Transitional elevation of anti-tissue transglutaminase antibodies in children with type 1 diabetes mellitus without coeliac disease / A szöveti antitranszglutamináz átmeneti emelkedése coeliakiával nem társult I-es típusú cukorbeteg gyermekekben.

Összefoglaló. Bevezetés: Az 1-es típusú diabetes mellitus és a coeliakia gyakori társulása jól ismert. Néhány tanulmány beszámol átmeneti antitranszglutamináz-emelkedésrol 1-es típusú diabeteses betegekben, akiknél az emelkedett antitestszint gluténmentes diéta bevezetése nélkül normalizálódik. Célkituzés: Kutatásunk során az átmeneti antitranszglutamináz-emelkedés gyakoriságának meghatározását tuztük ki célul. További célunk volt a coeliakia gyakoriságának megállapítása 1-es típusú diabetesszel gondozott betegeink között. Módszer: A Semmelweis Egyetem I. Gyermekgyógyászati Klinikáján 1-es típusú diabetesszel gondozott betegeket vontuk be vizsgálatunkba (238 lány, 265 fiú, medián [IR] életkor az 1-es típusú diabetes diagnózisakor: 7,83 [4,67-11] év). Vizsgáltuk a jelenség idobeli megjelenését, az emelkedés mértékét, gyakoriságát és az antitest típusát. Leíró statisztikai módszereket és khi-négyzet-próbát alkalmaztunk. Eredmények: A vizsgált populációban a coeliakia gyakorisága 12,52%. Átmeneti antitranszglutamináztiter-emelkedést 48 gyermeknél (10,9%) észleltünk. Összesen 71-szer mértünk átmeneti antitranszglutamináz-emelkedést. A gyermekek közül 34 esetben (70,83%) egyszer fordult elo emelkedést mutató antitest, a többi betegnél 2-8 alkalommal. Gyakrabban tapasztaltunk izolált IgA-típusú emelkedést, mint izolált IgG-típusút (54 vs. 5). Következtetés: Az átmeneti antitranszglutamináz-emelkedés gyakorisága magas, összevetheto a valódi coeliakiás csoporttal. Kutatásunk alátámasztja a nemzetközi ajánlást, miszerint mérsékelt mértéku antitranszglutamináz-emelkedés esetén, tünetmentes 1-es típusú diabetesszel gondozott betegben a gluténfogyasztás folytatása és az antitestszintek gyakori kontrollja javasolt. Orv Hetil. 2021; 162(48): 1924-1930. INTRODUCTION: The frequent association of type 1 diabetes mellitus with coeliac disease is well known. Development of transitional elevation of anti-tissue transglutaminase antibodies in the diagnosis of type 1 diabetes is reported in some studies. In these cases, the anti-tissue transglutaminase antibodies returned to normal without gluten-free diet. OBJECTIVE: Our aim was to assess the frequency of transitional elevation of anti-tissue transglutaminase in our type 1 diabetes patients. We aimed to investigate the prevalence of coeliac disease in patients with type 1 diabetes. METHOD: Patients with type 1 diabetes at the Ist Department of Paediatrics, Semmelweis University, were enrolled in the study (238 girls, 265 boys; the median age at the time of type 1 diabetes diagnosis was 7.83 [4.67-11] years). Descriptive statistical analysis was done and the time of appearance, extent, frequency and type of elevated anti-tissue transglutaminase antibodies were examined. RESULTS: The proportion of children with diagnosed coeliac disease was 12.52%. We detected transitional anti-tissue transglutaminase elevation in 48 cases (10.9%). Temporarily elevated antibody levels were measured 71 times. In 34 children (70.83%), the temporary elevation occured once, while in the others, antibody levels became positive 2-8 times. The elevation of the IgA antibody was more frequent than the elevation of the IgG antibody (54 vs. 5). CONCLUSION: The frequency of temporary elevated anti-tissue transglutaminase levels is considered high. Our study confirms the recommendation that in the case of moderate anti-tissue transglutaminase levels with lack of clinical symptoms, control antibody measurement is necessary with ongoing gluten consumption. Orv Hetil. 2021; 162(48): 1924-1930.

Association between interferon-induced helicase (IFIH1) rs1990760 polymorphism and seasonal variation in the onset of type 1 diabetes mellitus.

