Effects of inhaled budesonide on serum markers of bone metabolism in children with asthma.

The effects of inhaled glucocorticoids on serum markers of bone formation were evaluated in asthmatic children. Serum total alkaline phosphatase (AP), bone alkaline phosphatase (BAP), osteocalcin, and the novel marker of bone formation, carboxypropeptide of type I procollagen (PICP), were measured. In the cross-sectional part, long-term glucocorticoid users were compared with sodium cromoglycate (SCG) users. In the boys (n = 16), but not in the girls (n = 11), PICP was significantly lower in the glucocorticoid users than in the SCG users. PICP correlated positively with BAP (n = 54; groups combined, r = 0.29, p < 0.05). In the longitudinal part, the effects of inhaled budesonide or SCG, both used for the first time, were evaluated before and after 1 and 5 months of treatment. The budesonide dose was 800 micrograms/m2/day for 1 month and thereafter half of that. The SCG dose was 30 mg/day throughout the study. Only during budesonide use did osteocalcin and PICP decrease, the median osteocalcin by 8% at 1 month (p < 0.05) and by 6% at 5 months (n = 15), and PICP by 5% at 1 month (p < 0.05) and by 28% at 5 months (n = 7, p < 0.01). AP and BAP did not change significantly. Decreased PICP suggests decreased bone formation rate. PICP might be clinically useful as a marker of early adverse effects of glucocorticoids on bone.     

Abnormal myocardial kinetics of 123I-heptadecanoic acid in subjects with impaired glucose tolerance

Summary Increased triglyceride accumulation has been observed in the diabetic heart, but it is not known whether the abnormalities in myocardial fatty acid metabolism differ between insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetic patients or whether they are present even prior to overt diabetes. Therefore, we studied myocardial fatty acid kinetics with single-photon emission tomography using ¹²³I-heptadecanoic acid (HDA) in four groups of men: impaired glucose tolerance (IGT) (n = 13, age 53 ± 2 years, mean ± SEM), IDDM (n = 8, age 43 ± 3 years), NIDDM (n = 10, age 51 ± 2 years) and control subjects (n = 8, age 45 ± 4 years). Echocardiography and myocardial perfusion scintigraphy (IGT and NIDDM groups) were performed to study cardiac function and flow. In the IGT subjects, myocardial HDA beta-oxidation index was reduced by 53 % (4.6 ± 0.4 vs 9.7 ± 1.0 μmol · min^–1· 100 g^–1, p < 0.01) and HDA uptake by 34 % (3.7 ± 0.2 vs 5.6 ± 0.3 % of injected dose 100 g, p < 0.01) compared with the control subjects. The fractional HDA amount used for beta-oxidation was lower in the IGT compared with the control subjects (43 ± 4 vs 61 ± 4 %, p < 0.05). NIDDM patients also tended to have a lowered HDA beta-oxidation index, whereas IDDM patients had similar myocardial HDA kinetics compared to the control subjects. Myocardial perfusion imaging during the dipyridamole-handgrip stress was normal both in the IGT and NIDDM groups, indicating that abnormal myocardial perfusion could not explain abnormal fatty acid kinetics. In conclusion, even before clinical diabetes, IGT subjects show abnormalities in myocardial fatty acid uptake and kinetics. These abnormalities may be related to disturbed plasma and cellular lipid metabolism. [Diabetologia (1997) 40: 541–549] Received: 26 August 1996 and in revised form: 21 November 1996     

Study of the cytokine polymorphisms in correlation to rejection and graft survival in renal allograft donors and recipients from a homogenous Saudi population

