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PubMed2001

Lack of correlation between numbers of circulating t(14;18)-positive cells and response to first-line treatment in follicular lymphoma.

In follicular lymphoma, the t(14;18) status of the peripheral blood and bone marrow analyzed by polymerase chain reaction (PCR) is assumed to correlate with disease activity in patients with relapsed disease. The clinical significance of quantitating circulating lymphoma cells by real-time PCR is reported in patients on first-line treatment. Thirty-four consecutive patients with previously untreated follicular lymphoma and detectable t(14;18)-positive cells in pretreatment peripheral blood samples were monitored. All patients were treated with standard chemotherapy in combination with interferon alfa-2b. Before and after induction therapy, blood samples were taken for quantitative analysis of t(14;18). At presentation, a median of 262 t(14;18)-positive cells per 75,000 normal cells was found (range, 1-75 000). Patients with lower numbers of circulating tumor cells more frequently had bulky disease (P =.02). Seventy-nine percent of the patients responded clinically to treatment. In 22 of 28 patients, including 4 patients in whom treatment had failed clinically, the number of circulating t(14;18)-positive cells decreased to undetectable or low levels after therapy. In the remaining responding patients, circulating tumor cells persisted after therapy. These quantitative data on circulating t(14;18)-positive cells call into question the usefulness of molecular monitoring of the blood in a group of patients with follicular lymphoma uniformly treated with a noncurative first-line regimen. T(14;18)-positive cells decreased in peripheral blood after treatment, irrespective of the clinical response. Therefore, the significance of so-called molecular remission should be reconsidered in follicular lymphoma. (Blood. 2001;98:940-944)

Adult↗
PubMed2006

Seeding of epithelial cells into circulation during surgery for breast cancer: the fate of malignant and benign mobilized cells.

BACKGROUND: Surgery of malignant tumors has long been suspected to be the reason for enhancement of growth of metastases with fatal outcome. This often prevented surgeons from touching the tumor if not absolutely necessary. We have shown in lung cancer patients that surgery, itself, leads to mobilization of tumor cells into peripheral blood. Some of the mobilized cells finding an appropriate niche might grow to form early metastases. Monitoring of tumor cell release during and the fate of such cells after surgery for breast cancer may help to reveal how metastases develop after surgery. METHOD: We used the MAINTRAC analysis, a new tool for online observation of circulating epithelial cells, to monitor the number of epithelial cells before, 30 min, 60 min, three and seven days after surgery and during subsequent variable follow up in breast cancer patients. RESULTS: Circulating epithelial cells were already present before surgery in all patients. During the first 30-60 min after surgery values did not change immediately. They started increasing during the following 3 to 4 days up to thousand fold in 85% of treated patients in spite of complete resection of the tumor with tumor free margins in all patients. There was a subsequent re-decrease, with cell numbers remaining above pre-surgery values in 58% of cases until onset of chemotherapy. In a few cases, where no further therapy or only hormone treatment was given due to low risk stage, cell numbers were monitored for up to three years. They remained elevated with no or a slow decrease over time. This was in contrast to the observation in a patient where surgery was performed for benign condition. She was monitored before surgery with no cells detectable. Epithelial cells increased up to more than 50,000 after surgery but followed by a complete reduction to below the threshold of detection. CONCLUSION: Frequently before but regularly during surgery of breast cancer, epithelial cells are mobilized into circulation. Part of these cells, most probably normal or apoptotic cells, are cleared from the circulation as also shown to occur in benign conditions. After resection even if complete and of small tumors, cells can remain in the circulation over long times. Such cells may remain "dormant" but might settle and grow into metastases, if they find appropriate conditions, even after years.

Journal Article↗
PubMed2005

Circulating CD34+, CD133+, and vascular endothelial growth factor receptor 2-positive endothelial progenitor cells in myelofibrosis with myeloid metaplasia.

