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The identification of early markers of atopy in cord blood of newborns at delivery may offer prediction of future allergic sensitization. The aim of this study was to evaluate the relationship between cord blood interleukin-13 (IL-13) and interferon-gamma (IFN-γ) and development of allergic diseases during the first five years of life. Umbilical cord blood samples were collected at the time of delivery from 62 newborns. The families of these newborns were asked to complete a questionnaire about age and education of parents, number of siblings, allergic diseases in family members, cigarette exposure during pregnancy and presence of pets in their house. The same subjects were evaluated when they were five years old. Venous blood samples were drawn and epidermal skin prick tests were performed. IL-13 and interferon-gamma (IFN-γ) levels were studied from the blood samples which were taken during birth and five years later. There was no significant relationship between gender, type of delivery, educational levels of parents, exposure to cigarette smoke, atopy in parents, presence of pets in the house and IL-13 and IFN-γ levels in cord blood and at five years. Higher levels of IL-13 in newborns and five years olds, were found significantly related to skin prick test positivity (p=0.004 and p<0.0001, respectively) and presence of allergic diseases (p= 0.008 and p= 0.001, respectively). Levels of IFN-γ, both in cord blood and five years after, were not related with the future of allergic status of children. Higher levels of IL-13 in cord blood may be a predictor of future development of allergic sensitization.

The main pathophysiology in cerebral ischemia is the structural alteration in the neurovascular unit, coinciding with neurovascular matrix degradation. Among the human matrix metalloproteinases (MMPs), MMP-2 and -9, known as gelatinases, are the key enzymes for degrading type IV collagen, which is the major component of the basal membrane that surrounds the cerebral blood vessel. In the present study, we investigated the effects of resveratrol on cytotoxicity, reactive oxygen species (ROS), and gelatinases (MMP-2 and -9) in human cerebral microvascular endothelial cells exposed to 6 hours of oxygen-glucose deprivation and a subsequent 24 hours of reoxygenation with glucose (OGD/R), to mimic ischemia/reperfusion in vivo. Lactate dehydrogenase increased significantly, in comparison to that in the normoxia group. ROS was markedly increased in the OGD/R group, compared to normoxia. Correspondingly, ROS was significantly reduced with 50 μM of resveratrol. The proMMP-2 activity in the OGD/R group showed a statistically significant increase from the control cells. Resveratrol preconditioning decreased significantly the proMMP-2 in the cells exposed to OGD/R in comparison to that in the OGD/R group. Our results indicate that resveratrol regulates MMP-2 activity induced by OGD/R via its antioxidant effect, implying a possible mechanism related to the neuroprotective effect of resveratrol.

Endothelial cells lining the inner blood vessel walls play a key role in the response to hypoxia, which is frequently encountered in clinical conditions such as myocardial infarction, renal ischemia and cerebral ischemia. In the present study we investigated the effects of hypoxia and hypoxia/reoxygenation on gelatinases (matrix metalloproteinase-2 and -9), their inhibitor (TIMP-2) and activator (MT1-MMP), in human umbilical vein endothelial (HUVE) cells. HUVE cells were subjected to 4 h of hypoxia or hypoxia followed by 4 and 24 h of reoxygenation. The pro- and active forms of MMP-2 and MMP-9 were analyzed by gelatin zymography; TIMP-2 protein level was assayed using ELISA, while MT1-MMP activity was measured using an activity assay. The secretion of MMP-2 proform increased significantly in cells subjected to 4 h of hypoxia followed by 4 or 24 h of reoxygenation, compared with the normoxic group. TIMP-2 protein level also increased significantly in the hypoxia/reoxygenation groups, compared with the normoxic group. There were no statistically significant differences in the levels of active MT1-MMP in all groups. This study indicates that MMP-2 and TIMP-2 could be regarded as important components of a mechanism in the pathophysiology of ischemic injury following reperfusion.

