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PubMed1996

Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension.

OBJECTIVES: This study sought to determine the circulating levels of cytokines and their respective endogenous modulators in patients with congestive heart failure of variable severity. BACKGROUND: Activation of immune elements localized in the heart or periphery, or both, may promote release of cytokines in patients with congestive heart failure. Although an increased circulating level of tumor necrosis factor-alpha (TNF-alpha) and its soluble receptor type II (sTNF-RII) is well documented, less is known about other cytokines (i.e., interleukin-1-beta [IL-1-beta], interleukin-6 [IL-6] and interleukin-2 [IL-2] and their soluble receptor/receptor antagonists). METHODS: Circulating levels of TNF-alpha and sTNF-RII, IL-1-beta, IL-1 receptor antagonist (IL-1-Ra), IL-6, IL-6 soluble receptor (IL-6-sR), IL-2 and IL-2 soluble receptor-alpha were measured using enzyme-linked immunosorbent assay kits (Quantikine, R&D Systems) in 80 patients with congestive heart failure due to coronary artery disease or hypertension. The severity of their symptoms, which ranged from New York Heart Association functional class I to IV, was confirmed by measurement of peak oxygen consumption. RESULTS: The percentage of patients with elevated levels of cytokines and their corresponding soluble receptor/receptor antagonists significantly increased with functional class. For TNF-alpha and IL-1-beta, the percentage of patients with elevated levels of soluble receptor/receptor antagonists was higher than that of patients with elevated levels of the cytokine itself. For IL-6, the percentage of patients with elevated levels of IL-6-sR tended to be lower than that of patients with elevated levels of IL-6. All but two patients had undetectable levels of IL-2, and all but seven had levels of IL-2-sR within a normal range. CONCLUSIONS: In patients with congestive heart failure, circulating levels of cytokines increased with the severity of symptoms. In these patients, circulating levels of sTNF-RII and IL-1-Ra are more sensitive markers of immune activation than are circulating levels of TNF-alpha and IL-1-beta, respectively. Levels of IL-2 and IL-2-sR are not elevated when congestive heart failure is due to coronary artery disease or hypertension.

Aged↗
PubMed2000

On the track of a human circulating mesenchymal stem cell of neural crest origin.

The neural markers present in the normal circulating monocytoid cells able, in pathological situations, to trans-differentiate into different mesenchymal-type cells, confirm the hypothesis previously raised that these cells derive from the neural crest. In culture, the normal cells display a great plasticity very reminiscent of microglial cells in culture. Almost a quiescent cell in normal individuals, this monocytoid cell shows its division potentialities in pathological situations of fibrosis and cancer (chondrosarcoma) where it is found to spontaneously proliferate. While the normal neofibroblasts are rapidly recognized and destroyed by fibrophagic T-lymphocytes, the pathological cells escape this control and, as a result, they accumulate in vitro giving rise to a tissue sometimes organized as nodules. Although basically the transdifferentiation process is similar in all the pathological situations of fibrosis and cancer studied so far, the end-result phenotype evokes the pathology the patient is suffering from. It evokes osteoblasts in a case of osteomyelosclerosis, chondroïdocytes in a case of chondrosarcoma, myelofibroblasts in a case of fibrosis of lung and kidney in a patient under ciclosporine treatment. Hence, this circulating monocytoid cell is a multipotent cell with great division potentiality. These are characteristics of stem/preprogenitor cells. Since this circulating monocytoid cell also bears the neural markers we called it a monocytoid ectomesenchymal stem/preprogenitor cell. Therefore, the existence of an ectomesenchymal system is discussed here. The circulating monocytoid ectomesenchymal stem/preprogenitor cell might be involved in the normal cicatrisation process while the fibrophagic T lymphocytes might be involved in its termination. Impairment of this controlled mechanism might result in the development of fibrosis and/or cancer such as chondrosarcoma in vivo. Interestingly, at least in vitro, proliferation is restricted to the monocytoid cell before transdifferentiation takes place. In this model, fibrosis and cancer might share some common steps going from the proliferation of the monocytoid cells to their transdifferentiation into mesenchymal-type cells and the accumulation of these transdifferentiated cells in the tissues. Then, cancer might be distinguished from fibrosis by the additional acquisition of the ability to proliferate by the transdifferentiated cells. The monocytoid ectomesenchymal stem/preprogenitor cell might also be involved in brain neurodegenerative diseases characterized by an accumulation of microglia. The circulating monocytoid ectomesenchymal stem/preprogenitor cell appears as a target for gene therapy in pathological situations of fibrosis and/or cancer where it proliferates out of control. If the normal cell can be expanded and if its transdifferentiation can be directed, the circulating monocytoid ectomesenchymal stem/preprogenitor cell may become a useful tool for cellular therapy, in case of failure in wound healing and tissue regeneration.

