Biomedical subjects

T Ueland

Publications and source records attributed to T Ueland.

50 records · Page 3Linked to original sources

PubMed2000

Serum creatine kinase isoenzyme BB in mammalian osteopetrosis.

In mammalian osteopetrosis the different mutations exemplify reduced bone resorption leading to net accumulation of bone. Recently, high blood levels of creatine kinase-BB have been reported in some human forms, suggesting it as a marker of osteopetrosis. In the current study serum creatine kinase-BB was evaluated in relation to known osteoclastic pathophysiology in two human types of autosomal dominant osteopetrosis at baseline and after stimulation with triiodothyronine and in four different rodent mutations. Creatine kinase-BB was increased markedly in Type 2 autosomal dominant osteopetrosis and in the incisors absent rat, both characterized by large numbers of giant osteoclasts, and did not change significantly after stimulation. Although creatine kinase-BB was unchanged in Type 1 autosomal dominant osteopetrosis at baseline and after stimulation, the rodent counterparts characterized by small osteoclasts, microphthalmic and osteopetrotic mice and toothless rats, had significantly decreased levels. Similar differences were observed in both types of autosomal dominant osteopetrosis compared with controls concerning tartrate resistant acid phosphatase. Creatine kinase-BB in mammalian osteopetrosis is related to osteoclastic number and size, where it probably reflects the differentiation and maturation of inactive bone resorbing cells. The isoenzyme does not seem to be a valuable screening marker for osteopetrosis.

Adult↗

PubMed2000

Persistently elevated levels of von Willebrand factor antigen in HIV infection. Downregulation during highly active antiretroviral therapy.

Levels of circulating von Willebrand factor (vWf) antigen are thought to reflect endothelial involvement in various disorders. In the present study we found markedly elevated plasma levels of vWf in HIV-infected patients demonstrated on both cross-sectional and longitudinal testing. Notably, we found that a persistent rise in vWf antigen was associated with progression of HIV-related disease. This elevation of vWf antigen represented functionally normal vWf as evaluated by plasma FVIII, ristocetin cofactor assay and vWf multimer analyses. While HIV-infected patients showed enhanced platelet activation, platelets did not contribute substantially to the increased vWf levels. The high vWf levels were significantly correlated with high viral load, and during HAART, the pronounced decline in HIV RNA levels was accompanied by a corresponding decrease in vWf. The persistent elevation of functionally normal vWf during HIV infection, most probably reflecting a persistent endothelial cell activation, may have an important role in the pathogenesis of HIV infection.

Adult↗

PubMed1999

Possible role of proinflammatory cytokines in heart allograft coronary artery disease.

Transplant coronary artery disease (Tx-CAD) is the main determinant of long-term prognosis after heart transplantation. Immunologic processes may play a central role in the development of Tx-CAD, but the pathogenesis has not been fully clarified. We examined plasma levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL)-1beta and IL-6, and the CC-chemokine macrophage chemoattractant protein-1 (MCP-1) in 62 cardiac allograft recipients undergoing yearly heart catherization with coronary angiography for evaluation of graft disease. In this cross-sectional study, we found significantly increased levels of IL-1beta, IL-6, TNF-alpha, and MCP-1 compared with healthy controls even several years (median 7 years) after transplantation in periods with no intercurrent illness. Although no significant differences were found in plasma levels of IL-1beta and TNF-alpha between patients with (n = 25) and without (n = 37) Tx-CAD, the Tx-CAD group had significantly increased levels of IL-6 and MCP-1 compared with both controls and transplant recipients without Tx-CAD. Increased IL-6 levels compared with controls were found only in patients with Tx-CAD. Finally, while there was no significant relation between Tx-CAD and altered lipid status, the combination of high plasma concentrations of IL-6 or MCP-1 and high low-density lipoprotein cholesterol was strongly associated with increased occurrence of Tx-CAD. These findings indicate that cardiac allograft recipients have a persistent immune activation long term after transplantation. This activation, as particularly reflected in increased MCP-1 and IL-6 levels, may be related to the development of Tx-CAD.

Adult↗

PubMed1999

Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes.

