Circulating lectin pathway proteins do not predict short-term cardiac outcomes after myocardial infarction.

Despite improvements in treatment, coronary artery disease is still responsible for one-third of all deaths globally, due predominantly to myocardial infarction (MI) and stroke. There is an important potential in developing new strategies for treatment of patients with these conditions. Inflammation, and in particular the actions of the complement system, has emerged as part of the pathogenesis in reperfusion injury in patients with MI. To further qualify this, we examined the association between the plasma levels of lectin pathway proteins and myocardial end-points, left ventricular ejection fraction (LVEF) and infarct size in a cohort of patients with ST-elevation myocardial infarction (STEMI). A blood sample was drawn the day after percutaneous coronary intervention from 73 patients with STEMI. The primary end-points, LVEF and infarct size, were measured with magnetic resonance imaging 6-9 days after the infarct. Complement pattern-recognition molecules of the lectin pathway (mannan-binding lectin, H-ficolin, L-ficolin and M-ficolin) were analysed along with soluble membrane attack complex (sMAC) and C-reactive protein (CRP) in plasma with immunofluorometric assays <50%. CRP correlated negatively with LVEF, regression coefficient = -0·17 (P = 0·01). None of the lectin pathway proteins correlated to LVEF or infarct size, nor did soluble membrane attack complex (sMAC). There were no differences in plasma levels of these complement proteins when comparing patients with ejection fraction <50% to patients with ejection fraction <50%. Pattern-recognition molecules of the lectin pathway and sMAC do not predict short-term cardiac outcomes after MI.

Early-onset type 2 diabetes: Age gradient in clinical and behavioural risk factors in 5115 persons with newly diagnosed type 2 diabetes-Results from the DD2 study.

AIM: To examine the association between early onset of type 2 diabetes mellitus (DM) and clinical and behavioural risk factors for later complications of diabetes. METHODS: We conducted a cross-sectional study of 5115 persons with incident type 2 DM enrolled during 2010-2015 in the Danish Centre for Strategic Research in Type 2 Diabetes-cohort. We compared risk factors at time of diagnosis among those diagnosed at ≤45 years (early onset) with diagnosis age 46 to 55, 56 to 65 (average onset = reference), 66 to 75, and >75 years (late onset). Prevalence ratios (PRs) were computed by using Poisson regression. RESULTS: Poor glucose control, ie, HbA1c ≥ 75 mmol/mol (≥9.0%) in the early-, average-, and late-onset groups was observed in 12%, 7%, and 1%, respectively (PR 1.70 [95% confidence intervals (CI) 1.27, 2.28] and PR 0.17 [95% CI 0.06, 0.45]). A similar age gradient was observed for severe obesity (body mass index > 40 kg/m2 : 19% vs. 8% vs. 2%; PR 2.41 [95% CI 1.83, 3.18] and 0.21 (95% CI 0.08, 0.57]), dyslipidemia (90% vs. 79% vs. 68%; PR 1.14 [95% CI 1.10, 1.19] and 0.86 [95% CI 0.79, 0.93]), and low-grade inflammation (C-reactive protein > 3.0 mg/L: 53% vs. 38% vs. 26%; PR 1.41 [95% CI 1.12, 1.78] and 0.68 [95% CI 0.42, 1.11]). Daily smoking was more frequent and meeting physical activity recommendations less likely in persons with early-onset type 2 DM. CONCLUSIONS: We found a clear age gradient, with increasing prevalence of clinical and behavioural risk factors the younger the onset age of type 2 DM. Younger persons with early-onset type 2 DM need clinical awareness and support.

Plasma levels of MASP-1, MASP-3 and MAp44 in patients with type 2 diabetes: influence of glycaemic control, body composition and polymorphisms in the MASP1 gene.

