Predictors of bone mineral density in patients receiving glucocorticoid replacement for Addison's disease.

PURPOSE: Patients receiving long-term glucocorticoid (GC) treatment are at risk of osteoporosis, while bone effects of substitution doses in Addison's disease (AD) remain equivocal. The project was aimed to evaluate serum bone turnover markers (BTMs): osteocalcin, type I procollagen N-terminal propeptide (PINP), collagen C-terminal telopeptide (CTX), sclerostin, DKK-1 protein, and alkaline phosphatase (ALP) in relation to bone mineral density (BMD) during GC replacement. METHODS: Serum BTMs and hormones were assessed in 80 patients with AD (22 males, 25 pre- and 33 postmenopausal females) on hydrocortisone (HC) substitution for ≥3 years. Densitometry with dual-energy X-ray absorptiometry covered the lumbar spine (LS) and femoral neck (FN). RESULTS: Among BTMs, only PINP levels were altered in AD. BMD Z-scores remained negative except for FN in males. Considering T-scores, osteopenia was found in LS in 45.5% males, 24% young and 42.4% postmenopausal females, while osteoporosis in 9.0%, 4.0% and 21.1%, respectively. Lumbar BMD correlated positively with body mass (p = 0.0001) and serum DHEA-S (p = 9.899 × 10-6). Negative correlation was detected with HC dose/day/kg (p = 0.0320), cumulative HC dose (p = 0.0030), patient's age (p = 1.038 × 10-5), disease duration (p = 0.0004), ALP activity (p = 0.0041) and CTX level (p = 0.0105). However, only age, body mass, ALP, serum CTX, and sclerostin remained independent predictors of LS BMD. CONCLUSION: Standard HC substitution does not considerably accelerate BMD loss in AD patients and their serum BTMs: CTX, osteocalcin, sclerostin, DKK-1, and ALP activity remain within the reference ranges. Independent predictors of low lumbar spine BMD, especially ALP activity, serum CTX and sclerostin, might be monitored during GC substitution.

Assessment of steroid enzymes action in children and adolescents with obesity.

Rising prevalence of obesity has become an important impulse to investigate basic mechanisms involved in regulating the energy balance. It is widely accepted that steroids are potent factors affecting glucose, fat, and protein metabolism. Our study was aimed to analyze differences in the total amount of selected enzymes implicated in steroid metabolism in a group of children suffering from obesity and those with normal weight, further subdivided according to sex and pubertal stage. Data were obtained from 187 Caucasian children and adolescents, including 113 patients (63 girls, 50 boys) with obesity and 74 (34 girls, 40 boys) normal weight volunteers. Standard clinical examinations were performed in both groups. To evaluate the impact of puberty, preadolescent children and those with advanced puberty were assessed separately. Urine steroid excretion profiles were analyzed using gas chromatography/mass spectrometry method. Children with obesity revealed several changes in in the total amount of steroid enzymes as assessed by the relevant metabolite proportions, compared to their norm weight peers. Girls showed a significant increase in the activity of 11ßHSD1, while boys demonstrated a relevant elevation in 20αHSD action. Regardless of sex, children with obesity showed an increase in the activity of 5ß-reductase + 3αHSD complex and a decrease in the involvement of 11ßOH-lase. The effect is attenuated when consider pre- and pubertal subgroups. We hypothesize that changes in the activity levels of selected enzymes may be a compensatory mechanism to limit the glucocorticoid exposure of key target tissues as well as to improve metabolic control and reduce long-term complications of obesity.

Changes of androgen and corticosterone metabolites excretion and conversion in cystic fibrosis.