Animals↗
PubMed1990

Detection and characterization of circulating antigens in acute experimental infections of mice with four different strains of Toxoplasma gondii.

Acute infections with four different strains of Toxoplasma gondii, all of them being highly pathogenic for mice, were provoked by intraperitoneal injection of 2.2 x 10(7) trophozoites. The times of the appearance of circulating antigens in the sera of the infected mice were determined and the amounts of these antigens were measured by an enzyme-linked immunosorbent assay. The molecular weight of the circulating antigens was determined by gel filtration and by Western blot following PAGE. The isoelectric points of these antigens were determined by immunoblotting after isoelectric focusing. Circulating antigens were detectable up to ng amounts/ml serum from the 1st day p.i. onwards. The circulating antigens consisted of a number of proteins with molecular weights of greater than 10(4), 300, 65, 25, and less than 5 kd. The isoelectric points of these proteins were situated between pH 3.5 and pH 7. Time of appearance and structure of the circulating antigens were very similar in all four Toxoplasma strains. Circulating antigens are apparently generated regularly in experimental acute Toxoplasma infections, and lysis of parasite cells appears to be the major mechanism of their formation.

Animals↗
PubMed2004

Pulse dye densitometry using indigo carmine is useful for cardiac output measurement, but not for circulating blood volume measurement.

BACKGROUND AND OBJECTIVE: We evaluated the validity of a newly developed pulse dye densitometer for indigo carmine for measuring cardiac output and circulating blood volume. METHODS: Measurements of cardiac output and circulating blood volume were performed with the indigo carmine densitometer during normovolaemia, hypovolaemia and hypervolaemia in nine mongrel dogs under general anaesthesia. The validity was evaluated by comparison of the values of cardiac output and circulating blood volume obtained by the thermodilution technique and the 51Cr-labelled red blood cell method, respectively. We also examined indigo carmine removal by continuous veno-venous haemofiltration after indigo carmine injection. RESULTS: There was good agreement between dye densitometer- and thermodilution-derived cardiac output (r = 0.885, P < 0.001). The bias and limits of agreement of these values were 0.09 and+/-1.07 L min(-1) (2 SD, n 22), respectively. The dye-densitometer-derived circulating blood volume was greater than that of the 51Cr-labelled red blood cell method, and both values showed weak agreement (r = 0.587, P < 0.027). The sieving coefficient of indigo carmine through continuous veno-venous haemofiltration was 0.34+/-0.06. CONCLUSIONS: These data indicate that indigo carmine densitometry is a reliable method for cardiac output determination, but it overestimates circulating blood volume, probably due to the transition of indigo carmine into the extravascular space in the systemic circulation.

Algorithms↗
PubMed1999

Circulating eosinophil/basophil progenitors and nasal mucosal cytokines in seasonal allergic rhinitis.