BACKGROUND: Infections, mostly of viral origin, may contribute to the seasonal variation in the onset of type 1 diabetes mellitus (T1DM). The rs1990760 (A>G, Ala946Thr) polymorphism (GG genotype) of the interferon induced helicase (IFIH1), a virus recognition receptor, confers a modest protection for T1DM. The aim of our study was to evaluate a possible association between this IFIH1 polymorphism and the seasonal variation in the onset of T1DM. MATERIALS AND METHODS: The IFIH1 rs1990760 polymorphism was genotyped in 1055 patients of Central-Eastern European ancestry with T1DM (median age at diagnosis: 8.2 [interquartile range, IQR 4.8-11.8] years). T1DM onset was recorded in monthly intervals. RESULTS: The IFIH1 genotype distribution was the following: 436 patients (41.3%) had AA genotype, 483 patients (45.8%) had AG genotype, and 136 patients (12.9%) had GG genotype. Significant seasonal variation in manifestation of T1DM (highest rate in winter and lowest rate in summer period) was observed in the total cohort (n = 1055), irrespective of gender. The disease predisposing AA genotype was more frequently found among new cases with onset in summer vs in those with onset in winter (44.3% vs 37.9%); conversely, the protective GG genotype was less frequent (9.3% vs 12.9%, respectively; P = .0268 for trend). Significant effect of genotype (P = .0418) was found on the seasonal variability of T1DM onset in the total cohort. CONCLUSIONS: The IFIH1 rs1990760 polymorphism seems to be associated with the seasonal manifestation of T1DM. Our findings suggest that this virus receptor gene may contribute to T1DM manifestation primarily in the summer period.

Severe Hyperinsulinemic Hypoglycemia in a Neonate: Response to Sirolimus Therapy.

Hyperinsulinemic hypoglycemia (HH) is one of the most common causes of persistent hypoglycemic episodes in neonates. Current pharmacologic treatment of neonatal HH includes diazoxide and octreotide, whereas for diffuse, unresponsive cases a subtotal pancreatectomy may be the last resort, with questionable efficacy. Here we report a case of congenital diffuse neonatal HH, first suspected when severe hypoglycemia presented with extremely high serum insulin levels immediately after birth. Functional imaging and genetic tests later confirmed the diagnosis. Failure to respond to a sequence of different treatments and to avoid extensive surgery with predictable morbidity prompted us to introduce a recently suggested alternative therapy with sirolimus, a mammalian target of rapamycin inhibitor. Glucose intake could be reduced gradually while euglycemia was maintained, and we were able to achieve exclusively enteral feeding within 6 weeks. Sirolimus was found to be effective and well tolerated, with no major adverse side effects attributable to its administration.

Effects of pH, lactate, hematocrit and potassium level on the accuracy of continuous glucose monitoring (CGM) in pediatric intensive care unit.

BACKGROUND: Continuous glucose monitoring (CGM) originally was developed for diabetic patients and it may be a useful tool for monitoring glucose changes in pediatric intensive care unit (PICU). Its use is, however, limited by the lack of sufficient data on its reliability at insufficient peripheral perfusion. We aimed to correlate the accuracy of CGM with laboratory markers relevant to disturbed tissue perfusion. PATIENTS AND METHODS: In 38 pediatric patients (age range, 0-18 years) requiring intensive care we tested the effect of pH, lactate, hematocrit and serum potassium on the difference between CGM and meter glucose measurements. Guardian® (Medtronic®) CGM results were compared to GEM 3000 (Instrumentation laboratory®) and point-of-care measurements. The clinical accuracy of CGM was evaluated by Clarke Error Grid -, Bland-Altman analysis and Pearson's correlation. We used Friedman test for statistical analysis (statistical significance was established as a p < 0.05). RESULTS: CGM values exhibited a considerable variability without any correlation with the examined laboratory parameters. Clarke, Bland-Altman analysis and Pearson's correlation coefficient demonstrated a good clinical accuracy of CGM (zone A and B = 96%; the mean difference between reference and CGM glucose was 1,3 mg/dL, 48 from the 780 calibration pairs overrunning the 2 standard deviation; Pearson's correlation coefficient: 0.83). CONCLUSIONS: The accuracy of CGM measurements is independent of laboratory parameters relevant to tissue hypoperfusion. CGM may prove a reliable tool for continuous monitoring of glucose changes in PICUs, not much influenced by tissue perfusion, but still not appropriate for being the base for clinical decisions.