Cystic fibrosis (CF) is a life-threatening inherited disease related to a mutation in the CFTR gene, that leads to serious health complications such as chronic pulmonary infections, pancreatic insufficiency, dysfunction of the sweat glands and reproductive system. For the first time, we have described the profile of corticosterone and androgen metabolites in urine, as well as the activity of enzymes involved in steroid genesis and metabolism in people with CF, using gas chromatography/mass spectrometry. A significant reduction in the excretion of most of the measured metabolites in CF was found. These differences were observed in the group of progestagen metabolites, as well as among metabolites of corticosterone and androgens. We revealed higher activities of 17ß-hydroxysteroid dehydrogenase and 17,20-lyase in the Δ4 pathway compared with controls, what can promote the androgen synthesis through the backdoor androgen pathway. We have also found the increased conversion activity of 11-oxyganated steroids by 5a-reductase in backdoor pathway. Levels of the most potent and vital androgens (testosterone and dihydrotestosterone) are comparable in both groups. However, the excretion of dehydroepiandrosterone was lower in CF. Decreased cholesterol lipoprotein levels may contribute to limited intracellular cholesterol supply and reduced adrenal steroidogenesis in CF individuals. Changes in the activity of some steroidogenesis enzymes may suggest the presence of some peripheral adaptive mechanisms in CF to maintain androgen balance in the body despite the limited sufficiency of secretion by the adrenal cortex.

The Impact of Obesity on the Excretion of Steroid Metabolites in Boys and Girls: A Comparison with Normal-Weight Children.

Obesity in childhood is associated with several steroid changes, which result from excess body mass. The aim of this study was to evaluate steroid metabolism in children with obesity compared with those with normal weight, especially in relation to sex and puberty progress. We analyzed the clinical data of 191 children, aged between 5 and 18 years, with 115 affected (64 girls and 51 boys) and 76 unaffected (35 girls and 41 boys) by obesity. Routine clinical assessment and pubertal stage evaluation based upon Tanner's scale were performed. In addition, to evaluate the impact of puberty, children with pre-adolescence and advanced puberty were divided into separate subgroups. Then, 24 h urine steroid excretion profiles were analyzed by gas chromatography/mass spectrometry. Significant differences in the excretion of steroid metabolites were found between normal weight children and children with obesity, especially in the prepubertal cohort. In this group, we observed enhanced activity in all the pathways of adrenal steroidogenesis. Raised excretion of mineralocorticoid derivatives such as tetrahydro-11-deoxycorticosterone, tetrahydrocorticosterone, and 5α-tetrahydrocorticosterone supported increased activity of this track. No significant differences were detected in the excreted free forms of cortisol and cortisone, while the excretion of their characteristic tetrahydro-derivatives was different. In pre-adolescent children with obesity, α-cortol and especially α-cortolone appeared to be excreted more abundantly than ß-cortol or ß-cortolone. Furthermore, in children with obesity, we observed elevated androgen excretion with an enhanced backdoor pathway. As puberty progressed, remarkable reduction in the differences between adolescents with and without obesity was demonstrated.

Genetic variants and risk of endocrine autoimmunity in relatives of patients with Addison's disease.

Since individuals with Addison's disease (AD) present considerable co-occurrence of additional autoimmune conditions, clustering of autoimmunity was also predicted among their relatives. The study was aimed to assess circulating autoantibodies in first-degree relatives of patients with AD and to correlate them with the established genetic risk factors (PTPN22 rs2476601, CTLA4 rs231775, and BACH2 rs3757247). Antibodies were evaluated using validated commercial assays, and genotyping was performed using TaqMan chemistry. The studied cohort comprised 112 female and 75 male relatives. Circulating autoantibodies were found in 69 relatives (36.9%). Thyroid autoantibodies, that is antibodies to thyroid peroxidase (aTPO) and thyroglobulin (aTg), were detectable in 25.1 and 17.1% relatives, respectively. Antibodies to 21-hydroxylase (a21OH) were found in 5.8% individuals, and beta cell-specific antibodies to ZnT8, GAD, and IA2 were found in 7.5, 8.0, and 2.7%, respectively. The prevalence of a21OH (P = 0.0075; odds ratio (OR) 7.68; 95% CI 1.903-36.0), aTPO (P < 0.0001; OR 3.85; 95% CI 1.873-7.495), and aTg (P < 0.0001; OR 7.73; 95% CI 3.112-19.65), as well as aGAD (P = 0.0303; OR 3.38; 95% CI 1.180-9.123) and aZnT8 (P = 0.032; OR 6.40; 95% CI 1.846-21.91), was significantly increased in carriers of rs2476601 T allele. Moreover, T allele appeared to be a risk factor for multiple circulating autoantibody specificities (P = 0.0009; OR 5.79; 95% CI 1.962-15.81). None of the studied autoantibodies demonstrated significant association with rs231775 in CTLA4 (P > 0.05), and only weak association was detected between BACH2 rs3757247 and circulating aTPO (P = 0.0336; OR 2.12; 95%CI 1.019-4.228). In conclusion, first-degree relatives of patients with AD, carriers of the PTPN22 rs2476601 T allele, are at particular risk of developing autoantibodies to endocrine antigens.

