthine, which like PGE2 and histamine increase intracellular concentrations of cAMP, also act synergistically with 1,25-(OH)2D3 in this system. Culture of mitogen-stimulated adherent cell-depleted mononuclear cells with PGE2 increases the number of high affinity binding sites for 1,25-(OH)2D3. This finding may account for the synergistic interaction between the two agents.
1-Methyl-3-isobutylxanthine↗
Mononuclear cells from human neonates are partially resistant to the action of 1,25-dihydroxyvitamin D.
1,25-Dihydroxyvitamin D [1,25-(OH)2D] inhibits mitogen-induced proliferation of lymphocytes by a receptor-mediated mechanism. Peripheral blood lymphocytes may serve as a model for detecting hereditary defects in the response of classical target organs to 1,25-(OH)2D. Delayed bone mineralization and deficient intestinal calcium absorption are common in low birth weight formula-fed infants. The defect in calcium absorption exists despite normal or even elevated serum 1,25-(OH)2D levels, suggesting partial end-organ resistance to the hormone. We assessed the response to 1,25-(OH)2D of activated mononuclear cells obtained from cord blood of fullterm and preterm infants and from peripheral blood of adults. We found that the inhibitory effect of 1,25-(OH)2D on mitogen-induced [3H]thymidine incorporation was significantly less [mean, 34 +/- 8% (+/- SE)] in mononuclear cells from neonates (independent of gestational age) compared to mononuclear cells from adults (66 +/- 5%; P less than 0.001). This difference in the inhibitory effect was not due to a smaller number of high affinity receptors for 1,25-(OH)2D in activated cord blood lymphocytes. We conclude that the coupling between the receptors for 1,25-(OH)2D and the biological response in neonates is less efficient than that in adults.
Adult↗
Effect of Dead-Sea brine and its main salts on cell growth in culture.
Diluted Dead-Sea brine and solutions of certain of its salts (chlorides and bromides of Na, K and Mg) were found to reversibly inhibit cell proliferation in culture. Bromides were more powerful as inhibitors than their chloride counterparts, and K salts were more effective than those of Na and Mg. KBr had the strongest inhibitory effect, which equalled that of diluted Dead-Sea brine at the same concentration. The favourable results of the Dead-Sea Spa treatment of psoriasis may thus be partly due to the penetration of minerals into the body, via the skin, with subsequent reinforcement of anti-proliferative mechanisms.
Animals↗
1,25-Dihydroxyvitamin D3 enhances prostaglandin E2 production by monocytes. A mechanism which partially accounts for the antiproliferative effect of 1,25(OH)2D3 on lymphocytes.
Partial removal of monocytes from human peripheral blood mononuclear cells, or the addition of indomethacin, reduced the antiproliferative effect of 1,25(OH)2D3 on mitogen-stimulated mononuclear cells. Addition of 1,25(OH)2D3 (1 nM) to mitogen-stimulated mononuclear cells caused a 2-4-fold increase in prostaglandin E2 production during the second day of culture. The inhibitory effect of 1,25(OH)2D3 on lymphocyte proliferation is greatly augmented up to 7-fold in the presence of prostaglandin E2. We conclude that monocytes are involved in the inhibitory effect of 1,25(OH)2D3 on the mitogenic stimulation of human lymphocytes and that their action is probably mediated by prostaglandins.
Calcitriol↗
Isolation of the positive-acting regulatory gene PHO4 from Saccharomyces cerevisiae.
We have isolated a 10.2-kb fragment of yeast DNA from a genomic library of recombinant centromeric YCp50 plasmids, which complements a mutation in the PHO4 gene of Saccharomyces cerevisiae. The identity of the PHO4 gene on this plasmid was established by integration of a subfragment into the PHO4 region of the yeast chromosome. Analysis of a series of plasmid subclones covering different regions of the original yeast DNA insert localized the PHO4 gene within a 2.25-kb sequence. Southern hybridization of total genomic DNA prepared from wild-type strains and from integrative transformants show that the PHO4 gene consists of unique yeast DNA sequences and is present at a single copy in the S. cerevisiae genome. RNA blot hybridization mapping of transcripts within this genomic region identify the PHO4 transcript as a 1.7-kb, low-abundancy, constitutively expressed and polyadenylated RNA.
Acid Phosphatase↗
Control of cell growth and division in Saccharomyces cerevisiae.