ObjectivesAllograft outcome can be improved with the discovery of risk factors that influence adverse events and may allow individualization of patients' treatment. Rejection is the main hurdle to successful transplantation and the immune response is the key effecter to rejection development. Hence, the major objective of the present study was to assess the relationship between single nucleotide polymorphisms (SNPs) in 5 cytokine genes, HLA mismatch and graft outcome in a cohort of 100 Saudi kidney transplant recipients and 100 living related donors at a single transplant center.Materials & methodsGenotyping of the following positions: TNFA (? 308 G/A), TGFB1 (codon 10 T/C, codon 25 C/G), IL-10 (? 1082 G/A, ? 819 C/T, ? 592 C/A), IL-6 (? 174 C/G), and IFNG (+ 874 T/A) were performed.ResultsThe majority of the donors whose recipients presented with either cellular or antibody mediated graft rejection (90% and 100%) respectively were found to be significantly (p = 0.0351) associated with intermediate or high IL-10 producing haplotypes, compared to those with stable grafts (58.66%). Haplotypes linked with lower IL-10 production were not detected in the donors or their recipients with antibody mediated graft rejection compared to donors with stable graft (41.33%). The distribution of donor IL-10-1082 haplotypes (GG, GA, AA) showed a statistically significant association of IL-10-1082 GA genotype (p = 0.0351) with rejection, when grouped according to patients' rejection status. No other statistically significant deviations were observed in the donors' genotypes. Analyses of cytokine polymorphisms in the recipients revealed no significant association. Multivariate logistic regression analyses showed that only HLA-DRB1 mismatch significantly influenced graft loss (p = 0.0135).ConclusionThis study demonstrates that the donor IL-10 genotypes and HLA-DRB1 mismatch are key determinants in graft outcome after renal transplantation.     

The Plasma Level of Proprotein Convertase FURIN in Patients with Suspected Infection in the Emergency Room: A Prospective Cohort Study

There is an increasing need for novel biomarkers that enable better diagnostic and prognostic stratification of patients with suspected infection. A proprotein convertase enzyme FURIN is upregulated upon immune cell activation, and it promotes infectivity by cleaving and activating pathogens. In this study, we determined FURIN levels in plasma using ELISA from 537 patients that were admitted to emergency room with suspected infection. Patients were sorted to high‐ and low‐level FURIN groups with a cut‐off level of 370 pg/ml. The study cohort included five diagnostic groups: Group 1, no systemic inflammatory response syndrome (SIRS, n = 59 patients); Group 2, bacterial infection without SIRS (n = 67); Group 3, SIRS, but no bacterial infection (n = 308); Group 4, sepsis without organ failure (n = 308); and Group 5, severe sepsis (n = 49). Statistically significant associations were not found between the plasma level of FURIN and the prevalence of sepsis (P = 0.957), diagnostic group of a patient (P = 0.737) or the bacteria in blood culture (P = 0.499). Additionally, the concentration of FURIN did not predict the severity or case fatality of the infectious disease. However, statistically significant associations were found between high plasma level of FURIN and diagnosed rheumatic disease (P < 0.001) as well as with the prevalence of non‐smokers (P = 0.034). Thus, albeit the plasma level of FURIN does not predict the severity of infectious disease, it may be of use in the diagnostics of autoimmune diseases.     

Plant sterols and casein-derived tripeptides attenuate blood pressure increase in spontaneously hypertensive rats

In this study, we investigated the synergistic effects of plant sterols (PS) and casein-derived tripeptides on arterial tone and blood pressure in experimental hypertension. We hypothesized that PS and tripeptides could have positive, synergistic effects on the development of hypertension and endothelial dysfunction in young spontaneously hypertensive rats (SHR). Six-week-old male SHR were divided into 3 groups to receive milk products containing PS, or PS with tripeptides, or a control containing no active components for 8 weeks. Systolic blood pressure (SBP) was measured weekly, and vascular reactivity measurements with isolated mesenteric arteries were performed at the end of the study. Biochemical measurements for several parameters were performed by enzyme-linked immunosorbent assay using plasma samples. Levels of angiotensin-converting enzyme 1, cyclooxygenase-2, endothelial nitric oxide synthase, and P-selectin messenger RNA expressions were determined from aortic tissue by real-time polymerase chain reaction. The study showed that long-term treatment with PS + tripeptides attenuated the development of hypertension in SHR (SBP, 187 ± 5 mm Hg vs 169 ± 4 mm Hg in control group; P < .01). Plant sterols alone did not affect SBP significantly. Endothelial dysfunction was observed in all SHR; however, treatment with PS resulted in poorer endothelium-dependent and nitric oxide–mediated relaxation compared with other groups. Aortic cyclooxygenase-2 and P-selectin were significantly down-regulated in PS and PS + tripeptides groups when compared with the control group. The expression of endothelial nitric oxide synthase was significantly lower in PS than in PS + tripeptides group. In conclusion, long-term treatment with PS has a slight but not significant antihypertensive effect. Plant sterols do not provide any beneficial effects on endothelial function in hypertensive rats; however, treatment with both PS and tripeptides showed mild anti-inflammatory effects.     