Matrix metalloproteinases (MMPs), and, in particular, gelatinases (MMP-2 and MMP-9), have been implicated in vascular cell proliferation and/or migration, contributing to intimal thickening, an essential stage in the development of atherosclerosis and restenosis following balloon angioplasty. Endothelin, a strong chemoatractant and mitogen, has been shown to promote smooth muscle cell proliferation and migration by activating MMPs via endothelin-A (ETA) receptors. The positioning of a soft silicon collar around the left carotid artery in rabbits results in intimal thickening. In this study, we investigate the possible role of gelatinases and the effect of a nonselective ETA/ETB receptor antagonist, TAK-044 (5 mg/kg body weight/day, subcutaneously [sc]), on these enzymes. Our results demonstrated that both MMP-2 and MMP-9 activities increased in response to collaring in placebo group, while treatment with TAK-044 significantly suppressed both gelatinase activities and proMMP-2 levels, and inhibited intimal thickening in collared arteries. These results suggest that either enhanced MMP expression or endothelin receptor antagonism may be involved in the formation of intimal thickening in this model.

Maternal milk plays an important role in breast milk jaundice (BMJ) development and is the major source of epidermal growth factor (EGF) for neonates. The aim of this study was to investigate whether there is a relationship between EGF levels in the infant serum and in the milk of nursing mothers and BMJ. Two groups were defined: study group (n = 30), newborns who were followed up for BMJ without any identifiable pathologic cause; control group, healthy newborns whose serum total bilirubin levels were <10 mg/dL. Milk and infant plasma samples were collected between the third and the fourth postpartum week. EGF concentrations in all of the samples were determined by using ELISA. The infants with BMJ had higher concentrations of EGF in the serum and in the breast milk compared with that of the infants without BMJ. The milk concentrations of EGF were significantly correlated with neonatal bilirubin and blood EGF concentrations. The degree of BMJ was associated with the increased levels of milk borne EGF. Although the exact mechanisms of the hyperbilirubinemic action of EGF are not completely known, the inhibition of gastric motility, increased absorption, and activation of bilirubin transport have been suggested as possible mechanisms.

Lower respiratory tract infections are the most important factors among various causes which trigger wheezing in the first year of life. The factors associated with episodic wheezing in children with acute bronchiolitis are still subjects of research. Infections, environmental factors, immunologic mechanisms are sorted as etiologic risk factors of episodic wheezing. We aimed to investigate the relationship between serum interleukin (IL)-4, IL-13 and gamma-interferon (IFN-gamma) levels and recurrence of wheezing episodes in infants with acute bronchiolitis. One hundred twenty infants between 3 and 36 months with acute bronchiolitis enrolled in the study. Personal histories, clinical and laboratory data of infants were recorded. The patients were followed for a year. Venous blood samples were obtained to determine serum IL-4, IL-13, and IFN-gamma levels during acute bronchiolitis episode. The number of wheezing episodes was significantly higher in infants with a positive family history of allergy. A statistically significant correlation was determined between serum IL-13 levels of infants and number of wheezing episodes. High serum IL-13 levels and a positive history of allergy may have important roles in the recurrence of acute bronchiolitis.

Previous studies have shown that erythropoietin (EPO) has protective effects against ischemia/reperfusion (I/R) injury in several tissues. The aim of this study was to determine whether EPO could prevent intestinal tissue injury induced by I/R. Wistar rats were subjected to intestinal ischemia (30 min) and reperfusion (60 min). A single dose of EPO (5000 U/kg) was administered intraperitoneally at two different time points: either at five minutes before the onset of ischemia or at the onset of reperfusion. At the end of the reperfusion period, jejunum was removed for examinations. Myeloperoxidase (MPO), malondialdehyde (MDA), and antioxidant defense system were assessed by biochemical analyses. Histological evaluation was performed according to the Chiu scoring method. Endothelial nitric oxide synthase (eNOS) was demonstrated by immunohistochemistry. Apoptotic cells were determined by TUNEL staining. Compared with the sham, I/R caused intestinal tissue injury (Chiu score, 3+/-0.36 vs 0.4+/-0.24, P<0.01) and was accompanied by increases in MDA levels (0.747+/-0.076 vs 0.492+/-0.033, P<0.05), MPO activity (10.51+/-1.87 vs 4.3+/-0.45, P<0.05), intensity of eNOS immunolabelling (3+/-0.4 vs 1.3+/-0.33, P<0.05), the number of TUNEL-positive cells (20.4+/-2.6 vs 4.6+/-1.2, P<0.001), and a decrease in catalase activity (16.83+/-2.6 vs 43.15+/-4.7, P<0.01). Compared with the vehicle-treated I/R, EPO improved tissue injury; decreased the intensity of eNOS immunolabelling (1.6+/-0.24 vs 3+/-0.4, P<0.05), the number of TUNEL-positive cells (9.2+/-2.7 vs 20.4+/-2.6, P<0.01), and the high histological scores (1+/-0.51 vs 3+/-0.36, P<0.01), and increased catalase activity (42.85+/-6 vs 16.83+/-2.6, P<0.01) when given before ischemia, while it was found to have decreased the levels of MDA (0.483+/-0.025 vs 0.747+/-0.076, P<0.05) and MPO activity (3.86+/-0.76 vs 10.51+/-1.87, P<0.05), intensity of eNOS immunolabelling (1.4+/-0.24 vs 3+/-0.4, P<0.01), the number of TUNEL-positive cells (9.1+/-3 vs 20.4+/-2.6, P<0.01), and the number of high histological scores (1.16+/-0.4 vs 3+/-0.36, P<0.05) when given at the onset of reperfusion. These results demonstrate that EPO protects against intestinal I/R injury in rats by reducing oxidative stress and apoptosis. We attributed this beneficial effect to the antioxidative properties of EPO.

