Evaluation of glucose metabolism in children with growth hormone deficiency during long-term growth hormone treatment.

Growth hormone (GH) affects carbohydrate metabolism through direct negative effect on insulin sensitivity and indirectly, via insulin-like growth factor-1 (IGF-1), which exerts positive insulin-mimetic action. The aim of this retrospective study was to evaluate the influence of long-term GH treatment on glucose homeostasis in 118 children with isolated idiopathic GH deficiency (GHD). Based on this analysis we wanted to determine the usefulness of glycated haemoglobin (HbA1c) and parameters derived from the oral glucose tolerance test (OGTT) in the monitoring of disturbed glucose metabolism during GH treatment and to assess the value of IGF-1 in prediction of those changes. Mean duration of GH treatment was 2.5 ± 1.2 years. Data were analysed in the whole group and according to baseline pubertal status. Significant increases in insulin concentrations, both fasting and during the OGTT, accompanied by a significant increase in fasting glucose and unchanged glucose concentrations during the OGTT, were found after the initiation of GH treatment. HbA1c did not change significantly during GH treatment in comparison to baseline values and remained normal, even in patients with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) found during GH treatment. Changes in glucose metabolism observed after the onset of GH treatment were related to increment in IGF-1 SDS and to GH doses. Significant associations between changes in IGF-1 SDS in the first year of GH treatment and some of the glucose metabolism parameters evaluated after the first, the second and the third year of GH treatment were also confirmed in multiple regression analysis after taking the GH dose into consideration. All cases of IFG and/or IGT detected during GH treatment are reversible after dietary intervention, independently of pubertal status, and do not lead to diabetes mellitus.

Relationship Between 25(OH)D and IGF-I in Children and Adolescents with Growth Hormone Deficiency.

Recent studies have shown that vitamin D has an impact on the production and secretion of IGF-I in the liver. The aim of our study was to investigate the relationship between the concentrations of 25-hydroxy vitamin D [25(OH)D] and insulin-like growth factor I (IGF-I) in growth hormone deficient children and adolescents before recombinant human growth hormone (rhGH) treatment. The study was retrospective and included 84 children and adolescents aged 4-17. Prior to initiating rhGH therapy, concentrations of 25(OH)D and IGF-I were measured in all patients. IGF-I concentrations were normalized for bone age. The studied group was divided into two subgroups according to serum 25(OH)D levels. Significant positive correlations between 25(OH)D concentration and IGF-I SDS-normalized for bone age were observed in both studied subgroups. The results of our study suggest that vitamin D deficiency could influence IGF-I concentrations in children and adolescents with growth hormone deficiency, and vitamin D deficiency should be normalized before the measurement of IGF-I concentrations to obtain the reliable and unbiased IGF-I values.

Efficacy and safety of lenalidomide treatment in multiple myeloma (MM) patients--Report of the Polish Myeloma Group.

