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Deep water circulation, residence time, and chemistry in a karst complex.

We investigated the hydrochemistry of a complex karst hydrosystem made of two carbonate units along a coastal lagoon. Ground water emerges on the lagoon floor from a submarine spring. In addition, thermal waters circulate through the limestone and mix with karst water near the lagoon shore. A distinction between the water from the two carbonate units is related to marine influences and human activities. In one of the massifs, the data show an incongruent dissolution of dolomite with time. In the other system, a slight contamination by saline fluids from the thermal reservoir has led to high calcium and magnesium concentrations. 36Cl, 14C, and 3H data constrain the residence time of the water, and allow for the distinguishing of four circulation types: (1) shallow surface circulation (primarily above sea level) in the karstic units with short residence times (<20 years); (2) shallow subsurface circulation (approximately 0 to -50 m) below the karstic units with residence time in the order of 50 years; (3) deep circulation at depth of 700 to 1500 m in the Jurassic limestones below thick sedimentary cover, with residence time of several thousand years for a part of the water; and (4) deep circulation at a depth of approximately 2500 m, which represents the thermal reservoir in the Jurassic units with residence time of approximately 100,000 years. An interpretative hydrogeological framework is based on the constraints of the geochemical analyses of the deep thermal system, and by water flow from the surface to the deep parts of the carbonate formations.

Calcium↗

Staphylococcal enterotoxin A-induced fever is associated with increased circulating levels of cytokines in rabbits.

Rabbits were injected intravenously with 10 to 100 ng of staphylococcal enterotoxin A (SEA) per kg, and colonic temperatures were monitored. The febrile responses were compared with circulating levels of interferon (IFN), tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-2, and IL-6 just before the injection of SEA. Both colonic temperatures and circulating levels of IFN, TNF, and IL-2 started to rise at 1 to 2 h and reached their peak levels at 3 to 5 h after SEA injection. Both the fever and the increased circulating levels of IFN, TNF, and IL-2 produced by SEA were decreased by pretreatment with indomethacin (a cyclo-oxygenase inhibitor) (15 mg/kg, intraperitoneally), anisomycin (a protein synthesis inhibitor) (15 mg/kg, subcutaneously), or dexamethasone (an effective anti-inflammatory and immunosuppressive agent) (4 mg/kg, intravenously) in rabbits. Rabbits were injected intravenously with 30 ng of SEA per kg on four consecutive days, and colonic temperatures were monitored. Compared to rabbits that received the single injection of SEA, rabbits that received four consecutive injections of SEA showed a lesser increase in circulating levels of IFN, TNF, and IL-2 as well as colonic temperatures in response to an intravenous dose of SEA (30 ng/kg). The data suggest that the prevention of the febrile response elicited by SEA by indomethacin, anisomycin, or dexamethasone is due to prevention by these compounds of the increase in the circulating levels of IFN, TNF, and IL-2. The pyrogenic hyporesponsiveness to repeated injection of SEA is associated with decreased production of these circulating cytokines.

Animals↗

Increased circulating pro-brain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP) in patients with cirrhosis: relation to cardiovascular dysfunction and severity of disease.

BACKGROUND AND AIMS: Cardiac dysfunction may be present in patients with cirrhosis. This study was undertaken to relate plasma concentrations of cardiac peptides reflecting early ventricular dysfunction (pro-brain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP)) to markers of severity of liver disease, cardiac dysfunction, and hyperdynamic circulation in patients with cirrhosis. PATIENTS AND METHODS: Circulating levels of proBNP and BNP were determined in 51 cirrhotic patients during a haemodynamic investigation. RESULTS: Plasma proBNP and BNP were significantly increased in cirrhotic patients (19 and 12 pmol/l, respectively) compared with age matched controls (14 and 6 pmol/l; p<0.02) and healthy subjects (<15 and <5.3 pmol/l; p<0.002). Circulating proBNP and BNP were closely correlated (r = 0.89, p<0.001), and the concentration ratio proBNP/BNP was similar to that of control subjects (1.8 v 2.3; NS). Circulating proBNP and BNP were related to severity of liver disease (Child score, serum albumin, coagulation factors 2, 7, and 10, and hepatic venous pressure gradient) and to markers of cardiac dysfunction (QT interval, heart rate, plasma volume) but not to indicators of the hyperdynamic circulation. Moreover, in multiple regression analysis, proBNP and BNP were also related to arterial carbon dioxide and oxygen tensions. The rate of hepatic disposal of proBNP and BNP was not significantly different in cirrhotic patients and controls. CONCLUSION: Elevated circulating levels of proBNP and BNP in patients with cirrhosis most likely reflects increased cardiac ventricular generation of these peptides and thus indicates the presence of cardiac dysfunction, rather than being caused by the hyperdynamic circulatory changes found in these patients.