The interrelationship of HbA1c and real-time continuous glucose monitoring in children with type 1 diabetes.

AIMS: The aim of this observational study is to investigate the relationship between age, duration of diabetes, HbA1c and the parameters of glucose levels measured with real-time CGM in children with type 1 diabetes. METHODS: Glucose level was characterized with the relative time spent in hyper- and hypoglycemia, central tendency, variability and MAGE during (real-time) CGM. These parameters were measured in 57 children with type 1 diabetes mellitus. The univariate association of the measured parameters was investigated with scatterplots as well as with linear and distance correlation coefficients. RESULTS: Age and duration of diabetes were not clinically relevantly associated with any descriptor of glucose level. HbA1c had an overall positive association with variability and MAGE observed during CGM. Slight, but non-significant, positive association of HbA1c was observed with the time spent in hyperglycemia and the central tendency of glucose level. With the exception of MAGE, the associations of the descriptors with HbA1c are non-monotonic, with a temporary break in the positive correlation at 10%. CONCLUSIONS: The results confirmed the well-known positive association of HbA1c with the central tendency of glucose level. The non-monotonic relationship between HbA1c and the indicators of the central tendency of glucose level might be caused by the changed adherence of the patients during the period of CGM. HbA1c's positive association with MAGE without non-monotonicity underlines MAGE's usefulness in the reliable assessment of the patients' glycemic state.

[Role of continuous subcutaneous glucose monitoring in intensive care]. / A folyamatos szubkután glükózmonitorizálás szerepe az intenzív terápiában.

Critical care associated with stress hyperglycaemia has gained a new view in the last decade since the demonstration of the beneficial effects of strong glycaemic control on the mortality in intensive care units. Strong glycaemic control may, however, induce hypoglycaemia, resulting in increased mortality, too. Pediatric population has an increased risk of hypoglycaemia because of the developing central nervous system. In this view there is a strong need for close monitoring of glucose levels in intensive care units. The subcutaneous continuous glucose monitoring developed for diabetes care is an alternative for this purpose instead of regular blood glucose measurements. It is important to know the limitations of subcutaneous continuous glucose monitoring in intensive care. Decreased tissue perfusion may disturb the results of subcutaneous continuous glucose monitoring, because the measurement occurs in interstitial fluid. The routine use of subcutaneous continuous glucose monitoring in intensive care units is not recommended yet until sufficient data on the reliability of the system are available. The Medtronic subcutaneous continuous glucose monitoring system is evaluated in the review partly based on the authors own results.

Verification of skin autofluorescence values by mass spectrometry in adolescents with type 1 diabetes: brief report.

BACKGROUND: Accumulation of advanced glycation end products (AGEs) in tissues is a major risk factor for diabetes-associated complications. Skin autofluorescence (SAF) values measured by a specific noninvasive approach (AGE Reader; DiagnOptics Technologies B.V., Gröningen, The Netherlands) reflect the overall AGE exposure in skin. SUBJECTS AND METHODS: In 16 adolescents with type 1 diabetes (age range, 11-18 years) we tested the association between SAF measured with an AGE Reader and the presence of glucuronic acid, 3-indoxyl sulfate, 3-hydroxybutyrate, phenol sulfate, and pentosidine in skin tissue determined with desorption electrospray ionization mass spectrometry (DESI-MS). These compounds are implicated in long-term diabetes complications. RESULTS: SAF values significantly correlated with levels of compounds measured by DESI-MS (r>0.9 and P<0.001 for each). CONCLUSIONS: The strong correlation between adolescents' SAF values measured with the AGE Reader and some glycation products measured with DESI-MS indicates that SAF values may be used as surrogate markers of skin exposure to glycemic end products in type 1 diabetes.

Role of nitric oxide (NO) metabolism and inflammatory mediators in childhood obesity.