UNLABELLED: The aim of the multi-centre retrospective study was to evaluate the efficacy and safety of lenalidomide (LEN) therapy in patients with resistant or relapsed multiple myeloma (MM) as well as in patients with stable disease (LEN used due to neurological complications). The primary endpoint of this study was an overall response rate (ORR). The secondary endpoints were as follows: time to progression (TTP), overall survival (OS) and the safety of drug use. Data were collected in 19 centres of the Polish Multiple Myeloma Study Group. The study group consisted of 306 subjects: 153 females and 153 males. In 115 patients (38.8%, group A), a resistant myeloma was diagnosed; in 135 (44.1%, group B) a relapse, and in 56 (18.3%, group C) a stable disease were stated. In 92.8% of patients, LEN+DEX combination was used; in remaining group, LEN monotherapy or a combination therapy LEN+bortezomib or LEN+bendamustine and other were used. In the entire study group, ORR was 75.5% (including 12.4% patients achieving complete remission [CR] or stringent CR [sCR]). Median time to progression (TTP) was 20 months. Median overall survival (OS) was 33.3 months. The regression model for "treatment response" was on the borderline of statistical significance (p=0.07), however the number of LEN treatment cycles ≥ 6 (R(2)=17.2%), baseline LDH level (R(2)=1.1%) and no ASCT use (R(2)=1.7%) where the factors most affecting treatment response achievement. The regression model for dependant variable--"overall survival"--was statistically significant (p=0.0000004). Factors with the most impact on OS were as follows: number of LEN cycles treatment ≥ 6 (R(2)=16.7%), treatment response achievement (R(2)=6.9%), ß-2-microglobulin (ß-2-M) level (R(2)=4.8%), renal function (R(2)=3.0%) and lack of 3/4 grade adverse events (R(2)=1.4%). SUMMARY: LEN is an effective and safe therapeutic option, even in intensively treated resistant and relapsed MM patients, as well as in patients with stable disease and previous treatment-induced neurological complications. In particular, the number of LEN treatment cycles ≥ 6 was the factor which affected treatment response achievement the most, together with an important impact on OS.

Brown Adipose Tissue and Browning Agents: Irisin and FGF21 in the Development of Obesity in Children and Adolescents.

In the pediatric population, especially in early infancy, the activity of brown adipose tissue (BAT) is the highest. Further in life BAT is more active in individuals with a lower body mass index and one can expect that BAT is protective against childhood obesity. The development of BAT throughout the whole life can be regulated by genetic, endocrine, and environmental factors. Three distinct adipose depots have been identified: white, brown, and beige adipocytes. The process by which BAT can become beige is still unclear and is an area of intensive research. The "browning agents" increase energy expenditure through the production of heat. Numerous factors known as "browning agents" have currently been described. In humans, recent studies justify a notion of a role of novel myokines: irisin and fibroblast growth factor 21 (FGF21) in the metabolism and development of obesity. This review describes a possible role of irisin and FGF21 in the pathogenesis of obesity in children.

Immunological Characteristics of Children with Hashimoto's Autoimmune Thyroiditis.

The main cause of autoimmune thyroiditis of Hashimoto's type (HT) is a pathological immune response to thyroid antigens. The aim of the study was to present clinical characteristics and immune profile of children with HT. Ninety five children were examined: 45 with HT (age: 8-18 years) and 50 healthy age-matched controls. The peripheral blood mononuclear cells' (PBMC) phenotype was evaluated using a Beckman Coulter flow cytometer with the following monoclonal antibodies: CD4-FITC, CD28-PC5, CD152-PE and CD8-FITC, CD28-PC5, CD152-PE. The thyroid stimulating hormone, thyroid hormones, and antibodies against thyroid peroxidase (TPO) and thyroglobulin (TG) were evaluated by a microparticle enzyme immunoassay. We found that goiter was present in 53% of children, the thyroid had an increased density in palpation in 98%, and hypothyroidism was diagnosed in 11% of HT patients. The number of CD152+ was lower in HT than in healthy children (p<0.05). CD4+ and CD8+ PBMC subsets did not differ between the groups at baseline. After stimulation with phytohemagglutinine (PHA), CD4+ cells decreased in healthy controls and remained constant in HT children. Anti-TPO and anti-TG antibodies were higher in children with a lower percentage of CD152+. No other markers correlated with the immunological profile of PBMC. The percentages of CD4+ and CD152+ negatively correlated with the anti-TG concentration. We conclude that children with HT have a different PBMC profile than healthy children and show a different pattern of response to stimulation.

Metabolic and immunological consequences of vitamin D deficiency in obese children.

Numerous studies highlighted the link between vitamin D deficiency and cardiovascular, autoimmune, metabolic diseases, and obesity. However, a clear role of vitamin D in these disorders is still unknown. Vitamin D deficiency in children can be a potential risk factor for developing diseases at a later age. Early prevention and vitamin D supplementation should become a public health priority. This review highlights the clinical implications of vitamin D deficiency in adults and children with obesity.

