Biomedical subjects
Publications and source records attributed to Allan Flyvbjerg.
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BACKGROUND: From animal studies it is known that currently used pesticides can disturb thyroid function. METHODS: In the present study we investigated the thyroid function in 122 Danish greenhouse workers, to evaluate if greenhouse workers classified as highly exposed to pesticides experiences altered thyroid levels compared to greenhouse workers with lower exposure. Serum samples from the greenhouse workers were sampled both in the spring and the fall to evaluate if differences in pesticide use between seasons resulted in altered thyroid hormone levels. RESULTS: We found a moderate reduction of free thyroxine (FT4) (10-16%) among the persons working in greenhouses with a high spraying load both in samples collected in the spring and the fall, but none of the other measured thyroid hormones differed significantly between exposure groups in the cross-sectional comparisons. However, in longitudinal analysis of the individual thyroid hormone level between the spring and the fall, more pronounced differences where found with on average 32% higher thyroid stimulating hormone (TSH) level in the spring compared to the fall and at the same time a 5-9% lower total triiodthyroxin (TT3), free triiodthyroxine (FT3) and FT4. The difference between seasons was not consistently more pronounced in the group classified as high exposure compared to the low exposure groups. CONCLUSION: The present study indicates that pesticide exposure among Danish greenhouse workers results in only minor disturbances of thyroid hormone levels.
BACKGROUND: Metabolic bone disease (MBD) and muscle wasting (MW) are serious complications in adults suffering from inflammatory bowel disease (IBD). The inflammatory process and corticosteroid treatment may lead to changes in the IGF-system associated with MBD and MW. AIM: To assess changes in the IGF-system and clinical and biochemical markers in ulcerative colitis (UC) and Crohn's disease (CD). METHODS: We studied 37 IBD patients with severe clinical exacerbation (20 with UC, 17 with CD) before and during high dose corticosteroid treatment and tapering (8-12 weeks). RESULTS: Total IGF-I was reduced in CD (36% p<0.01) and UC (41% p<0.001) before treatment and normalized completely. Free IGF-I baseline levels were unchanged compared to controls. In UC, free IGF-I levels increased significantly at week 1 and week 4 (p<0.01, respectively). In CD, no changes in free IGF-I levels were observed. IGFBP-2 baseline levels were increased by a factor 2.3 in UC and CD compared to controls (p<0.01 respectively) and normalized during treatment. IGFBP-3 was reduced by 38% (p<0.01) in CD and 32% (p<0.01) in UC with only partial normalization. Harvey-Bradshaw index, C - reactive protein and albumin normalized during treatment. CONCLUSIONS: Significant changes in total and free IGF-I and IGFBP-2 and IGFBP-3 were demonstrated in CD and UC patients in exacerbation with only partial normalization during high dose corticosteroid treatment and tapering without differences between UC and CD. These changes may be part of MBD and MW in active IBD.
CONTEXT: Cross-sectional and nested case-control studies indicate a relationship between adiponectin, obesity, and coronary heart disease (CHD). OBJECTIVE: Our objective was to investigate whether adiponectin could predict CHD in a population-based cohort of elderly men. DESIGN AND SETTING: From 1991-1995 a baseline investigation was carried out in 832 healthy men aged 70 yr in the Uppsala Longitudinal Study of Adult Men (ULSAM study). They were followed up to 10.4 yr using Swedish national registry data. The baseline investigation included anthropometry, blood pressure, smoking, serum lipids, a euglycemic insulin clamp, and fasting serum adiponectin. MAIN OUTCOME MEASURES: Main outcome measures were defined as death or first-time hospitalization for CHD (n = 116), recorded in the Cause of Death Registry or in the Hospital-Discharge Registry of the National Board of Health and Welfare, Sweden. Associations were analyzed using Cox's proportional hazards regression, presented as hazard ratios (HR) with 95% confidence intervals (CI) for 1 sd increase in the predictor variable. RESULTS: In a multivariable analysis including total cholesterol (HR, 1.24; CI, 1.02-1.50), high-density lipoprotein cholesterol (HR, 0.72; CI, 0.58-0.89), smoking (HR, 1.39; CI, 0.91-2.14), and systolic blood pressure (HR, 1.26; CI, 1.05-1.52), serum adiponectin was associated with lower risk for CHD (HR, 0.81; CI, 0.66-0.99). The association was independent of BMI and remained significant after adjustment for insulin sensitivity index. CONCLUSIONS: In this population-based cohort of healthy men, elevated serum levels of adiponectin were associated with a lower risk for CHD. Importantly, the association between adiponectin and CHD was independent of other well-known risk factors.