Mounting evidence indicates that adverse activation of the complement system plays a role in the development of diabetic vascular complications. Plasma levels of the complement proteins mannan-binding lectin (MBL) and its associated serine proteases (MASP-1 and MASP-2) are elevated in diabetes. We hypothesized that single nucleotide polymorphisms (SNPs) in the MASP1 gene may contribute to altered plasma levels of the belonging gene products; MASP-1, MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44) in patients with type 2 diabetes. To investigate this, we compared plasma levels of MASP-1, MASP-3 and MAp44 in 100 patients with type 2 diabetes and 100 sex- and age-matched controls. Ten carefully selected SNPs were analysed using TaqMan® genotyping assay. Additionally, we included a streptozotocin-induced diabetes mouse model to directly examine the effect of inducing diabetes on MASP-1 levels. MASP-1 levels were significantly higher among patients with type 2 diabetes compared with healthy controls (P = 0·017). Five SNPs (rs874603, rs72549254, rs3774275, rs67143992, rs850312) in the MASP1 gene were associated with plasma levels of MASP-1, MASP-3 and MAp44. In the diabetes mouse model, diabetic mice had significantly higher MASP-1 levels than control mice (P = 0·003). In conclusion, MASP-1 levels were higher among patients with type 2 diabetes and diabetic mice. The mechanism behind this increase remains elusive.

Incident microalbuminuria and complement factor mannan-binding lectin-associated protein 19 in people with newly diagnosed type 1 diabetes.

BACKGROUND: Evidence links the lectin pathway of complement activation to diabetic kidney disease. Upon carbohydrate-recognition by pattern-recognition molecules, eg, mannan-binding lectin (MBL), the MBL-associated serine protease (MASP-2) is activated and initiates the complement cascade. The MASP2 gene encodes MASP-2 and the alternative splice product MBL-associated protein 19 (MAp19). Both MAp19 and MASP-2 circulate in complex with MBL. We tested the hypothesis that MAp19 and MASP-2 concentrations predict the risk of incident microalbuminuria. METHODS: Baseline MAp19 and MASP-2 were measured in 270 persons with newly diagnosed type 1 diabetes tracked for incidence of persistent microalbuminuria in a prospective observational 18-year-follow-up study. RESULTS: Seventy-five participants (28%) developed microalbuminuria during follow-up. MBL-associated protein 19 concentrations were higher in participants that later progressed to microalbuminuria as compared with those with persistent normoalbuminuria (268 ng/mL [95% CI, 243-293] vs 236 ng/mL [95% CI, 223-250], P = .02). Participants with MAp19 concentration within the highest quartile of the cohort had an increased risk of microalbuminuria as compared with participants with MAp19 concentration within the combined lower 3 quartiles in unadjusted Cox analysis, hazard ratio 1.86 ([95% CI, 1.17-2.96], P = .009). This remained significant in adjusted models, eg, adjusting for age, sex, HbA1c , systolic blood pressure, urinary albumin excretion, smoking, serum creatinine, and serum cholesterol. MBL-associated serine protease concentration was not associated with incidence of microalbuminuria. CONCLUSIONS: In conclusion, the results show an association between baseline MAp19 concentration and the incidence of microalbuminuria in an 18-year-follow-up study on persons with newly diagnosed type 1 diabetes.

Cardiac vagal tone, a non-invasive measure of parasympathetic tone, is a clinically relevant tool in Type 1 diabetes mellitus.

AIMS: To compare a novel index of parasympathetic tone, cardiac vagal tone, with established autonomic variables and to test the hypotheses that (1) cardiac vagal tone would be associated with established time and frequency domain measures of heart rate and (2) cardiac vagal tone would be lower in people with Type 1 diabetes than in a matched healthy cohort and lower still in people with established neuropathy. METHODS: Cardiac vagal tone is a validated cardiometrically derived index of parasympathetic tone. It is measured using a standard three-lead electrocardiogram which connects, via Bluetooth, to a smartphone application. A 5-min resting recording of cardiac vagal tone was undertaken and observational comparisons were made between 42 people with Type 1 diabetes and peripheral neuropathy and 23 without peripheral neuropathy and 65 healthy people. In those with neuropathy, 24-h heart rate variability values were compared with cardiac vagal tone. Correlations between cardiac vagal tone and clinical variables were also made. RESULTS: Cardiac vagal tone was lower in people with established neuropathy and Type 1 diabetes in comparison with healthy participants [median (interquartile range) linear vagal scale 3.4 (1.6-5.5 vs 7.0 (5.5-9.6); P < 0.0001]. Cardiac vagal tone was positively associated with time (r = 0.8, P < 0.0001) and frequency domain markers of heart rate variability (r = 0.75, P < 0.0001), representing established measures of parasympathetic function. Cardiac vagal tone was negatively associated with age (r=-0.32, P = 0.003), disease duration (r=-0.43, P < 0.0001) and cardiovascular risk score (r=-0.32, P = 0.006). CONCLUSIONS: Cardiac vagal tone represents a convenient, clinically relevant method of assessing parasympathetic nervous system tone, potentially facilitating the earlier identification of people with Type 1 diabetes who should undergo formal autonomic function testing.