PURPOSE: Endothelial progenitor cells (EPCs) are present in circulation and contribute to vasculogenesis in adults. We measured the number of circulating EPCs in patients with myelofibrosis with myeloid metaplasia (MMM), and we examined the relationship between the number of EPCs and severity of the MMM disease process. PATIENTS AND METHODS: The number of EPCs was measured by assaying the CD34+CD133+ vascular endothelial growth factor receptor 2 (VEGFR2) -positive cell phenotype in 110 MMM patients, 16 patients with other Philadelphia-negative chronic myeloproliferative disorders (Ph-negative CMPDs), and 14 healthy participants. In four MMM patients, the capacity of selected CD34+ cells to form endothelial colonies (CFU-End) in vitro was tested. RESULTS: CD34+, CD133+, and VEGFR2-positive EPCs were detectable in unselected peripheral-blood cells of 50.9% MMM patients, 37.5% control patients, and 21% healthy participants. Patients with MMM had a median of 0.26% EPCs, significantly higher than that in healthy controls (median, 0%) and in patients with other Ph-negative CMPDs (median, 0.1%). In 14.5% of MMM patients, the numbers of EPCs were greater than the highest value found in patients with other Ph-negative CMPDs. CD34+ selected cells produced colony-forming unit-endothelial (CFU-End), which were vascular endothelial (VE) -cadherin positive, CD31+, von Willebrand factor positive, and CD45-. In MMM patients, the larger the number of EPCs, the smaller the number of circulating immature myeloid cells and circulating CD45+CD34+ hematopoietic progenitor cells. Increased numbers of EPCs were associated with younger age and a diagnosis of prefibrotic MMM. CONCLUSION: Circulating EPCs are elevated in MMM patients in the early stage of the disease. Heightened mobilization of EPCs may represent an important mechanism for development of neoangiogenesis in MMM.

AC133 Antigen↗
PubMed1989

Inhibition of pancreatic exocrine secretion in the rat by calcitonin gene-related peptide: involvement of circulating somatostatin.

Calcitonin gene-related peptide (CGRP), a 37-amino acid peptide, has been shown to be a potent inhibitor of pancreatic exocrine secretion when administered exogenously The present study was performed to determine if this inhibitory effect is due to the direct actions of exogenous CGRP on the exocrine pancreas or to the effects of another inhibitor released by CGRP. To this end, we first confirmed the inhibitory effects of the peptide on exocrine function by infusing the peptide into conscious rats previously prepared with bile-pancreatic fistulas and measuring cholecystokinin-stimulated amylase and protein outputs. CGRP produced a dose-dependent inhibition of both protein and amylase outputs in vivo. In marked contrast, CGRP in vitro had no direct inhibitory effect on amylase output from either the isolated buffer-perfused pancreas or dispersed acinar cells. Thus, the inhibitory effects of exogenous CGRP on pancreatic exocrine function appear to be indirect. In an attempt to determine the mediator of the inhibitory effects of CGRP, we assessed the ability of similar doses of CGRP to stimulate the release of a potential endogenous inhibitor of pancreatic exocrine function, circulating somatostatin. In conscious rats, iv CGRP dose-dependently increased circulating plasma somatostatin-like immunoreactivity from 35 +/- 5 to 86 +/- 7 fmol/ml. To determine if these increments in circulating somatostatin were sufficient to impair exocrine function, the isolated pancreas was exposed in vitro to a similar concentration of somatostatin. Somatostatin perfusion resulted in a significant inhibition of pancreatic amylase output (73%). Overall, these results support the hypothesis that 1) the inhibitory effect of exogenous CGRP on pancreatic exocrine function is indirect; 2) exogenous CGRP stimulates the release of endogenous somatostatin into the systemic circulation; and 3) the concentration of circulating somatostatin is sufficient to mediate the effect of exogenous CGRP on the exocrine pancreas.

Amylases↗
PubMed1991

Circulating half-lives of follicle-stimulating hormone and luteinizing hormone in pituitary extracts and isoform fractions of ovariectomized and intact ewes.