Culture of osteogenic cells on a porous scaffold could offer a new solution to bone grafting using autologous human mesenchymal stem cells (hMSC) from the patient. We compared coralline hydroxyapatite scaffolds with pore sizes of 200 and 500 microm for expansion and differentiation of hMSCs. We cultivated the hMSC statically or in spinner flasks for 1, 7, 14 and 21 days and found that the 200-microm pore scaffolds exhibited a faster rate of osteogenic differentiation than did the 500-microm pore scaffolds as shown by an alkaline phosphatase activity assay and real-time reverse transcriptase polymerase chain reaction for 10 osteogenic markers. The 500-microm scaffolds had increased proliferation rates and accommodated a higher number of cells (shown by DNA content, scanning electron microscopy and fluorescence microscopy). Thus the porosity of a 3D microporous biomaterial may be used to steer hMSC in a particular direction. We found that dynamic spinner flask cultivation of hMSC/scaffold constructs resulted in increased proliferation, differentiation and distribution of cells in scaffolds. Therefore, spinner flask cultivation is an easy-to-use inexpensive system for cultivating hMSCs on small to intermediate size 3D scaffolds.
BACKGROUND: We recently described increased insulin-like growth factor binding protein 3 (IGFBP-3) proteolysis in the circulation in adult Turner syndrome (TS), with normalization during sex hormone replacement therapy (HRT), suggesting the presence of a sex hormone regulated IGFBP-3 proteolytic activity. OBJECTIVE: To study the GH-IGF-IGFBP axis in TS without and during HRT, and to further characterize the nature of the IGFBP-3 proteolytic activity. MATERIAL: 23 women with TS before and during HRT, and 24 healthy age-matched women. METHODS: The study included measurements of the acid-labile subunit (ALS), IGFBP-1, -2 and -3 (immunoreactive and Western ligand blot (WLB)), IGFBP-4 (WLB) and IGF-I bioactivity. To determine the molecular distribution of IGFBP-3, serum from patient and controls was subjected to neutral size-exclusion chromatography followed by determination of the IGFBP profile by WLB and immunoassay. Finally, the inhibitor characteristic of in vitro IGFBP-3 proteolytic activity in serum was determined. RESULTS: Immunoreactive IGF-I was normal, while IGF-I bioactivity was decreased in TS. Immunoreactive IGFBP-1, -2 and -3 were normal, while WLB-IGFBPs were all reduced, but increased in response to HRT. The IGFBP-3 ternary complex was significantly reduced in TS, and increased in response to HRT, while the non-ternary complexed IGFBP-3 remained unaffected by treatment. In vitro IGFBP-3 proteolytic activity in serum was abolished by aprotinin, while EDTA and zinc chloride had no inhibitory effects, suggesting the presence of a serine protease. 17beta-estradiol had no direct inhibitory effect on the IGFBP-3 proteolytic activity in vitro. Size-exclusion chromatography showed that the protease had a molecular mass of more than 500 kDa. CONCLUSION: The GH-IGF-IGFBP axis is profoundly disturbed in TS, with a partly normalizing effect of HRT. A sex hormone-dependent IGFBP-3 proteolytic activity (serine protease) leads to destabilization of the 150 kDa IGFBP-3 ternary complex in TS. During HRT both IGFBP-3 proteolytic activity and ternary complex formation is normalized.
