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Byline: A. Nobilis (1), I. Kocsis (2), P. Toth-Heyn (3), A. Treszl (2), A. Schuler (4), T. Tulassay (2), B. Vasarhelyi (2) Keywords: Keywords Acute renal failure; Very low birth weight infant; Angiotensin converting enzyme; Angiotensin II type 1 receptor; Genetic polymorphism Abstract: High neonatal activity of the renin-angiotensin system (RAS) is crucial for the maintenance of glomerular filtration of the newborn. The aim of the present study was to investigate whether genetic polymorphisms leading to lower angiotensin converting enzyme activity (ACE) or impaired functionality of angiotensin II (AII) type 1 receptor (AT1R) might predispose very low birth weight newborns (VLBWs) to the development of acute renal failure (ARF). The medical records of 110 VLBW infants were analyzed. ARF developed in 42 of them during the first postnatal week, while 68 neonates exhibited normal renal function. The ACE I/D polymorphism and the [A.sup.1166]C variants of AT1R were determined from dried blood samples. The frequency of the ACE I allele did not differ in ARF and non-ARF groups (0.307 and 0.284) the frequency of the AT1R C.sup.1166 variant was also the same in ARF and non-ARF groups (0.250 and 0.227). Although low activity of RAS has been implicated in the development of neonatal ARF and data indicated that the functionality of RAS is influenced by the I/D variants of the ACE gene and the [A.sup.1166]C variant of the AT1R gene, we could not demonstrate any effect of these polymorphisms on the development of ARF in VLBW infants. Author Affiliation: (1) Second Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary, HU (2) Joint Research Program of the First Department of Pediatrics and the Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary, HU (3) First Department of Pediatrics, Semmelweis University, Bokay u. 53, 1083 Budapest, Hungary. Vasbar@gyer1.sote.hu, HU (4) Budai Children's Hospital PKU Laboratory, Budapest, Hungary, HU Article note: Received: 7 March 2001 / Revised: 9 August 2001 / Accepted: 10 August 2001

Byline: G. Miltenyi (1), K. Tory (1), G. Stubnya (1), P. Toth-Heyn (1), B. Vasarhelyi (2), P. Sallay (1), A. Szabo (1), T. Tulassay (2), M. Dobos (1), G. S. Reusz (1) Keywords: KeywordsaCardiac output; Chronic renal failure; Endogenous digoxin-like factor; Impedance cardiography; Sodium pump Abstract: Hemodialysis (HD) causes rapid volume shifts and circulatory changes. In chronic renal failure (CRF) Na.sup.+/[K.sup.+]ATP-ase is depressed, whereas endogenous digoxin-like factor (EDLF) is elevated. Our aim was to characterize HD-induced cardiovascular adaptation and its possible links to Na.sup.+/[K.sup.+]ATP-ase and EDLF. Eleven children with CRF on HD (aged 14.7+-3.7 years) and 11 healthy children were investigated for basic circulatory parameters. Thoracic impedance (Zo) and circulatory parameters were monitored by impedance cardiography (ICG) during HD. Erythrocyte Na.sup.+/[K.sup.+]ATP-ase and EDLF were measured before and after HD. Up to the loss of 6% of total body weight, Zo rose linearly with fluid removal, above this no further increase occurred. Heart rate and mean arterial pressure (MAP) were inversely related (r=--0.97) MAP rose in the first and decreased in the second part of HD. Systemic vascular resistance paralleled MAP, whereas stroke volume rapidly decreased, but stabilized in the second part of HD. The ratio of preejection period/ventricular ejection time (PEP/VET) correlated positively with HD duration (r=0.92), suggesting diminished cardiac filling. Cardiac index (CI) remained stable. EDLF was high in uremia accompanied by depressed Na.sup.+/[K.sup.+]ATP-ase (P&lt 0.05 and P&lt 0.01, respectively). Following HD Na.sup.+/[K.sup.+]ATP-ase normalized. Correlation between Na.sup.+/[K.sup.+]ATP-ase activity and MAP was linear (r=0.85). In conclusion, ICG during HD provides detailed information concerning circulatory adaptation resulting in stable CI, suggesting that the dialysis-induced hypovolemia is compensated by the centralization of the blood volume. Changes of Na.sup.+/[K.sup.+]ATP-ase indicate that dialyzable blood pressure-regulating substance(s) inhibit(s) the pump. However, lack of further correlation between Na.sup.+/[K.sup.+]ATP-ase, EDLF, and cardiovascular parameters indicates the complexity of the regulatory processes. Author Affiliation: (1) Ist Department of Pediatrics, Semmelweis Medical University, Bokay u. 53, 1083 Budapest, Hungary, HU (2) Research Laboratory of the Hungarian Academy of Sciences, Bokay u. 53, 1083 Budapest, Hungary, HU (3) First Department of Pediatrics, Semmelweis Medical University, Bokay u. 53, 1083 Budapest, Hungary e-mail: reusz@gverl.sote.hu Fax: +36-1-3247795, HU Article note: Received: 12 May 2000 / Revised: 28 August 2000 / Accepted: 30 August 2000