Adult↗

Multiple acute infarcts in the posterior circulation.

OBJECTIVE: to evaluate clinical, radiological, and prognostic features of patients with multiple acute infarcts in remote arterial territories of the posterior circulation. DESIGN: Data analysis from a prospective acute stroke registry in a community based primary care centre using a standard protocol including MRI and MRA. RESULTS: In three and a half years, 27 of the 236 patients (11%) with posterior circulation stroke had multiple acute infarcts in the posterior circulation as shown by gadolinium enhancement on MRI. Eighteen patients had multiple infratentorial and supratentorial infarcts including the cerebellum and posterior cerebral artery territory, with coexisting brainstem involvement in seven patients. Fourteen patients had a rostral basilar artery syndrome and cerebellar signs; four patients had a visual field defect with cerebellar signs. Causes were vertebral (six) or basilar (four) artery atheromatosis, and cardioembolism (four). Seven patients had multiple acute infarcts in the posterior circulation of the cerebellum and lower brainstem. Brainstem and cerebellar signs were found in most patients (five); aetiologies were small vessel disease (four), cardioembolism (one), and vertebral artery dissection (one). Two patients with large artery atheromatosis had multiple acute infarcts in the posterior circulation in the brainstem and posterior cerebral artery territory. One month after stroke more than 25% of the patients were dependent or had died. There was no difference in the outcome between the three groups, and recovery was linked to the size of infarcts rather than to a high number of infarcts. CONCLUSIONS: multiple acute infarcts in the posterior circulation usually involve the cerebellum. Simultaneous brainstem and posterior cerebral artery territory infarcts sparing the cerebellum are uncommon. They can be suspected clinically before neuroimaging, mainly when supratentorial and infratentorial infarcts coexist. This may be important, because different patterns of infarction are associated with different causes of stroke.

Activities of Daily Living↗

Increased circulating 92 kDa matrix metalloproteinase (MMP-9) activity in exacerbations of asthma.

BACKGROUND: The 72 kDa matrix metalloproteinase 2 (MMP-2) and the 92 kDa matrix metalloproteinase 9 (MMP-9) are type IV collagenases implicated in various aspects of inflammation including accumulation of inflammatory cells, tissue injury, and development of remodelling. The role of these enzymes in the pathogenesis of asthma exacerbations is unknown. METHODS: Circulating levels of MMP-2 and MMP-9 proteins and the expression of their inhibitor, tissue inhibitor of metalloproteinase 1 (TIMP-1), were measured in 21 patients experiencing an asthma exacerbation and 21 age matched patients with stable asthma. Circulating gelatinolytic activity was compared during the asthma exacerbation and during subsequent convalescence by gelatin zymography in the same individuals. In addition, MMP-9 specific activity was quantified with a colorimetric assay which uses an artificial proenzyme containing a specific domain recognised by MMP-9 in the same paired samples. RESULTS: A significant increase in the circulating level of MMP-9 was seen in patients with an asthma exacerbation compared with patients with stable asthma (202.9 (22.0) v 107.7 (9.9) ng/ml, p=0.0003). There were no significant differences in the circulating levels of MMP-2 or TIMP-1. Gelatin zymography identified two major circulating gelatinolytic activities corresponding to MMP-2 and MMP-9, and showed that asthma exacerbations are characterised by markedly increased MMP-9 activity with no significant change in MMP-2 activity compared with the activities during convalescence in the same individuals. Direct measurement showed that MMP-9 specific activity is significantly increased during asthma exacerbations compared with subsequent convalescence (269.6 (31.7) v 170.4 (12.6) ng/ml, p=0.0099). CONCLUSIONS: Asthma exacerbations are characterised by increased circulating MMP-9 activity. This increased activity may be related to exaggerated airway inflammation and airway remodelling.