Growth hormone (GH) has antidiuretic and antinatriuretic effects in rats and humans, but the molecular mechanisms responsible for these effects are unknown. The aim of this study was to investigate the mechanisms behind the acute renal effects of GH in rats. Female rats received rat (r)GH (2.8 mg/kg sc) or saline and were placed in metabolic cages for 5 h. Urinary excretion of electrolytes and urinary volume were reduced after rGH injection, while urine osmolality was increased. Creatinine and lithium clearance remained unchanged, suggesting that rGH increases reabsorption in segments distal to the proximal tubule. Total plasma insulin-like growth factor I (IGF-I) levels did not change, while cortical IGF-I mRNA abundance was increased. The relative abundance of total and Ser(256)-phosphorylated aquaporin 2 was found to be unchanged by immunoblotting, whereas a significant increase of Thr(96) and Thr(101)-phosphorylated NKCC2 (renal Na(+), K(+), 2Cl(-) cotransporter) was found in the inner stripe of outer medulla thick ascending limbs (mTAL). Additionally, an increased NKCC2 expression was observed in the cortical region. Immunohistochemistry confirmed these findings. The density of NKCC2 molecules in the apical membrane of mTAL cells appeared to be unchanged after rGH injection evaluated by immunoelectron microscopy. Basolateral addition of rGH or IGF-I to microperfused rat mTAL segments did not change transepithelial voltage. In conclusion, GH appears to exert its acute antinatriuretic and antidiuretic effects through indirect activation of NKCC2 in the mTAL.
BACKGROUND: Circulating adiponectin is a marker for insulin sensitivity, derived from fat cells. It is largely unknown if adiponectin is also an independent marker for early atherosclerosis. METHODS AND RESULTS: Plasma adiponectin levels were measured in 373 men and 514 women of middle-age by a time-resolved immunofluorometric assay. The subjects were sampled stratified for degree of insulin sensitivity (HOMA-IR). An ultrasound measurement of the right common carotid artery intima media thickness (IMT) was made. When the distribution of adiponectin was stratified into sex-specific quartiles (Q1 to Q4), men in Q4 differed from Q1 in higher mean age and high-density lipoprotein (HDL) cholesterol, but lower blood pressure, HbA1c, HOMA-index, and body mass index. Women showed similar associations. Mean IMT for men was significantly lower (P=0.03) in adiponectin Q4 as compared with Q1 when adjusted for age, waist, smoking, HDL cholesterol, and diastolic blood pressure. When adding HbA1c and HOMA to the model, the association was no longer significant (P=0.15). In women no difference in IMT was noticed across adiponectin quartiles. CONCLUSIONS: Plasma adiponectin is a marker of glucose metabolism and obesity and shows an inverse age-adjusted association with carotid ultrasound IMT in men, but not in women. This association is attenuated after adjustments for other risk factors.
BACKGROUND: Inflammation and complement activation initiated by mannose-binding lectin (MBL) may be implicated in the pathogenesis of diabetic vascular complications. We evaluated the relationship between serum MBL and mortality and development of albuminuria in type 2 diabetes. METHODS: Levels of MBL and C-reactive protein (CRP) were measured at baseline in 326 patients with type 2 diabetes who attended the Steno Diabetes Center, Gentofte, Denmark, for control. Urinary albumin excretion was determined annually, and the vital status of all patients was traced after more than 15 years of follow-up. RESULTS: During follow-up, 169 patients died. The risk of dying was significantly higher among patients with MBL levels greater than or equal to 1000 microg/L than among patients with levels less than 1000 microg/L (hazard ratio, 1.5; 95% confidence interval, 1.1-2.1; P = .005). After adjustment for known confounders, MBL remained a significant risk factor for death from any cause. It added to the predictive power of CRP, and mortality was significantly higher among patients with both high MBL (> or =1000 microg/L) and high CRP (above the median, 3.6 mg/L) levels than among patients with both low MBL and low CRP levels (hazard ratio, 2.7; 95% confidence interval, 1.7-4.3; P<.001). Normoalbuminuric patients with both high MBL and high CRP levels at baseline had a significantly increased risk of developing microalbuminuria or macroalbuminuria compared with patients with both low MBL and low CRP levels (hazard ratio, 2.6; 95% confidence interval, 1.5-4.4; P<.001). CONCLUSION: In patients with type 2 diabetes, measurements of MBL alone or in combination with CRP can provide prognostic information on mortality and the development of albuminuria.