Byline: B. Vasarhelyi (2), M. Dobos (2), G. S. Reusz (2), A. Szabo (2), T. Tulassay (1) Keywords: Key wordsaLow birth weight; Renal function; Natriuresis; Blood pressure; Na+/K+-ATPase activity Abstract: The aim of our study was to characterize renal function and its relationship to blood pressure in healthy young Caucasian men born with a birth weight under 2,500 g (LBW). Urinary protein patterns, N-acetylglucosamine and I3-glutamyltransferase activities, fractional sodium and potassium excretions, glomerular filtration rate, blood pressure, and erythrocyte Na.sup.+/K.sup.+-ATPase activities were determined in 65 subjects, of whom 49 were born with LBW. Signs of glomerular or tubular damage were not detected in the LBW population. However, the blood pressure and the renal sodium excretion were inversely correlated to the subjects' birth weight and were higher in LBW subjects than in controls. In contrast, the erythrocyte Na.sup.+/K.sup.+-ATPase activities were lower in LBW subjects. An inverse correlation was detected between the subjects' Na.sup.+/K.sup.+-ATPase activities and the renal sodium excretion or blood pressure. In summary, our results suggest that: (1) in young LBW Caucasian males signs of early glomerular and tubular impairment are not present (2) the elevated renal sodium excretion may be a result of higher blood pressure (3) the alteration of Na.sup.+/K.sup.+-ATPase activity might play a role either in the elevation of blood pressure and/or in the enhanced natriuresis of LBW subjects. Author Affiliation: (1) First Department of Pediatrics, Bokay u. 53, 1083 Budapest, Hungary e-mail: tulas@gyer1.sote.hu Tel.: +36-1-3142858, Fax: +36-1-3138212, HU (2) First Department of Pediatrics, Semmelweis Medical University, Budapest, Hungary, HU Article note: Received: 29 November 1999 / Revised: 20 March 2000 / Accepted: 22 March 2000

Byline: T. Tulassay (1), M. Dobos (1), A. Luczay (1), G. Stubnya (1), G. S. Reusz (1), B. Vasarhelyi (1), P. Sallay (1), A. Szabo (1) Keywords: Key wordsaNephrotic syndome; Sodium-lithium countertransport; Natrium-hydrogen exchanger; Edema sodium homeostasis Abstract: The mechanisms of sodium retention in edema-forming minimal change nephrotic syndrome (MCNS) have not been completely evaluated. The aim of this study was to characterize the transmembrane sodium transport in nephrotic syndrome by measuring the erythrocyte sodium-lithium countertransport (SLC) in vitro. Eighteen children with MCNS were studied in the edema-forming state, and subsequently at the beginning of remission. Nephrotic children with edema retained sodium (10+-12 umol/day) and had a higher SLC [426+-118 vs. 281+-60 Aumol/l red blood cells (RBC) per hour, P=0.003). The intracellular sodium concentration of nephrotics was 6.1+-2.1 mmol/l RBC, which did not differ from that of controls (6.42+-2.24, n=13). In remission sodium balance became negative (--30 +-21 mmol/day), and the SLC decreased but still differed significantly from control values (P=0.009). The intracellular sodium content decreased to 4.4+-0.9 mmol/l RBC (P=0.002). There was a negative correlation between erythrocyte SLC and plasma albumin concentration (r=0.48, P=0.003), and urinary sodium excretion rate (r=0.66, P=0.001). In conclusion, erythrocyte SLC is high in the edema-forming state of childhood nephrotic syndrome and decreases with the onset of remission. A role for the SLC in the altered sodium homeostasis of nephrotic syndrome is suggested. Author Affiliation: (1) 1st Department of Paediatrics, Semmelweis Medical University, Bokay utca 53, H-1083 Budapest, Hungary e-mail: tulas@gyer1.sote.hu Tel.: +36-1-31-42858, Fax: +36-1-30-36077, HU Article note: Received: 6 April 1998 / Revised: 5 October 1998 / Accepted: 4 November 1998