Previous studies have shown that the circulating half-life (t 1/2) of serum FSH in ewes after hypophysectomy (HPX) increased 10-fold after ovariectomy (OVEX). The basis for this difference was examined in this study by determining the circulating half-life of serum FSH and LH in HPX ewes after administration of pituitary extracts and gonadotropin isoform fractions. High-speed supernatants of pituitaries from gonadal-intact and OVEX ewes were fractionated by electrofocusing in sucrose gradients and based on the pI distribution of FSH and LH divided into four pools, pH 4.3-4.8, 4.8-5.55, 5.8-6.7, and 6.7-10. These extracts were administered by iv bolus injection to HPX gonadal-intact ewes and blood samples collected between 15-1000 min later. The clearance pattern for both serum FSH and LH was heterogenous, indicative of a major rapid and a minor slow dissociating component. A significant (P less than 0.05) difference in circulating half-lives (rapid component) was observed between pituitary extracts from intact and OVEX ewes for FSH (t 1/2 = 32.8 +/- 8.6 min vs. 89.9 +/- 32.3 min) but not LH (31.3 +/- 9.2 min vs. 39.3 +/- 6.1 min, respectively), whereas no significant difference was observed between the corresponding FSH or LH isoform preparations. To establish if the difference in circulating half-lives obtained after HPX and bolus iv injection was due to mode of delivery, an extract of pituitaries from OVEX ewes was infused for 12 h into HPX sheep and the t 1/2 values determined after cessation of treatment and compared to those after a bolus injection. The clearance of both FSH and LH from plasma after infusion was significantly prolonged than after a bolus injection. It is concluded that the difference in circulating half-lives of FSH between pituitary extracts from intact and OVEX ewes after bolus administration is due to a difference in pituitary FSH composition. However, the prolonged clearance with infusion compared to bolus administration suggests that extrapituitary factors are also responsible.

Animals↗
PubMed1975

Sequential patterns of circulating LH and FSH in female sheep during the early postnatal period: effect of gonadectomy.

To determine the basis for the marked daily variability in circulating luteinizing hormone (LH) in the female lamb shortly after birth and to determine whether circulating follicle-stimulating hormone (FSH) exhibits similar variability during this period of life, serum levels of both gonadotropins were monitored frequently (20-min intervals) over a 3- or 6-hr period each week for the first 9 weeks of life. Similar measurements of circulating LH and FSH were made in lambs ovariectomized at 2 weeks of age to assess whether the ovary influences the secretion of these gonadotropins. Pulsatile release of LH, but not FSH, was observed in both groups of lambs. Although mean concentrations of circulating FSH in intact female lambs were similar to basal levels of the cyclic adult, mean concentrations of serum LH were much higher. Because of the discontinuous release of LH in intact lambs after 4-5 weeks of age, patterns of LH were often indistinguishable from those of the long-term ovariectomized adult. At 9 weeks of age the frequency of episodic LH release in intact lambs ranged from 0.33-1.1 pulses/hr. Castration at 2 weeks of age produced a concomitant, but delayed, rise in mean serum LH and FSH beginning 4-5 weeks later. By 9 weeks of age serum LH, but not FSH, had attained levels comparable to those of the castrated adult, and the mean frequency of LH release (about hourly) was similar for both groups. The results indicate that by 9 weeks of age the ovary of the lamb influences the secretion of LH and FSH. Because in the 9-week-old intact female lamb episodic release of LH occurs producing high (castrate) levels of this gonadotropin while circulating concentrations of FSH remain stable and within basal levels of the adult cycling female, it is suggested that acute concomitant release of LH and FSH does not occur at this age and that separate negative feedback loops for the control of LH and FSH secretion may exist during early postnatal life.

Aging↗
PubMed1994

Characterization of the translocation process of vitamin D3 from the skin into the circulation.