OBJECTIVE AND DESIGN: The role of NO and adipocytokines in childhood obesity was studied, supposing that obesity provokes inflammation. Children were admitted to the pediatric clinic for a regular check up because of obesity. SUBJECTS: Obese (n = 79) and healthy (n = 12) children were selected and divided into subgroups according to their age, gender, glucose tolerance and nitric oxide synthase (NOS II) positivity. METHODS: Urine and blood nitrite plus nitrate, the expression of NOS II in white blood cells, serum adipocytokines and clinical characteristics were analyzed in each group. Significance was tested by unpaired two-tailed t test and by ANOVA. RESULTS: NOS II was only detected in the white blood cells of a subgroup (17/79) of obese children. Serum leptin and resistin concentrations were significantly higher, adiponectin was lower compared to healthy children. Significant correlations were observed between serum adiponectin and resistin levels (reciprocal, R (2) = 0.4), and between body mass index and serum leptin levels. CONCLUSIONS: NOS II expression in white blood cells was observed in a minority of patients. Low-grade inflammation in obese children was suggested by the increased resistin levels, particularly in NOS II-positive patients. Correlation between different adipocytokines was restricted for a few subgroups.

PPAR-gamma2 pro12Ala polymorphism is associated with post-challenge abnormalities of glucose homeostasis in children and adolescents with obesity.

AIM: The aim of the study was to investigate the association between PPAR-gamma2 Pro12Ala polymorphism and laboratory characteristics of carbohydrate metabolism in children and adolescents with obesity. In addition, serum levels of tumor necrosis factor (TNF)-alpha, and soluble form of its receptors (sTNFR1 and sTNFR2) were assessed. METHODS: In a cross-sectional study, 79 obese children and adolescents of Caucasian origin were investigated. PPAR-gamma2 Pro12Ala polymorphism was determined using polymerase chain reaction--restriction fragment length polymorphism technique. Serum levels of TNF-alpha, sTNFR1 and sTNFR2 were measured by enzyme amplified sensitivity immunoassay. RESULTS: The minor Ala allele frequency was found to be 14.56% in our cohort. No significant differences in age, BMI, waist circumference, blood pressure, serum lipid, uric acid, TNF-alpha, sTNFR1 and sTNFR2 values were found between carriers of the Ala allele (Pro/Ala and Ala/Ala; n=21) vs. homozygous carriers of the Pro allele (Pro/Pro; n=58). However, post-challenge (120 min) plasma glucose and insulin values were significantly lower in Ala allele carriers vs. homozygous Pro allele carriers (6.56 +/- 0.26 vs. 7.36 +/- 0.25 mmol/L and 65.9 +/- 13.8 vs. 111.8 +/- 20.7 microU/mL, respectively; p < 0.05); while no significant differences were found at fasting state. CONCLUSIONS: The association between PPAR-gamma2 Prol2Ala polymorphism and glucose metabolism is already present in children and adolescents with obesity who might be at the very beginning of the natural course of type 2 diabetes. At this stage, higher insulin sensitivity can be detected in Ala allele carriers compared to homozygous Pro subjects at post-challenge but not in fasting state; however, the TNF-system seems not to be involved in the alteration of glucose homeostasis due to PPAR-gamma2 Pro12Ala polymorphism.

Association between toll-like receptor polymorphisms and serum levels of tumor necrosis factor-alpha and its soluble receptors in obese children.

BACKGROUND: In obesity, increased tumor necrosis factor (TNF)-alpha level is involved in the development of insulin resistance. Toll-like receptor (TLR)-4 and TLR2 are expressed in adipose tissue, and polymorphisms of these receptors may influence TNF-alpha secretion from adipocytes. In our study, TNF-alpha, soluble TNF receptor 1 (sTNFR1), and soluble TNF receptor 2 (sTNFR2) levels were determined, and any association between polymorphisms of TLR4 (D299G, T399I), TLR2 (R753Q, R677W), and cytokine levels was assessed in obese children and non-obese control subjects. MATERIAL/METHODS: In a cross-sectional study, 79 obese children and 42 matched non-obese control children were investigated. Cytokine levels were measured by enzyme amplified sensitivity immunoassay. TLR4 and TLR2 polymorphisms were determined using polymerase chain reaction - restriction fragment length polymorphism technique. RESULTS: TNF-alpha and sTNFR2 levels in obese children were significantly (P<.01) higher than controls. Significant (P<.05), positive, linear correlations were observed between TNF-alpha, sTNFR2 levels, and BMI. Patients carrying the mutant alleles of TLR4 (299G and 399I) had lower TNF-alpha and sTNFR2 levels compared to patients carrying wild-type alleles (299D and 399T) (TNF-alpha 4.4+/-0.7 pg/mL vs 5.5+/-0.9 pg/mL; sTNFR2 2.9+/-1.2 ng/mL vs 4.4+/-1.1 ng/mL; P<.001). The R753Q polymorphism of TLR2 was not associated with altered cytokine levels, and the R677W polymorphism was not detected in the sample population. CONCLUSIONS: Serum levels of TNF-alpha and its soluble receptors are elevated and associated with increasing BMI values in obese children. Serum cytokine levels, as modifying factors of insulin resistance, may be affected by TLR4 polymorphisms in obese children.

