Vitamin D effects on monocytes' CCL-2, IL6 and CD14 transcription in Addison's disease and HLA susceptibility.

Addison's disease is a rare autoimmune disorder leading to adrenal insufficiency and life-long glucocorticoid dependency. Vitamin D receptor (VDR) polymorphisms and vitamin D deficiency predispose to Addison's disease. Aim of the current study was, to investigate potential anti-inflammatory vitamin D effects on monocytes in Addison's disease, focusing on inflammatory CCL-2 and IL6, as well on monocyte CD14 markers. Addison's disease is genetically linked to distinct HLA susceptibility alleles. Therefore we analyzed, whether HLA genotypes differed for vitamin D effects on monocyte markers. CD14+ monocytes were isolated from Addison's disease patients (AD, n=13) and healthy controls (HC, n=15) and stimulated with 1,25-dihydroxyvitamin D3 and IL1ß as an inflammatory stimulant. Cells were processed for mRNA expression of CCL-2, IL6 and CD14 and DNA samples were genotyped for major histocompatibility class (MHC) class II-encoded HLA- DQA1-DQB1 haplotypes. We found a downregulation of CCL-2 after vitamin D treatment in IL1ß-stimulated monocytes both from AD patients and HC (AD p<0.001; HC p<0.0001). CD14 expression however, was upregulated in both HC and AD patients after vitamin D treatment (p<0.001, respectively). HC showed higher CD14 transcription level than AD patients after vitamin D treatment (p=0.04). Compared to IL1ß-induced inflammation, HC have increased CD14 levels after vitamin D treatment (p<0.001), whereas the IL1ß-induced CD14 expression of AD patients' monocytes did not change after vitamin D treatment (p=0.8). AD patients carrying HLA high-risk haplotypes showed an increased CCL-2 expression after IL1ß-induced inflammation compared to intermediate-risk HLA carriers (p=0.05). Also HC monocytes' CD14 transcription after IL1ß and vitamin D co-stimulation differed according to HLA risk profile. We show that vitamin D can exert anti-inflammatory effects on AD patients' monocytes which may be modulated by HLA risk genotypes.

Guideline Compliance in Surgery for Thyroid Nodules - A Retrospective Study.

Diagnostic guidelines for thyroid nodules focus on malignancy risk assessment to avoid unnecessary diagnostic operations. These guidelines recommend a combination of tests in form of a diagnostic algorithm. The present study analyzed the recommended algorithm and its implementation by different medical professionals. Preoperative diagnostic procedures, laboratory tests and histopathological findings of patients who underwent thyroid surgery between 2006 and 2013 were analyzed. The results were stratified by the assignation by specialized endocrinologists (ENP), general practitioners (GP) or Goethe-University Hospital Frankfurt (UKF). 677 patients were enrolled, of these 62% were assigned by UKF, 18.5% by an ENP and 19.5% by a GP. Ultrasonography rate was significantly higher in UKF (97.6%) compared to patients assigned by GP (90.9%, p<0.0001). Rates for fine-needle aspiration cytology ranged between 47.6% in UKF and 23.2% in ENP (p<0.0001). In over 93% of the patients an analysis of thyroid-stimulating hormone and triiodothyronine/thyroxin was realized. The overall malignancy rate was 11.82%. The malignancy rate was significantly higher if a FNA biopsy was performed (16.35 vs. 8.94%; p=0.0048). A higher malignancy rate could only be seen if the preoperative diagnostic workup included FNA. Besides this, the grade of algorithm adherence showed no effect on the malignancy rate.

T-lymphocyte and glycemic status after vitamin D treatment in type 1 diabetes: A randomized controlled trial with sequential crossover.