The cutaneous synthesis of vitamin D3 and the subsequent translocation of vitamin D3 into the circulation are two key steps in the vitamin D endocrine system. To study the kinetic aspects of cutaneous synthesis and translocation of vitamin D3, both in vitro and in vivo chicken models have been developed. To assess the capacity of chicken skin to generate vitamin D3, the concentrations of 7-dehydrocholesterol (7-DHC) in different skin areas were determined. It was found that the highest concentration of 7-DHC was in the leg skin (3524 +/- 937 ng cm-2), which was about 30 times greater than that in the back (120 +/- 62 ng cm-2). Whole body exposure of chickens to UV-B radiation (0.5 J cm-2) resulted in the production of previtamin D3 (preD3) in the skin of the legs and feet (43 +/- 7 and 54 +/- 17 ng cm-2, respectively), whereas no preD3 was detected in the back skin. In vitro, at 40 C, the forward (k1) and reverse (k2) rate constants of the preD3<-->vitamin D3 reaction in the leg skin were greatly increased compared to those in n-hexane (k1, 0.367 vs. 0.0369 h-1; k2, 0.042 vs. 0.0059 h-1). In vivo, the determined rate constants k1, k2, and k3 for the consecutive reactions preD3<-->vitamin D3-->vitamin D3 were 0.257, 0.034, and 0.114 h-1, respectively. To evaluate the circulating concentration of vitamin D3 in response to UV-B radiation, chicken legs were irradiated. The time course revealed a 4-fold increase in the circulating concentration of vitamin D3, with a peak about 30 h postradiation. No appreciable amount of preD3 could be detected in the circulation in the early hours after UV-B radiation, suggesting the existence of a process responsible for the specific translocation of vitamin D3 from the skin into the circulation.

Animals↗
PubMed1997

Circulating leptin does not appear to provide a signal for triggering the initiation of puberty in the male rhesus monkey (Macaca mulatta).

The notion that circulating leptin may provide a somatic signal for timing the onset of puberty was examined in the male rhesus monkey. Circulating leptin levels were determined at weekly or biweekly intervals by RIA in intact (N=6) and prepubertally castrated monkeys (N=5) from approximately 18 to 30 months of age. Circulating testosterone (T) and gonadotropin levels were used as indices to identify the onset of the pubertal reaugmentation of pulsatile GnRH release (week 0) in intact and castrated animals, respectively. Time courses of the peripubertal changes in leptin concentrations in individual monkeys were normalized to week 0. In the intact group, mean leptin concentrations at this critical stage of development (week -26 to week +9) were unremarkable, ranging from 1.6+/-0.3 (SEM) to 2.4+/-0.6 ng/ml (P>0.05). In agonadal males, the pubertal onset of GnRH pulse generator activity, as reflected by sustained increments in plasma gonadotropin concentrations, also occurred in the absence of changes in circulating leptin levels (P>0.05). These findings indicate that the timing of the onset of puberty in male monkeys is not triggered by rising circulating leptin concentrations.

Animals↗
PubMed2002

Elevating circulating leptin in prepubertal male rhesus monkeys (Macaca mulatta) does not elicit precocious gonadotropin-releasing hormone release, assessed indirectly.

The purpose of this study was to examine the hypothesis that the pubertal reaugmentation of pulsatile GnRH release in male primates is triggered by a rise in circulating leptin concentrations. Agonadal juvenile male rhesus monkeys (n = 7) were implanted with indwelling venous catheters and housed in specialized cages that allow continuous access to the venous circulation. GnRH release was monitored indirectly using LH secretion from the in situ pituitary sensitized to the LH releasing action of GnRH as a bioassay for the hypothalamic peptide. Infusion of recombinant human leptin (5 micro g/kg body weight.h for 16 d resulted in a marked square wave increment in circulating leptin concentration from approximately 2-20 ng/ml but did not elicit precocious GnRH release. GH secretion, however, was stimulated confirming that the heterologous leptin preparation was bioactive in the monkey. Parenthetically, recombinant human leptin was found to be immunogenic in the monkey and circulating antileptin IgG was demonstrable 22-35 d after the initial exposure to the human protein. These findings further support the view that circulating leptin is unlikely to provide the signal that triggers the onset of puberty in male primates.

Animals↗
PubMed2004

Circulating fatty acids, non-high density lipoprotein cholesterol, and insulin-infused fat oxidation acutely influence whole body insulin sensitivity in nondiabetic men.