Considerable advances have been made in recent years in our understanding of the biochemistry of protein and nucleic acid synthesis and, particularly, the molecular biology of gene expression in eukaryotes. The yeast Saccharomyces cerevisiae, and to a lesser extent Schizosaccharomyces pombe, has had a preeminent role as a focus for these studies, principally because of the facility with which these organisms can be experimentally manipulated biochemically and genetically. This review will be designed to critically examine and integrate recent advances in several vital areas of regulatory control of enzyme synthesis in yeast: structure and organization of DNA, transcriptional regulation, post-transcriptional modification, control of translation, post-translational modification and secretion, and cell-cycle modulation. It will attempt to emphasize and illustrate, where detailed information is available, principal underlying molecular mechanisms, and it will attempt to make relevant comparisons of this material to inferred and demonstrated facets of regulatory control of enzyme and protein synthesis in higher eukaryotes.
Cell Division↗
Defective binding and function of 1,25-dihydroxyvitamin D3 receptors in peripheral mononuclear cells of patients with end-organ resistance to 1,25-dihydroxyvitamin D.
Lectin-induced DNA synthesis by peripheral mononuclear cells from 17 normal donors was inhibited (40-60%) by 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) at physiological concentrations (10(-10)-10(-9) M). The lymphocytes acquire specific receptors for 1,25(OH)2D3 upon activation by the lectins. This process precedes the inhibitory effect of 1,25(OH)2D3. We studied lymphocytes from six patients from four different kindreds with the syndrome of hereditary end-organ resistance to 1,25(OH)2D (the so-called vitamin D-dependent rickets type II). In five patients (three kindreds) peripheral blood mononuclear cells did not acquire receptors for 1,25(OH)2D3 upon phytohemagglutinin-induced activation. Moreover, in contrast to normal lymphocytes, the mitogenic stimulation of these patients' lymphocytes by phytohemagglutinin and concanavalin A was not inhibited by 1,25(OH)2D3. Activated lymphocytes of the sixth patient from a fourth kindred exhibited normal binding of [3H]1,25(OH)2D3 but the hormone failed to inhibit the mitogenic stimulation. A similar pattern of the vitamin D effector system was previously observed in fibroblasts cultured from skin biopsies of the same group of patients. The conclusions from these findings are: (a) the inhibition of mitogenic stimulation by 1,25(OH)2D3 is mediated by specific functional receptors to the hormone; and (b) the receptors for 1,25(OH)2D3 in mononuclear cells are probably controlled genetically by the same mechanisms as the effector system in well-characterized target organs of the hormone, such as intestine and kidney.
Adolescent↗
Sex and aphasic syndromes.
Sex differences in the incidence of aphasia and its types has been the subject of interest in recent literature. We studied the records of 275 patients with C.V.A. and 62 with C.C.I., serially admitted to the Loewenstein Rehabilitation Hospital between 1965 and 1980. Aphasia Test results were recorded within one month of onset and again 3-5 months later. No significant sex differences were found in the incidence of aphasia or in aphasia syndromes in C.V.A. patients, but males far outnumbered female patients with C.C.I. The average ages of males and females in our aphasia population and among the syndrome types were not significantly different. We found that severity of disabilities, as measured by auditory comprehension, failed to show significant sex differences, although males tended to have more severe types of aphasia with poorer prognosis for recovery. Patterns of improvement to less severe types of aphasia were not statistically significant in males and females.
Adult↗
The Word Retrieval Fluency Test: what does it assess?
The term fluency in aphasia is ambiguous. It can relate to the rate of speech--normal vs. laborious or the ability to retrieve words. In this report, to avoid confusion we refer to fluency in a word retrieval task. Different authors have ascribed defective performance on these tasks to Frontal Lobe Syndrome or Aphasia. Our patient material adds dementia as a causative condition. To determine whether subnormal test performance is due to generalized brain dysfunction or only to left hemisphere disorders, we tested left hemisphere damaged patients, without aphasia as well as right hemisphere damaged patients, obtaining non-significant differences between the two groups. This supports our experience that such a test is highly sensitive to generalized brain dysfunction i.e. to a variety of cerebral disorders and therefore seems not to be highly pathognomonic of aphasia.
Adolescent↗
1,25-Dihydroxyvitamin D3 inhibits selectively the mitogenic stimulation of mouse medullary thymocytes.