Adult↗

Roles of uptake1 and catechol-O-methyltransferase in removal of circulating catecholamines in the rabbit.

Anesthetized rabbits were simultaneously infused with [3H]norepinephrine (NE), [3H]epinephrine (Epi), [3H]dopamine (DA), and [3H]isoproterenol (Iso), and their plasma clearances and fractional extractions across the systemic (ERS), as well as pulmonary (ERP), circulation were determined before and after blockade of uptake1 by desipramine (2 mg/kg). Desipramine reduced the clearance of NE, Epi, and DA by 39, 13, and 14%, respectively, but did not affect Iso clearance. Similar results were obtained with respect to the effects of desipramine on ERS. By contrast, desipramine reduced ERP of NE and DA (which for both amines was markedly lower than ERS) by > 70%; its effect on the very low ERP of Epi was not determinable. Comparison of the desipramine-sensitive components of ERS and ERP indicated that for uptake1 NE was the preferred substrate in the systemic circulation and DA was preferred in the pulmonary circulation. In the absence and presence of desipramine, catechol-O-methyltransferase inhibition had no effect on the clearance of NE, Epi, and DA and decreased Iso clearance by 25%. Hence the contribution by uptake1 to the removal of circulating catecholamines depends on the type of amine and on whether the systemic or pulmonary circulation is considered. Moreover catechol-O-methyltransferase does not appear to contribute to the clearance of NE, Epi, and DA but plays a definite role in the removal of circulating Iso.

Animals↗

Circulating neutrophil kinetics during tolerance in hemorrhagic shock using bacterial lipopolysaccharide.

The objective of this study was to investigate mechanisms by which circulating polymorphonuclear neutrophils (PMNs) may contribute to the tolerance to hemorrhagic shock induced by pretreatment with lipopolysaccharides (LPS). Tolerance was developed by daily injections of sublethal doses of LPS for four subsequent days while controls received saline injections. During shock, both groups of rats were maintained for 3 h at 40 mmHg mean arterial pressure and were then observed for survival during a 24-h period. This protocol resulted in 40% survival in the untreated controls and 89% survival in the tolerant group (P < 0.0068). Hypotension caused an initial neutropenia in both groups. The circulating PMN counts remained lower in the tolerant than in the controls rats for most of the low flow period. The number of circulating activated PMNs in whole blood, as assessed by spontaneous nitroblue tetrazolium reduction, was lower in tolerant animals before and during most of the hypotensive period, except immediately after bleeding when both groups have low circulating leukocyte counts. No detectable tumor necrosis factor activity was observed in the plasma of either group. Adhesion of circulating PMNs to nylon fibers in vitro and the number of PMNs adhering to the endothelium in the mesentery in vivo was significantly lower in the tolerant rats. We conclude that LPS pretreatment produces a reduction in the activated circulating PMNs and in the degree of PMN adhesion to endothelium with subsequent improvement of survival after hemorrhagic shock.

Analysis of Variance↗

Circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response produced by peripheral E. coli challenge.

Peripheral administration of a variety of inflammatory stimuli, such as endotoxin or cytokines, induces an orchestrated set of brain-mediated events referred to as the sickness response. The mechanism for how immune products signal the brain is not clear, but accumulating evidence supports the existence of neural as well as blood-borne pathways. Although endotoxin or cytokine administration results in sickness responses, few data exist regarding the role of circulating endotoxin or cytokines in the induction of sickness during a real bacterial infection. Thus the present studies examined whether subcutaneously administered Escherichia coli can activate sickness responses and whether circulating endotoxin and/or proinflammatory cytokines are a prerequisite for these responses. Male Sprague-Dawley rats were injected subcutaneously with one of three doses (2.5 x 10(7), 2.5 x 10(8), 2.5 x 10(9) colony-forming units) of replicating E. coli, a ubiquitous bacterial strain, or vehicle. Core body temperature (Tc) and activity were measured for 3 days after the injection. A second set of groups of animals were killed 3, 6, 12, 18, 24, and 48 h after the injection, and blood samples and brains were collected. Injections dose dependently and consistently increased Tc and decreased activity, with increases in Tc beginning 4 h after the injection. In addition, E. coli significantly increased serum interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha and brain IL-1beta levels beginning at the 6-h time point. Corticosterone and endotoxin were first elevated in the circulation at 3 and 18 h after the injection, respectively. Because fever onset preceded brain cytokine induction, we also examined cytokine levels in the serum, brain, and inflammation site 2 and 4 h after injection. Cytokines were elevated at the inflammation site but were not detectable in the serum or brain at 2 and 4 h. We conclude that subcutaneous injection of replicating E. coli induces a consistent and naturalistic infection that includes features of the sickness response as well as increases in circulating, brain, and inflammation site tissue cytokines. In addition, injection of replicating E. coli produces a robust fever and corticosterone response at a time when there are no detectable increases in circulating cytokines or endotoxin. These results suggest that elevated levels of circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response. Therefore, fever, activity reduction, and corticosterone elevation induced by E. coli infection may have been evoked by a neural, rather than a humoral, pathway from the periphery to the brain.