Alteration in glucocorticoids secretion and metabolism in patients affected by cystic fibrosis.

Cystic fibrosis (CF) is an inherited syndrome associated with a mutation in a cystic fibrosis transmembrane conductance regulator gene, composed of exocrine gland dysfunction involving multiple systems that may result in chronic respiratory infections, pancreatic enzyme deficiency, and developmental disorders. Our study describes for the first time the urinary profile of glucocorticoid metabolites and the activity of the enzymes involved in the development and metabolism of cortisol in patients with CF, using a gas chromatography/mass spectrometry method. Data were obtained from 25 affected patients and 70 sex- and age- matched healthy volunteers. We have shown a general decrease in the activity of enzymes involved in the peripheral metabolism of cortisol, such as 11ß-hydroxysteroid dehydrogenase type 2, 5α- and 5ß-reductases. In contrast, the activity of 11ß-hydroxysteroid dehydrogenase type 1, the enzyme that converts cortisone to cortisol, increased. Furthermore, our study found a significant decrease in glucocorticoid excretion in patients with CF. This may suggest adrenal insufficiency or dysregulation of the HPA axis and the development of peripheral mechanisms to counteract cortisol degradation in the case of reduced synthesis of glucocorticoids by the adrenal glands. Furthermore, the activity of 5α-reductase seems to be enhanced only through the backdoor pathway, especially when we taking into consideration 11ß-hydroxyandrosterone/11ß-hydroxyetiocholanolone ratio which has been shown to be the best differential marker for enzyme activity. CF impairs nutritional effects and energetic balance in patients; thus, our findings suggest the existence of adaptive mechanisms due to limited secretion of adrenal steroids and subsequent diminished amounts of their metabolites in urine. On the other hand, local control of cortisol availability is maintained by enhanced 11ßHSD1 activity and its recovery from cortisone in organs and tissues which need this. Steroid hormone dysregulation might be another important factor in the course of CF that should be taken into account when planning an effective and comprehensive therapy.

Historical and cultural aspects of obesity: From a symbol of wealth and prosperity to the epidemic of the 21st century.

World Health Organization defines obesity as abnormal or excess adipose tissue accumulation. Nowadays, this condition is a serious threat to the public health in most countries around the world. Obesity adversely affects physical, mental, and in most cultures, social well-being. However, throughout the ages-from ancient times to the 21st century-this condition has been subject to various interpretations. As a matter of fact, obesity has not always been regarded as a disease. For many decades, excessive body weight has been considered rather a symbol of health. It was a marker of wealth and prosperity, as well as a sign of high social status. The centuries that passed on the development of science and medicine have gradually changed its face, but significant progress in understanding the causes and consequences of obesity has been made in the last 30 years. This paper presents the historical outline of obesity and its treatment from ancient times to the present-from its affirmation to the epidemic in the late 20th and 21st century.

Aggregation of autoimmunity in extended families of people with autoimmune Addison disease.

BACKGROUND: Autoimmunity accounts for 90% of cases of primary adrenal insufficiency (Addison disease (AD)). Affected people present a significant co-occurrence of autoimmune conditions; hence, clustering of autoimmunity is also predicted among their relatives. AIMS: To evaluate the burden of autoimmunity in families of people with AD. METHODS: A total of 116 individuals with AD was surveyed regarding the occurrence of 23 autoimmune diseases among their relatives. RESULTS: A total of 74.1% of persons with AD reported at least one relative with an autoimmune disorder - 257 cases were diagnosed in 221 relatives. Hashimoto thyroiditis was found in 100 individuals, followed by Graves disease and vitiligo, in 25 and 24 relatives respectively. Type 1 diabetes was diagnosed in 23 relatives, psoriasis in 15, rheumatoid arthritis in 12, pernicious anaemia in 11, multiple sclerosis in 8, and premature menopause in 8 women. AD was found in seven relatives, alopecia in six and celiac disease in five. Other conditions were rare. Significant correlation was noticed between the number of autoimmune conditions in AD proband and the number of affected relatives (P = 0.031). A total of 66.4% of people with AD had a first-degree relative suffering from autoimmunity. Autoimmune conditions were more frequent among females: sisters (P < 0.001), mothers (P = 0.002) and grandmothers (P = 0.002). CONCLUSIONS: Considerable prevalence of autoimmune conditions in relatives of people with AD confirms substantial risk of autoimmunity, especially in females and relatives of patients affected by multiplex autoimmunity. Our data corroborate the recommendation of active screening for autoimmune disorders, particularly thyroid disease, among AD family members.