Heart rate time series characteristics for early detection of infections in critically ill patients.

It is difficult to make a distinction between inflammation and infection. Therefore, new strategies are required to allow accurate detection of infection. Here, we hypothesize that we can distinguish infected from non-infected ICU patients based on dynamic features of serum cytokine concentrations and heart rate time series. Serum cytokine profiles and heart rate time series of 39 patients were available for this study. The serum concentration of ten cytokines were measured using blood sampled every 10 min between 2100 and 0600 hours. Heart rate was recorded every minute. Ten metrics were used to extract features from these time series to obtain an accurate classification of infected patients. The predictive power of the metrics derived from the heart rate time series was investigated using decision tree analysis. Finally, logistic regression methods were used to examine whether classification performance improved with inclusion of features derived from the cytokine time series. The AUC of a decision tree based on two heart rate features was 0.88. The model had good calibration with 0.09 Hosmer-Lemeshow p value. There was no significant additional value of adding static cytokine levels or cytokine time series information to the generated decision tree model. The results suggest that heart rate is a better marker for infection than information captured by cytokine time series when the exact stage of infection is not known. The predictive value of (expensive) biomarkers should always be weighed against the routinely monitored data, and such biomarkers have to demonstrate added value.

Diabetes-induced changes in mannan-binding lectin levels and complement activation in a mouse model of type 1 diabetes.

Circulating mannan-binding lectin (MBL) levels are elevated in type 1 diabetes. Further, high MBL levels are associated with the development of diabetic nephropathy. In animals, a direct effect of MBL on diabetic kidney changes is observed. We hypothesized that MBL levels and detrimental complement activation increase as a consequence of diabetes. We measured plasma MBL before and 7 weeks after inducing diabetes by streptozotocin. Mice have two MBLs, MBL-A and MBL-C. Diabetes induction led to an increase in MBL-C concentration, whereas no change during the study was found in the control group. The increase in MBL-C was associated with the increasing plasma glucose levels. In accordance with the observed changes in circulating MBL levels, liver expression of Mbl2mRNA (encoding MBL-C) was increased in diabetes. Mbl1expression (encoding MBL-A) did not differ between diabetic and control animals. The estimated half-life of recombinant human MBL was significantly prolonged in mice with diabetes compared with control mice. Complement activation in plasma and glomeruli did not differ between groups. We demonstrate for the first time that MBL levels increase after induction of diabetes and in parallel with increasing plasma glucose. Our findings support the previous clinical observations of increased MBL in type 1 diabetes. This change may be explained by alternations in both MBL production and turnover.

Objective measurements of activity patterns in people with newly diagnosed Type 2 diabetes demonstrate a sedentary lifestyle.

AIMS: To evaluate physical activity in people with newly diagnosed Type 2 diabetes using objective measures. METHODS: We analysed data from a study aimed at assessing carotid femoral pulse wave velocity in which a piezoelectric accelerometer was worn by 100 people with newly diagnosed Type 2 diabetes and by 100 age- and sex-matched control subjects. Differences in physical activity patterns were investigated. RESULTS: Compared with the control group, the people with Type 2 diabetes spent significantly more time engaged in sedentary or lower level activities during the day, with a mean (sd) time of 926 (44) vs 898 (70) min, P < 0.001). This difference remained significant after correction for differences in BMI between the two groups. CONCLUSIONS: Using objective measurements, our findings demonstrate that people with newly diagnosed Type 2 diabetes have a more sedentary lifestyle compared with well-matched controls.