The aim of this study was to evaluate respiratory function tests, total eosinophil counts, serum immune globulin E (IgE), and serum concentrations of soluble intercellular adhesion molecule (sICAM)1, soluble vascular cell adhesion molecule (sVCAM) 1, and soluble P-selectin (sP-selectin) levels in the children with mild and/or moderate asthma before and 3 months after inhaled steroids and to determine whether adhesion molecule levels showed any difference between asthmatic and healthy children and whether these levels changed with disease activity. A total of 28 children with bronchial asthma and 24 children as a control group were included in the study. All of the patients in the study group were administered inhaled budesonide treatment. The patients were reevaluated 3 months later. Respiratory functions tests were performed and total eosinophil count and serum total IgE level were determined. Serum levels of sICAM-1, sVCAM-1, and sP-selectin were determined and skin-prick tests were performed. Significant difference paralleled to clinical improvement was found in the study group for respiratory function tests, total eosinophil count, serum IgE level, and sICAM-1 levels determined before and after the treatment. However, no significant difference was found for sP-selectin and sVCAM-1 levels before and after the treatment. The higher level of sICAM-1 before the treatment suggests that leukocyte-endothelial adhesion have a role in bronchial asthma, which is an inflammatory airway disease. Reduction in the level of sICAM-1 after the treatment may be related to the decreased inflammation in response to therapy. However, no strong relationships were found between the determinants representing the inflammation and respiratory function tests.

This study evaluated the superiority of combination therapy over steroid therapy alone by using clinical and laboratory data including interleukin (IL)-13 and interferon (IFN) gamma, which participate in the characteristic inflammation and have not been studied to evaluate the efficiency of asthma treatment sufficiently. Moderate persistent asthma patients, aged 7-17 years were included in the study. Patients were randomized to three groups. Group 1 used inhaled budesonide, group 2 used inhaled budesonide plus inhaled formoterol fumarate, and group 3 used inhaled budesonide and oral montelukast sodium therapy. At the beginning and at the end of the 2nd month a detailed physical examination and clinical evaluation; total IgE levels and total eosinophil count in peripheral venous blood, serum IL-13, and IFN-gamma levels; pulmonary function tests; and an assessment questionnaire (Pediatric Asthma Quality-of-Life Questionnaire with Standardized Activities [PAQLQ{S}] were performed. Sixty-seven patients completed the study. Serum IL-13 levels and PAQLQ(S) scores before the therapy and serum IL-13 levels after the therapy were significantly different between the groups and other parameters did not show any significant differences. Serum IgE level was decreased after the therapy in group I and increased in groups 2 and 3, but the difference was insignificant. In all groups total eosinophil levels were decreased insignificantly. After the therapy, IL-13 levels were decreased in groups 1 and 2 and increased in group 3, but the difference was not statistically significant. When compared with the levels before the therapy IFN-gamma levels were decreased after the therapy but the difference was not statistically significant. When the improvement rates for IgE, total eosinophil, IL-13, and IFN-gamma levels and each parameter of respiratory function tests were compared, there were no significant differences between the therapy groups. In all groups PAQLQ(S) scores were significantly improved after the therapy. Our results showed that steroid and other agent combinations do not have any superiority to steroids only; but according to pulmonary function tests and clinical indicators, all three therapy models are effective. These results suggested that the inhalation steroids, as the oldest agents, are still preserving their place and importance in asthma therapy.