Objective: The aim of our study was to determine, how severe calorie restriction in anorexia nervosa (AN) may influence regulatory T (Treg) cells and their cellular networks, that is, their main inducers (dendritic cells (DC) and monocytes) and their target cells, CD4+ lymphocytes. Design: We measured the prevalence of Tregs, myeloid and plasmocytoid DC. The prevalence of tumor necrosis factor-[alpha] (TNF-[alpha]) and interleukin (IL)-12-positive monocytes, IL-2, IL-4 and interferon (IFN)-[gamma] positive CD4+ cells was determined by intracellular staining after activation. Setting and subjects: In total, 21 AN patients and 19 healthy age-matched controls (body mass index values, median (range): 14.9 (11.1-17.4) vs 23.2 (19.5-27.4) kg/m[sup.2]) have been recruited. Results: Prevalence of Tregs, DCs, TNF-[alpha] and IL-12-positive monocytes, IL-4 and IFN-[gamma]-producing CD4+ cells were similar in AN and controls. The prevalence of IL-2-positive CD4+ cells was somewhat lower in AN (% value, median (range): 12.05 (7.50-16.70) vs 14.40 (12.00-22.00), P [less than] 0.05). None of these parameters correlated with the patients' clinical characteristics. Conclusions: Our results suggest that the antigen presenting cell - regulatory T cell - CD4+ lymphocyte axis is not affected by calorie and nutritional deficiency. European Journal of Clinical Nutrition (2007) 61, 1245-1249; doi: 10.1038/sj.ejcn.1602651; published online 7 February 2007 Keywords: anorexia, Treg, antigen presenting cell, monocyte, interleukin, dendritic cell, Author(s): B Paszthy [1]; P [S caron]vec [2]; B Vasarhelyi [3]; F Tury [4]; J Mazzag [4]; T Tulassay [3]; A Treszl [3] Introduction Anorexia nervosa (AN) is an extreme [...]

A. Arato [1] H. Bodanszky [1] B. Vasarhelyi [1] I. Kocsis [1] I. Kiss [1] L. Szonyi [1] Z. Tulassay [2] T. Tulassay [1] [14/24] Transport Enzyme Activities of Gastric [...]

The Hardy-Weinberg law (1-4) presents a mathematical statement that describes the relationship between gene frequencies and genotype frequencies: gene frequencies at a locus in a randomly interbreeding diploid population and [...]

Aim: To study the relation between erythrocyte Na(+),K(+)-ATPase subunit isoform composition, Na(+),K(+)-ATPase activity, and cation pump function in preterm and term neonates.Design: Erythrocyte Na(+),K(+)-ATPase subunit isoform abundance, Na(+),K(+)-ATPase activity, and cation pump function were studied in blood samples obtained from 56 preterm neonates of 28-32 weeks gestation (group 1), 58 preterm neonates of 33-36 weeks gestation (group 2), and 122 term neonates (group 3) during the first two postnatal days.Results: alpha(1) isoform abundance was higher and beta(2) isoform abundance was lower in group 1 than in group 3 (p = 0.0002). alpha(2) and beta(1) isoform abundance did not change with maturation and there was no evidence for the presence of the alpha(3) isoform. Gestational age was inversely related to Na(+), K(+)-ATPase activity (p = 0.0001) and directly related to intracellular Na(+) concentration (p = 0.0025).Conclusions: Expression of the alpha(1) and beta(2) Na(+),K(+)-ATPase subunit isoforms is developmentally regulated. The increased abundance of alpha(1) isoforms of immature neonates translates to increased ATPase activity. The lower intracellular Na(+) concentration of immature neonates suggests that their erythrocyte Na(+),K(+)-ATPase cation pump function may also be increased. [ABSTRACT FROM AUTHOR]