Circulating lipids and tissue lipid depots predict insulin sensitivity. Associations between fat oxidation and insulin sensitivity are variable. We examined whether circulating lipids and fat oxidation independently influence insulin sensitivity. We also examined interrelationships among circulating lipids, fat oxidation, and tissue lipid depots. Fifty-nine nondiabetic males (age, 45.4 +/- 2 yr; body mass index, 29.1 +/- 0.5 kg/m(2)) had fasting circulating nonesterified fatty acids (NEFAs) and lipids measured, euglycemic-hyperinsulinemic clamp for whole body insulin sensitivity [glucose infusion rate (GIR)], substrate oxidation, body composition (determined by dual energy x-ray absorptiometry), and skeletal muscle triglyceride (SMT) measurements. GIR inversely correlated with fasting NEFAs (r = -0.47; P = 0.0002), insulin-infused NEFAs (n = 38; r = -0.62; P < 0.0001), low-density lipoprotein cholesterol (r = -0.50; P < 0.0001), non-high-density lipoprotein cholesterol (r = -0.52; P < 0.0001), basal fat oxidation (r = -0.32; P = 0.03), insulin-infused fat oxidation (r = -0.40; P = 0.02), SMT (r = -0.28; P < 0.05), and central fat (percentage; r = -0.59; P < 0.0001). NEFA levels correlated with central fat, but not with total body fat or SMT. Multiple regression analysis showed non-high-density lipoprotein cholesterol, fasting NEFAs, insulin-infused fat oxidation, and central fat to independently predict GIR, accounting for approximately 60% of the variance. Circulating fatty acids, although closely correlated with central fat, independently predict insulin sensitivity. Insulin-infused fat oxidation independently predicts insulin sensitivity across a wide range of adiposity. Therefore, lipolytic regulation as well as amount of central fat are important in modulating insulin sensitivity.

Adult↗
PubMed2005

Acute regulation of circulating parathyroid hormone (PTH) molecular forms by calcium: utility of PTH fragments/PTH(1-84) ratios derived from three generations of PTH assays.

CONTEXT: The quantitative evaluation of circulating PTH peaks revealed by PTH assays after HPLC separation constitutes the best way to study the behavior of PTH molecular forms, but it is also impractical. OBJECTIVE: The objective of the study was to investigate the regulation of circulating PTH molecular forms by calcium through the use of PTH fragments/PTH (1-84) ratios derived from PTH assays with different specificities before and after HPLC separation of circulating PTH. DESIGN: CaCl2 and Na citrate were infused in eight volunteers. PTH was measured in serum and HPLC fractions at different calcium concentrations in PTH assays reacting with regions 1-2 (CA), 12-18 (T), and 65-69 (C) of the PTH structure. RESULTS: From hypo- to hypercalcemia, the C/CA ratio had the highest range (1.92 to 9.75; P < 0.001), and the C/T ratio had a higher range (1.69 to 6.11; P < 0.01) than the T/CA ratio (1.15 to 1.86). Human (h) PTH (1-84) represented 32.7 and 4.3% of circulating PTH in hypo- and hypercalcemic HPLC profiles, respectively. These numbers were 5 and 0.9% for amino-terminal (N)-PTH, an amino-terminal form of PTH distinct from hPTH (1-84), 7.3 and 6.8% for non-(1-84) PTH or large C-PTH fragments with a partially preserved N structure, and 54.9 and 88.1% for C-PTH fragments missing a N structure. The HPLC C-PTH fragments to hPTH (1-84) ratio had the most extensive range (1.67 to 20.58). Despite their quantitative differences, all ratios identified identical behavior of PTH fragments relative to PTH (1-84). CONCLUSIONS: PTH assay ratios are an adequate tool to investigate the modulation of PTH molecular forms, even if all PTH assays show some undesirable cross-reactivity with certain circulating forms of PTH.

Adult↗
PubMed2006

Reduced number of circulating endothelial progenitor cells in hypogonadal men.