Animals↗

Alzheimer's disease patients display gender dimorphism in circulating anorectic adipokines.

Among neurodegenerative diseases, Alzheimer's disease (AD) is a leading cause of death in elderly individuals. AD is characterized, among other clinical findings, by unexplained weight loss, cachexia and altered immune function. To explore whether any relationship between gender and circulating levels of several eating-controlling metabolites exist, we evaluated leptin, tumor necrosis factor (TNF)-alpha, triiodothyronine (T(3)), free (F) thyroxine (T(4)), TSH, PRL, insulin (INS), and cortisol in 15 AD-treated patients (age range 55-82 years): 9 postmenopausal females (without hormone replacement therapy) and 6 males. The results (mean +/- SEM) indicated that circulating leptin levels were significantly (p < 0.05) higher in female AD (40.34 +/- 11.1 ng/ml) than in male AD (6.07 +/- 1.39 ng/ml) patients. The difference found in circulating leptin levels was noticed regardless of BMI (26.75 +/- 1.77 and 24.55 +/- 1.93 kg/m(2), in females and males, respectively) and waist:hip ratios (0.91 +/- 0.03 and 0.94 +/- 0.02, in females and males, respectively). Moreover, serum TNF-alpha concentrations were also significantly (p < 0.02) higher in AD females (12.24 +/- 1.47 pg/ml) than in AD males (6.62 +/- 1.44 pg/ml), regardless of TNF-alpha:BMI ratios (0.50 +/- 0.09 and 0.28 +/- 0.08, in females and males, respectively; p > 0.05). Finally, no differences were observed between gender (in female and male AD patients, respectively) in circulating levels of T(3) (151.33 +/- 9.91 vs. 116 +/- 17.04 ng/dl), FT(4) (1.26 +/- 0.08 vs. 1.24 +/- 0.06 ng/dl), TSH (1.28 +/- 0.16 vs. 2.46 +/- 0.67 microIU/ml), PRL (10.53 +/- 2.47 vs. 12.61 +/- 2.37 ng/ml), INS (11.76 +/- 1.95 vs. 8.59 +/- 1.34 microIU/ml) and cortisol (15.71 +/- 1.23 vs. 12.63 +/- 1.47 microg/dl). These results indicate that our AD group of patients, with normal corticoadrenal and thyroid functions and normoprolactinemia, displayed a gender-related characteristic in the circulating levels of two very important anorectic signals, leptin and TNF-alpha, being both higher in female than in male AD patients, regardless of BMI. Our study suggests that increased circulating levels of both anorexigenic adipokines may contribute to the metabolic changes observed in AD females.

Aged↗

Relation between theophylline and circulating vitamin levels in children with asthma.