Accumulation of eosinophils in the airways is characteristic of allergic rhinitis and asthma. The tissue eosinophilia may involve both recruitment of mature eosinophils and proliferation of their progenitors. This study examines mature eosinophils (nasal and circulating), their circulating progenitors, and a potential role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in stimulating these progenitors. Twelve subjects with a history of seasonal allergic rhinitis and positive skin prick test for birch pollen were studied during four periods: shortly before, in the early and intense phase, at the end, and well after the Swedish birch-pollen season. Nasal mucosal and circulating eosinophils were examined in both nasal brushings and peripheral blood samples. Eosinophil/basophil progenitors were determined by counting colony-forming units in nonadherent mononuclear blood-cell cultures in methylcellulose at 14 days. The nasal mucosal cytokines GM-CSF, interleukin (IL)-1beta, IL-3, IL-5, IL-6, IL-8, and RANTES were analyzed (ELISA) in nasal lavage (NAL) fluids. All patients developed severe symptoms of rhinitis at the height of the season, with increased numbers of eosinophils in the nasal mucosa (P<0.05) and in the circulation (P<0.05). At this time point, the number of circulating progenitors (P<0.05) and the NAL fluid level of GM-CSF (P<0.05) were also increased. In contrast, there was no change in the NAL fluid levels of IL-1beta, IL-3, IL-6, or IL-8. Neither IL-5 nor RANTES could be detected in any of the NAL fluids. At the end of or after the season, there was no increase in nasal eosinophils or circulating eosinophils or progenitors (P>0.05). Ex vivo addition of GM-CSF (10-100 U) increased the number of blood progenitors grown before (P<0.01) and after (P<0.05) the season, compared with during the season. The in vitro GM-CSF responsiveness of progenitors may be related to whether or not these already have been stimulated endogenously by GM-CSF. Taken together, our data thus suggest that GM-CSF may play a role in vivo to increase production of eosinophilic progenitors in allergic airway disease.

Adult↗
PubMed1991

The effect of circulating antigen and radiolabel stability on the biodistribution of an indium labelled antibody.

This study has investigated two of the main problems with radiolabelled antibody imaging, the formation of circulating immune complexes (I.C.) and the non specific binding of radiolabel to the antibody molecule. Patients undergoing immunoscintigraphy with 111In labelled monoclonal antibody ICR2 were divided into three groups who received either the radiolabelled antibody alone (control, n = 12), the radiolabelled antibody which was incubated with the chelating agent diethylene triamine pentacetic acid (DTPA) prior to size exclusion chromatography (n = 6) or whose injectate was treated with DTPA and cold MAb administered intravenously prior to radiolabelled MAb administration (n = 6). Radiolabelled antibody uptake in abdominal organs was measured by region of interest analysis using a gamma camera with online computer and that in tumour and normal tissues by gamma well counting of biopsies. Circulating antigen and immune complex was measured by high pressure liquid chromatography (HPLC). The sensitivity of tumour imaging and the tumour uptake of radiolabelled antibody was not significantly different between the groups. Patients with high circulating antigen levels developed high levels of circulating immune complex but also had high tumour uptakes of radiolabelled antibody. Administration of cold MAb increased the splenic, but did not effect the tumour uptake of radiolabelled antibody and only minimally reduced levels of circulating immune complex. Chelate administration reduced the urinary excretion of radioactivity but increased the liver uptake of radioactivity. These results have shown that successful antibody imaging can be carried out despite high levels of circulating antigen, that large doses of unlabelled antibody are required to prevent immune complex formation and that removal of non specifically bound 111In does not reduce the liver uptake of radioactivity.

Aged↗
PubMed2003

Southern Ocean origin for the resumption of Atlantic thermohaline circulation during deglaciation.

During the two most recent deglaciations, the Southern Hemisphere warmed before Greenland. At the same time, the northern Atlantic Ocean was exposed to meltwater discharge, which is generally assumed to reduce the formation of North Atlantic Deep Water. Yet during deglaciation, the Atlantic thermohaline circulation became more vigorous, in the transition from a weak glacial to a strong interglacial mode. Here we use a three-dimensional ocean circulation model to investigate the impact of Southern Ocean warming and the associated sea-ice retreat on the Atlantic thermohaline circulation. We find that a gradual warming in the Southern Ocean during deglaciation induces an abrupt resumption of the interglacial mode of the thermohaline circulation, triggered by increased mass transport into the Atlantic Ocean via the warm (Indian Ocean) and cold (Pacific Ocean) water route. This effect prevails over the influence of meltwater discharge, which would oppose a strengthening of the thermohaline circulation. A Southern Ocean trigger for the transition into an interglacial mode of circulation provides a consistent picture of Southern and Northern hemispheric climate change at times of deglaciation, in agreement with the available proxy records.

Journal Article↗
PubMed1997

Insulin resistance in obese subjects and newly diagnosed NIDDM patients and derangements of pyruvate dehydrogenase in their circulating lymphocytes.