Introduction: Estrogen hormones and their metabolites are implicated in the maintenance of healthy pregnancy and adequate fetal development. Abnormal levels were related to increased risk of pregnancy complications, particularly preeclampsia. Our aims were (1) to develop a methodological platform for the comprehensive assessment of estrogen metabolome in pregnancy; (2) to collect healthy reference data for relevant elements of estrogen metabolome in each trimester; (3) to assess unconjugated fractions of the estrogen metabolome, (4) to assess the dominant metabolic pathways of estrogen compounds., Methods: We enrolled healthy pregnant mothers between gestational week 5-15 (on the confirmation of pregnancy; 79 samples), gestational weeks 19-27 (70 samples), and gestational week 34-39 (54 samples). A method employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed to assess estrone, 17-beta-estradiol, estriol levels, and their metabolites as conjugated and unconjugated forms. Descriptive statistics were used to characterize the level of compounds in each trimester., Results: Estrone, 17-beta-estradiol and estriol levels are dramatically increasing with the advancement of pregnancy. Measured levels were in a very wide range. 17-beta-estradiol is neither glucuronated nor sulphated. To the contrary, estriol and estrone are significantly conjugated; unconjugated fraction is <15% of total hormone levels in any trimester. Regarding metabolism, 4-methoxy-estradiol and 17-epiestriol were not detected., Conclusion: We concluded that (1) the levels of estrogen compounds and metabolites increase with advancing gestational age; (2) the wide ranges of levels challenge the establishment of a healthy reference range for clinical purposes; (3) 17-beta-estradiol is not conjugated significantly; (4) 4-methylation and 17-epimerization pathways of estrogens are negligible with our LC-MS/MS method., Competing Interests: Declaration of competing interest As the corresponding author of this submitted manuscript hereby I declare that there is NO conflict of interest regarding the present study and any of co-authors., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Antibiotics that inhibit multiple bacterial targets offer a promising therapeutic strategy against resistance evolution, but developing such antibiotics is challenging. Here we demonstrate that a rational design of balanced multitargeting antibiotics is feasible by using a medicinal chemistry workflow. The resultant lead compounds, ULD1 and ULD2, belonging to a novel chemical class, almost equipotently inhibit bacterial DNA gyrase and topoisomerase IV complexes and interact with multiple evolutionary conserved amino acids in the ATP-binding pockets of their target proteins. ULD1 and ULD2 are excellently potent against a broad range of gram-positive bacteria. Notably, the efficacy of these compounds was tested against a broad panel of multidrug-resistant Staphylococcus aureus clinical strains. Antibiotics with clinical relevance against staphylococcal infections fail to inhibit a significant fraction of these isolates, whereas both ULD1 and ULD2 inhibit all of them (minimum inhibitory concentration [MIC] ≤1 μg/mL). Resistance mutations against these compounds are rare, have limited impact on compound susceptibility, and substantially reduce bacterial growth. Based on their efficacy and lack of toxicity demonstrated in murine infection models, these compounds could translate into new therapies against multidrug-resistant bacterial infections., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: A PCT patent application (New class of DNA gyrase and/or topoisomerase IV inhibitors with activity against gram-positive and gram-negative bacteria: PCT/EP2019/073412073412073412), has been filed by the T. Tomašič, N. Zidar, M. Durcik, J. Ilaš, A. Zega, C. Durante Cruz, P. Tammela, C. Pál, Á. Nyerges, D. Kikelj, L. Peterlin Mašič.

The assessment of the general inflammatory condition of patients with autoimmune connective tissue disorders (ACTD) is a major challenge. The use of traditional inflammatory markers including CRP-levels and erythrocyte sedimentation rate (ESR) is limited by several preanalytical factors and their low specificities. Soluble urokinase plasminogen activator receptor (suPAR) is one of the novel candidate markers that is increasingly used in immune mediated disorders. In our studies we compared suPAR levels of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and ankylosing spondylitis with those of healthy controls. suPAR provided valuable clinical information on disease activity in RA, SLE and SSc. We identified a subgroup of remitted RA patients, who presented still clinical symptoms of inflammatory activity which correlated to high plasma suPAR (while ESR and CRP were normal). In SLE we established specific suPAR cut-off values that support the discrimination between patients with high and those with moderate SLE activity. In patients with SSc suPAR correlated with objective measures of lung and other complications. In the majority of ACTDs including SLE, SSc or RA, suPAR is seemingly a good biomarker that would provide valuable clinical information. However, before the introduction of this novel parameter in laboratory repertoire important issues should be elucidated. These include the establishment of appropriate and disease specific cutoff values, clarification of interfering preanalytical values and underlying conditions and declaration of age- and gender-specific reference ranges.