We investigated the effect of theophylline administration on circulating vitamin levels in children with asthma. Twenty-three asthmatic children, ranging in age from 7 to 15 with a mean of 10.8 years and including 16 patients who were treated with slow-release theophylline and 7 patients not receiving any type of theophylline preparation, were enrolled in this study. They all were inpatients who had been hospitalized for the control of asthma. Steady-state serum theophylline and vitamin A, B1, B2, B6, B12 and C levels were evaluated in these patients. Circulating vitamin B1 and B6 levels were depressed in asthmatic children treated with theophylline compared to those not receiving the agent (38.4 +/- 1.6 (mean +/- SEM) vs. 46.4 +/- 3.5 ng/ml and 7.1 +/- 0.5 vs. 11.8 +/- 2.1 ng/ml, respectively, p < 0.05). A significant negative correlation between theophylline and circulating levels of vitamin B6 was demonstrated in the subjects of this study (rs = -0.657, p < 0.001). In contrast, no relationship was noted between theophylline and circulating vitamin B1 levels. Theophylline did not affect circulating vitamin A, B2, B12 or C levels. We conclude that theophylline induces depression of circulating vitamin B1 and B6 levels in asthmatic children, although a dose-dependent interaction between theophylline and vitamin B1 would be unlikely.

Adolescent↗

Circulating myeloid progenitor cell kinetics during hematologic recovery from chemotherapy and subsequent recombinant human granulocyte-macrophage colony-stimulating factor administration.

Hematopoietic recovery from chemotherapy may be associated with an increase in circulating myeloid progenitor cell concentration (CFU-GM); these cells may be harvested by apheresis and used for autologous transplantation after high-dose cytoreductive therapy. Not all patients will demonstrate this increase, possibly due to damage to the stem cell compartment from prior chemoradiotherapy. Elevated circulating CFU-GM has also been reported in patients after short-term administration of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF); whether elevation would persist during longer duration is unknown. We measured circulating CFU-GM (by both limiting dilution in liquid culture and colony formation in semisolid media) in patients with sarcoma who began infusion of rhGM-CSF during recovery from chemotherapy. Patients with elevated circulating CFU-GM did not sustain these levels during subsequent rhGM-CSF infusion. By contrast, patients without rebound elevation of circulating CFU-GM following chemotherapy recovery did increase CFU-GM levels with rhGM-CSF administration. The proportion of marrow CFU-GM in cell cycle during chemotherapy recovery was elevated in both patient groups and remained elevated with rhGM-CSF administration. Both marrow and peripheral blood limiting dilution assays demonstrated linear growth kinetics, indicating a direct effect of the in vitro growth factor (also rhGM-CSF) on progenitor cells without excessive influence or dependence on accessory cells in culture. The use of rhGM-CSF to restore circulating CFU-GM for apheresis during recovery in patients lacking such elevation merits further study.

Antineoplastic Agents↗

Studies on immune responses to parasite antigens in mice. II. Aspects of the T cell dependence of circulating reagin production to Ascaris suum antigens.

Heat-labile, rat skin-fixing antibodies were detected readily in the sera of young female mice dosed intranasally with the body fluid of Ascaris suum (ABF) and the adjuvant, Bordetella pertussis vaccine (BPV). In addition, washed cell suspensions prepared from spleen and the lymph nodes regional to the lungs were positive in an adoptive cutaneous anaphylaxis assay, an assay which may detect activities of reagins associated with mast cells rather than reaginic antibody-secreting cells. The intraperitoneal route was a poor means of inducing circulating anti-ABF reagins and an intraperitoneal injection of ABF + BPV delayed the appearance of circulating reagins in mice dosed at the same time with ABF + BPV intranasally. Hypothymic female BALB/c. nu/nu ('nude') mice failed to produce circulating reagins to ABF but an injection of normal thymocytes or cortisone-resistant thymocytes from syngeneic female mice led to higher titers of circulating reagins than found in normal female BALB/c. nu/+ littermates. Using cells from young male or female syngeneic donors and male and female BALB/c. nu/mu recpiients, evidence was obtained for a defect in the thymus of young male mice and conceivably this defect may extend to the peripheral T cell population in such mice. Cyclophosphamide pretreatment or adrenalectomy increased circulating reagin titers in normal mice dosed intranasally with ABF + BPV, and pretreatment with lipopolysaccharide intranasally markedly reduced titers of circulating anti-ABF reagins. In the discussion, emphasis is given to the hypothesis that potent allergens are T cell-stimulating, relatively persistent antigens which, when located in submucosal lymphoid sites and under conditions of limited antibody production as a result of limited recruitment of 'helper' T cells systemically, lead to the induction and sustained production of IgE by resident Bxi cells and their progeny.