BACKGROUND: In circulating lymphocytes of individuals with insulin resistance and overt hyperglycaemia (NIDDM patients), alterations, affecting pyruvate dehydrogenase (PDH), the key enzyme in glucose oxidative breakdown, have been observed. They include below normal enzyme activity and, in vitro, no enzyme response to insulin at low physiological levels (5 microU/ml) as well as activation up to the basal values of controls with insulin at high physiological levels (50 microU/ml), instead of activation and inhibition respectively, as in controls. OBJECTIVE: To investigate whether these alterations characterize circulating lymphocytes of individuals with insulin resistance in whom derangements of glucose homeostasis are absent (obese subjects with normal glucose tolerance), or present but still controllable (nonobese and obese newly diagnosed NIDDM patients on an appropriate diet). SUBJECTS: Thirty obese subjects (BMI 36 +/- 3) responding normally to an oral glucose tolerance (OGT) test; 60 newly diagnosed NIDDM patients (30 nonobese, BMI 22 +/- 4 and 30 obese, BMI 38 +/- 2); 30 nonobese (BMI 21 +/- 5) and nondiabetic subjects, with no family history for NIDDM, served as controls. METHODS: Evaluation of PDH activity in circulating lymphocytes before and after exposure to insulin at 5 and 50 microU/ml, and of clinical parameters before and during an OGT test. RESULTS: 1) in circulating lymphocytes of obese nondiabetic subjects as well as obese and nonobese newly diagnosed NIDDM patients, PDH activity was significantly below normal. In vitro, enzyme response to insulin at 5 microU/ml was reduced in nonobese NIDDM patients with respect to controls, and absent in obese nondiabetic subjects and obese NIDDM patients. Enzyme response to insulin at 50 microU/ml was reversed in all individuals, which allowed enzyme activity to recover up to the basal level of controls. 2) In NIDDM patients and obese nondiabetic subjects, undergoing an OGT test, the area under the glycaemic curve (g-AUC) was as expected; the area under the insulinaemic curve (i-AUC) was increased in both groups with respect to controls, but significantly only in the latter. CONCLUSION: In individuals with insulin resistance PDH activity in their circulating lymphocytes rises up to basal levels of controls, only if these cells are exposed to insulin at high physiological concentrations, and g-AUC is normal only in those subjects who have significantly increased i-AUC. This suggests that with insulin at sufficiently high concentrations both parameters can be corrected. We conclude that the derangements responsible for the alterations of the two parameters share common features and thus the described PDH alterations in circulating lymphocytes reflect systemic insulin resistance whether accompanied by hyperglycaemia or not.

Adult↗
PubMed1998

An increase of circulating leptin in patients with liver cirrhosis.

OBJECTIVE: Leptin, the ob gene product, is an anorexigenic peptide secreted from adipose tissue. However, the mechanism of leptin clearance/degradation has not been well determined in humans. The present study was undertaken to examine a possible involvement of liver in determining circulating leptin concentrations in humans. SUBJECTS: In the present study 58 healthy control subjects and 68 patients with liver cirrhosis (LC) without any renal dysfunction were randomly included. METHOD: The serum immunoreactive leptin (IRL) concentrations relative to the body mass index (BMI) were determined. Serum IRL and estradiol (E2) concentrations were assayed by radioimmunoassay (RIA). RESULTS: The correlations between the BMI and circulating IRL concentrations were all significant in male healthy controls (M-C), male patients with LC (M-LC), female healthy controls (F-C) and female patients with LC (F-LC). Circulating IRL concentrations were significantly higher than control in F-LC but not M-LC groups. The ratio of circulating IRL concentrations to the BMI was significantly higher in the M-LC group than in the M-C group and also significantly higher in the F-LC group than in the F-C group. The correlation between the IRL/BMI ratio and serum total bilirubin concentrations was significant (r = 0.417, P < 0.05) in the M-LC group, but not in the F-LC group. There was no significant correlation of the IRL/BMI ratio to serum E2 or albumin concentrations in either M-LC or F-LC groups. CONCLUSION: The present data demonstrated that the rate of increase in circulating IRL concentrations with the BMI was higher in LC patients of both genders. Liver may play a role in determining circulating leptin levels.

Aged↗
PubMed2001

Sexual dimorphism in circulating leptin concentrations is not accounted for by differences in adipose tissue distribution.