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease involving several organs, including the lungs. Previous results confirmed changes of peripheral T cell subsets in lupus patients; however no data are available about their possible relationship with pulmonary involvement., Objective: To determine pulmonary manifestations and potential relationship in changes of peripheral CD4+ T cell subsets., Methods: Patients with SLE (N = 28) were enrolled in complex pulmonary examination. Patients were divided into groups with pleuropulmonary manifestations (SLEpulm N = 13 age: 44.9 ± 3.3 years, female: male = 11:2) or without (SLEc N = 15 age: 27.2 ± 3.7 years, female: male = 12:3). Peripheral blood was taken for T helper (Th)1, Th2, Th17, CD4+CD25hi+ and regulatory T (Treg: CD4+CD25hi+ CD127-) cell analysis from SLE patients and healthy volunteers (controls, N = 40)., Results: SLEpulm patients were older, had more pulmonary symptoms and significantly decreased pO2 as compared to SLEc group. Ventilatory disorder was present in 92% of SLEpulm patients, with significantly decreased lung volumes, signs of airway involvement and decrease in DLco. Significant increase in Th1/Th2, while decrease in Th17/Treg ratios was present in all SLE compared to controls. In SLEpulm CD4+CD25hi+ subset without changes in Treg number was significantly increased as compared to SLEc and this subgroup of T cell showed significant positive correlation with dynamic lung function parameters and DLco (p < 0.05)., Conclusion: In lupus patients pleuropulmonary manifestations are prevalent and lung function and blood gas measurements should be regularly performed in the daily clinical assessment. Significant increase of activated CD4+CD25hi+ T cells, but not Treg is associated with decreased lung function parameters in SLEpulm patients., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Stroke-induced immunosuppression (SIIS) leads to severe complications in stroke patients, including an increased risk of infections. However, functional alterations of T lymphocytes during SIIS are poorly described in acute ischemic stroke (AIS). We aimed to characterize Ca(2+) influx kinetics in major lymphocyte subsets (CD4, Th1, Th2, CD8) in AIS patients without infection 6 hours and one week after the CNS insult. We also assessed the sensitivity of the above subsets to specific inhibition of the Kv1.3 and IKCa1 lymphocyte K(+) channels. We took peripheral blood samples from 12 non-stroke individuals and 12 AIS patients. We used an innovative flow cytometry approach to determine Ca(2+) influx kinetics and the surface expression of Kv1.3 channels. Our results indicate that Ca(2+) influx kinetics is altered in the Th2 and CD8 subsets in AIS which may play a role in the development of SIIS. Specific inhibition of Kv1.3 channels selectively decreased Ca(2+) influx in the CD8 and Th2 subsets of AIS patients. The surface expression of Kv1.3 channels is also altered compared to non-stroke individuals. Kv1.3 channel inhibition might have beneficial therapeutic consequences in AIS, selectively targeting two distinct T cell subsets at two different time points following the CNS insult. Within hours after the insult, it might prevent excessive tissue injury through the inhibition of CD8 cells, while at one week after the insult, it may improve the inflammatory response through the inhibition of Th2 cells, thus reducing the unwanted clinical consequences of SIIS.

Aseptic inflammation due to activated immune cells has been implicated in the pathomechanism of migraine. We measured the prevalence of regulatory T cells (Tregs), along with that of CD4(+)/CD8(+) lymphocytes and their Th1/Th2 commitment in pediatric migraine. Children and adolescents suffering from migraine without aura, migraine with aura and hemiplegic migraine ictally (n = 53, 27, and 20, respectively), also interictally (n = 33) were recruited and compared to 24 healthy children. Our results indicated comparable prevalence of Tregs, CD4(+) and Th1/Th2 committed cells. CD8(+) prevalence was lower, and CD4(+)/CD8(+) ratio was higher in ictal phase irrespective of the subtype of migraine. No association between CD8(+) prevalence and gender, body weight, disease onset and attack duration in migraine subtypes was found. CD8(+) prevalence was normal in patients in interictal phase. These results suggest the absence of major systemic alteration of adaptive immunity in children and adolescents suffering from migraine; however, a transient decrease of CD8(+) prevalence during the ictal phase was detected irrespective of the subtype of migraine.