The protective effect of the Cornus mas fruits (cornelian cherry) on hypertriglyceridemia and atherosclerosis through PPARα activation in hypercholesterolemic rabbits.

Cornelian cherry (Cornus mas L.) fruits have been used in traditional cuisine and in folk medicine in various countries. This study was conducted to evaluate the constituents and impact of cornelian cherry (C. mas L.) fruits lyophilisate on lipid levels, PPARα protein expression, atheromatous changes in the aorta, oxido-redox state, and proinflammatory cytokines in hypercholesterolemic rabbits. The HPLC-MS method was used for determining active constituents in cornelian cherry. In a subsequent in vivo study the protective effect of the cornelian cherry on diet-induced hyperlipidemia was studied using a rabbit model fed 1% cholesterol. Cornelian cherry (100mg/kg b.w.) or simvastatin (5mg/kg b.w.) were administered orally for 60 days. Two iridoids - loganic acid and cornuside - and five anthocyanins were identified as the main constituents of the cornelian cherry. The administering of the cornelian cherry led to a 44% significant decrease in serum triglyceride levels, as well as prevented development of atheromatous changes in the thoracic aorta. Cornelian cherry significantly increased PPARα protein expression in the liver, indicating that its hypolipidemic effect may stem from enhanced fatty acid catabolism. Simvastatin treatment did not affect PPAR-α expression. Moreover, the cornelian cherry had a significant protective effect on diet-induced oxidative stress in the liver, as well as restored upregulated proinflammatory cytokines serum levels. In conclusion, we have shown loganic acid to be the main iridoid constituent in the European cultivar of the cornelian cherry, and proven that the cornelian cherry could have protective effects on diet-induced hypertriglicerydemia and atherosclerosis through enhanced PPARα protein expression and via regulating oxidative stress and inflammation.

Content of polyphenols in coloured and yellow fleshed potatoes during dices processing.

The purpose of the research was to examine the effect of the laboratory production of dried potato dice on the content of phenolic compounds in one yellow-fleshed potato variety and four blue-fleshed potatoes varieties. Coloured-flesh potato varieties were characterised by about three times higher amount of total phenolic content than traditional yellow-fleshed ones. The predominating phenolic acids in potato were chlorogenic acid and its isomers, which account about 90% of total phenolic content in tubers. The phenolic acid content decreased by 80% after peeling the blue-fleshed potatoes and by 60% after peeling the yellow variety. The dried potato dice obtained from yellow-fleshed potatoes had no content of phenolic acids but produced from colour-fleshed potatoes contained about 4% of the original phenolic content of the raw material. Chlorogenic acid amounted about 97% of total phenolic acid content, and the rest was neochlorogenic acid.

Cognitive functions and mood during chronic thyrotropin-suppressive therapy with L-thyroxine in patients with differentiated thyroid carcinoma.

BACKGROUND: Subclinical thyroid dysfunctions may cause cognitive deficits and mood disorders. Chronic TSH-suppressive therapy with L-T(4) causing subclinical hyperthyroidism has been widely used in treatment of patients with thyroid differentiated carcinoma. The impact of this therapy on cognitive functions and mood have not been systematically studied. The aim of this study was to asses executive functions, working memory, attention, and depression in patients with subclinical hyperthyroidism in the course of TSH-suppressive therapy. METHODS: Thirty-one patients with subclinical hyperthyroidism in the course of suppressive treatment with L-T(4) following the total thyroidectomy and radioiodine ablative therapy were included in the study. Cognitive functioning in patients and control group were investigated using the battery of neuropsychological tests [Wisconsin Card Sorting Test (WCST), The Oral Word Association Test (OWAT), Trail Making Test, The Stroop Color-Word Interference test and Digit span]. Psychometric evaluation was performed using 17-items the Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). RESULTS: The performance on tests assessed executive functions, psychomotor speed, and attention was significantly lower in patients group. There was no differences in results of Stroop test and Digit Span forward and backwards between both groups. The intensity of depressive symptoms negatively correlated with a number of completed categories on WCST and results of OWAT. Cognitive deficits were still observed when patients with concomitant general medical conditions and depression were excluded from the analysis. CONCLUSION: Our findings provide evidence of neuropsychological impairment in patients with differentiated thyroid carcinoma treated with chronic TSH-suppressive therapy.