Adrenalectomy↗

C5a-induced bronchoconstriction: absence of a role of circulating white blood cells and platelets.

C5a causes an intense bronchoconstriction when injected intravenously into the guinea pig. The present study was designed to determine if circulating white blood cells or platelets were important target cells for the induction of bronchoconstriction on intravenous injection of C5a. To accomplish this, we examined the effect of C5a on numbers of circulating cells as well as the effect of depletion of various circulating cell populations on C5a-induced bronchoconstriction. Intravenous injection of C5a caused a precipitous drop in circulating granulocytes which preceded the maximum bronchoconstrictor response. The levels of circulating platelets and mononuclear cells were unchanged by intravenous injection of C5a. Depletion of either white blood cells or platelets did not significantly alter either the maximum bronchoconstrictor response to C5a or the time course of the response. Thus, these studies suggest that C5a-induced bronchoconstriction in the guinea pig is not dependent on an interaction of C5a with circulating white blood cells or platelets.

Airway Resistance↗

Circulating oxidized LDL is a useful marker for identifying patients with coronary artery disease.

Our aim was to determine the usefulness of circulating oxidized low density lipoprotein (LDL) in the identification of patients with coronary artery disease (CAD). A total of 304 subjects were studied: 178 patients with angiographically proven CAD and 126 age-matched subjects without clinical evidence of cardiovascular disease. The Global Risk Assessment Score (GRAS) was calculated on the basis of age, total and high density lipoprotein cholesterol, blood pressure, diabetes mellitus, and smoking. Levels of circulating oxidized LDL were measured in a monoclonal antibody 4E6-based competition ELISA. Compared with control subjects, CAD patients had higher levels of circulating oxidized LDL (P<0.001) and a higher GRAS (P<0.001). The sensitivity for CAD was 76% for circulating oxidized LDL (55% for men and 81% for women) compared with 20% (24% for men and 12% for women) for GRAS, with a specificity of 90%. Logistic regression analysis revealed that the predictive value of oxidized LDL was additive to that of GRAS (P<0.001). Ninety-four percent of the subjects with high (exceeding the 90th percentile of distribution in control subjects) circulating oxidized LDL and high GRAS had CAD (94% of the men and 100% of the women). Thus, circulating oxidized LDL is a sensitive marker of CAD. Addition of oxidized LDL to the established risk factors may improve cardiovascular risk prediction.

Aged↗

Circulating cardiac troponin T in potential heart transplant donors.

BACKGROUND: Brain death may induce myocardial dysfunction, the mechanisms of which are not yet fully understood. Circulating cardiac troponin T is considered a highly sensitive and specific marker of myocardial cell injury. METHODS AND RESULTS: We prospectively measured circulating cardiac troponin T in 100 brain-dead patients and measured the left ventricular ejection fraction area (LVEFa), using transesophageal echocardiography. Sixty-one patients had normal LVEFa, 25 had moderate decrease in LVEFa (30% to 50%), and 14 had severe decrease in LVEFa (< or = 30%). Circulating cardiac troponin T concentrations were significantly higher (1.68 +/- 1.03 micrograms/L-1, P < .01) in patients with a severe decrease in LVEFa than in the two other groups (0.42 +/- 0.43 and 0.12 +/- 0.16 microgram/L-1, respectively), and there was a significant correlation between LVEFa and cardiac troponin T concentration (p = -0.59, P < .0001). An elevated circulating cardiac troponin T concentration (> or = 0.5 microgram/L-1) was more accurate (sensitivity, 1.00; specificity, 0.84) in predicting a severe decrease in LVEFa than an elevated CKMB value or an increased CKMB/CK ratio. CONCLUSIONS: An elevated circulating cardiac troponin T was associated with a severe decrease in LVEFa in brain-dead patients, suggesting that severe and potentially irreversible myocardial cell damage occurred. In contrast, CKMB determination was not useful. Since the quality of the donor's heart is considered an important prognosis factor in heart transplantation, the determination of circulating cardiac troponin T concentration could be useful to the heart transplantation team.

Adult↗

Circulating endothelial cells are a novel marker of cyclosporine-induced endothelial damage.