BACKGROUND: Type 1 diabetes mellitus (T1D) is mediated by autoaggressive T effector cells with an underlying regulatory T-cell (Treg) defect. Vitamin D deficiency is highly prevalent in T1D, which can aggravate immune dysfunction. High-dose vitamin D treatment may enhance Tregs and improve metabolism in T1D patients. METHODS: In a randomized double-blind placebo-controlled trial with crossover design, patients received either for 3 months cholecalciferol 4000 IU/d followed by 3 months placebo or the sequential alternative. Thirty-nine T1D patients (19 women and 20 men) completed the trial. RESULTS: Primary outcome was a change of Tregs, secondary HbA1C, and insulin demand. Effects were evaluated based on intra-individual changes between treatment and placebo periods for outcome measures. Exploratory analyses included vitamin D system variant genotyping and C-peptide measurements. Median 25(OH)D3 increased to 38.8 ng/ml with males showing a significantly stronger increase (p = .003). T-lymphocyte profiles did not change significantly (p > 2); however, the intra-individual change of Tregs between males and females was different with a significantly stronger increase in men (p = .017), as well as between genotypes of the vitamin D receptor (Apa, Taq, and Bsm: genotypes aa, TT, and bb; p = .004-0.015). Insulin demands declined significantly (p = .003-.039) and HbA1C improved (p < .001). Random C-peptide levels were low but rising (median, 0.125 ng/ml; range, 0.02-0.3) in 6 patients. No toxicity was observed. CONCLUSION: A daily vitamin D dose of 4000 IU for 3 months was well tolerated and enhanced Tregs in males. Glucometabolic control improved in all. Subsequent larger trials need to address ß-cell function and genotyping for individualized vitamin D doses.

IL28B gene variants and glucose metabolism in Type 2 Diabetes.

Type 2 Diabetes (T2D) develops, when ß-cell insulin response fails to compensate for insulin resistance. Recent studies reported associations between the IL28B polymorphisms (rs12979860 and rs8099917) and T2D development in Hepatitis C virus (HCV) patients. To identify possible association with T2D independent from virus infection, we investigated both IL28B polymorphisms in T2D patients and healthy controls (HC). No association was found comparing the genotype and allele frequencies of both IL28B polymorphisms between T2D patients and HC. However, higher glucose levels were found in T2D patients carrying the IL28B CT/TT rs12979860 and GT/GG rs8099917 HCV risk genotypes compared to those with the protective CC and TT genotype (p=0.06 and p=0.02, respectively). Moreover, T2D patients with CT/TT rs12979860 HCV risk genotypes possessed significantly higher HbA1c levels than CC carriers (p=0.04). In conclusion, the IL28B HCV risk genotypes may influence glucose homeostasis in T2D patients without HCV.

Insufficient Vitamin D Response to Solar Radiation in German Patients with Type 2 Diabetes or Gestational Diabetes.

Vitamin D deficiency is highly prevalent in all forms of diabetes mellitus. Recently, we reported how ultraviolet B (UVB) radiation affected vitamin D [25(OH)D3] concentrations in patients with type 1 diabetes. Our aim was to analyze whether patients with non-autoimmune diabetes, such as type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) also show the same vitamin D profile in relation to environmental factors including ambient temperature as an indirect parameter for outdoor activities. We analyzed 25(OH)D3 concentrations of T2DM (n=349) and GDM patients (n=327) at the University Hospital Frankfurt from 2005 to 2007. Additionally, daily UVB and monthly outside air temperature measurements for Frankfurt/Germany were obtained. We detected a positive correlation between UVB irradiation and 25(OH)D3 concentrations of T2DM and GDM patients (rho=0.50 and rho=0.63, p=0.003 and p<0.0001, respectively). UVB irradiation was in summer (April-October) higher than in winter (November-March) (5.6 kJ/m² vs. 0.5 kJ/m², p<0.0001). However, the prevalence of vitamin D deficiency in summer remained high with 76% in T2DM and 59% in GDM. In a stepwise regression analysis for the 25(OH)D3 concentration, significant predictors were outdoor temperature (estimate=0.02, p<0.0001), UVB radiation (estimate=-0.0015, p=0.02), year (2006 vs. 2005 estimate=-0.06, p>0.05, 2007 vs. 2005: estimate=-0.13, p<0.0001) and diabetes type (estimate=0.06, p=0.03). In conclusion, the strong correlation between UVB radiation and 25(OH)D3 concentrations in T2DM and GDM patients determines the seasonal variation. Additional determinants for the 25(OH)D3 concentrations were outdoor temperature, year, and diabetes type. Despite the effects of solar radiation both patients groups remain largely vitamin D deficient during summers.