Leptin receptors.

Leptin or obesity receptor (Ob-R) is a member of class I cytokine receptor family. Ob-R, expressed in six isoforms, is the product of alternative RNA splicing of db gene. According to its structural differences, the receptor's isoforms are divided into three classes: long, short, and secretory isoforms. A long, fully active isoform of Ob-Rb is expressed mainly in the hypothalamus, where it takes part in energy homeostasis and in the regulation of secretory organs' activity. Ob-Rb is also present on all types of immune cells, involved in innate and adaptive immunity. Short leptin isoforms (Ob-Ra, Ob-Rc, Ob-Rd, and Ob-Re) that contain box 1 motif are able to bind JAK kinases (Janus kinases) as well as to activate some other signal transduction cascades. A soluble isoform (Ob-Re) can regulate serum leptin concentration and serve as a carrier protein delivering the hormone to its membrane receptors and is able to transduce the signal into the cell. JAK/STAT pathway plays the major role in leptin signal transduction through membrane receptors. Among all Ob-R isoforms, only full-length isoform (Ob-Rb) is able to fully transduce activation signal into the cell.

Association between anthropometric measures of obesity, metabolic disturbances and polymorphism G-308A of the tumor necrosis factor-alpha gene in children.

INTRODUCTION: TNF--α is one of the most important factors in the development and course of inflammation. It is suggested that polymorphism located in the 5'regulatory region of the TNF-α gene at position 308 (guanine [G]→adenine[A]) may increase the expression of this cytokine in fat tissue and influence the fat mass and insulin resistance. OBJECTIVE: To investigate whether the G-308A polymorphism of the TNF-α gene may influence obesity, insulin resistance, fasting plasma lipids, serum leptin levels, and the incidence of metabolic syndrome. MATERIAL AND METHODS: The obese group included 124 children with simple obesity (72 girls and 52 boys) aged 10-18 (mean age 15 years) with SDS of BMI ≥2.0. A control group consisted of 56 healthy non-obese children (36 girls and 20 boys) aged 11-18 (mean age 14 years) with SDS of BMI <1.0. Polymorphism identification was performed in total genomic DNA, using PCR-RFLP method. RESULTS: Carriers of A (AG+AA) allele among the obese children were significantly more frequent than in the control group (OR = 2.29, 95% CI 1.2-4.4, χ⊃2 = 6.24, P<0.05). Carriers of A alleles showed a higher concentrations of fasting glucose (81.3 ±10.5 vs. 77.4 ±10.3 mg/dl; P<0.05), but lower values of fasting insulin (15.1 ±7.3 vs. 19.0 ±9.5 µIU/ml; P<0.05), lower values of HOMA index (3.0 ±1.5 vs. 3.7 ±2.0; P <0.05). In the group of boys, carriers of A alleles showed a tendency for lower concentrations of HDL (43.8 ±12.6 vs. 48.3 ±11.8 mg/dl; P<0.05). Blood pressure and leptin level did not differ between the obese children with gene polymorphism and those of wild homozygous. The incidence of the full metabolic syndrome (MetS) in the children, according to the IDF definition, was 33%. The presence of the MetS in children with wild homozygous GG and carriers of A allele of TNF-α polymorphism gene did not show statistical differences (OR = 1.38; 95% CI 0.6-3.1, χ⊃2 = 0.58). CONCLUSIONS: 1/ Polymorphism G-308A of the TNF-α gene is more common in children with obesity; and 2/ Polymorphism G-308A of the TNF-α gene does not seem to be associated with the grade of obesity, insulin resistance, lipid profile, leptin levels, and the incidence of metabolic syndrome in obese children.