Microvascular endothelial cells play a key role in transplant immunology. They are also important targets for calcineurin inhibitors. We recently demonstrated elevated numbers of circulating endothelial cells in renal transplant recipients with and without rejection in comparison with healthy controls. Because these patients received either cyclosporine or tacrolimus, we speculated that endothelial damage from calcineurin inhibitors might be responsible for these findings. In the present study, we tested the hypothesis that treatment with calcineurin inhibitors leads to an increase in circulating endothelial cells. We studied 57 renal transplant recipients: 19 on a calcineurin inhibitor-free immunosuppressive regimen and 38 patients on a standard immunosuppressive regimen, including cyclosporine, and matched them for age and serum creatinine. Endothelial cells were isolated from peripheral blood with anti-CD-146-coated immunomagnetic Dynabeads and were counted by fluorescence microscopy. Patients with cyclosporine therapy had elevated numbers of circulating endothelial cells (median 26, range 12 to 82 cells/mL) compared with healthy controls (median 6, range 0 to 82 cells/mL; P<0.001). Patients without calcineurin inhibitor treatment had significantly lower cell numbers (median 12, range 0 to 32 cells/mL; P<0.003) and were not significantly different from normal, untreated controls. In conclusion, renal transplant recipients who do not receive calcineurin inhibitors have significantly lower numbers of circulating endothelial cells than their age- and creatinine-matched counterparts who receive these drugs. We suggest that elevated numbers of circulating endothelial cells indicate damage from calcineurin inhibitors in renal transplant recipients and that circulating endothelial cells are a novel marker of endothelial damage.

Adult↗

Effects of volume change on circulating immunoreactive atrial natriuretic factor in rats.

The mammalian atrial hormone atrial natriuretic factor (ANF) has been shown to have potent natriuretic and diuretic actions as well as vasodilator effects when released into the circulation. To investigate how the levels of the circulating form of this peptide change with alteration of intravascular fluid volume, we measured immunoreactive ANF in the plasma of Wistar rats after acute saline load, acute furosemide treatment, and chronic water restriction. Circulating levels of immunoreactive ANF increased significantly (p less than 0.001) 1 minute after acute saline load and returned to normal levels within 5 minutes. Volume contraction induced by furosemide treatment of chronic water restriction significantly reduced the circulating immunoreactive ANF. These data indicate that acute volume expansion causes an immediate release of immunoreactive ANF into the general circulation and acute volume contraction results in a decline of circulating levels of immunoreactive ANF, which is maintained during chronic volume contraction. These results suggest that the atria detect alterations in intravascular fluid volume and respond by changing the levels of ANF acutely as well as chronically and thereby participate in the regulation of body fluids and, perhaps, of blood pressure.

Animals↗

Circulating nonesterified fatty acid level as a predictive risk factor for sudden death in the population.

BACKGROUND: In ischemic conditions, concentration of circulating nonesterified fatty acids (NEFA) is increased and has a proarrhythmic effect that is responsible for ventricular tachyarrhythmias. In nonischemic patients, high NEFA plasma concentration has been shown to be associated with frequent premature ventricular complexes and increased familial risk of cardiovascular disease, but its relation to sudden death has not been studied. We assessed the role of circulating NEFA in sudden death in asymptomatic men in a long-term cohort study. METHODS AND RESULTS: A total of 5250 men employed by the city of Paris, aged 42 to 53 in 1967 to 1972, free of known ischemic cardiac disease, and included in the Paris Prospective Study I, completed a second annual examination and had fasting plasma circulating NEFA measured. Each subject underwent a physical examination and ECG, provided blood for laboratory tests, and answered questionnaires administered by trained interviewers. Vital status was obtained for each subject from specific inquiries until he retired; after retirement, it was obtained from death certificates. Body mass index, systolic and diastolic blood pressures, tobacco consumption, parental history of sudden death, fasting cholesterol level, and circulating NEFA concentration were independent factors associated with sudden death during follow up (average, 22 years). When adjusted for confounding factors, circulating NEFA concentration remained an independent risk factor for sudden death (relative risk, 1.70; 95% confidence interval, 1.21 to 2.13) but not for fatal myocardial infarction. CONCLUSIONS: Circulating NEFA concentration is an independent risk factor for sudden death in middle-aged men. Some form of primary prevention could be envisaged in subjects at high risk of sudden death.

Adult↗