[Vitamin D : More than just a bone hormone]. / Vitamin D : Mehr als ein Knochenhormon.

Vitamin D plays an essential role in the primary therapy and prevention of osteoporosis. Established vitamin D effects are renal and intestinal resorption of calcium and phosphate for optimal bone mineral density; however, the widespread distribution of the vitamin D receptor (VDR), a member of the nuclear steroid hormone receptor family, provides extensive evidence for additional pleiotropic effects of the vitamin D ligand. Vitamin D deficiency and insufficiency are common and were reported as risk factors for a variety of diseases in observational studies. In addition, extensive research from experimental studies also illustrated extraskeletal effects of vitamin D. More randomized controlled trials are ongoing to test the effects of high dose vitamin D supplementation in numerous chronic diseases. This article summarizes the current state of knowledge regarding effects on muscle, on glucose metabolism in type 2 diabetes mellitus and on cardiovascular risk factors and diseases. Furthermore, we discuss the influence of vitamin D on the immune system, whereby vitamin D might provide beneficial effects not only for infectious but also for autoimmune diseases, such as type 1 diabetes mellitus. Current evidence leads to the conclusion that vitamin D deficiency should be avoided in these diseases. Recommendations for optimal dosage are discussed.

CTLA-4 as a genetic determinant in autoimmune Addison's disease.

In common with several other autoimmune diseases, autoimmune Addison's disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events. To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4. The contribution of other genetic variants has been inconsistent. We have studied the association of 16 single-nucleotide polymorphisms (SNPs) within the CD28-CTLA-4-ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls. We have also performed a meta-analysis including 1002 patients from European countries. The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10-1.66), P=0.004), but not in UK patients. The same allele is associated with AAD in the total European population (OR=1.37 (CI 1.13-1.66), P=0.002). A three-marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 (CI 1.68-3.51), P=0.00013). This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus.

Focus on vitamin D and the adrenal gland.

The main role of vitamin D is to maintain calcium and phosphorus homeostasis, thus preserving bone health. However, recent evidences have demonstrated that vitamin D may also play a role in a variety of nonskeletal disorders such as endocrine diseases and in particular type 1 diabetes, type 2 diabetes, adrenal diseases, and the polycystic ovary syndrome. Despite controversial results on an association of low vitamin D levels with cortisol and aldosterone overproduction, encouraging in vitro findings have been reported on vitamin D effects in adrenocortical cancer cells. The focus of this review is the role of vitamin D in adrenal diseases and the results of vitamin D supplementation studies in patients. Although many studies support a beneficial role of vitamin D in adrenal disease, randomized controlled trials and mechanistic studies are required to provide more insight into the efficacy and safety of vitamin D as a therapeutic tool.

VDR FokI polymorphism is associated with a reduced T-helper cell population under vitamin D stimulation in type 1 diabetes patients.

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease mediated by T-helper (Th) cells. Additionally, the immune system regulator vitamin D, exerts its modulatory effects through the vitamin D receptor (VDR) expressed in Th cells. Furthermore, several genetic variants in the VDR gene including the VDR FokI (rs10735810) polymorphism have been implicated in T1D susceptibility in some Caucasian populations. Aim of the present study was to investigate the possible functional role of the VDR FokI gene polymorphism in Th cells from T1D patients and healthy controls (HC). METHODS: Isolated Th cells from 23 HC and 20 T1D patients were stimulated for 72h with 25-hydroxyvitamin D3 (25(OH)D3) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). After in vitro culture CD3(+)CD4(+) (CD4(+)) Th cell subsets were characterized by flow cytometry and gene expression of VDR was measured by Taqman assay. Finally, the VDR FokI polymorphism was genotyped. RESULTS: Significant lower VDR gene expression was observed in non-stimulated and 25(OH)D3 stimulated Th cells from T1D compared to HC (p=0.04 and p=0.005, respectively). In addition, by stratifying subjects into VDR FokI genotypes, significant lower percentage of CD4(+) cells was observed in 25(OH)D3 and 1,25(OH)2D3 stimulated Th cells from T1D patients carrying the "FF" genotype compared to those with the genotypes "Ff/ff" (p=0.02 and p=0.05, respectively). Moreover, looking at vitamin D effects according to VDR FokI genotypes, CD4(+) cells were significantly down-regulated by 25(OH)D3 and 1,25(OH)2D3 only in T1D "FF" carriers (p=0.01 and p=0.02; respectively). CONCLUSION: According to these results, T1D patients carrying the "FF" genotype with an adequate vitamin D therapy may benefit from a more balanced T cell immunity. However, further research is needed to confirm these premilinary findings and to elucidate functional mechanisms of genetic variation in the vitamin D system. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.