CONTEXT: Endothelial dysfunction seems to be the first step of the atherosclerotic process. In the past few years, it has been demonstrated that injured endothelial monolayer is restored by a premature pool of circulating progenitor cells (PCs) and a more mature one of circulating endothelial PCs (EPCs). Even though there is increasing evidence that estrogens play a beneficial role on EPCs and, even if debated, on the cardiovascular system, less is known about androgens. OBJECTIVE: Our objective was to evaluate the levels of circulating PCs and EPCs in men with hypogonadotropic hypogonadism (HH) and the effect of prolonged testosterone (T) replacement therapy on these cells. DESIGN AND SETTING: We conducted a prospective study on males with HH at a university andrological center. PATIENTS: The study included 10 young HH patients (28.6 +/- 3.1 yr) and 25 age-matched controls. INTERVENTIONS: Idiopathic HH patients were treated with T gel therapy, 50 mg/d for 6 months. MAIN OUTCOME MEASURES: We assessed circulating PC and EPC concentrations and immunocytochemistry for androgen receptor expression on cultured EPCs. RESULTS: At baseline, HH patients showed a significant reduction of both PCs and EPCs with respect to controls. T replacement therapy induced a significant increase of these cells with respect to baseline. Immunocytochemistry on cultured EPCs showed strong expression of the androgen receptor. CONCLUSIONS: Hypotestosteronemia is associated with a low number of circulating PCs and EPCs in young HH subjects. T treatment is able to induce an increase in these cells through a possible direct effect on the bone marrow.

Adult↗
PubMed1996

Adrenocorticotropin causes vasodilatation in the human fetal-placental circulation.

During human pregnancy, ACTH is produced by both the placenta and fetal pituitary. ACTH has been shown to cause vasodilatation in the adrenal cortex in vitro. In this context we have investigated the vasoactive effects of ACTH in the human fetal-placental circulation. Single lobules of term human placentas were bilaterally perfused in vitro with Krebs solution (maternal and fetal, 5 mL/min; 95% O2-5% CO2; 37 C; pH 7.3), and changes in fetal placental arterial perfusion pressure (FAP) were measured. ACTH (40-4000 pmol/L; n = 5) caused a dose-dependent reduction of both KC1 and PGF2alpha-induced increases in FAP in the fetal placental circulation. The reductions were of a similar magnitude in the presence of either constrictor agent. ACTH was 187.4 (95% confidence limits, 162.7-215.9) times more potent than prostacyclin (PGI2; 1.2-1180 nmol/L; n = 6), which is a known vasodilator of the fetal-placental circulation. The threshold concentrations for ACTH and PGI2 were 40 pmol/L and 1.2 nmol/L, respectively. ACTH-induced reductions in PGF2alpha-induced increases in FAP in the fetal placental circulation were not inhibited by the nitric oxide synthase inhibitor, N omega-nitro-L-arginine (100 micromol/L; n = 5), the cyclooxygenase inhibitor indomethacin (3 micromol/L; n = 5), or a guanylate cyclase inhibitor LY83583(1 micromol/L; n = 5). The inhibitory effect of ACTH was attenuated by the antagonist, ACTH-(7-38) (240 pmol/L; n = 4), and a polyclonal ACTH antiserum (1:1000 dilution; n = 4). We have demonstrated that ACTH causes a reduction in fetal placental vascular resistance in the human fetal-placental circulation in vitro. The mechanism by which it exerts these effects has not been defined, but neither nitric oxide nor PG-mediated pathways appear to be involved.

Adrenocorticotropic Hormone↗
PubMed1998

The acid-labile subunit of human ternary insulin-like growth factor binding protein complex in serum: hepatosplanchnic release, diurnal variation, circulating concentrations in healthy subjects, and diagnostic use in patients with growth hormone deficiency.

Circulating insulin-like growth factor-I (IGF-I) is predominantly bound in the trimeric complex comprised of IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS). Circulating concentrations of IGF-I, IGFBP-3 and ALS are believed to reflect the GH secretory status, but the clinical use of ALS determination is not known. We therefore, determined the: 1) hepatosplanchnic release of ALS by liver vein catheterization (n=30); 2) 24-h diurnal variation of ALS (n=8); 3) normal age-related ranges of circulating ALS (n=1158); 4) diagnostic value of ALS in 108 patients with childhood-onset GH deficiency (GHD). We found: 1) no significant arteriovenous gradient over the liver ofALS, IGF-I, and IGFBP-3; 2) the diurnal variation of ALS was 12% (mean coefficient of variation percent); 3) ALS levels increased throughout childhood with maximal levels in puberty, with a subsequent decrease with age in adults; and 4) ALS levels were below -2 SD in 57 of 79 GHD patients (sensitivity 72%) and above 2 SD in 22 of 29 patients with normal GH response (specificity 76%), which was similar, compared with the diagnostic utility of IGF-I and IGFBP-3. Finally, our findings indicate that hepatic ALS production is not measurable by this approach or, alternatively, that the liver is not the primary source of circulating ALS, IGF-I, or IGFBP-3 in humans. In conclusion, we have provided extensive normal data for a novel ALS assay and found that circulating ALS levels exhibit minor diurnal variation. We suggest that ALS determination may be used in future classification of adults suspected of GHD.