Aim: We aimed to investigate in children with a history of acute pyelonephritis the influence of unilateral post-pyelonephritic renal scarring detected by DMSA scan on serum (S(CysC)) and urine cystatin C (U(CysC)) as well as upon other traditional markers of renal damage., Methods: Children with DMSA proven pyelonephritis (n = 28) were grouped as either scar [+] (n = 19, unilateral renal scarring) or scar [-] (no scarring, n = 9). The scar [+] group was further divided into scar-1 (differential DMSA uptake, Delta(DMSA) 10%, n = 11) subgroups. S(CysC), serum creatinine, urine NAG, microalbumin, protein, fractional sodium excretion (FE(Na)), tubular phosphate reabsorption (TPR), and U(CysC/Cr) were evaluated in all patients., Results: Neither S(CysC) nor U(CysC) were affected by age, height, and weight. scar [+] versus scar [-] groups and scar-1 versus scar-2 subgroups were not different with regard to all studied parameters. S(CysC) did not increase in children with post-pyelonephritic unilateral renal scarring. However, 11 children with slightly increased (>0.95 mg/l) S(CysC) levels in scar [+] group tended to have higher Delta(DMSA), albeit not significantly. Furthermore, U(CysC/Cr) correlated well with urine microalbumin, NAG, and FE(Na) in all children and the scar [+] group (P < 0.05)., Conclusion: S(CysC) and U(CysC) did not differ among pediatric patients with and without unilateral post-pyelonephritic renal scarring. However, Delta(DMSA) uptake between the two kidneys tended to be raised in children with S(CysC) levels higher than the reference ranges. Additionally, U(CysC/Cr) exhibits parallelism with tubular functions.

Intimal thickening, due to smooth muscle cell migration and proliferation, is considered to be one of the major components of vascular proliferative disorders such as atherosclerosis and restenosis. One experimental model, resulting in intimal thickening in the rabbit, involves placing a silicon collar around the carotid artery, and is used in this study. Endothelin is known to act as a strong mitogen and to stimulate smooth muscle cell proliferation and migration. We investigated the contribution of endothelin to the development of collar-induced intimal thickening and the effects of TAK-044, (5 mg kg(-1) daily, s.c.), a non-selective ET(A)/ET(B) receptor antagonist, on intimal thickening and vascular reactivity changes in the collared rabbit carotid artery. Endothelin levels and the intimal cross-sectional area, as well as the ratio of intimal area to media (index), increased significantly in collared arteries as compared with those in sham-operated arteries. TAK-044 significantly inhibited intimal thickening and also decreased the index without affecting increased endothelin levels in collared arteries. Vascular reactivity changes in response to collaring produced predictable effects, such as decreased contractile responses to vasoconstrictor agents and increased sensitivity to serotonin (5-hydroxytryptamine, 5-HT). In terms of contractile responses in this model, TAK-044, in particular, did not affect collar-induced vascular reactivity changes. These results suggest that endothelin may be involved in the pathogenesis of collar-induced intimal thickening. As an endothelin receptor antagonist, TAK-044 may potentially be beneficial in the treatment of atherosclerosis.

Objectives: To determine the clinical effectiveness, tolerability and reliability of montelukast and to compare this drug with inhaled corticosteroids., Methods: We performed a randomized, 14-week, 2-period, prospective parallel group study. After a 2-week run-in period, patients received treatment for 12 weeks. Sixty-three clinically stable outpatients aged 8 to 14 years with a history of mild persistent asthma for at least 1 year and a forced expiratory volume in one second (FEV1) greater than 80 % of the predicted value were evaluated., Results: Montelukast produced improvement in airway obstruction, daily symptom scores, total daily as-needed beta-agonist use, nocturnal awakenings, percentage of days and percentage of patients with asthma exacerbations, and urinary leukotriene E4 levels. These beneficial effects were similar to those produced by inhaled corticosteroids. There were no significant adverse effects requiring treatment discontinuation., Conclusions: Montelukast may be a well-tolerated and effective therapeutic option in 8 to 14-year-old patients with mild persistent asthma.