Expression of CD152 (CTLA-4) in children with autoimmune thyroiditis and +49 A/G polymorphism of exon 1 of the CTLA-4 gene.

CTLA-4 gene is one of the strongest locus of genetic susceptibility to autoimmune thyroid diseases. The aim of the present study was to investigate surface expression of CTLA-4 on peripheral T cells in homozygotes AA and GG at position +49 of CTLA-4 gene in children with Hashimoto's thyroiditis and in healthy controls. Blood samples were obtained from 100 children: 45 with Hashimoto's thyroiditis and 55 controls. CTLA-4 exon 1 polymorphism was defined by SSCP and RFLP with BbvI enzyme. T cells were analyzed with three color flow cytometry by Coulter EPICS XL. We found that CTLA-4 expression was significantly lower in the thyroiditis patients than in controls, but CTLA-4 expression in homozygotes GG and AA was comparable. We therefore conclude that decreased expression of CTLA-4 on T cells in children with Hashimoto's thyroiditis is not dependent on polymorphic changes at position +49 of CTLA-4 gene.

No association of LEPR Gln223Arg polymorphism with leptin, obesity or metabolic disturbances in children.

OBJECTIVE: The aim of the study was to investigate whether the Gln223Arg in the leptin receptor may influence body weight, leptin concentration, and metabolic parameters in children. MATERIALS AND METHODS: The examined group included 101 obese children (58 girls and 43 boys) with BMI 31.41 +/-5.03 kg/m(2) (BMI > or = 2 SDS) and the control group consisted of 41 children with BMI 20.0 +/-0.80 kg/m2 (BMI <1.0 SDS). Polymorphism identification was performed in total genomic DNA using PCR-RFLP method. RESULTS: The distribution of genotypes LEPR was the following: in the obese group: AA - 20.8%, AG- 55.4%, GG-23.8 %; in the control group AA-31.7%, AG- 53.65%, GG-14.65%. Comparative analyses between AA homozygous children and carriers of G alleles did not confirm any relation between the analyzed polymorphism and BMI, leptin concentrations, and metabolic disturbances in children with obesity. CONCLUSION: In children with obesity we did not observe association of the LEPR Gln223Arg gene polymorphism with obesity, leptin, insulin resistance, and metabolic abnormalities.

Altered expression of T lymphocyte surface markers in children with chronic autoimmune thyroiditis.

CTLA-4 and CD28+ are regulators of T cell activation. The CTLA-4 gene is associated with variety of autoimmune diseases. The aim of the study was to evaluate changes in basic T cell subpopulations, and the expression of CD152+ and CD28+ before and after T cell stimulation in children with autoimmune thyroiditis (AT), as compared with control subjects. Blood samples were obtained from 35 AT children and 25 healthy children. CD markers were evaluated by flow cytometry at baseline, after the culture with phytohemagglutinin and without stimulation. At baseline, CD152+ expression was lower in patients than in controls (P<10(-6)). After stimulation, there were an increase in CD152+ T cells and decreases in CD28+ and CD4+ cells in controls (P<0.01). In AT children, CD152+ T cells remained stable. CD4+CD152+ T cells correlated inversely with antithyroglobulin antibodies. We conclude that alterations in lymphocyte markers are associated with AT. Stimulation leads to differing changes in T-lymphocyte subsets in both examined children populations.

Asymmetric induction in the [4+2]cycloaddition of cyclopentadiene and furan to chiral derivatives of fumaric acid.