BACKGROUND: The CD40 ligand (CD40L) on activated T cells and platelets may be activating matrix metalloproteinases, inducing procoagulant activity, and be involved in the pathogenesis of acute coronary syndromes by promoting plaque rupture in atheroma. METHODS AND RESULTS: To study the role of CD40L-CD40 interaction in coronary disease, we analyzed levels of soluble (s) and membrane-bound CD40L in the peripheral blood from 29 patients with stable angina, 26 with unstable angina, and 19 controls. Our main findings follow. (1) Patients with unstable angina had significantly raised serum levels of sCD40L when compared with patients with stable angina and controls. (2) Platelets could release large amounts of sCD40L when stimulated ex vivo with the thrombin receptor-agonist peptide SFLLRN in both patients and controls. (3) Platelets in patients with unstable angina were characterized ex vivo by decreased intracellular levels and decreased SFLLRN-stimulated release of sCD40L, which may possibly represent a higher percentage of degranulated platelets in these patients. (4) T cells in patients with unstable angina had enhanced surface expression of CD40L and increased release of sCD40L on anti-CD3/anti-CD28 stimulation in vitro when compared with patients with stable angina and controls. (5) Recombinant CD40L and serum from patients with unstable angina who had high sCD40L levels induced enhanced release of monocyte chemoattractant peptide-1 from mononuclear cells, a CC-chemokine involved in the pathogenesis of atherosclerosis. CONCLUSIONS: This first demonstration of enhanced levels of soluble and membrane-bound forms of CD40L in angina patients, with particularly high levels in patients with unstable angina, suggests that CD40L-CD40 interaction may play a pathogenic role in both the long-term atherosclerotic process and in the triggering and propagation of acute coronary syndromes.

Acute Disease↗

PubMed1999

Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

Inflammatory cytokines may play a pathogenic role in the development of congestive heart failure (CHF). Elevated circulating levels of inflammatory cytokines have been reported in CHF, but most studies have focused on only a few cytokine parameters. However, the activity of these cytokines are modulated by soluble cytokine receptors and cytokines with anti-inflammatory activities, and in the present study several of these interacting factors were examined simultaneously in 38 CHF patients with various degrees of heart failure and in 21 healthy controls. Patients with CHF had increased plasma concentrations of tumor necrosis factor (TNF)alpha, interleukin-6, soluble TNF receptors and the soluble interleukin-6 receptor, glycoprotein (gp)130. They also had elevated ratios of TNFalpha/soluble TNF receptors and interleukin-6/soluble gp130 as well as enhanced interleukin-6 bioactivity in serum, suggesting inflammatory net effects. In addition to raised circulating levels of inflammatory cytokines, CHF patients with severe heart failure also had abnormalities in the levels of anti-inflammatory cytokines, with decreased levels of transforming growth factor beta1 and inadequately raised interleukin-10 in relation to the elevated TNFalpha concentrations. This dysbalance between inflammatory and anti-inflammatory cytokines was also found in monocyte supernatants from CHF patients. The abnormalities in the cytokine network were most pronounced in patients with the most severe heart failure, and several of the immunologic parameters, in particular soluble gp130, were correlated with variables reflecting deranged hemodynamic status. The present study analyzing the complexity of the cytokine network in CHF, demonstrates profound disturbances in the levels of both inflammatory and anti-inflammatory mediators with a marked dysbalance favoring inflammatory effects.

Adult↗

PubMed1999

Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure.

OBJECTIVES: We examined the effect of long-term treatment with two doses of the angiotensin converting enzyme (ACE) inhibitor enalapril on various immunological variables in patients with chronic congestive heart failure (CHF). BACKGROUND: Immunological mediators are increasingly recognized to play a pathogenic role in the pathophysiology of CHF. Whether ACE inhibitor therapy modifies immunological variables has not previously been investigated. METHODS: Seventy-five patients (mean age 52 +/- 11 years) with CHF were randomized between low-(5 m g daily) and high-dose (40 mg daily) enalapril in a double-blind trial. Circulating levels of immunological parameters (i.e., proinflammatory cytokines, chemokines and adhesion molecules) were measured at baseline, at 10 weeks and at the end of the study (34 weeks). RESULTS: All immunological parameters, except soluble interleukin (IL)-6 receptor, were increased in CHF compared with 21 healthy controls. During the study immunoreactive IL-6 levels decreased (p < 0.05) and soluble IL-6 receptor increased (p < 0.05) during high-dose but not during low-dose enalapril therapy. Furthermore, IL-6 bioactivity decreased only during the high-dose (p < 0.001), resulting in a significant difference in change during treatment between the two dosage groups (p < 0.001). This decrease in IL-6 bioactivity was significantly associated with decreased interventricular septum thickness as assessed by echocardiography (r = 0.56, p = 0.013). No other variables changed during treatment. CONCLUSIONS: In patients with severe CHF, high-dose enalapril therapy is associated with a significant decrease in IL-6 activity. However, despite treatment with a high-dose ACE inhibitor, a persistent immune activation exists in these patients which may be of importance for the progression of CHF.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1999

Increased cortical bone content of insulin-like growth factors in acromegalic patients.