The effect of weight loss on serum mannose-binding lectin levels.

BACKGROUND: Serum levels of the mannose-binding lectin (MBL), which is an activator of the complement system, have been considered as a pathogenic factor in a broad range of diseases, and means of modulating MBL are therefore being evaluated. In this study we examine the effects of weight loss on MBL levels, and in continuation of this if MBL is synthesized in human adipose tissue. METHODS: 36 nondiabetic obese subjects received a very low-calorie diet (VLCD) of 800 kcal/day for 8 weeks. Blood samples were collected at baseline and after VLCD. Furthermore, we measured MBL mRNA levels by the real-time RT-PCR on human adipose tissue compared to liver tissue. RESULTS: The mean body weight was reduced from 106.3 ± 2.6 kg to 92.8 ± 2.4 kg, P < 0.0001. Median MBL at baseline was 746 µg/L (IQR 316-1190) versus 892 µg/L (IQR 336-1511) after 8 weeks, P = 0.23. No correlations were found between weight loss and changes in MBL (r = -0.098, P = 0.57). MBL real-time RT-PCR showed no expression of mRNA in adipose tissue, but as expected a good expression in liver tissue was seen. CONCLUSIONS: MBL levels are not affected by weight loss and MBL is not synthesized in human adipose tissue.

High MBL-expressing genotypes are associated with deterioration in renal function in type 2 diabetes.

Introduction: Accumulating evidence support that mannan-binding lectin (MBL) is a promising prognostic biomarker for risk-stratification of diabetic micro- and macrovascular complications. Serum MBL levels are predominately genetically determined and depend on MBL genotype. However, Type 1 diabetes (T1D) is associated with higher MBL serum levels for a given MBL genotype, but it remains unknown if this is also the case for patients with T2D. In this study, we evaluated the impact of MBL genotypes on renal function trajectories serum MBL levels and compared MBL genotypes in newly diagnosed patients with T2D with age- and sex-matched healthy individuals. Furthermore, we evaluated differences in parameters of insulin resistance within MBL genotypes. Methods: In a cross-sectional study, we included 100 patients who were recently diagnosed with T2D and 100 age- and sex-matched individuals. We measured serum MBL levels, MBL genotype, standard biochemistry, and DEXA, in all participants. A 5-year clinical follow-up study was conducted, followed by 12-year data on follow-up biochemistry and clinical status for the progression to micro- or macroalbuminuria for the patients with T2D. Results: We found similar serum MBL levels and distribution of MBL genotypes between T2D patients and healthy individuals. The serum MBL level for a given MBL genotype did not differ between the groups neither at study entry nor at 5-year follow-up. We found that plasma creatinine increased more rapidly in patients with T2D with the high MBL expression genotype than with the medium/low MBL expression genotype over the 12-year follow-up period (p = 0.029). Serum MBL levels did not correlate with diabetes duration nor with HbA1c. Interestingly, serum MBL was inversely correlated with body fat percentage in individuals with high MBL expression genotypes both at study entry (p=0.0005) and 5-years follow-up (p=0.002). Discussion: Contrary to T1D, T2D is not per se associated with increased MBL serum level for a given MBL genotype or with diabetes duration. Serum MBL was inversely correlated with body fat percentage, and T2D patients with the high MBL expression genotype presented with deterioration of renal function.

Association between mannose-binding lectin, high-sensitivity C-reactive protein and the progression of diabetic nephropathy in type 1 diabetes.