Adolescent↗
PubMed2000

Effects of hyperinsulinemia on plasma levels of circulating adhesion molecules.

Plasma levels of circulating intercellular adhesion molecule-1 (cICAM-1), a potential cardiovascular risk factor, are increased in diabetics. Among other factors, hyperinsulinemia has been proposed to enhance its release into the circulation. Thus, we directly examined the effects of insulin infusion on plasma levels of circulating adhesion molecules, and two other endothelial markers, i.e. von Willebrand factor (vWF) and soluble thrombomodulin (sTM). The study design was balanced, randomized, placebo-controlled, double blind, and cross-over. Twelve healthy male subjects received, on separate study days, a euglycemic hyperinsulinemic clamp (3 mU/kg x min) or placebo over 6 h. Plasma levels of cICAM-1, vascular cell adhesion molecule-1, circulating E-selectin, and sTM were measured by enzyme immunoassay; vWF-Ag was measured using a STA clot analyzer. Plasma levels of these adhesion molecules and endothelial cell activation markers were not affected despite a 30-fold increase in insulin levels. Hyperinsulinemia has no adverse effect on circulating ICAM-1, vascular cell adhesion molecule-1, E-selectin, vWF, or sTM and therefore does not directly induce endothelial activation.

Adult↗
PubMed1994

Serial analysis of circulating adhesion molecules and TNF receptor in serum from patients with multiple sclerosis: cICAM-1 is an indicator for relapse.

We determined the serum levels for circulating adhesion molecules (circulating intercellular adhesion molecule-1 [cICAM-1], circulating endothelial leukocyte adhesion molecule-1 [cELAM-1], and circulating L-selectin [cL-selectin]) and circulating tumor necrosis factor receptor (cTNF-R) p60 in 29 patients with relapsing-remitting MS serially over a period of 12 months. During this period there were 27 relapses in 14 patients (48%). There was progression of disease activity in 12/25 patients (48%), as assessed by the occurrence of new lesions on nonenhancing, T2-weighted MRIs of the head. Clinically active patients with relapse or disease progression on MRI (n = 18) had frequent fluctuations in their serum levels for cICAM-1 if compared to patients with stable MS (n = 11). There were significant differences in the cumulative cICAM-1 production between the two groups (502 +/- 218 ng/ml in active versus 225 +/- 82 ng/ml in stable MS patients; p < 0.001). cTNF-R p60 serum levels were higher in patients with stable compared to active disease (2.3 +/- 0.5 ng/ml versus 1.5 +/- 0.6 ng/ml; p < 0.005). A significant increase in cICAM-1 levels was present at the time of a relapse (799 +/- 263 ng/ml versus 449 +/- 95 ng/ml; p < 0.001), whereas the highest serum levels for cTNF-R p60 occurred 4 weeks after the onset of a relapse (1.8 +/- 0.5 ng/ml at relapse versus 2.3 +/- 0.6 ng/ml 4 weeks after a relapse; p < 0.01). Interestingly, the cL-selectin serum levels in all MS patients were significantly higher than in healthy donors, whereas there were no differences for cELAM-1. These results reflect distinct changes of inflammatory variables in serum of patients with MS and revealed that cICAM-1 is an indicator for disease activity and that high serum levels for cTNF-R p60 are associated with remission.

Adult↗
PubMed1998

Antitumor activity of 5'-O-dipalmitoylphosphatidyl 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine is enhanced by long-circulating liposomalization.