Swelling and polymer erosion for poly(ethylene oxide) tablets of different molecular weights polydispersities.

The aim of the study was to determine and compare the degree of swelling and the swelling kinetics of poly(ethylene oxide) (PEO) hydrophilic matrix tablets without any additives for matrixes with different molecular weight polydispersities. A wide range of "mixed" polydisperse PEO tablets were obtained by mixing two PEO batches with average molecular weights of 10(5) and 2 x 10(6), respectively. These were compared with "single-batch" tablets with narrower mono-modal molecular weight distributions. A texture analyzer (TA) was used to determine, during the entire dissolution process, the thickness of the "gel" layer, the height of the dry tablet core and the total height of the tablet. The release of polymer from the tablet was also measured using a chromatographic method. Both the swelling histories and the polymer release rates varied strongly with molecular weight and agitation rate, whereas the rate of dissolution of the solid core varied much less with molecular weight. For single-batch and mixed tablets, tuned to give the same release rate, the swelling process was found to be very similar, regardless of the molecular polydispersity (between 1.2 and 8.8). These results support a previously proposed dissolution model with the key assumption of a constant critical viscosity, independent of time or polymer molecular weight, at the surface of the gel layer of a dissolving tablet.

Influence of different polymer types on the overall release mechanism in hydrophilic matrix tablets.

The effect of three different types of polymer chain structures on the polymer release from hydrophilic matrix tablets was investigated by comparing a synthetic semi-crystalline linear polymer (PEO), a branched amorphous polysaccharide (dextran) and an amorphous substituted cellulose derivative (HPMC). The polymer release rates for tablets containing mixtures of high and low molecular weight grades in different ratios were determined by using a modified USP II method and a SEC-RI chromatography system. The results showed that independent of polymer type: (i) plots of the release versus time had similar shapes, (ii) the release of long and short polymer chains was equal and no fractionation occurred during the release and (iii) the release rate could be related to the average intrinsic viscosity of the polymer mixtures. This confirms the hypothesis that the release rate can be related to a constant viscosity on the surface of the hydrophilic matrix tablet and that it is valid for all the investigated polymers.

Improved glycemic control through continuous glucose sensor-augmented insulin pump therapy: prospective results from a community and academic practice patient registry.

BACKGROUND: Conducted by highly experienced investigators with abundant time and resources, phase III studies of continuous glucose sensing (CGS) may lack generalizability to everyday clinical practice. METHOD: Community or academic practices in six Central and Eastern European or Mediterranean countries prospectively established an anonymized registry of consecutive patients with type 1 insulin-dependent diabetes mellitus starting CGS-augmented insulin pump therapy with the Paradigm X22 (Medtronic MiniMed, Northridge, CA) under everyday conditions, without prior CGS with another device. We compared glycosylated hemoglobin (GHb) values before and after 3 months of CGS and assessed relationships between insulin therapy variables and glycemia-related variables at weeks 1, 4, and 12 of CGS. RESULTS: Of 102 enrolled patients, 85 (83%) with complete weeks 1, 4, and 12 sensor data and baseline/3-month GHb data were evaluable. Evaluable patients were approximately 54% male and approximately 75% adult (mean age, 33.2 +/- 16.9 years) with longstanding diabetes and high personal/family education levels. Mean GHb declined significantly after 3 months of CGS (7.55 +/- 1.33% at baseline to 6.81 +/- 1.08% after 12 weeks, 0.74% absolute decrease, P < 0.001). The absolute GHb reduction correlated significantly (P < 0.0005) with baseline GHb: larger absolute reductions tended to occur when baseline levels were higher. An increased basal insulin dose as a percentage of the total daily insulin dose and a decreased daily bolus count from week 1 to week 12 of CGS predicted GHb improvement from baseline to week 12. CONCLUSIONS: CGS-augmented insulin pump therapy appears to improve glycemic control in type 1 diabetes in varied everyday practice settings.

