Kuzma M.,Comenius University |
Kuzmova Z.,Comenius University |
Zelinkova Z.,Comenius University |
Killinger Z.,Comenius University |
And 3 more authors.
Growth Hormone and IGF Research | Year: 2014
Introduction: Growth hormone deficiency (GHD) is associated with reduced bone mineral density (BMD). GH replacement has positive effect on BMD but the magnitude of this effect and its mechanism are debated. Objectives: The objectives of this study was first, to assess the effect of GH replacement on BMD, and second, to evaluate the effect of GH treatment on bone turnover and microarchitecture and to assess the factors influencing the effect of the therapy on BMD. Patients and Methods: Adult GHD (AO-GHD) and childhood onset GHD (CO-GHD) patients treated with GH using IGF-I normalization GH replacement regimen were prospectively followed during 2. years. Lumbar spine (L1-L4) and total femur BMD by Hologic discovery, in the subset of patients also bone turnover markers; osteocalcin and carboxy-terminal collagen crosslinks (CTx) were assessed at baseline and at months 3, 6, 12 and 24, respectively. The trabecular bone score (TBS) derived from lumbar spine DXA by the iNsight® software was assessed in a subset of study population at baseline and months 12 and 24. Results: In total, 147 GHD patients (age 35.1. years, 84 males/63 females, 43 of childhood onset GHD/104 AO-GHD) were included. BMD of lumbar spine and femur increased significantly during the treatment (14% and 7% increase at 2. years, respectively; p<. 0.0001).Bone markers increased during the first 12. months of treatment with subsequent decrease of CTx. At month 24, significant increase in TBS was observed (4%, p= 0.02).BMD increase was significantly higher in males (15% increase in males vs. 10% in females, p= 0.037) and childhood onset GHD (CO-GHD) patients (13% increase in CO-GHD, p= 0.004). Conclusion: GH supplementation leads to an increase of BMD with corresponding changes in bone turnover markers and changes in microarchitecture as assessed by trabecular bone score. Positive effect of GH on bone status is more pronounced in males and CO-GHD adults. © 2013 Elsevier Ltd.
Kisand K.,University of Tartu |
Boe Wolff A.S.,University of Bergen |
Podkrajsek K.T.,University of Ljubljana |
Tserel L.,University of Tartu |
And 21 more authors.
Journal of Experimental Medicine | Year: 2010
Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A-producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle. In contrast, the subsequent endocrine features are clearly autoimmune, resulting from defects in thymic self-tolerance induction caused by mutations in the autoimmune regulator (AIRE). We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis. © 2010 Kisand et al.
PubMed | OPKO BiologicsKiryat Gat, Charité - Medical University of Berlin, Internal Clinic in University Hospital St AnnaBrno, Ludwig Maximilians University of Munich and 2 more.
Type: Journal Article | Journal: European journal of endocrinology | Year: 2016
Growth hormone (GH) replacement therapy currently requires daily injections, which may cause distress and low compliance. C-terminal peptide (CTP)-modified growth hormone (MOD-4023) is being developed as a once-weekly dosing regimen in patients with GH deficiency (GHD). This studys objective is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of MOD-4023 administered once-weekly in GHD adults.54 adults with GHD currently treated with daily GH were normalized and randomized into 4 weekly dosing cohorts of MOD-4023 at 18.5%, 37%, 55.5% or 123.4% of individual cumulative weekly molar hGH dose. The study included 2 stages: Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023. Stage B was an extension period of once-weekly MOD-4023 administration (61.7% molar hGH content) to collect further safety data and confirm the results from Stage A.Dose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment. Insulin-like growth factor I (IGF-I) SDS levels were maintained within normal range. The 18.5% cohort was discontinued due to low efficacy. MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts. The reported adverse events were consistent with known GH-related side effects.Once-weekly MOD-4023 administration in GHD adults was found to be clinically effective while maintaining a favorable safety profile and may obviate the need for daily injections. Weekly GH injections may improve compliance and overall outcome. The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial, which is currently ongoing.