Mouse thymocytes were separated into cortical and medullary subpopulations by differential agglutination with peanut agglutinin. A high-affinity receptor for 1,25-dihydroxyvitamin D3 is present in medullary immunocompetent mouse thymocytes and is absent from cortical immature cells. 1,25-dihydroxyvitamin D3, at physiological concentrations, inhibits the mitogenic response of the medullary cells to phytohemagglutinin and interleukin-2, but has no effect on the cortical subpopulation. Other less active metabolites of vitamin D had little or no effect on medullary cell stimulation.
Animals↗
The kinetics of dissociation of the inhibitor of nucleoside transport, nitrobenzylthioinosine, from the high-affinity binding sites of cultured hamster cells.
Nucleoside transport in various types of animal cells is inhibited by the binding of nitrobenzylthioinosine (NBMPR) to a set of high-affinity sites on the plasma membrane. This work examined the binding of [3H]NBMPR to the nucleoside transporters of cultured Nil 8 hamster fibroblasts and of cells of a virus-transformed clone (Nil SV) derived from Nil 8. Experiments conducted with intact Nil 8 and Nil SV cells and with membrane preparations indicated that the two lines differed significantly in the cellular content of binding sites and only slightly in the affinities of these sites for NBMPR. Nil 8 and Nil SV cells possessed (4.2-8.0) X 10(5) and (2.0-4.0) X 10(6) sites per cell respectively, whereas the dissociation constants of site-bound NBMPR obtained with intact cells and with membrane preparations were similar, ranging from 0.29 to 1.5 nM. Dilazep, a potent inhibitor of nucleoside transport that is structurally unrelated to NBMPR, appeared to compete with NBMPR for binding to the high-affinity sites when tested under equilibrium conditions with Ki values for inhibition of NBMPR binding to Nil 8 and Nil SV cells respectively of 15 +/- 4 and 32 +/- 4 nM. The dissociation of NBMPR from the binding site--NBMPR complex of Nil SV membrane preparations was a first-order decay process with a rate constant of 0.68 +/- 0.26 min-1. The rate of dissociation of NBMPR from the binding-site complex of membrane preparations and intact cells was decreased significantly in the presence of dilazep and increased in the presence of the permeant uridine. These results suggest that the apparent competitive-inhibition kinetics obtained for dilazep under equilibrium conditions should not be interpreted as binding of dilazep to the same site as NBMPR but rather as binding of the two inhibitors to closely associated sites on the nucleoside transporter. Similarly, uridine also appears to bind to a site separate from the NBMPR-binding site.
Animals↗
Positive cooperativity in binding by albumin: the system bovine serum albumin and alizarin yellow G cobinding by salicylic acid.
The binding of alizarin yellow G--an azo derivative of salicylic acid--by bovine serum albumin has been investigated using the method of equilibrium dialysis. Six strong and a number of additional, weak binding sites have been found to be present. The system is characterized by strong positive cooperativity between the first and second sites. Six binding constants have been determined on the basis of a simplified mathematical model. The results are approximately 2 X 10(4) M-1 for the first binding site, 6 X 10(5) M-1 for the second, and between 4 X 10(4) and 10(5) M-1 for the rest. The phenomenon is discussed in terms of the existence of various conformers or of the conformational adaptability of albumin. Cobinding by salicylic acid does not displace alizarin yellow G but induces a conformational change in the protein which affects the absorption spectrum of the bound dye. As expected for this kind of heterotropic interaction, the spectrum of the system albumin-salicylic acid is similarly affected by the cobinding of alizarin yellow G.
Animals↗
The effect of verapamil, a calcium antagonist, on the serum-dependent regulation of uridine uptake by cells in culture.
The stimulation of uridine uptake is one of the early events that occur when quiescent cells are stimulated to grow by adding fresh serum. Serum depletion of cells in their exponential phase of growth results in a decrease of uridine uptake rate, a process which is complete before a significant reduction in DNA synthesis is observed. Elevation of extracellular potassium can stimulate the role of serum as an activator of uridine uptake, and can prevent the inhibition of uptake that results from serum depletion. Verapamil, a known antagonist of calcium movement across biological membranes, inhibits uridine uptake. This inhibition is much stronger in serum- or KCl-activated cells than in serum-depleted or quiescent cells. Verapamil can partially prevent the serum-dependent stimulation of uridine uptake. The effect of Verapamil does not depend on the presence of calcium in the extra-cellular medium. Verapamil may interfere with serum-dependent redistribution of Ca2+ within the cells, and thus uncouple the initial event of binding of serum growth factors to membrane receptors, from the subsequent intracellular response-regulation of uridine uptake rates.
Animals↗