Steroid Metabolism in Children and Adolescents With Obesity and Insulin Resistance: Altered SRD5A and 20α/20ßHSD Activity.

Alterations in glucocorticoid metabolism may contribute to the development of obesity and insulin resistance (IR). Obesity in turn affects the androgen balance. The peripheral metabolism of steroids is equally an important determinant of their bioavailability and activity. The aim of this study was to evaluate steroid metabolism in obese children and to define which enzyme alterations are associated with IR. Clinical characteristics and anthropometric measurements were determined in 122 obese children and adolescents (72 girls, 50 boys) aged 8 - 18 years. 26 of them (21.3%) were diagnosed with IR (13 boys, 13 girls). Routine laboratory tests were performed and 24h urinary steroid excretion profiles were analyzed by gas chromatography/mass spectrometry. Positive relationship between 5α-reductase (SRD5A) activity and IR was found. According to the androsterone to etiocholanolone (An/Et) ratio the activity of SRD5A was significantly increased in obese children with IR, but the difference remained insignificant once the 5α-dihydrotestosterone to testosterone (5αDHT/T) ratio was considered. Furthermore, this relationship persisted in boys but was not observed in girls. The activity of 20α-hydroxysteroid dehydrogenase (20αHSD) and 20ß-hydroxysteroid dehydrogenase (20ßHSD) was reduced only in obese girls with IR. Conclude, in the context of obese children and adolescents with IR, we surmise that increased SRD5A represents a compensatory mechanism to reduce local glucocorticoid availability. This phenomenon is probably different in the liver (restriction) and in the adipose tissue (expected increase in activity). We show significant changes in 20αHSD and 20ßHSD activity in obese girls with IR, but it is difficult to clearly determine whether the activity of these enzymes is an indicator of the function in their ovaries or adrenal glands.

Overexpression of miR-7977 in CD4+ T cells is associated with multiplex autoimmunity in patients with Addison's disease.

OBJECTIVE: Autoimmune Addison's disease (AD) results from a combination of the genetic predisposition, unclear environmental triggers and ensuing immune dysfunction. MicroRNA molecules (miRNAs) are involved in post-transcriptional regulation of numerous target genes, hence may affect the immune function and promote autoimmunity. A deregulated miRNAs profile was reported in several autoimmune conditions. Our study was aimed at a global analysis of miRNA expression in CD4+ T cells from patients with AD. METHODS: CD4+ T cells were separated from peripheral blood, total RNA enriched in miRNAs extracted, and miRNA expression determined by small RNA sequencing. Global miRNA was investigated in 11 AD subjects and 9 age-matched healthy controls, with subsequent validation of the differentially expressed miRNAs by RT-qPCR in 29 patients and 28 controls. RESULTS: The analysis revealed upregulation of 9 miRNAs and downregulation of miR-509-3p in CD4+ T cells from patients with AD (cut-off fold change (FC) >2, Benjamini-Hochberg P < 0.05). RT-qPCR validation confirmed overexpression of miR-7977 (P < 0.0001, FC = 2.7), miR-374a-5p and miR-1260b (P < 0.05, FC = 1.3 and 1.2, respectively). miR-7977 was upregulated in patients with coexisting autoimmune conditions vs those with isolated AD (P = 0.005, mean FC = 2.2). Moreover, miR-7977 abundance appeared correlated with the number of autoimmune comorbidities (P <0.0001, r = 0.736) and serum autoantibodies against thyroid peroxidase (P < 0.001, r = 0.588). CONCLUSIONS: Our study demonstrates upregulated expression of miR-7977 in CD4+ T cells from patients with AD, especially with its polyendocrine form. Further analyses are warranted to replicate our results, establish the marker utility of miR-7977, and elucidate its functional role in autoimmunity.