Microdialysis studies indicate that mechanical loading of human tendon during exercise elevates type I collagen production in tendon. However, the possibility that the insertion of microdialysis fibers per se may increase the local collagen production due to trauma has not been explored. Insulin-like growth factor I (IGF-I) and its binding proteins (IGFBPs), which are known to stimulate collagen production in animal tendons, may regulate the translation of mechanical loading to collagen synthesis. Systemic and tissue levels of IGF-I, IGFBP, and type I collagen metabolism markers [procollagen I COOH-terminal propeptide (PICP) and COOH-terminal telopeptide of type I collagen] were measured by microdialysis in peritendinous tissue of the human Achilles tendon in an exercise group (performing a 36-km run, n = 6) and a control group (no intervention, n = 6). An increase in local PICP concentration was seen in both groups after 72 h and stayed elevated in the exercise group at 96 h (P < 0.05). IGFBP-1 in both serum and dialysate increased in the exercise group immediately after exercise (P < 0.05), whereas IGFBP-3 decreased systemically (P < 0.05). Elevation of local IGFBP-4 was observed in both the control and exercise groups after 48 h (P < 0.05). Total IGF-I did not change in locally or systemically in either group. Our results indicate an increased local production of PICP in human peritendinous tissue in response to prolonged mechanical loading with part of the increase due to trauma from the sampling technique. Care must therefore be emphasized to minimize the numbers of insertions with microdialysis. We demonstrated an elevation of IGFBP-1 both systemically and peritendinously in response to prolonged acute exercise. The local increased collagen synthesis was preceded by an elevation of local concentration of IGFBP-4, suggesting that IGFBP-4 may have a key role in the IGF-axis effect on the human collagen synthesis in vivo.
Accumulating epidemiological evidence shows that being either overweight or obese, in other words having excess body weight (EBW), is associated with an increased risk of several, common, adult cancers. The molecular mechanisms that underlie these associations are not understood fully, but insulin resistance is likely to be important. The insulin-cancer hypothesis postulates that chronic hyperinsulinemia is associated with decreased concentrations of insulin-like growth factor binding protein1 (IGFBP-1) and IGFBP-2, leading to increased availability of IGF-I and concomitant changes in the cellular environment that favor tumor formation. However, the situation is likely to be more complex because hyperinsulinemia is also associated with alterations in related molecular systems (e.g. sex steroids and adipocytokines). As the prevalence of EBW increases to epidemic proportions, untangling the links between EBW and the insulin-IGF axis and its wider molecular interactions will become increasingly important in the development of preventive strategies.
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The primary objectives of this analysis were to examine the effects of early posttransplantation (10 wk) serum levels of osteoprotegerin (OPG), mannose-binding lectin (MBL), and MBL-associated serine proteases (MASP; MASP-2 and MASP-3) on long-term (8-yr) patient survival, graft survival, and cardiovascular (CV) death. During a period of 16 mo (1995 to 1996), a total of 173 consecutive renal transplant recipients without diabetes before transplantation were included in a prospective study that was designed to address the impact of metabolic CV risk factors on survival and CV end points. Baseline sera from 172 patients were available for analysis. Follow-up data until January 1, 2004, were obtained from a national renal registry. Patients with high (fourth quartile) serum levels of OPG had significantly higher all-cause mortality (hazard ratio [HR] 6.3; 95% confidence interval [CI] 3.3 to 11.8; P<0.001) and CV death (HR 10.8; 95% CI 3.8 to 30.4; P<0.001) than patients with lower OPG concentrations. After multiple Cox regression analysis, high serum levels of OPG remained an independent predictor of all-cause mortality (HR 6.0; 95% CI 3.1 to 11.6, P<0.001) and CV death (HR 8.2; 95% CI 2.5 to 26.4; P<0.001). Multiple linear regression analysis revealed that age, creatinine clearance, and high-sensitivity C-reactive protein all were independently associated with OPG (R2=0.42). No significant association between OPG and death-censored graft loss was revealed. Serum levels of MBL, MASP-2, and MASP-3 were not significantly associated with patient survival, CV death, or graft loss. Early measured posttransplantation serum OPG is a highly significant independent predictor of death from any cause or CV death in white renal transplant recipients.