[Incidence of thyroid autoimmunity in children with type 1 diabetes mellitus]. / Pajzsmirigy-autoimmunitás elôfordulása 1-es típusú diabéteszes gyermekekben.

UNLABELLED: It is well known that patients suffering from an autoimmune disease are more prone to develop another one, too. The authors have previously shown frequent occurrence of celiac disease in patients with type 1 diabetes mellitus compared to the background population. Autoimmune thyroid disease, the most common autoimmune disease associated with type 1 diabetes mellitus, generally occurs after the manifestation of diabetes, in the second decade of life. The aim of the study was to investigate the prevalence of thyroid autoimmunity as well as the frequency of autoimmune thyroid disease in patients with type 1 diabetes mellitus. Their aim was also to compare the prevalence of autoimmune thyroid disease in patients with type 1 diabetes mellitus and in those with type 1 diabetes mellitus and celiac disease. METHODS: Screening was performed in 268 patients with type 1 diabetes mellitus alone and in 48 children with type 1 diabetes mellitus and celiac disease, with anti-peroxidase and anti thyroglobulin antibody. In case of autoantibody positivity, testing thyroid function and ultrasonography confirmed the autoimmune thyroid disease. According to the results, frequency of autoantibody positivity was significantly higher in diabetic patients suffering from celiac disease (type 1 diabetes mellitus: 43 (16%), type 1 diabetes mellitus + celiac disease: 16 (33,3%), p < 0,01). Hypothyroidism due to thyroiditis was also more prevalent in patients with type 1 diabetes mellitus and celiac disease. CONCLUSIONS: Due to increased risk, the authors emphasise the need of frequent screening for autoimmune thyroid disorder in patients with type 1 diabetes mellitus and celiac disease.

Reduced CD4+T cell activation in children with type 1 diabetes carrying the PTPN22/Lyp 620Trp variant.

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.

New release cell for NMR microimaging of tablets. Swelling and erosion of poly(ethylene oxide).

A small release cell, in the form of a rotating disc, has been constructed to fit into the MRI equipment. The present work show that both qualitative and quantitative information of the swelling and erosion behavior of hydrophilic extended release (ER) matrix tablets may be obtained using this release cell and non-invasive magnetic resonance imaging (MRI) studies at different time-points during matrix dissolution. The tablet size, core size and the gel layer thickness of ER matrix formulations based on poly(ethylene oxide) have been determined. The dimensional changes as a function of time were found to correspond well to observations made with texture analysis (TA) methodology. Most importantly, the results of the present study show that both the erosion (displacement of the gel-dissolution media interface) and the swelling (decrease of dry tablet core size) proceed with a faster rate in radial than in axial direction using the rotating disk set-up. This behavior was attributed to the higher shear forces experienced in the radial direction. The results also indicate that front synchronization (constant gel layer thickness) is associated with the formation of an almost constant polymer concentration profile through the gel layer at different time-points.

The HLA 8.1 ancestral haplotype is strongly linked to the C allele of -429T>C promoter polymorphism of receptor of the advanced glycation endproduct (RAGE) gene. Haplotype-independent association of the -429C allele with high hemoglobinA1C levels in diabetic patients.