Gestational diabetes outcome in a single center study: higher BMI in children after six months.

The aim of the study was to examine obstetric outcomes and metabolic disorders in patients with gestational diabetes mellitus (GDM) and their offspring compared to mothers without GDM and their offspring. We performed a retrospective single center cohort study of mothers with GDM using a questionnaire with items concerning the maternal medical history, neonatal complications, and child development. Mothers with gestational diabetes (GDM; n=130) and those with normal glucose tolerance (NGT; n=77) were recruited. GDM mothers were older (37.58 years vs. 34.32 years, p<0.0001) and had a greater body mass index (25.18 kg/m² vs. 23.37 kg/m², p<0.01). There were no significant differences regarding the mean birth weight, the frequency of Cesarean sections, and the prevalence of macrosomia (> 4 000 g). At follow-up (pediatric U5 screening visit after 6 months of birth) children of mothers with GDM had significantly higher BMI than the children of the NGT group (17.07 kg/m² vs. 16.59 kg/m², p=0.042). GDM women in need of insulin therapy during pregnancy had higher BMI than dieting GDM mothers and experienced more frequently an operative vaginal delivery (17.95% vs. 6.17%, OR 3.23, p=0.04). We found less significant differences between GDM mothers with treatment of impaired glucose tolerance and NGT mothers concerning the neonatal outcome than expected. Despite higher BMI of the GDM group's offspring at follow-up U5 visit, the children did not show any other development disorder. In conclusion treatment of GDM could minimize the frequency of obstetric and neonatal complications in this risk group.

Effect of a randomised controlled vitamin D trial on insulin resistance and glucose metabolism in patients with type 2 diabetes mellitus.

The aim of our study was to investigate the influence of a 6-month vitamin D supplementation in patients with noninsulin-requiring type 2 diabetes mellitus. We included 86 patients in a placebo-controlled, randomised, double-blind study. During 6 months patients received Vigantol oil once a week corresponding to a daily dose of 1904 IU or placebo oil, followed by 6 months of follow-up. At start and at 3-month intervals 25OHD, PTH, body mass index, HbA1c, insulin, C-peptide, and homeostasis model assessment-index were measured. The primary outcome was a change in fasting blood glucose and insulin levels. After 6 months of therapy, the verum group's 25OHD had increased to a median of 35 ng/ml in comparison to the placebo group (median 20 ng/ml, p<10-6). PTH tended to decrease in the verum group (25.5 pg/ml vs. 35.0 pg/ml, p=0.08). After 6 months of therapy, 31 patients (78%) achieved a 25OHD concentration of >20 ng/ml. Their HbA1c was significantly lower at baseline (p=0.008) and after therapy (p=0.009) than in patients with 25OHD below 20 ng/ml. C-Peptide, insulin, and HOMA-index did not change significantly in the verum group but fasting insulin was positively correlated with 25OHD concentrations after 6 months of therapy in both groups. There were no significant effects of vitamin D with a daily dose of 1904 IU on metabolic parameters in type 2 diabetes. However, the correlative findings of this study suggest a link of the 25OHD status and metabolic function in type 2 diabetes. Whether vitamin D therapy with higher doses can improve glucose metabolism needs to be investigated in follow-up trials.

Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency.

Primary adrenal insufficiency (PAI), or Addison's disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow-up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21-hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life-threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow-up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self-adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addison's disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium's investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow-up.

Vitamin D status and gene transcription in immune cells.