[4+2]Cycloaddition reactions of cyclopentadiene (1a) and furan (1b) to N,N'-fumaroyldi[(2R)-bornane-10,2-sultam] (2) and to N,N'-fumaroyldi[(2R)-bornane-10,2-(2'-phenyl-pyrazol-3'-one)] (3) are presented. A correlation between the solvent polarity and the logarithm of the diastereoisomer ratio (dr) was found for the uncatalyzed [4+2]cycloaddition of 1a to 3.

Combined delivery of an antiangiogenic protein (angiostatin) and an immunomodulatory gene (interleukin-12) in the treatment of murine cancer.

We investigated the feasibility of a novel therapeutic approach to treat neoplastic diseases in mice. This novel strategy consists in delivering a protein (angiostatin) with strong antiangiogenic properties, followed by administration of the interleukin 12 gene that is strongly immunomodulatory and has also some antiangiogenic effects. When angiostatin-mediated antiangiogenic therapy was used in combination with intratumor delivery of the IL-12 gene (a strategy much safer than IL-12 protein administration), this produced a synergistic therapeutic effect.

[Developmental disorders in the fourth edition of the American classification: diagnostic and statistical manual of mental disorders (DSM IV -- optional book)]. / Zaburzenia psychiczne wieku rozwojowego w roboczej wersji IV edycji klasyfikacji amerykanskiej--Diagnostic and Statistical Manual of Mental Disorders (DSM IV--Options Book).

In 1991 the American Psychiatric Association proposed a draft version of the IV edition of the Diagnostic and Statistical Manual of Mental Disorders--the DSM IV Options Book. Authors of this version wanted to increase clarity of the criteria sets and to provide compatibility with the Tenth Edition of the International Classification of Diseases (ICD - 10). The purpose of this Options Book is to propose some changes in wording, diagnostic divisions and to discuss various options concerning the placement of sections and disorders within the classification. The "Disorders of Infancy, Childhood or Adolescence" section was renamed "Disorders Usually First Evident in Infancy, Childhood or Adolescence" and moved to the front of the classification and also was expended to 11 groups of disorders. Several suggestions have been made about including new diagnostic groupings such as: Rett's Disorder, Eating Disorders and Voice Disorder. The Options Book introduces a superior category for Attention Deficit Disorders (with and without hyperactivity) and for Conduct Disorder/Oppositional Defiant Disorder. Several options are proposed regarding The Anxiety Disorders of Childhood or Adolescence. There is no evidence for a distinction in this category according to the age criterion. One option would be to move these disorders into the adult anxiety section (similarly as in the Mood Disorders and Schizophrenia). In the new version the title "Specific Developmental Disorders" is omitted. The suggestion is to include Phonological Disorder (Articulation Disorders) and Elective Mutism into Speech and Language Disorders section.

Biochemical characterization of long-term culture of the Swarm rat chondrosarcoma chondrocytes in agarose.

Difficulty in maintaining phenotypic stability of the Swarm rat chondrosarcoma in long-term monolayer cultures has prompted investigation of alternative conditions that would enable extended maintenance of these cells, permitting use of the tumor as a model system for the long-term study of proteoglycan metabolism. Morphological analysis of the growth of the chondrosarcoma chondrocytes in agarose has shown stability of the culture over a 20 day period with respect to the ability of the cells to proliferate and synthesize an Alcian blue-positive extracellular matrix. The present study confirms these findings through analysis of the growth characteristics of the culture and the pattern of proteoglycan and collagen synthesis. The chondrocytes actively synthesize a proteoglycan-rich matrix at a rate dependent on the initial plating density and concentration of serum in the culture medium. These factors similarly affect the proliferative capabilities of the culture as demonstrated by the growth curves obtained at different culture conditions. During 20 days in culture, the cells synthesize an aggregating chondroitin sulfate proteoglycan and collagen type II, typical of cartilage and this chondrosarcoma. In addition, small molecular weight proteoglycans were found to be present at concentrations of up to 10% of the total proteoglycan population. Degradative rates are slow, the proteoglycan half-life is about 30 days, but can be enhanced with retinol, reducing the half-life to 2 days.