BACKGROUND: Circulating concentrations of leptin normalized to total adipose tissue mass are significantly greater in females than in males. Rates of leptin expression (per gram of adipose tissue) are significantly greater in subcutaneous (SAT) than visceral (VAT) adipose tissue and the relative amount of fat stored as SAT vs VAT is significantly greater in pre-menopausal females than in males. Gender-related differences in the relative amounts of SAT and VAT may account for the greater circulating leptin concentration relative to fat-mass in females than males. METHODS: We examined body composition and anatomic fat distribution by dual energy X-ray-absorptiometry (DEXA) and magnetic resonance imaging (MRI), and post-absorptive circulating concentrations of leptin and insulin in 58 subjects (26 females, 32 males). Stepwise multiple linear regression analyses, treating gender as a dichotomous variable, were performed to determine inter-relationships among leptin concentrations and insulin concentrations, VAT and SAT. RESULTS: Body composition by DEXA and MRI were highly correlated (r(2)=0.97, P<0.0001). There were significant gender effects on leptin/total fat mass (males, 0.17+/-0.01 ng/ml/kg; females, 0.49+/-0.05 ng/ml/kg; P<0.0001) and relative amounts of fat in SAT and VAT depots (ratio of SAT/VAT; males, 12.3+/-1.5; females, 32.9+/-3.2; P<0.0001). Circulating leptin concentration was significantly correlated with insulin concentration (P=0.001), SAT (P<0.0001) and gender (P=0.033). Circulating concentrations of insulin were significantly correlated with VAT, but not SAT, in males and with SAT, but not VAT, in females. CONCLUSIONS: The sexual dimorphism in the relationship between leptin and adipose tissue mass cannot be explained by differences in the relative amounts of VAT and SAT. Thus, the sexual dimorphism in plasma leptin concentration appears to reflect, at least in part, effects of circulating concentrations of gonadal steroids (especially androgens) and/or primary genetic differences that are independent of amounts of VAT or SAT.

Absorptiometry, Photon↗
PubMed2006

Circulating endothelial progenitor cell deficiency contributes to impaired arterial elasticity in persons of advancing age.

Reduced arterial elasticity is a hallmark of ageing in healthy humans and appears to occur independently of coexisting disease processes. Endothelial-cell injury and dysfunction may be responsible for this fall in arterial elasticity. We hypothesized that circulating endothelial progenitor cells (EPCs) are involved in endothelial repair and that lack of EPCs contributes to impaired arterial elasticity. A total of 56 healthy male volunteers were divided into young (n=26) and elderly (n=30) groups. Large and small artery elasticity indices were noninvasively assessed using pulse wave analysis. The number of circulating EPCs was measured by using flow cytometry. Cells demonstrating DiI-acLDL and FITC-ulex lectin double-positive fluorescence were identified as EPCs. C1 large artery elasticity and C2 small artery elasticity indices were significantly reduced in the elderly group compared with the young group (11.73+/-1.45 vs 16.88+/-1.69 ml/mm Hg x 10, P<0.001; 8.40+/-1.45 vs 10.58+/-1.18 ml/mm Hg x 100, P<0.001, respectively). In parallel, the number of circulating EPCs was significantly reduced in the elderly group compared with the young group (0.13+/-0.02 vs 0.17+/-0.04%, P<0.05). The number of circulating EPCs correlated with C1 large and C2 small artery elasticity indices (r=0.47, P<0.01; r=0.4, P<0.01). The present findings suggest that the fall in circulating EPCs with subsequently impaired endothelial-cell repair and function contributes to reduced arterial elasticity in humans with ageing. The decrease in circulating EPCs may serve as a surrogate biologic measure of vascular function and human age.

Adult↗
PubMed2002

Responses of the bronchial and pulmonary circulations to short-term nitric oxide inhalation before and after endotoxaemia in the pig.