BACKGROUND: Vitamin D is a modulator of the immune system. Its insufficiency has been implicated in type 1 diabetes (T1D) and studies showed significant associations with polymorphisms of vitamin D genes. Aim of the study was to investigate whether gene expression in immune cells, vitamin D status and genetic variants are correlated in healthy controls (HC). METHODS: From 23 HC monocytes (Mo), T-helper cells (Th) and natural killer cells (NK) were isolated. In all immune cells gene expression of vitamin D receptor (VDR), 25-vitamin-D-hydroxylase (CYP2R1) and 25-hydroxyvitamin-D3-1a-hydroxylase (CYP27B1) were measured by Taqman assay. Furthermore, CYP2R1 (rs10741657), CYP27B1 (rs10877012) and the VDR-FokI (rs10735810) polymorphisms in HC were genotyped. Finally, 25-hydroxyvitamin D3 (25(OH)D3) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) plasma levels in HC were measured by radioimmunoassay. RESULTS: All studied immune cells showed a significantly different gene expression of CYP2R1 and CYP27B1 (p=1×10(-6), respectively). When stratifying the HC according to vitamin D deficiency and vitamin D sufficiency, within the 25(OH)D3 deficient group significantly lower 1,25(OH)2D3 plasma levels (p=0.02) in HC and a significant down-regulation of the VDR expression only in Mo were observed (p=0.04). Furthermore, a significant correlation between CYP2R1 gene transcription and 1,25(OH)2D3 plasma levels in Th cells was found (p=0.04). No associations between the gene expression levels and the investigated polymorphism in all different immune cells were detected. However, vitamin D deficiency in combination with the "AC" CYP27B1 genotype appeared to inhibit the CYP27B1 expression in NK cells (p=0.03). CONCLUSION: both 25(OH)D3 deficiency and low 1,25(OH)2D3 levels appear to interact with its system gene transcription illustrating the relevance for targeted vitamin D therapy. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

What affects the quality of life in autoimmune Addison's disease?

INTRODUCTION: Several studies have shown a reduced quality of life in patients with Addison's disease, but little is known about the potential influences. METHODS: We determined the quality of life in 200 patients with Addison's disease using an Addison's disease-specific quality-of-life questionnaire. Data about first symptoms, time to diagnosis and current medication were collected by questionnaires. RESULTS: With increasing latency between first symptoms and diagnosis of adrenal insufficiency, the quality of life decreased in highly significant manner (p<0.001). Age at manifestation correlated negatively with quality of life (p=0.01). Significantly lower scores were observed in females versus males (141 vs. 159, p<0.001). Quality of life decreased significantly with increasing autoimmune comorbidity (p=0.01). Coeliac disease (p=0.05), atrophic gastritis (p=0.01) and primary ovarian failure (p=0.01) were highly correlated with reduced scores. CONCLUSIONS: Quality of life was significantly lower in female patients and in those with manifestation at older ages. With more autoimmune comorbidities, the quality of life scores dropped. The most important factor, however, was latency between first symptoms and diagnosis that affected patients' quality of life even years after manifestation of the disease. These results confirm and extend previous observations and emphasize the importance of a timely diagnosis. Therefore, medical awareness for this rare but easily treatable disorder needs to be sharpened.

Influence of the vitamin D plasma level and vitamin D-related genetic polymorphisms on the immune status of patients with type 1 diabetes: a pilot study.

Vitamin D (VD) has been implicated in type 1 diabetes (T1D) by genetic and epidemiological studies. Individuals living in regions with low sunlight exposure have an increased T1D risk and VD supplementation reduced the risk in human individuals and mouse models. One possibility of how VD influences the pathogenesis of T1D is its immunomodulatory effect on dendritic cells (DC), which then preferentially activate regulatory T cells (T(regs) ). In the present pilot study, we collected blood samples from a small cohort of patients with T1D at baseline and months 6 and 12. VD-deficient patients were advised to supplement with 1000 IU/day VD. We found a considerable variation in the VD plasma level at baseline and follow-up. However, with higher VD plasma levels, a lower frequency of interleukin (IL)-4-producing CD8 T cells was observed. We further performed a comprehensive genotyping of 13 VD-related polymorphisms and found an association between VD plasma level and the genotype of the VD binding protein (DBP). The frequency of DC and T cell subsets was variable in patients of all subgroups and in individual patients over time. Nevertheless, we found some significant associations, including the 1,25-dihydroxyvitamin D(3) hydroxylase (CYP27B1) genotype with the frequency of DC subtypes. In summary, our preliminary results indicate only a limited influence of the VD plasma level on the immune balance in patients with T1D. Nevertheless, our pilot study provides a basis for a follow-up study with a larger cohort of patients.