AIMS/HYPOTHESIS: Diabetic nephropathy has been associated with low-grade inflammation and activation of the complement system in cross-sectional studies. Data from prospective studies are sparse. We investigated the associations of the complement activator mannose-binding lectin (MBL) and the inflammatory marker high-sensitivity C-reactive protein (hsCRP) with the development of nephropathy in a large prospective study of patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study. METHODS: Baseline MBL and hsCRP were measured in 1,564 type 1 diabetes patients from the FinnDiane study, of whom 1,010 had a normal albumin excretion rate, 236 had microalbuminuria and 318 had macroalbuminuria. The main outcome was progression in renal disease during follow-up. RESULTS: Both baseline MBL (p = 0.038) and hsCRP (p < 0.001) increased with increasing level of albuminuria. During 5.8 +/- 2.2 years of follow-up, progression to a higher albuminuria level or end-stage renal disease (ESRD) occurred in 201 patients. MBL levels were higher in progressors compared with non-progressors at all steps of progression, and in a covariate adjusted multivariate Cox-regression analysis MBL levels above the median were significantly associated with progression from macroalbuminuria to ESRD (hazard ratio 1.88, 95% CI 1.06-3.32, p = 0.030). In a univariate analysis, hsCRP levels above the median were significantly associated with progression from normal albumin excretion rate to microalbuminuria, but the association was only borderline significant after adjustment for covariates (hazard ratio 1.56, 95% CI 0.97-2.51, p = 0.068). CONCLUSIONS/INTERPRETATION: This study demonstrates that concentrations of both MBL and hsCRP are associated with the progression of renal disease in type 1 diabetes.

The prevalence of food hypersensitivity in young adults.

rising prevalence of food hypersensitivity (FHS) and severe allergic reactions to foods have been reported in the last decade. However, little is known on the prevalence in young adults. This study estimated the prevalence of FHS to the most common allergenic foods in an unselected population of young adults. We investigated a cohort of 1272 young adults 22 years of age by questionnaire, skin prick test (SPT) and histamin release (HR) followed by oral challenge to the most common allergenic foods. FHS was divided into primary and secondary FHS. Primary FHS was defined as being independent of pollen sensitization, whereas secondary FHS was defined as reactions to pollen related fruits and vegetables in pollen allergic patients. The questionnaire was returned by 77.1%. Primary FHS was reported by 19.6% and secondary FHS by 16.7% of the participants. Confirmed primary FHS by oral challenge was 1.7% [1.1% - 2.95%]. In primary FHS, the most common allergenic food was peanut (0.6%) followed by additives (0.5%), shrimp (0.2%), codfish (0.1%), cow's milk (0.1%), octopus (0.1%) and soy (0.1%). In secondary FHS, kiwi allergy was reported by 7.8% of the participants followed by hazelnut (6.6%), pineapple (4.4%), apple (4.3%), orange (4.2%), tomato (3.8%), peach (3.0%) and brazil nut (2.7%). This study found a 1.7% [1.1% - 2.95%] prevalence of primary FHS confirmed by oral challenge to the most common allergenic foods in an unselected population of young adults.

Effects of GH replacement therapy in adults on serum levels of leptin and ghrelin: the role of lipolysis.

OBJECTIVE: The regulation and function of systemic ghrelin levels appear to be associated with food intake and energy balance rather than GH. Since GH, in turn, acutely induces lipolysis and insulin resistance in skeletal muscle, we aimed to study the isolated and combined effects of GH, free fatty acids (FFAs) and insulin sensitivity on circulating ghrelin levels in human subjects. DESIGN: Seven GH-deficient patients (aged 37 +/- 4 years (mean +/- s.e.)) were studied on four occasions in a 2 x 2 factorial design with and without GH substitution and with and without administration of acipimox, which lowers FFA levels by inhibition of the hormone-sensitive lipase, in the basal state and during a hyperinsulinemic euglycemic clamp. RESULTS: Serum FFA levels decreased with acipimox administration irrespective of GH status. The GH-induced reduction in insulin sensitivity was countered by acipimox. Fasting ghrelin levels decreased insignificantly during GH administration alone, but were reduced by 33% during co-administration of GH and acipimox (Aci) (in ng/l): 860 +/- 120 (-GH - Aci), 711 +/- 130 (-GH + Aci), 806 +/- 130 (+GH - Aci), 574 +/- 129 (+GH + Aci), P < 0.01. The clamp was associated with a further, moderate lowering of ghrelin. GH and acipimox induced a reciprocal 25% increase in serum leptin levels (microg/l): 11.2 +/- 4.4 (-GH - Aci), 11.7 +/- 4.4 (-GH + Aci), 11.5 +/- 4.4 (+GH - Aci), 13.9 +/- 4.2 (+GH + Aci), P = 0.005. CONCLUSION: Our data suggest that antilipolysis via suppression of the hormone-sensitive lipase in combination with GH administration is associated with significant and reciprocal changes in ghrelin and leptin.