Polymorphism in BACH2 gene is a marker of polyglandular autoimmunity.

PURPOSE: Genetically predisposed individuals may develop several autoimmune diseases-autoimmune polyendocrine syndromes (APS). APS types 2-4, are complex disorders, which combine various organ-specific autoimmune conditions. Recent reports support the considerable role of the BACH2 gene in immune cell differentiation and shifting the T-cell balance towards regulatory T-cells. BACH2 polymorphisms are associated with autoimmune disorders, including Addison's disease (AD), Graves' disease (GD), and probably type 1 diabetes (T1D). Our study was aimed to investigate the BACH2 variant, rs3757247, in endocrine autoimmunity in the Polish population. METHODS: The analysis comprised 346 individuals with APS, 387 with T1D only, and 568 controls. Genotyping was performed using TaqMan chemistry. RESULTS: APS type 2 was found in 219 individuals, type 3 in 102, and type 4 in 25 subjects. Overall, AD was diagnosed in 244 subjects, Hashimoto's thyroiditis-in 238, T1D-in 127, GD-in 58, vitiligo and chronic gastritis each in 40 patients, celiac disease-in 28, premature menopause in 18, and alopecia in 4 patients. Minor T allele at rs3757247 was found in 56.4% APS vs. 44.1% control alleles (OR 1.59; 95%CI: 1.30-1.95, p < 0.0001). The distribution of genotypes revealed excess TT homozygotes in the APS cohort (33.2 vs. 20.1% in controls, p < 0.0001). The frequencies of rs3757247 alleles and genotypes in T1D patients did not present significant differences vs. controls (p-values > 0.05). CONCLUSIONS: These results provide evidence of the association between BACH2 polymorphism and polyglandular autoimmunity. Since carriers of rs3757247 display increased risk for additional autoimmune conditions, this variant could identify individuals prone to develop APS.

Upregulation of FOXO3 in New-Onset Type 1 Diabetes Mellitus.

Forkhead box O (FOXO) transcription factors have been implicated in the development and differentiation of the immune cells. FOXO3 plays a crucial role in physiologic and pathologic immune response. FOXO3, cooperatively with FOXO1, control the development and function of Foxp3+ regulatory T cells (Treg). Since the lack of Treg-mediated control has fundamental impact on type 1 diabetes mellitus (T1DM) development, we investigated FOXO3 expression in patients with T1DM. FOXO3 expression was estimated in peripheral blood mononuclear cells (PBMCs) from newly diagnosed T1DM pediatric patients (n = 28) and age-matched healthy donors (n = 27) by reahavel-time PCR and TaqMan gene expression assays. Expression analysis revealed significant upregulation of FOXO3 in T1DM (P = 0.0005). Stratification of the T1DM group according to the presence of initial diabetic ketoacidosis (DKA) did not indicate differences in FOXO3 expression in patients with DKA compared to a mild T1DM onset (P > 0.05). In conclusion, overexpression of FOXO3 is correlated with the ongoing islet autoimmune destruction and might suggest a potential role for this gene in the pathogenesis of type 1 diabetes mellitus.

Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report.

Congenital adrenal hyperplasia (CAH) is the most common cause of primary adrenal insufficiency in children and adolescents. It comprises several clinical entities associated with mutations in genes, encoding enzymes involved in cortisol biosynthesis. The mutations lead to considerable (non-classic form) to almost complete (classic form) inhibition of enzymatic activity, reflected by different phenotypes and relevant biochemical alterations. Up to 95% cases of CAH are due to mutations in CYP21A2 gene and subsequent 21α-hydroxylase deficiency, characterized by impaired cortisol synthesis and adrenal androgen excess. In the past two decades an alternative ("backdoor") pathway of androgens' synthesis in which 5α-androstanediol, a precursor of the 5α-dihydrotestosterone, is produced from 17α-hydroxyprogesterone, with intermediate products 3α,5α-17OHP and androsterone, in the sequence and with roundabout of testosterone as an intermediate, was reported in some studies. This pathway is not always considered in the clinical assessment of patients with hyperandrogenism. The article describes the case of a 17-year-old female patient with menstrual disorders and androgenization (persistent acne, advanced hirsutism). Her serum dehydroepiandrosterone sulfate and testosterone were only slightly elevated, along with particularly high values for 5α-dihydrotestosterone. In 24 h urine collection, an increased excretion of 16α-OHDHEA-a dehydroepiandrosterone metabolite-and pregnanetriolone-a 17α-hydroxyprogesterone metabolite-were observed. The investigations that we undertook provided evidence that the girl suffered from non-classic 21α-hydroxylase deficiency with consequent enhancement of the androgen "backdoor" pathway in adrenals, peripheral tissues or both, using adrenal origin precursors. The paper presents diagnostic dilemmas and strategies to differentiate between various reasons for female hyperandrogenism, especially in childhood and adolescence.