The physiological responses of the bronchial circulation to acute lung injury and endotoxin shock are largely unexplored territory. This study was carried out to study the responsiveness of the bronchial circulation to nitric oxide (NO) inhalation before and after endotoxaemia, in comparison with the pulmonary circulation, as well as to study changes in bronchial blood flow during endotoxaemia. Six anaesthetized pigs (pre-treated with the cortisol-synthesis inhibitor metyrapone) received an infusion of 10 microg/kg endotoxin during 2 h. Absolute bronchial blood flow was measured via an ultrasonic flow probe around the bronchial artery. The pigs received increasing doses of inhaled NO over 5 min each (0, 0.2, 2 and 20 ppm) before and after 4 h of endotoxaemia. The increase in bronchial vascular conductance during 5 min of inhalation of 20 ppm NO before endotoxin shock was significantly higher (area under curve (AUC) 474.2 +/- 84.5% change) than after endotoxin shock (AUC 118.2 +/- 40.4%, P < 0.05 Mann-Whitney U-test). The reduction of the pulmonary arterial pressure by 20 ppm NO was not different. A short rebound effect of the pulmonary arterial pressure occurred after discontinuation of inhaled NO before endotoxaemia (AUC values above baseline 54.4 +/- 19.7% change), and was virtually abolished after endotoxaemia (AUC 6.1 +/- 4.0%, P = 0.052, Mann-Whitney U-test). Our results indicate that the responsiveness of the bronchial circulation to inhalation of increasing doses of inhaled NO during endotoxin shock clearly differ from the responsiveness of the pulmonary circulation. The reduced responsiveness of the bronchial circulation is probably related to decreased driving pressure for the bronchial blood flow. The absence of the short rebound effect on pulmonary arterial pressure (PAP) after induction of shock could be related to maximum constriction of the pulmonary vessels at 4 h.

Administration, Inhalation↗
PubMed1998

Circulating T lymphocyte subsets in coeliac disease (CoD) patients and healthy family members.

Increased proportions of circulating antigen-primed CD45RO+ TCR gammadelta cells have been found in untreated CoD patients. As certain immunological features are now found in both CoD and healthy persons carrying the HLA DQ2 heterodimer, we sought to establish whether healthy members of the families of CoD patients who are positive for HLA DQ2 and also have increased densities of TCR gammadelta intraepithelial lymphocytes (IEL) in their small bowel mucosa have elevated levels of circulating TCR gammadelta memory cells. Peripheral blood T cells were analysed by flow cytometry in 22 patients with CoD and 16 healthy family members. Untreated CoD patients had higher percentages of circulating CD45RO+ TCR gammadelta cells and CD45RO+ Vdelta1+ cells than healthy family members. On the other hand, the amount of circulating Vdelta1+ lymphocytes was lower in patients with CoD compared with healthy family members. In contrast, no differences were found between HLA DQ2+ and HLA DQ2- healthy family members in respect of circulating TCR gammadelta cell subsets. The change in circulating TCR gammadelta cell subsets found in patients with CoD is thus a consequence of an ongoing immunological process which diminishes on a gluten-free diet rather than a phenomenon directly caused by DQ2. These changes in peripheral blood are not found in healthy individuals who have the same HLA alleles DQA1*0501 and DQB1*0201 encoding the HLA DQ2 and who also have increased densities of TCR gammadelta IEL in their otherwise normal jejunal mucosa.

Adolescent↗
PubMed1999

The relationship among circulating insulin-like growth factor components, biochemical markers of bone turnover and bone mineral density in postmenopausal women under the age of 60.

OBJECTIVES: The changes in circulating IGF components after the menopause and the potential role of new markers of bone turnover and circulating IGF components in predicting bone mass in postmenopausal women are still controversial and the relationship between these two systems has not been investigated. The aims of this study were to investigate the changes in circulating IGF components after the menopause, to evaluate whether new markers of bone turnover and circulating IGF components reflect bone mass in postmenopausal women under the age of 60 and to study the relationship between these two systems. DESIGN, PATIENTS AND MEASUREMENTS: Serum IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3, osteocalcin (OST), bone specific alkaline phosphatase (BAP), urinary deoxypyridinoline (DPYD) and N-telopeptide of type I collagen (NTX) were measured in 31 premenopausal women aged 31-43 and 65 postmenopausal women aged 47-60: this latter group comprised 30 normal healthy women and 35 osteoporotic women. RESULTS: Compared with premenopausal women or normal postmenopausal women, serum IGF-1 and IGFBP-3 levels were significantly lower in osteoporotic postmenopausal women while no significant differences in serum levels of IGF-II, IGFBP-1 and IGFBP-2 were observed. The correlations between bone turnover markers and circulating IGF components (except between serum BAP and IGF-II), and between bone turnover markers and bone mineral density (BMD) in postmenopausal women were not significant. However, serum IGF-I and IGFBP-3 correlated positively with BMD of the lumbar spine and/or Ward's triangle even if age, BMI and menopause duration were taken into account in a multiple regression analysis model. CONCLUSIONS: Circulating IGF-I and IGFBP-3 may be involved in the mechanism of bone loss in postmenopausal women under the age of 60. They may also provide indirect information on the current bone microenvironment different from that provided by new markers of bone turnover.