Relation among mannose-binding lectin 2 genotype, beta-cell autoantibodies, and risk for type 1 diabetes in Finnish children

Mannose-binding lectin (MBL) is a key mediator of innate immunity, the insufficiency of which is caused by point mutations in the MBL2 gene. MBL insufficiency is associated with increased susceptibility to infections and certain autoimmune diseases, but its impact in the pathogenesis and risk of type 1 diabetes (T1D) is controversial. We investigated the significance of the MBL2 genotype on the risk of T1D in a Finnish study population comprising 470 diabetic children and 501 controls. Furthermore, the effect of MBL2 gene polymorphism on the emergence of beta-cell autoantibodies in 289 unaffected children with human leukocyte antigen-conferred susceptibility to T1D was assessed. MBL genotype had no significant effect on the risk or onset age of T1D. However, children with the biallelic variant genotype reflecting total MBL deficiency tested positive more frequently for > or =3 autoantibodies compared with children with another genotype (odds ratio = 6.0, 95% confidence interval 1.3-28; p = 0.013). In conclusion, the MBL2 genotype did not affect susceptibility to T1D in children, and this finding does not support previous reports implicating a role of the MBL2 genotype as a factor predisposing to T1D. The association of the biallelic variant genotype with positivity for multiple autoantibodies suggests that intermolecular epitope spreading may be linked with impaired clearance of autoantigens as a result of MBL deficiency.     

Targeted mutation of CCK2 receptor gene modifies the behavioural effects of diazepam in female mice

Rationale Evidence suggests that GABA and CCK have opposite roles in the regulation of anxiety. Objective The aim of the present work was to study diazepam-induced anxiolytic-like action and impairment of motor co-ordination, and the parameters of benzodiazepine receptors in mice lacking CCK₂ receptors. Methods The action of diazepam (0.5–3 mg/kg IP) was studied in the elevated plus-maze model of anxiety and rotarod test using mice lacking CCK₂ receptors. The parameters of benzodiazepine receptors were analysed using [³H]-flunitrazepam binding. Results In the plus-maze test, the exploratory activity of the homozygous (−/−) mice was significantly higher compared to their wild-type (+/+) littermates. However, the wild-type (+/+) mice displayed higher sensitivity to the anxiolytic-like action of diazepam. Even the lowest dose of diazepam (0.5 mg/kg) induced a significant increase of open arm entries in the wild-type (+/+) mice. A similar effect in the homozygous (−/−) mice was established after the administration of diazepam 1 mg/kg. The highest dose of diazepam (3 mg/kg) caused a prominent anxiolytic-like effect in the wild-type (+/+) mice, whereas in the homozygous (−/−) animals suppression of locomotor activity was evident. The performance of the homozygous (−/−) mice in the rotarod test did not differ from that of the wild-type (+/+) littermates. However, a difference between the wild-type (+/+) and homozygous (−/−) animals became evident after treatment with diazepam. Diazepam (0.5 and 3 mg/kg) induced significantly stronger impairment of motor co-ordination in the homozygous (−/−) mice compared to their wild-type (+/+) littermates. The density of benzodiazepine binding sites was increased in the cerebellum, but not in the cerebral cortex and hippocampus, of the homozygous (−/−) mice. Conclusions Female mice lacking CCK₂ receptors are less anxious than their wild-type (+/+) littermates. The reduced anxiety in homozygous (−/−) mice probably explains why the administration of a higher dose of diazepam is necessary to induce an anxiolytic-like action in these animals. The highest dose of diazepam (3 mg/kg) induced significantly stronger suppression of locomotor activity and impairment of motor co-ordination in the homozygous (−/−) mice compared to the wild-type (+/+) littermates. The increase in the action of diazepam is probably related to the elevated density of benzodiazepine receptors in the cerebellum of homozygous (−/−) mice. The present study seems to be in favour of increased tone of the GABAergic system in mice without CCK₂ receptors.