Increased risk of endocrine autoimmunity in first-degree relatives of patients with autoimmune Addison's disease.

OBJECTIVE: Autoimmune conditions tend to cluster in subjects with Addison's disease (AD) and probably also among their relatives. The aim of the study was to estimate the frequency of the endocrine gland-specific autoantibodies in first-degree relatives of patients with AD. METHODS: Autoantibodies were investigated in 113 family members using RIA and ELISA assays. The control group comprised 143 age-matched volunteers. RESULTS: Autoimmune diseases were diagnosed in 38.1% relatives. Hashimoto's thyroiditis was found in 20.3%, Graves' disease in 8.0%, vitiligo and type 1 diabetes in 3.5%, whereas AD, rheumatoid arthritis and atrophic gastritis with pernicious anaemia in 2.7% each. All studied antibodies except for islet antigen-2 (P = 0.085) were significantly more frequent in AD relatives than in controls (P < 0.05). Antibodies to 21-hydroxylase were detected in 6.2% relatives, thyroid peroxidase in 28.3%, thyroglobulin in 19.5%, glutamic acid decarboxylase in 8.0%, and zinc transporter-8 in 7.1%. Two and more autoantibodies were detected in 18.6% subjects. Significant gender difference was revealed only for aTPO, more common in female relatives (P = 0.014; OR: 3.16; 95% CI: 1.23-8.12). Circulating autoantibodies were found more frequently in the relatives of affected males (P = 0.008; OR: 3.31; 95% CI: 1.33-8.23), and in family members of patients with polyendocrine autoimmunity (P = 0.009; OR: 3.55; 95% CI: 1.31-9.57). CONCLUSIONS: This study provides evidence of increased susceptibility for the endocrine autoimmunity, especially thyroid disease, in close relatives of patients with AD. Relatives of the male AD patients and of those with autoimmune polyendocrine syndrome are at particular risk and should undergo periodic screening for autoimmune endocrine disorders.

STAT4 sequence variant and elevated gene expression are associated with type 1 diabetes in Polish children.

INTRODUCTION: Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic ß cells, resulting from coincident genetic predisposition and some environmental triggers. Signal transducer and activator of transcription 4 (STAT4) gene encodes a transcription factor, which promotes Th1 cell differentiation, interferon γ production, and development of Th17 cells. Polymorphisms of STAT4 are associated with several autoimmune conditions, while studies in T1D provided inconsistent results. This analysis was designed to investigate the association of STAT4 rs7574865 with T1D in Polish children and to assess STAT4 expression in newly diagnosed subjects. MATERIAL AND METHODS: Rs7574865 was genotyped in 656 T1D children and 782 healthy individuals. STAT4 mRNA expression was analyzed in peripheral blood mononuclear cells (PBMCs) from 29 children with T1D and 27 age-matched controls. ß-cell and thyroid-specific serum autoantibodies were assessed with radioimmunoassays. RESULTS: The distribution of rs7574865 genotypes and alleles demonstrated significant difference (p = 0.002, p < 0.001, respectively) between patients vs. controls. Carriers of the minor T allele presented earlier T1D onset (p = 0.017). No differences were found in γ-cell autoantibody in genotype-stratified patients (p > 0.050), while anti-thyroid antibodies were more frequent in carriers of the minor allele(p = 0.039 for anti-thyroperoxidase, p = 0.007 for anti-thyroglobulin antibodies, respectively). STAT4 was overexpressed in PBMCs from T1D patients (p = 0.008), especially subjects with two/three circulating ß-cell antibodies (p < 0.001). CONCLUSIONS: The study confirms an association of STAT4 rs7574865 with T1D in Polish patients, and provides an evidence for its relationship with an earlier disease onset and concomitant thyroid autoimmunity. STAT4 expression appears elevated in T1D, especially with more severe reaction against ß-cell antigens.