GH strongly affects serum concentrations of mannan-binding lectin: evidence for a new IGF-I independent immunomodulatory effect of GH.

Studies in animals and humans indicate that GH and IGF-I modulate immune function. Recently, it was reported that GH therapy increased the mortality in critically ill patients. The excessive mortality was almost entirely attributable to septic shock or multiorgan failure, suggesting that a GH-induced modulation of immune function was involved. In the present study, we examined whether GH or IGF-I influences the serum concentrations of mannan-binding lectin (MBL). MBL is a plasma protein of the innate immune system that initiates the complement cascade and activates inflammation after binding to carbohydrate structures on microbial surfaces. We performed a cross-over study of 16 healthy men examined during a control period, and during treatment with either GH or IGF-I for 6 d. The levels of MBL were more than doubled during GH treatment, whereas no changes were observed in the IGF-I group or during the control period (P < 0.001). IGF-I levels were elevated similarly during treatment with GH and IGF-I. Subsequently, we studied 30 healthy persons and 25 GH-deficient (GHD) patients randomized to treatment with GH or placebo in a double-blinded manner, and further included samples from 23 patients with active acromegaly examined before and after treatment with octreotide or the GH-receptor antagonist pegvisomant for 3 months. Baseline concentrations of MBL were lower in GHD patients and higher in acromegalic patients than in healthy subjects (P < 0.02). Treatment with GH doubled the MBL concentrations in healthy subjects and almost quadrupled the concentrations in GHD patients; whereas in acromegalic patients, the levels of MBL were reduced to approximately two thirds of the initial values during treatment with octreotide or pegvisomant. Our results demonstrate that treatment with GH, but not IGF-I, significantly increases MBL concentrations. The clinical consequences of this new link between the endocrine and the immune system remain to be elucidated.

A new series of highly potent growth hormone-releasing peptides derived from ipamorelin.

A new series of GH secretagogues derived from ipamorelin is described. In an attempt to obtain oral bioavailability, by reducing the size and the number of potential hydrogen-bonding sites of the compounds, a strategy using the peptidomimetic fragment 3-(aminomethyl)benzoic acid and sequential backbone N-methylations was applied. Several compounds from this series release GH with high in vitro potency and efficacy in a rat pituitary cell assay and high in vivo potency and efficacy in anesthetized rats. The tetrapeptide NNC 26-0235 (3-(aminomethyl)benzoyl-D-2Nal-N-Me-D-Phe-Lys-NH2) shows, following iv administration, comparable in vivo potency to ipamorelin, GHRP-2, and GHRP-6 with an ED50 in swine at 2 nmol/kg. NNC 26-0235 demonstrated a 10% oral bioavailability in dogs, and NNC 26-0235 and ipamorelin were able to increase basal GH level by more than 10-fold after oral administration of a dose of 1.8 and 2.7 mg/kg, respectively. The tripeptide NNC 26-0323 (3-(aminomethyl)benzoic acid-N-Me-D-2Nal-N-Me-D-Phe-ol) which showed moderate in vitro potency but lacked in vivo potency demonstrated a 20% oral bioavailability in rats.

Novel orally active growth hormone secretagogues.

A novel class of growth hormone-releasing compounds with a molecular weight in the range from 500 to 650 has been discovered. The aim of this study was to obtain growth hormone secretagogues with oral bioavailability. By a rational approach we were able to reduce the size of the lead compound ipamorelin (4) and simultaneously to reduce hydrogen-bonding potential by incorporation of backbone isosters while retaining in vivo potency in swine. A rat pituitary assay was used for screening of all compounds and to evaluate which compounds should be tested further for in vivo potency in swine and oral bioavailability, fpo, in dogs. Most of the tested compounds had fpo in the range of 10-55%. In vivo potency in swine after iv dosing is reported, and ED50 was found to be 30 nmol/kg of body weight for the most potent compound.

Pharmacological characterisation of a new oral GH secretagogue, NN703.