Adult↗
PubMed1999

Measurement of circulating red cell volume using biotin-labeled red cells: validation against 51Cr-labeled red cells.

BACKGROUND: Anemia is a serious problem in the fetus and preterm infant. To investigate the physiology and pathophysiology of anemia and to assess responses to blood transfusions or erythropoietin therapy, measurement of circulating red cell volume would be useful. Because the standard 51Cr method exposes the subject to radiation, a method of measuring circulating red cell volume without radiation exposure, sufficiently sensitive for use in fetuses and infants, was developed. STUDY DESIGN AND METHODS: In 10 healthy adults whose body mass ranged from 56.8 to 115.9 kg, aliquots of autologous red cells were labeled with biotin or with 51Cr, mixed, and transfused intravenously. Circulating red cell volume was measured in posttransfusion blood by quantitating the in vivo dilution of biotinylated red cells. Biotinylated red cells were detected by two methods: 1) 125I-streptavidin and 2) fluorescein-labeled avidin with flow cytometry. RESULTS: Circulating red cell volume measured by 125I-streptavidin detection agreed well with that measured by 51Cr (slope = 1.07, y-intercept = -97, correlation = 0.987). Similarly, circulating red cell volume measured by flow cytometry agreed well with that measured by 51Cr (slope = 1.05, y-intercept = -20, correlation = 0.987). CONCLUSIONS: Circulating red cell volume measured by the use of biotin with either 125I-streptavidin or flow cytometry agrees with that measured by 51Cr. Each system provides a method of performing these studies without exposing the subject to radiation.

Adult↗
PubMed1998

Membranoproliferative glomerulonephritis type III: association of glomerular deposits with circulating nephritic factor-stabilized convertase.

Deposits in the glomerular ultrastructure of 44 renal biopsy specimens from 21 patients with membranoproliferative glomerulonephritis (MPGN) type III have been compared with those in the ultrastructure of 34 biopsy specimens from 19 patients with MPGN type I. Previous studies have concluded that subepithelial deposits on the paramesangial portion of the glomerular basement membrane in MPGN types II and III are closely associated with circulating nephritic factor-stabilized convertase. In the present study, subendothelial deposits in MPGN type III were also found to be closely associated with nephritic factor; they were present in 14 of 26 (54%) biopsy specimens obtained during hypocomplementemia but in none of the 18 biopsy specimens obtained during normocomplementemia (P < 0.001). Subepithelial loop deposits in type III were also more frequent in biopsy specimens obtained during hypocomplementemia and are probably in some way also associated with circulating stabilized convertase. Taken together, the results of this and previous studies are compatible with the hypothesis that an excess of the C3b-dependent convertase in the circulation is basic to the pathogenesis of MPGN types II and III as well as of several other nephritides associated with factor H dysfunction. The half-life, structural complexity, and size of the convertases circulating in these nephritides increase in the following order: native convertase, convertase stabilized by the nephritic factor of the amplification loop (NFa), and convertase stabilized by nephritic factor of the terminal pathway (NFt). In the same order, the nephritides associated with these convertases more frequently manifest and have increasing amounts of glomerular deposit. This relationship of glomerular deposits with circulating convertase, however, is only circumstantial. There is no evidence that the convertase or a part thereof is a constituent of the deposits. The lesion that is the hallmark of MPGN type III is one in which interruptions of lamina densa are associated with subendothelial and subepithelial deposits, often confluent, and interspersed with multiple layers of new lamina densa-like material. This "type III lesion," which by implication is also associated with circulating nephritic factor, is the most persistent of the glomerular deposits. For reasons that are not yet clear, the type III lesion was absent in three patients who were severely hypocomplementemic, and the diagnosis of type III was made only after this lesion appeared in biopsy specimens obtained later. In MPGN type I, differing from type III, subendothelial deposits were present in 100% of biopsy specimens obtained during hypocomplementemia and in 47% of those obtained during normocomplementemia. Their persistence in type I may reflect rearrangement and condensation of the deposited material, shown by other investigators to be dependent on the presence of immunoglobulin G, which is largely absent from the deposits in type III. The comparison of deposits in types I and III indicates that relating the presence of subendothelial and paramesangial deposits to the C3 level at the time of biopsy can be helpful in distinguishing types I and III when the type III lesion is not present.