Aim: To characterize the prevalence of subpopulations of CD4+ cells along with that of major inhibitor or stimulator cell types in therapy-naïve childhood Crohn's disease (CD) and to test whether abnormalities of immune phenotype are normalized with the improvement of clinical signs and symptoms of disease., Methods: We enrolled 26 pediatric patients with CD. 14 therapy-naïve CD children; of those, 10 children remitted on conventional therapy and formed the remission group. We also tested another group of 12 children who relapsed with conventional therapy and were given infliximab; and 15 healthy children who served as controls. The prevalence of Th1 and Th2, naïve and memory, activated and regulatory T cells, along with the members of innate immunity such as natural killer (NK), NK-T, myeloid and plasmocytoid dendritic cells (DCs), monocytes and Toll-like receptor (TLR)-2 and TLR-4 expression were determined in peripheral blood samples., Results: Children with therapy-naïve CD and those in relapse showed a decrease in Th1 cell prevalence. Simultaneously, an increased prevalence of memory and activated lymphocytes along with that of DCs and monocytes was observed. In addition, the ratio of myeloid /plasmocytoid DCs and the prevalence of TLR-2 or TLR-4 positive DCs and monocytes were also higher in therapy-naïve CD than in controls. The majority of alterations diminished in remitted CD irrespective of whether remission was obtained by conventional or biological therapy., Conclusion: The finding that immune phenotype is normalized in remission suggests a link between immune phenotype and disease activity in childhood CD. Our observations support the involvement of members of the adaptive and innate immune systems in childhood CD.

Genetic polymorphisms of the genes involved in angiogenesis, the inflammatory cascade or apoptosis control can influence the chronic complications of diabetic patients. Parallel evaluation of multiple genetic polymorphisms became available with the development of DNA resequencing arrays. We aimed to develop a 16-gene, 18,859-nucleotide resequencing array to analyze the genetic background of uremic and gastrointestinal complications. DNA was isolated from 10 ml of peripheral blood of 41 non-uremic and 37 uremic patients with type II diabetes mellitus (DM); 32 suffering from gastric erosion complications. An Affymetrix Customseq Resequencing array was developed containing a total of 37 PCR products of selected genes. Confirmatory analysis was performed for 5 known polymorphisms by RFLP and for 4 others by capillary sequencing. Statistical analysis was performed using the Fisher's exact test. Correlations between the DNA resequencing array and the confirmatory methods were 96% for RFLP and 99.4% for capillary sequencing. The genetic polymorphisms of the ApoE, HSD3B1, IL-1beta and p53 genes were found to be significantly different (p<0.05) between the uremic and non-uremic diabetes group. In regards to the gastric erosion complications of the diabetic uremic patients, the A17708T polymorphism of the p53 intron 10 was found to have a statistically significant (p<0.05) role. In conclusion, DNA sequencing arrays can contribute to a multiparameter genetic analysis yielding highly correlating results using a single method in patients suffering type II DM.

The 620Trp variant of the LYP protein, encoded by the lymphoid tyrosine phosphatase 22 gene (PTPN22), is associated with autoimmunity. In this study we aimed at characterising the role of this variant on lymphocyte activation. We analysed cytokine secretion and proliferation of peripheral blood mononuclear cells (PBMCs) and CD4(+)T cells in a cohort of clinically non-diabetic, multiple autoantibody-positive children, healthy controls and in children with type 1 diabetes (T1D). We found a decreased proliferation and IL-2 production of CD4(+)T cells after anti-CD3/anti-CD28 stimulation (p=0.04 for IL-2) among T1D patients. In addition, a profoundly decreased intracellular calcium flux in CD4(+)T cells after PHA stimulus was detected among 620Trp carriers. In contrast, no effect of this polymorphism on tuberculin and tetanus toxoid induced PBMC proliferation and cytokine secretion was observed in autoantibody positive children, healthy controls and children with newly-diagnosed T1D. In conclusion, the LYP 620Trp variant is associated with reduced activation, proliferation and IL-2 production in CD4(+)T cells among T1D patients. In accordance with our previous findings on the key role of this variant on disease progression, this mechanism is likely to contribute to the development of beta-cell specific autoimmunity.