NN703 is a novel orally active GH secretagogue (GHS) derived from ipamorelin. NN703 stimulates GH release from rat pituitary cells in a dose-dependent manner with a potency and efficacy similar to that of GHRP-6. The effect is inhibited by known GHS antagonists, but not by a GH-releasing hormone antagonist. Binding of (35)S-MK677 to the human type 1A GHS receptor (GHS-R 1A) stably expressed on BHK cells was inhibited by GHRP-6 and MK677 as expected. NN703 was also able to inhibit the binding of (35)S-MK677. However, the observed K(i) value was lower than expected, as based on the observed potencies regarding GH release from rat pituitary cells. Similarly, the effect of NN703 on the GHS-R 1A-induced inositol phosphate turnover in these cells showed a lower potency, when compared with GHRP-6 and MK677, than that observed in rat pituitary cells. The effect of i.v. administration of NN703 on GH and cortisol release was studied in swine. The potency and efficacy of NN703 on GH release were determined to be 155+/-23 nmol/kg and 91+/-7 ng GH/ml plasma respectively. A 50% increase of cortisol, compared with basal levels, was observed for all the tested doses of NN703, but no dose-dependency was shown. The effect of NN703 on GH release after i. v. and oral dosing in beagle dogs was studied. NN703 dose-dependently increased the GH release after oral administration. At the highest dose (20 micromol/kg), a 35-fold increase in peak GH concentration was observed (49.5+/-17.8 ng/ml, mean+/-s.e.m.). After a single i.v. dose of 1 micromol/kg the peak GH plasma concentration was elevated to 38.5+/-19.6 ng/ml (mean+/-s.e.m.) approximately 30 min after dosing and returned to basal level after 360 min. The oral bioavailability was 30%. The plasma half-life of NN703 was 4.1+/-0.4 h. A long-term biological effect of NN703 was demonstrated in a rat study, where the body weight gain was measured during a 14-day once daily oral challenge with 100 micromol/kg. The body weight gain was significantly increased after 14 days as compared with a vehicle-treated group. In summary, we here describe an orally active and GH specific secretagogue, NN703. This compound acts through a similar mechanism as GHRP-6, but has a different receptor pharmacology. NN703 induced GH release in both swine and dogs after i.v. and/or p.o. administration, had a high degree of GH specificity in swine and significantly increased the body weight gain in rats.

Growth hormone treatment in adults: is there a true gender difference?

The importance of growth hormone (GH) deficiency in adults became evident at the end of the 1980s, when the first clinical studies on GH replacement therapy in adults were published. Since then, accumulated experience has shown a great individual variability in the response to GH replacement, including a potential difference in responsiveness between genders. The aim of this paper is to review the data regarding the effects of gender differences on GH pharmacokinetics, pharmacodynamics, and efficacy of replacement. In addition, we start with a short review of the possible role of GH in sexual development and sexual life.

Helicobacter felis does not stimulate human neutrophil oxidative burst in contrast to 'Gastrospirillum hominis' and Helicobacter pylori.

Helicobacter pylori is a human pathogen, whereas the natural hosts for 'Gastrospirillum hominis' and Helicobacter felis are animals. 'G. hominis' is occasionally found to cause infection in humans, whereas H. felis only rarely infects humans. The pathogenesis of H. pylori infection is not completely understood and in order to reveal differences in immune response to the three Helicobacter species, the upregulation of adherence molecule CD11b/CD18, chemotactic activity and oxidative burst response of neutrophils after stimulation with H. pylori, 'G. hominis' and H. felis sonicates, were compared. Like H. pylori, 'G. hominis' and H. felis induced upregulation of CD11b/CD18 and chemotaxis of neutrophils. 'G. hominis' demonstrated a more pronounced upregulation of CD11b/CD18, whereas H. felis was the strongest stimulant of neutrophil chemotaxis. H. felis was unable to stimulate neutrophils to oxidative burst response, whereas 'G. hominis' activated neutrophils in a dose-dependent way similar to H. pylori. 'G. hominis' and H. felis were both able to prime neutrophils for oxidative burst response similar to H. pylori. In conclusion, we observed clear differences in neutrophil responses to different Helicobacter species, which indicates that bacterial virulence factors may be important for the diversity in the pathogenetic outcome of Helicobacter infections.