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Decreased left ventricular long-axis function may be the earliest stage in subclinical heart failure in Type II diabetes. To assess whether a decrease in SBP (systolic blood pressure) or a change in metabolic control would improve the long-axis function, 48 Type II diabetic patients participating in the CALM II (Candesartan and Lisinopril Microalbuminuria II) study were included in the present study. Patients were examined with tissue Doppler echocardiography at baseline and after 3 and 12 months of follow-up. Corresponding blood pressure, fructosamine and HbA(1c) (glycated haemoglobin) values were obtained. During the follow-up period, a decrease in SBP of 8 mmHg was seen (from 141+/-11 mmHg at baseline to 133+/-12 mmHg; P<0.001) and the peak systolic strain rate was significantly improved (from -1.10+/-0.25 at baseline to -1.25+/-0.22; P<0.01). There was a highly significant relationship between the changes in systolic strain rate, HbA(1c) (P<0.001) and fructosamine (P<0.05), and similarly to changes in left ventricular mass (P<0.05), whereas the correlation to the SBP reduction was not significant. Patients with improved glycaemic control, defined as a reduced HbA(1c) value after 12 months of follow-up, had a significantly improved strain rate (from -1.07+/-0.3 s(-1) at baseline to -1.32+/-0.25 s(-1); P<0.01) compared with patients with increases in HbA(1c) (from -1.14+/-0.25 s(-1) at baseline to -1.16+/-0.27 s(-1); P=not significant). The two groups had comparable baseline values of SBP, left ventricular mass, age and disease duration. In conclusion, changes in left ventricular systolic long-axis function are significantly correlated with changes in left ventricular mass, as well as metabolic control, in hypertensive patients with Type II diabetes mellitus.
In animals insulin-like growth factor I (IGF-I) stimulates collagen production by fibroblasts and is expressed in tendons together with its binding protein 4 (IGFBP-4). However, the presence of IGF-I and IGFBP-4 in human tendon tissue is not described. Tissue IGF-I content was examined by immunoflourometric assay, real-time PCR, and immunohistochemistry used to localize and determine expression of IGF-I and IGFBP-4 in 6 postmortem human Achilles tendons. Tendon tissue concentrations of IGF-I were found to be 0.53 +/- 0.10 ng/g. Furthermore, we demonstrated that IGF-I and IGFBP-4 are localized around the tendon fibroblasts and that mRNA for IGF-I and IGFBP-4 can be determined in human tendon tissue. The present study adds support for the roles of IGF-I and IGFBP-4 in the regulation of tendon adaptive responses to mechanical loading.
OBJECTIVE: To study circulating adiponectin concentrations in relation to diabetes duration and endogenous insulin secretion in patients with type 1 diabetes. PATIENTS: Patients with haemoglobin A1c (HbA1c) < 6% (reference range 3.6-5.4%) were selected for the study. Twenty-two men and 24 women [age 41.3 +/- 13.8 years (mean +/- SD), diabetes duration 4 months to 52 years] participated. Healthy controls (15 women and nine men, age 41.3 +/- 13.0 years) were also included. Overnight fasting serum samples were analysed for adiponectin, HbA1c, C-peptide and lipoproteins. RESULTS: Significant positive associations were found between adiponectin concentrations and diabetes duration in univariate and multiple regression analyses. Serum adiponectin averaged 9.7 +/- 5.3 [median 8.1, interquartile range (IQR) 3.6] mg/l in patients with diabetes duration less than 10 years and 17.8 +/- 10.7 (median 14.7, IQR 7.5) mg/l in patients with longer duration (P = 0.0001). Among the patients, 24 were without detectable (< 100 pmol/l) and 22 with detectable C-peptide levels (185 +/- 91 pmol/l). C-peptide levels in controls averaged 492 +/- 177 pmol/l. HbA1c was 5.7 +/- 0.6% in patients without detectable C-peptide and 5.6 +/- 0.4% in patients with detectable C-peptide (ns). Serum adiponectin was higher in patients without detectable C-peptide than in patients with detectable C-peptide [17.3 +/- 11.1 vs. 10.6 +/- 5.8 mg/l (P < 0.005)] and in the controls [10.1 +/- 2.9 mg/l (P < 0.001 vs. patients without detectable C-peptide)]. CONCLUSIONS: The increase in circulating adiponectin concentrations in patients with type 1 diabetes appears to be strongly associated with long diabetes duration, irrespective of the metabolic control. Among other factors, a putative role for residual beta-cell function in the regulation of circulating adiponectin levels can be considered but we did not find sufficient evidence for this in the present study.