We previously synthesized the 5'-O-diacylphosphatidyl derivative of 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (CNDAC), a novel antitumor nucleoside, and observed it to have a high antitumor activity. Since this compound is readily incorporated into liposomal membranes, we liposomalized the compound using a formulation for conventional and long-circulating liposomes, and investigated the antitumor activity of liposomal 5'-O-dipalmitoylphosphatidyl CNDAC (DPP-CNDAC). Long-circulating liposomes composed of DPP-CNDAC, dipalmitoylphosphatidylcholine, cholesterol and palmityl-D-glucuronide (PGlcUA) (2:2:2:1 as a molar ratio), as well as liposomes containing dipalmitoylphosphatidylglycerol (DPPG) instead of palmityl-D-glucuronide and those composed of only DPP-CNDAC, were injected intravenously into Meth A sarcoma-bearing mice. DPP-CNDAC showed suppression of tumor growth, whereas CNDAC did not at the same concentration, suggesting that 5'-phosphatidylation is useful to enhance therapeutic efficacy. Furthermore, liposomal DPP-CNDAC reduced the acute toxicity, and liposomes containing PGlcUA showed more enhanced activities of reducing tumor growth and increasing the lifetime of the mice than liposomes containing DPPG. To obtain a higher therapeutic efficacy, we injected long-circulating liposomal DPP-CNDAC 5 times. The tumor growth was suppressed to 13.2% (86.8% inhibition), and the survival time of the tumor-bearing mice increased to 128.5% with one completely cured mouse out of five. Next, the effect of DPP-CNDAC incorporation on the in vivo behavior of PGlcUA and DPPG liposomes was examined by a non-invasive method using positron emission tomography (PET). Liposomes were labeled with [2-(18)F]-2-fluoro-2-deoxy-D-glucose, and administered to tumor-bearing mice. PET images and time-activity curves indicated that DPP-CNDAC/PGlcUA-liposomes tended to accumulate in tumor tissues a little bit more than DPP-CNDAC/DPPG-liposomes, although the difference between the two kinds of liposomal distribution was not as marked as between PGlcUA and DPPG liposomes, suggesting that DPP-CNDAC incorporation partly affected the liposomal behavior in vivo but that the long-circulating character of PGlcUA-liposomes might not be fully abolished. Thus, the enhanced therapeutic efficacy of long circulating liposomalized DPP-CNDAC observed here may be due to passive targeting of DPP-CNDAC to the tumor tissue, making this formulation of DPP-CNDAC useful for cancer chemotherapy.

Animals↗
PubMed2005

Serial changes in circulating concentrations of soluble CD40 ligand and C-reactive protein in patients with unstable angina undergoing coronary stenting.

BACKGROUND: This study tested the hypothesis that serum concentrations of high-sensitivity C-reactive protein (hs-CRP) and soluble CD40 ligand (sCD40L) significantly reflect serial changes in patients with unstable angina, and thus the serum concentrations of these inflammatory biomarkers may be good candidates for predicting late restenosis after coronary stenting. METHODS AND RESULTS: The circulating concentrations of sCD40L and hs-CRP were prospectively measured (both pre-procedure, and on days 21, 90, and 180 after the procedure) in 77 consecutive patients with unstable angina undergoing coronary stenting. These inflammatory mediators were also evaluated in 30 healthy volunteers. The serum concentrations of sCD40L and hs-CRP were significantly higher pre-procedure in study patients than in normal control subjects (all p values < 0.0001). These inflammatory markers then declined to a substantially lower concentration by day 21 (all p values < 0.05). Circulating concentrations of hs-CRP in each patient then differed little from each other afterwards. However, the sCD40L concentration was once again raised significantly on days 90 and 180 as compared to day 21 (both p values < 0.05). This study found no significant link between raised circulating concentrations of sCD40L and hs-CRP and late restenosis. CONCLUSIONS: Circulating concentrations of sCD40L and hs-CRP were significantly increased in unstable angina patients pre-procedure and declined substantially thereafter. However, the circulating concentrations of these 2 inflammatory mediators were not useful in predicting late restenosis following coronary stenting.

Aged↗