Serum Visfatin does not seem to be a Useful Marker to Guide Glucocorticoid Substitution in Adrenal Insufficiency.

Primary adrenal insufficiency (Addison's disease, AD) requires lifelong steroid substitution. Excess exogenous glucocorticoids promote abdominal obesity, insulin-glucose imbalance, and hypertension. Reliable markers of the adequate glucocorticoid replacement are lacking. Visfatin is a pro-inflammatory adipokine, with enzymatic activity of nicotinamide phosphoribosyltransferase. It enhances leukocyte function and synthesis of tumour necrosis factor α (TNFα) and interleukin-6 (IL-6). Serum visfatin is elevated in autoimmunity, but also in obesity, insulin resistance, and metabolic syndrome. This study was aimed to investigate whether serum visfatin could guide the glucocorticoid substitution in AD. Biochemical analyses were performed in 96 patients with AD (mean age 43.3±14.9 years) and 91 controls (43.5±12.5 years). Visfatin level was significantly elevated in patients with AD compared to controls (p<0.0001). Higher circulating IL-6 was also detected among subjects with AD (p=0.006). In AD, visfatin level was positively correlated with IL-6 (p=0.014), TNFα (p=0.001), body mass (p=0.015), fasting insulin (p=0.001) and HOMA-IR (p=0.001). No relationship was noticed with daily hydrocortisone (p=0.096) and urinary free cortisol excretion (p=0.499). Only the correlations with IL-6 and fasting insulin survived multiple regression analysis (p=0.049 and p=0.005, respectively). Additionally, positive correlation between visfatin and autoantibodies to 21-hydroxylase was noted (p=0.005). In the control group serum visfatin was correlated with IL-6 (p=0.009) and TNFα (p=0.0002). The current study reveals elevated serum visfatin in autoimmune AD. Visfatin does not seem a useful marker of the glucocorticoid replacement, although it correlates with fasting insulin and pro-inflammatory molecules. Further functional analyses are warranted to elucidate the role of visfatin in autoimmunity.

A genome-wide association study on medulloblastoma.

INTRODUCTION: Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark. METHODS: Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2. RESULTS: Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p < 1 × 10-5), but none were statistically significant after adjusting for multiple testing (p < 5 × 10-8). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (ORT = 1.59, pvalidation = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, ORT = 3.76, p = 3.2 × 10-4) and rs79036813 (PTCH1, ORA = 0.42, p = 2.6 × 10-3). CONCLUSION: The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.

Vitamin D deficiency and thyroid autoantibody fluctuations in patients with Graves' disease - A mere coincidence or a real relationship?

PURPOSE: The aim of this study was to evaluate the association between vitamin D (vitD) and changes in the titers of anti-TSH receptor (TSHR-Abs), antithyroglobulin (Tg-Abs), and antiperoxidase (TPO-Abs) autoantibodies. MATERIALS/METHODS: The study involved 269 patients with Graves' disease (GD), divided into four subgroups (1-4), i.e. 65 smokers treated with vitD(+) (1), 76 smokers not treated with vitD(-) (2), 61 non-smokers treated with vitD(+) (3) and 67 non-smokers with vitD(-) (4). All thyroid parameters were analyzed at entry and 1, 3, 6, 9 and 12 months later. RESULTS: The titer of TSHR-Abs in group 3 was significantly lower than in groups 1 and 2 across all time points. At 3, 6 and 12 months, the titers of TSHR-Abs were also lower in group 4 compared to groups 1 and 2. At 9 months, the titers in group 3 were lower than in all other groups. There was a significant inverse correlation between baseline levels of vitD and baseline titers of Tg-Abs (in group 1 only), Tg-Abs after 12 months (in group 1 only), TPO-Abs after 12 months (in groups 1 and 3), fT4 (in group 4 only), and a significant positive correlation with TPO-Abs (in group 2 only). VitD levels at 12 months were inversely correlated with Tg-Abs in group 1. CONCLUSIONS: VitD measurements in patients with GD, especially smokers with an increased TSHR-Ab titers before 131I therapy, are recommended. Immunological remission is more likely in patients with GD who receive vitD, particularly smokers.