Time trend of UVB irradiation and the vitamin D concentration in German type 1 diabetes patients.

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease which is characterised by the destruction of insulin-producing beta cells in human pancreas leading consequently to a hyperglycaemic metabolism. Recent studies have shown that low cholecalciferol (25(OH)D3) concentrations may contribute to the development of T1D. The 25(OH)D3 status depends mostly on human skin production influenced by exposure to UVB radiation. Our intention was to examine whether there was a change in UVB radiation in the past years and if this has an impact on patients' vitamin D status. METHODS: We analysed the 25(OH)D3 concentration of blood samples from 287 T1D patients in the years 2004-2007 at the University Hospital Frankfurt. Moreover, daily UVB irradiation data of this time were received. Wilcoxon-Mann-Whitney test and Spearman correlation test were used for statistical analyses. RESULTS: We observe a strong correlation between UVB irradiation and the 25(OH)D3 concentration of German T1D patients (correlation coefficient=rho=0.56, p=7×10(-3)). Moreover, 25(OH)D3 blood levels obtained in summer (Apr-Oct) were significantly higher than in the winter season (p=8×10(-3)). In the years 2004-2007 there was a significant decline of UVB radiation in the summers (rho=-0.21, p<10(-6)) but no change was found in (rho=-0.07, p=0.12). This corresponds to a significant decrease of 25(OH)D3 levels in T1D patients over the summers (rho=-0.24, p=2×10(-3)) but not in winters (rho=-0.03, p=0.73). CONCLUSION: Our results reveal a significant correlation of UVB irradiation and the vitamin D concentration of German T1D patients. A decrease of UVB irradiation over the summers 2004-2007 is accompanied by a decline of 25(OH)D3 levels observed in those summer months which may indicate a local time trend requiring further investigation into the environmental factors of vitamin D deficiency. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Efficacy and acceptability of lanreotide Autogel® 120 mg at different dose intervals in patients with acromegaly previously treated with octreotide LAR.

OBJECTIVE: To assess the efficacy of different dosing intervals of lanreotide, Somatuline Autogel® (Lan-ATG) 120 mg in patients with acromegaly, previously treated with octreotide, long-acting release (Oct-LAR). PATIENTS AND STUDY DESIGN: Patients previously on Oct-LAR 10, 20, or 30 mg were switched to 6 repeated deep subcutaneous injections of Lan-ATG 120 mg at intervals of 56, 42, or 28 days, respectively. After the third injection, dose intervals were adjusted on the basis of insulin-like growth factor 1 (IGF-1) levels. RESULTS: The ITT (Intention To Treat) population comprised 35 patients who received at least one dose of study medication and at least one post-baseline efficacy assessment. Overall, 62.9% (n=22) of patients had normalised IGF-1 levels with Lan-ATG at study end (one injection interval after the 6 (th) injection of Lan-ATG), which was similar to the proportion at baseline (60.0% [n=21]). QoL did not change from baseline to study end. Patient preference for Lan-ATG was highest in the 56-day dosing interval group: 71%, 54% and 41% of the patients in the 56, 42 and 28 day groups, respectively, expressed a preference for treatment with Lan-ATG (preference for Oct-LAR: 29%, 9% and 35%, respectively, while the remainder had no preference). CONCLUSION: Lan-ATG 120 mg injected at intervals of 56, 42 and 28 days provided equivalent hormonal control and QoL to Oct-LAR 10, 20 and 30 mg injected every 28 days, respectively. The proportion of patients preferring Lan-ATG treatment was greater in the longer injection interval groups.

Real-time elastography and contrast-enhanced ultrasound for the assessment of thyroid nodules.