Biopsy, Needle↗
PubMed1988

Detection of circulating tumor necrosis factor after endotoxin administration.

Cytokines, products of stimulated macrophages, are thought to mediate many host responses to bacterial infection, but increased circulating cytokine concentrations have not been detected consistently in infected patients. We measured plasma concentrations of circulating tumor necrosis factor alpha (cachectin), interleukin-1 beta, and gamma interferon, together with physiologic and hormonal responses, in 13 healthy men after intravenous administration of Escherichia coli endotoxin (4 ng per kilogram of body weight) and during a control period of saline administration. Eight additional subjects received ibuprofen before receiving endotoxin or saline. Plasma levels of tumor necrosis factor were generally less than 35 pg per milliliter throughout the control period, but increased 90 to 180 minutes after endotoxin administration to mean peak concentrations of 240 +/- 70 pg per milliliter, as compared with 35 +/- 5 pg per milliliter after saline administration. Host responses were temporally associated with the increase in circulating tumor necrosis factor at 90 minutes, and the extent of symptoms, changes in white-cell count, and production of ACTH were temporally related to the peak concentration of tumor necrosis factor. Ibuprofen pretreatment did not prevent the rise in circulating tumor necrosis factor (mean peak plasma level, 170 +/- 70 pg per milliliter) but greatly attenuated the symptoms and other responses after endotoxin administration. Concentrations of circulating interleukin-1 beta and gamma interferon did not change after endotoxin administration. We conclude that the response to endotoxin is associated with a brief pulse of circulating tumor necrosis factor and that the resultant responses are effected through the cyclooxygenase pathway.

Adrenocorticotropic Hormone↗
PubMed2000

Chlamydia pneumoniae DNA in non-coronary atherosclerotic plaques and circulating leukocytes.

Earlier studies have associated atherosclerosis with Chlamydia pneumoniae infection. C. pneumoniae may circulate via monocytes and migrate into plaques by leukocyte infiltration; however, detection is difficult. We developed a novel polymerase chain reaction (PCR) method to test the hypothesis that C. pneumoniae DNA in circulating leukocytes is correlated with C. pneumoniae DNA in plaque material and that C. pneumoniae copy number is associated with disease severity. We obtained plaques from 130 patients who underwent surgery for carotid stenosis, aneurysm, or peripheral vascular disease. From 60 patients and 51 normal control subjects we also obtained circulating leukocytes. The C. pneumoniae 16 S rRNA gene was amplified with a highly specific quantitative PCR protocol relying on the TaqMan technology. Immunohistochemistry was performed with antibody against the C. pneumoniae outer membrane protein. C. pneumoniae DNA was present in 25% of atherosclerotic plaques and 20% of circulating leukocytes from patients. The copy number was not correlated with disease severity. C. pneumoniae DNA was more common in younger patients and smokers. C. pneumoniae antibody titers, C-reactive protein, fibrinogen, leukocyte count, cholesterol, and diabetes were not associated with C. pneumoniae DNA. Although immunostaining of plaque and PCR results were highly correlated, we found no relationship between C. pneumoniae DNA in plaques and that in circulating leukocytes. Finally, 13% of normal control subjects had positive leukocytes; however, their copy number was significantly lower than that of the patients. C. pneumoniae DNA is frequent in atherosclerotic plaques and is correlated with positive immunohistochemistry. C. pneumoniae DNA may also be found in circulating leukocytes; however, infected leukocytes and plaques do not coincide. Serology is unreliable in predicting C. pneumoniae DNA. Smoking increases the risk of harboring C. pneumoniae DNA. Our results do not suggest that either test for antibodies or C. pneumoniae DNA from leukocytes in blood is of value in predicting infected plaques.

Aged↗