To investigate cortical bone composition and the role of the insulin-like growth factor (IGF) system in active acromegaly, iliac crest bone biopsies were obtained from 15 patients (3 women and 12 men), aged 21-64 yr (mean, 45.6 yr), and 25 age- and sex-matched controls (8 women and 17 men), aged 22-66 yr (mean, 44.6 yr). Levels of IGF-I, IGF-II, IGF-binding protein-3 (IGFBP-3), IGFBP-5, and total protein were determined in extracts obtained after ethylenediamine tetraacetate and guanidine hydrochloride extraction. Osteocalcin and calcium were determined in extracts after HCl hydrolysis. Cortical bone contents of IGF-I, IGF-II, and IGFBP-5 were significantly elevated in the acromegalic patients compared with control values [91% (P < 0.001), 44% (P < 0.04), and 115% (P < 0.004), respectively]. There was no significant difference in IGFBP-3, osteocalcin, protein, and calcium between patients and controls. This study suggests that the increased levels of growth factors in cortical bone from acromegalics is a reflection of local production, secondary to a chronic systemic excess of GH and IGF-I.

Acromegaly↗

PubMed1999

Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy.

As cytokines and 1,25-dihydroxyvitamin D [1,25-(OH)2D] appear to have an important role in bone homeostasis, we examined the possibility that human immunodeficiency virus (HIV)-infected patients, characterized by enhanced levels of proinflammatory cytokines and 1,25-(OH)2D deficiency, have disturbed bone metabolism by analyzing serum markers of bone formation (osteocalcin) and bone resorption (C-telopeptide) in 73 HIV-infected patients. HIV-infected patients with advanced clinical and immunological disease and high viral load were characterized by increased C-telopeptide and particularly by markedly depressed osteocalcin levels. HIV-infected patients had enhanced activation of the TNF system. Serum concentrations of p55 and p75-TNF receptors were negatively correlated with osteocalcin, and p75-TNF receptor was positively correlated with C-telopeptide. HIV-infected patients with advanced disease also had decreased serum concentrations of 1,25-(OH)2D, but this parameter was not correlated with osteocalcin or C-telopeptide. During 24 months with highly active antiretroviral therapy there was a marked rise in serum osteolcalcin levels together with a profound fall in viral load and TNF components and a marked rise in CD4+ T cell counts. Also, there was a shift from no correlation to a significant correlation between osteocalcin and C-telopeptide levels during such therapy. The present study suggests disturbed bone formation and resorption during HIV infection. Our findings indicating synchronization of bone remodeling during highly active antiretroviral therapy may represent a previously unrecognized beneficial effect of such therapy and expand our knowledge of the interactions between cytokines and bone in the bone-remodeling process.

Adult↗

PubMed1999

Decreased bone area, bone mineral content, formative markers, and increased bone resorptive markers in endogenous Cushing's syndrome.

It is well established that chronic excess of glucocorticoids has negative effects on bone and collagen turnover, and that secondary osteoporosis is a known clinical complication of endogenous Cushing's syndrome (CS). The aim of the present study was to evaluate bone dimension and bone mineral content in relation to biochemical markers of bone and collagen turnover, in a consecutive series of 23 patients with endogenous CS (18 with pituitary adenoma and 5 with adrenal tumor; 17 women, 6 men; mean age 39.7+/-2.8 (S.E. M.) and 44.3+/-3.1 years respectively), compared with 23 age-, sex- and body mass index-matched healthy controls. Bone mineral densities were uniformly reduced in the different regions analyzed: lumbar spine (16.1%, P<0.001), femoral neck (15.2%, P<0.001), total body (11.5%, P<0.001), and the subregions of arms (8.4%, P<0.05), legs (10.1%, P<0.05) and trunk (15.8%, P<0.001). Similar results were observed for bone mineral content, although these were less prominent. The calculated area was significantly decreased in trunk (13.8%, P<0.01) and total body (11.6%, P<0.05). Serum levels of osteocalcin were significantly decreased (28%, P<0.03) in patients with CS. No significant differences were observed for the formative markers carboxyterminal propeptide of type I procollagen and aminoterminal propeptide of type I procollagen. Markers of bone resorption, serum Crosslaps and carboxyterminal cross-linked telopeptide of type I collagen were increased in patients compared with controls, although only significantly for Crosslaps (P<0.02). No correlations between formative and resorptive markers were found in the patients, but in controls, the formative markers were positively correlated with resorptive markers. In conclusion, bone dimension and bone mineral content of the entire skeleton are found to be decreased in endogenous CS. As judged by biochemical markers of bone remodeling, this is caused by decreased bone formation and an increased bone resorption.