OBJECTIVE: Work-up of thyroid nodules remains challenging. Recent technologies enable determination of tissue elasticity and perfusion using ultrasound devices. The aim of the present study was to evaluate real-time elastography (RTE) and contrast-enhanced ultrasound with Sonovue (CEUS) for the differentiation of benign and malignant thyroid nodules. MATERIALS AND METHODS: Inclusion criteria were: nodules ≥1 cm, non-functioning or hypo-functioning on radionuclide scanning, and cytological/histological assessment. All patients received conventional ultrasound, RTE and CEUS. RTE was classified as: Elasticity-Score (ES)1 = soft, ES2 = predominantly soft, ES3 = predominantly hard, ES4 = hard nodule. CEUS-video clips were digitally recorded and analyzed using time-intensity-curves within selected regions-of-interest. RESULTS: Fifty-three nodules in 50 patients were available for analysis. Forty-six nodules were benign on cytology/histology, 6 nodules were papillary carcinoma and one nodule was a follicular carcinoma. Nodule margin irregularity was the ultrasound pattern most predictive of malignancy with sensitivity 57% (95% confidence interval: 18-90%) and specificity 85% (71-94% p<0.05). When using ES3&4 for the diagnosis of malignant nodules sensitivity and specificity were 86% (42-99.7%) and 87% (75-95%), respectively (p = 0.0003). The only malignant nodule missed with RTE was a follicular carcinoma. Sensitivity for the diagnosis of papillary carcinoma therefore was 100%. No specific CEUS pattern could be identified to differentiate between benign and malignant nodules. CONCLUSIONS: RTE seems to be a useful tool in the work-up of thyroid nodules to exclude papillary thyroid cancer. However, follicular carcinoma remains a challenging problem. CEUS did not improve the characterization of thyroid nodules in this preliminary study.

Association analyses of the vitamin D receptor gene in 1654 families with type I diabetes.

Type I diabetes (T1D) results from interactions between environmental exposures and genetic susceptibility leading to immune dysfunction and destruction of the insulin-producing beta cells of the pancreas. Vitamin D deficiency is likely to be one of the many environmental factors influencing T1D development and diagnosis, and, hence, the hormone receptor gene, VDR, was examined for association with T1D risk. The Type I Diabetes Genetics Consortium genotyped 38 single nucleotide polymorphisms (SNPs) in 1654 T1D nuclear families (6707 individuals, 3399 affected). Genotypes for 38 SNPs were assigned using the Illumina (ILMN) and Sequenom (SQN) technology. The analysis of data release as of July 2008 is reported for both platforms. No evidence of association of VDR SNPs with T1D at P<0.01 was obtained in the overall sample set, nor in subgroups analyses of the parent-of-origin, sex of offspring and HLA risk once adjusted for multiple testing.

Association of KIR2DL2 polymorphism rs2756923 with type 1 diabetes and preliminary evidence for lack of inhibition through HLA-C1 ligand binding.

Killer cell immunoglobulin-like receptors (KIRs) on chromosome 19q13.4 regulate the function of not only human natural killer (NK) cells but also T cells. An increase in activating KIR- human leucocyte antigen ligand pairs has been associated with an additional risk to develop type 1 diabetes (T1D). T1D families [n = 184 (552 individuals); n = 176 (528 subjects)], unrelated T1D patients (n = 380; n = 394) and healthy controls (n = 315; n = 401) from Germany and Belgium, respectively, were genotyped for the rs2756923 polymorphism within the KIR gene cluster haplotype B in exon 8 of the KIR2DL2 gene. We observed in both Germans and Belgians an overtransmission of the allele 'G' of the KIR2DL2-rs2756923 polymorphism (64.2% vs 35.8%, P = 3 x 10(-4) and 60.0% vs 40.0%, P = 0.02, respectively). In addition, this allele was more frequent in German patients than in healthy controls (78.4% vs 21.6%, P = 1 x 10(-3)). Preliminary results from a cytotoxicity assay suggest that inhibition of NK-cell cytotoxicity may be impaired in individuals carrying the rs2756923 G allele. These data suggest a potential role of the KIR2DL2-rs2756923 polymorphism in T1D in Germans and Belgians.