Induction of colitis by acetic acid (AA) in the rat is widely used experimental model of inflammatory bowel disease (IBD) and ulcerations. AA as an irritant induces colitis involving infiltration of colonic mucosa with neutrophils and increased production of inflammatory mediators, such as hydrogen peroxide (H2O2), nitric oxide (NO), myeloperoxidase activity (MPO), and tumor necrosis factor (TNF-alpha). Trimetazidine (TMZ), an antianginal compound, was administered to investigate if its cytoprotective features in cardiac tissue are also effective in AA colitis where ischemic injury contributes to colitis. Administration of TMZ intraperitoneally improved the macroscopic and microscopic score alterations produced by AA. AA administration significantly elevated colonic MPO activity; however, treatment with TMZ significantly lowered this enzyme activity compared to AA. AA administration significantly enhanced superoxide dismutase (SOD) activities, except for AA + TMZ given rectally. TMZ treatment significantly lowered nitrate levels, but AA increased these levels. AA administration markedly lowered TNF-alpha levels, but TMZ treatment elevated these levels to control. These findings indicate that overproduction of NO may be involved in the immunosuppression observed during acute AA-induced rat colitis. In conclusion, TMZ treatment was more effective via the intraperitoneal than rectal route, and may be beneficial in therapy of colitis.

Objective: To determine the changes in levels of urinary NTx at the end of the 6th month of oral and transdermal hormone replacement therapy (HRT) and the effects of additional alendronate therapy for osteoporotic women., Method: Of 66 postmenopausal women 23 were treated with oral estradiol+norethisterone acetate (E+P), and 22 were treated with transdermal estradiol+norethisterone acetate. The third group consisted of 21 women with osteoporosis (bone mineral density < 100 mg/cm(3)) and treated with oral E+P plus alendronate 10 mg/day., Result: Significant decreases of urinary NTx levels were seen after HRT in all study groups (P < 0.05). But the decline of NTx levels was not different between the oral and transdermal HRT groups (P > 0.05). There was no additional decrease in the levels of NTx with alendronate therapy (P > 0.05) but NTx excretion diminished more in patients with high baseline levels., Conclusion: The decline of NTx at the end of the 6th month of HRT reflects the decrease of bone resorption and it is not related to the route of administration., (Copyright 2002 Elsevier Science Ireland Ltd.)

Increased nitric oxide (NO) levels are thought to play an important role in the pathophysiology of the systemic inflammatory response syndrome (SIRS) which is caused by disseminated vascular endothelial damage. Clinical studies have shown that urinary nitrite (NO2-) and nitrate (NO3-) excretions can be utilized as indexes of NO formation. The SIRS and NO relationship was investigated in 15 neonates with SIRS, gestational age 32.5 +/- 4.4 weeks and weight 1,737 +/- 753 g. The control group comprised 18 neonates with a gestational age of 32.8 +/- 3.5 weeks and a weight of 1,778 +/- 538 g. There was no significant difference in birth weights and gestational ages between the two groups (p > 0.05 and p > 0.05). The urinary nitrite levels obtained in the subjects were normalized for urinary creatinine concentrations. The mean urinary nitrite levels in the control group neonates were found to be 4.22 +/- 1.8 micromol/mmol creatinine on the 1st day, 4.09 +/- 2.28 on the 2nd, 3.62 +/- 1.6 on the 3rd, and 4.01 +/- 1.12 micromol/mmol creatinine on the 7th day. There were no statistically significant differences between these levels (p > 0.05). We determined urinary levels of nitrite in neonates in the study group within the first 24 h of SIRS symptoms and found these levels (18.35 +/- 11.16 micromol nitrite/mmol creatinine) to be elevated as compared with those of the control subjects on the 7th day of life (p < 0.0005). In conclusion, urinary nitrite excretion is significantly elevated in neonates with SIRS due to septic events, and these results suggest that NO might play a part in SIRS.