Adult↗

PubMed1998

Neuropeptide Y receptor 1 (NPY-Y1) expression in human heart failure and heart transplantation.

Neuropeptide Y (NPY) is a neurotransmitter released from cardiac sympathetic nerve terminals along with catecholamines. It influences vascular tone and cardiac function, probably through the receptor subtype Y1. The present study examined the expression of Y1 in patients with end-stage heart failure and in heart transplant recipients. Y1 mRNA was analyzed in right ventricular endomyocardial biopsies taken from 12 donor hearts prior to implantation (controls), 15 patients with end stage heart failure at time of transplantation, and 16 patients more than 1 year after transplantation. RT-PCR (reverse transcription polymerase chain reaction) was used to detect mRNA for the Y1 receptor, the beta1-adrenergic-receptor, and beta-actin. Y1 mRNA was present in biopsies of all donor hearts, but was observed significantly less frequently in the two patient groups; only 5 out of 15 (P < 0.01) heart failure and 9 out of 16 (P < 0.05) transplant recipients demonstrated visible PCR product. In contrast, mRNA for the beta1-adrenergic receptor and beta-actin were detected by RT-PCR in all samples. Our results provide the first evidence for altered regulation of the neuropeptide Y1 receptor in heart failure and transplant patients, and suggests that loss of signal transduction by this receptor may be adaptive in both groups.

Actins↗

PubMed1998

Elevated circulating levels of C-C chemokines in patients with congestive heart failure.

BACKGROUND: Immunologic and inflammatory responses appear to play a pathogenic role in the development of congestive heart failure (CHF). Activation and migration of leukocytes to areas of inflammation are important factors in these immunologic responses. Because the C-C chemokines are potent chemoattractants of monocytes and lymphocytes and can modulate other functions of these cells (eg, generation of reactive oxygen species), we measured circulating levels of three C-C chemokines in CHF. METHODS AND RESULTS: Levels of macrophage chemoattractant protein-1 (MCP-1), macrophage inflammatory protein- 1alpha (MIP-1alpha), and RANTES (regulated on activation normally T-cell expressed and secreted) were measured by enzyme immunoassays in 44 patients with CHF and 21 healthy control subjects. CHF patients had significantly elevated levels of all chemokines with the highest levels in New York Heart Association class IV, and MCP-1 and MIP-1alpha levels were significantly inversely correlated with left ventricular ejection fraction. Elevated C-C chemokine levels were found independent of the cause of the heart failure, but MCP-1 levels were particularly raised in patients with coronary artery disease. Studies on cells isolated from peripheral blood suggested that platelets, CD3+ lymphocytes, and in particular, monocytes, might contribute to the elevated C-C chemokine levels in CHF. The increased MCP-1 levels in CHF were correlated with increased monocyte activity reflected in an enhancing effect of serum from CHF patients on O2-generation in monocytes, which was inhibited by neutralizing antibodies against MCP-1. CONCLUSIONS: This first demonstration of increased circulating levels of C-C chemokines in CHF with particularly high levels in patients with severe disease may represent previously unrecognized pathogenic factors in CHF.

Adult↗

PubMed1998

Levels of circulating adhesion molecules in congestive heart failure and after heart transplantation.