Previously we reported on strong linkage disequilibrium (LD) between the mono-S-C4B-RCCX module (mono-S) and the TNF2 allele (both known constituents of the 8.1 ancestral haplotype (8.1 AH)) in two Caucasian populations. The gene for the receptor of advanced glycation endproducts (RAGE) is encoded between the RCCX module and the HLA class II genes in the central MHC region. In order to assess the relationship between the promoter polymorphisms of the RAGE gene and the 8.1 AH, we performed a family study in eight informative families affected with type 1 diabetes mellitus; haplotypes of a RAGE promoter SNP (-429T>C) with the HLA-DQ2, -DR-3(17) and TNF2 alleles, as well as the mono-S genotype were determined. A similar analysis was performed in 82 unrelated patients with type 1 diabetes mellitus, and in unrelated healthy individuals of three different Caucasian populations (Hungarians, Ohioian females, Icelandics). In the diabetic patients clinical correlations were also investigated. Out of the 32 paternal and maternal chromosome 6 from the eight families, 15 different MHC haplotypes were found. Haplotypes containing at least three of the known constituents of the 8.1 AH (HLA-DQ2, -DR17, mono-S, TNF2) were always linked to the RAGE -429C allele. The RAGE -429C allele exhibited highly significant (p<0.0001) LD coefficients to known constituents of the 8.1 AH both in healthy persons and patients with type 1 diabetes. In the group of patients with diabetes we found significantly (p=0.013) higher maximal hemoglobinA1C concentration in the carriers of the RAGE -429C allele, this trait, however was not linked to the 8.1 AH. Our present findings indicate that the RAGE -429C allele can be considered as a candidate member of the 8.1 AH. The results also reveal a spectrum of recombinant MHC haplotypes in addition to the conserved ancestral haplotypes.

A model for the drug release from a polymer matrix tablet--effects of swelling and dissolution.

A model for simulating the drug release from a swelling and dissolving polymer tablet is presented and verified to data. The model is based on a mechanistic approach, and it can therefore be employed to study the sensitivity of true physical constants, for instance the drug diffusion coefficient or the drug solubility. The model generates the drug and polymer release profiles and the front positions of the total tablet, the solid core, and of the solid-drug-solubilized-drug interface. The convective contribution to mass transfer is shown to be of great importance. This is most markedly noticed for slowly diffusing drugs. In a simulation with a low value of the drug diffusion coefficient, it is shown that the initial drug release rate is faster than the polymer dissolution rate, followed by a second stage with a slower drug release rate. Furthermore, it is shown that polymer dissolution influences the drug release profile significantly, but not the front position of saturated drug in the gel layer. The model is verified against drug release and polymer dissolution data for the slightly soluble drug Methyl paraben and the soluble drug Saligenin in a poly (ethylene oxide) tablet, resulting in good agreement between model and experiments.

Differences in the nitric oxide metabolism in streptozotocin-treated rats and children suffering from Type 1 diabetes.

The relationship between diabetes mellitus Type 1 and nitric oxide (NO) synthesis was studied in multiple low-dose streptozotocin (STZ)-treated rats and diabetic children. The aim of our experimental work was to test the effect of hyperglycemic state on the level of urinary stable NO end products and on the expression of inducible nitric oxide synthase (NOS II) in white blood cells (WBC). It was also studied whether the measurements of these parameters were suitable to predict the presence of early diabetes before its onset. The occurrence of insulitis in streptozotocin-treated rats could not be clearly demonstrated. Urinary nitrite plus nitrate level significantly increased both in diabetic rats and in children compared to controls. However, the increase of the activity and the expression of inducible NOS II were only observed in rat white blood cells and this effect was prevented by insulin treatment. In human samples, less than 25% of children showed elevated NOS II expression in white blood cells without any correlation to the level of urinary NO end products and glycated hemoglobin in blood. Correlation was found only between the activity and expression of NOS II in white blood cells of patients whose white blood cells were positive for the presence of NOS II. Measurement of urinary nitrite plus nitrate content as well as the determination of NOS II expression of white blood cells in an early phase of diabetes are not suitable predictors in humans probably due to the basic differences in the mechanism of streptozotocin-induced rat and spontaneous human Type 1 diabetes.

[Diabetes mellitus in children]. / Diabetes mellitus gyermekkorban.

The review is covering different forms of diabetes mellitus occurring in children and adolescents. Main characteristics of childhood diabetes are based on the continuous changes in growth and development of children. The review is focusing on the diagnostics, epidemiology, etiopathogenesis and natural course of type 1 diabetes, the dominant form in the pediatric age group. Insulin treatment, nutritional management and education, including age related special problems are covered. Due to space limitations, acute and late complications, as well as possible prevention of type 1 diabetes are shortly mentioned. Beside type 1 diabetes, other forms of carbohydrate intolerance occurring in children are also also included. Among those, special emphasis is put on type 2 diabetes, due to its increasing incidence in children and adolescents parallel to the increased prevalence of childhood obesity.