Endogenous and exogenous glucocorticoids influence fetal growth and development, and maternal administration of synthetic glucocorticoids may decrease the risk of perinatal morbidity including lung disease in preterm neonates. Because polymorphisms of the glucocorticoid receptor gene are known to influence the sensitivity to glucocorticoids, in the present study we examined whether any associations could exist among the BclI, N363S and ER22/23EK polymorphisms of the glucocorticoid receptor gene and gestational age, birth weight and/or perinatal morbidity of 125 preterm neonates born at 28-35 weeks' gestation with (n=57) or without maternal dexamethasone treatment (n=68). The prevalence of the three polymorphisms in the whole group of preterm infants was similar to that reported in healthy adult Hungarian population. However, we found that the BclI polymorphism significantly associated with higher birth weight adjusted for the gestational age (p=0.004, ANOVA analysis). None of the three polymorphisms showed an association with perinatal morbidities, including necrotizing enterocolitis, intraventricular hemorrhagia, patent ductus arteriosus, respiratory distress syndrome, bronchopulmonary dysplasia and sepsis in the two groups of preterm neonates with and without maternal dexamethasone treatment. These results suggest that the BclI polymorphism of the glucocorticoid receptor gene may have an impact on gestational age-adjusted birth weight, but it does not influence perinatal morbidities of preterm neonates.

Necrotizing enterocolitis (NEC) is a common, life-threatening neonatal gastrointestinal disease; it affects approximately 11% of extremely premature neonates. The etiology of NEC is multifactorial. Risk factors may roughly be grouped into four main categories: prematurity; transient ischemia of the intestine; local/systemic inflammation predisposing the bowel to injury, and therapeutic interventions. Recent studies have shown that carrier state of genetic polymorphisms may be associated with perinatal morbidity, including NEC. In perinatal disorders, the significance of genetic variants of cytokines, the renin-angiotensin-aldosterone system, and surfactant proteins have been investigated most widely. Positive findings indicate the implication of genetic polymorphisms of proinflammatory cytokines in premature birth; angiotensin converting enzyme in perinatal adaptation and angiotensin type 1 receptor in the closure of ductus arteriosus; surfactant proteins A and B in respiratory distress syndrome; interleukin (IL)-6 in sepsis, and IL-4-receptor alpha chain and IL-18 in NEC. This review provides an insight into the genetics of NEC and summarizes genetic data in light of pathologic processes leading to NEC.

Altered pulmonary vascular resistance might be a factor for delayed closure of the ductus arteriosus (DA) in preterm infants. Angiotensin II plays a central role in the elevation of pulmonary vascular resistance. Angiotensin II exerts its vasoconstrictor effect on the angiotensin II type 1 receptor (AT1R). Homozygous carriers of the AT1R A1166C genetic variant present an exaggerated vasoconstrictor response to angiotensin II. We have investigated whether the presence of AT1R CC1166 influences the effect of prophylactic indomethacin treatment on the closure of DA until the fifth postnatal day in preterm infants. In this retrospective study detailed medical history of the first postnatal week was obtained in 159 infants born before the 33rd gestational week. All were treated by prophylactic indomethacin to induce permanent closure of the DA. On the sixth postnatal day the DA was still open in 56, whereas it was permanently closed in 103. The AT1R A1166C genotype of the infants was determined from Guthrie spots. Stepwise binary logistic regression analysis was used to assess the effect of medical conditions and genotype on the risk of patent DA (PDA). Birth weight, infantile respiratory distress, and severe hypotension were independent risk factors for PDA (p < 0.01, p < 0.05, p < 0.05, respectively). The carrier state of AT1R CC1166 was protective against PDA (p < 0.05; odds ratio, 0.067). AT1R AC1166 genotype was not associated with PDA. Our results indicate that the risk of PDA might be lower in infants of AT1R CC1166 than in those with AC or AA genotypes.

Background: Despite new immunosuppressive drugs, only a minority of graft survive over 15 years. The aim of our study was to determine the influence of gene polymorphisms in the G-protein-beta(3) subunit (Gbeta3) and endothelial nitric oxide synthase (eNOS) on the long-term outcome of kidney grafts., Methods: Using PCR, corresponding genotypes in Gbeta3 (C825T) and eNOS (G894T) gene polymorphism were evaluated in patients with preserved graft function over 15 years and in a control group of transplant recipients., Results: There were no differences in allele and genotype distributions of both polymorphisms between groups. In Gbeta3 polymorphism, the 825T allele carriers had a significantly lower body mass index while in eNOS polymorphism there were no links between genotypes, renal function and atherosclerosis risk factors., Conclusions: Our data suggest that these gene polymorphisms have only a minor influence on long-term renal graft function., (Copyright 2002 S. Karger AG, Basel)