Recent reports suggest a role for immunologic and inflammatory processes in the pathogenesis of congestive heart failure (CHF) and accelerated coronary artery disease (CAD) after heart transplantation (HT). The interaction between endothelial cells, leukocytes, and platelets involving various adhesion molecules may be of particular importance. We therefore measured serum levels of soluble(s) vascular cell adhesion molecule-1 (VCAM-1), sP-selectin, and sE-selectin in 34 patients with severe CHF (23 with CAD and 11 with idiopathic dilated cardiomyopathy) and in 20 healthy controls. Twenty of the patients were followed with serial measurements of these circulating adhesion molecules (CAMs) for up to 2 years after HT. Levels of all 3 CAMs were significantly elevated in patients with CHF compared with controls irrespective of the etiology of heart failure, with particularly high concentrations of sVCAM-1. After HT, different patterns in CAMs were found over time. Whereas there was a normalization of sE-selectin levels after HT, concentrations of sVCAM-1 also declined, but without normalization. In contrast, sP-selectin levels were persistently elevated, with the highest concentrations at the end of the study period. The persistent elevation of sP-selectin and the lack of normalization of sVCAM-1 levels were associated with persistently raised serum levels of tumor necrosis factor-alpha, and these findings were not related to either acute episodes of allograft rejection or intercurrent infections. These results support the notion that immunologic and inflammatory processes are important features of CHF. Furthermore, the persistently elevated levels of CAMs and tumor necrosis factor-alpha found up to 2 years after HT may reflect a state of persistent immune activation in these patients, possibly involved in the development of CAD after HT.

Adolescent↗

PubMed1998

Angiotensin II receptor subtype AT1 and AT2 expression after heart transplantation.

OBJECTIVE: Cardiac hypertrophy appears early after heart transplantation, and may represent a myocardial response to injury. Recent evidence suggests that angiotensin II (Ang II) may promote growth through the AT1 and inhibit growth through the AT2 receptor subtypes. We therefore asked whether hypertrophy after heart transplantation is characterized by alterations in Ang II receptor gene expression. METHODS: The expression of Ang II receptor subtypes. AT1 and AT2, was analyzed in right ventricular endomyocardial biopsies taken from 10 human donor hearts prior to implantation (controls) and from 17 heart transplant recipients, 11 studied during annual evaluation (> 1 year after transplantation) and 6 one week after transplantation. Competitive reverse transcription polymerase chain reaction (RT-PCR) was performed using synthetic RNA internal standards for both receptor subtypes. RESULTS: AT1 and AT2 receptor mRNAs were detected in all samples. AT1 receptor mRNA decreased 4.5 fold (p < 0.01) and AT2 receptor mRNA 4.2 fold (p < 0.001) in transplant patients compared with controls. In the subgroup of patients examined one week after surgery AT1 was reduced relative to AT2 receptor mRNA, resulting in an altered ratio of AT1 to AT2 early after transplantation. There was no correlation between Ang II receptor levels and left ventricular wall thickness, and the decrease in receptor level did not correlate with any hemodynamic parameters, cyclosporine blood levels, or plasma renin, Ang II or pANP, except for a negative correlation between AT2 mRNA and plasma renin (r = -0.49, p = 0.05). CONCLUSIONS: Contrary to our expectations, mRNA for both Ang II receptors was downregulated after heart transplantation. The cause of myocardial hypertrophy after heart transplantation is still unclear, but the hypertrophy does not appear to be driven by increased transcription of the AT1 receptor.

Adult↗

PubMed1998

Biochemical markers of bone metabolism in benign human osteopetrosis: a study of two types at baseline and during stimulation with triiodothyronine.

Biochemical markers of bone remodelling were used to evaluate bone turnover in two types of autosomal dominant osteopetrosis (ADO) at baseline and during stimulation with triiodothyronine (T3). Eight patients with Type I (aged 23-61 years, mean 40.4 years) and nine patients with Type II ADO (aged 20-49 years, mean 32.8 years) were compared with 10 normal controls (aged 22-54 years, mean 35.4 years). The participants were treated with 100 microg T3 daily for 7 days and followed for a total of 16 weeks. Serum concentrations of T3 increased and corresponding suppression of TSH was observed in all participants. Both formative and resorptive bone markers were normal at baseline. After stimulation with T3, a significant increase was seen in all groups for the formative markers used. Secondary increments were observed at the end of the observation period for all groups, indicating activation of bone remodelling. A variety of resorptive markers was assessed, but no differences between patients and controls were seen. After stimulation, highly significant responses were found in all parameters in all groups, in accordance with stimulation of existing resorptive cells. However, no secondary increments were seen at the end of the observation period. A more pronounced response was found in crosslinks-related assays. The study demonstrates that it is possible to stimulate bone resorptive and formative cells with thyroid hormones in both types of ADO. Moreover, it indicates that the remodelling process is activated by a short course of T3 treatment.

Adult↗