PubMed | Comenius University, 1st Private Hospital and National Institute of Endocrinology and Diabetology
Type: Comparative Study | Journal: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society | Year: 2014
Growth hormone deficiency (GHD) is associated with reduced bone mineral density (BMD). GH replacement has positive effect on BMD but the magnitude of this effect and its mechanism are debated.The objectives of this study was first, to assess the effect of GH replacement on BMD, and second, to evaluate the effect of GH treatment on bone turnover and microarchitecture and to assess the factors influencing the effect of the therapy on BMD.Adult GHD (AO-GHD) and childhood onset GHD (CO-GHD) patients treated with GH using IGF-I normalization GH replacement regimen were prospectively followed during 2 years. Lumbar spine (L1-L4) and total femur BMD by Hologic discovery, in the subset of patients also bone turnover markers; osteocalcin and carboxy-terminal collagen crosslinks (CTx) were assessed at baseline and at months 3, 6, 12 and 24, respectively. The trabecular bone score (TBS) derived from lumbar spine DXA by the iNsight software was assessed in a subset of study population at baseline and months 12 and 24.In total, 147 GHD patients (age 35.1 years, 84 males/63 females, 43 of childhood onset GHD/104 AO-GHD) were included. BMD of lumbar spine and femur increased significantly during the treatment (14% and 7% increase at 2 years, respectively; p<0.0001). Bone markers increased during the first 12 months of treatment with subsequent decrease of CTx. At month 24, significant increase in TBS was observed (4%, p=0.02). BMD increase was significantly higher in males (15% increase in males vs. 10% in females, p=0.037) and childhood onset GHD (CO-GHD) patients (13% increase in CO-GHD, p=0.004).GH supplementation leads to an increase of BMD with corresponding changes in bone turnover markers and changes in microarchitecture as assessed by trabecular bone score. Positive effect of GH on bone status is more pronounced in males and CO-GHD adults.
Pirags V.,University of Latvia |
El Damassy H.,Ain Shams University |
Dabrowski M.,University of Rzeszow |
Gonen M.S.,Selcuk University |
And 4 more authors.
International Journal of Clinical Practice | Year: 2012
Aims: The choice of insulin at initiation in type 2 diabetes remains controversial. The aim of this study was to assess the occurrence of self-reported severe hypoglycaemia associated with premixed insulin analogues in routine clinical care. Methods: A 12-month, prospective, observational, multicentre study in patients starting a commonly prescribed premixed insulin analogue (either insulin lispro 25/75 or biphasic insulin aspart 30/70, twice daily) after suboptimal glycaemic control on oral antidiabetic agents. Treatment decisions were made solely in the course of usual practice. Results: Study follow-up was completed by 991 (85.5%) of the 1150 patients enrolled. At baseline, mean (SD) age was 57.9 (10.1) years; mean diabetes duration was 9.2 (5.9) years; mean haemoglobin A1c (HbA1c) was 9.9 (1.8) % and the rate of severe hypoglycaemia was 0.03 episode/patient-year. At 12 months, the rate of severe hypoglycaemia was 0.04 episode/patient-year (95% CI 0.023, 0.055 episode/patient-year) and mean insulin dose was 41.5 (19.4) units. Changes from baseline to 12 months for mean fasting plasma glucose and HbA 1c were -5.1 mmol/l and -2.5%, respectively. Conclusions: After initiation of premixed insulin analogues in patients with type 2 diabetes in real-world settings, the incidence of severe hypoglycaemia was lower than expected from previously reported studies. © 2012 Blackwell Publishing Ltd.
Pura M.,National Institute of Endocrinology and Diabetology |
Kreze A.,Bulovka Faculty Hospital |
Kento P.,National Institute of Endocrinology and Diabetology |
Vauga P.,National Institute of Endocrinology and Diabetology
Experimental and Clinical Endocrinology and Diabetes | Year: 2010
Background: The validity of low-dose 1g cosyntropin test (LDT) is reported mainly for the assessment of secondary adrenocortical insufficiency (AI). Likewise the hypothalamic-pituitary disorders, early diagnosis of the initial or partial stages of primary AI has an important role. Objective: The aim of study was to: 1) establish the normal cut-off level at which the stimulated plasma cortisol (FP) in LDT excludes primary AI; 2) compare the results in elderly subjects to those in younger ones; 3) compare the results between normal and obese subjects; and 4) verify the established cut-off values on the sample of patients suspected to have primary AI. Subjects and Methods: 110 subjects (99 women and 11 men, aged 1980 years, mean 46.2±16.1 years, without suspicion for impairment of the hypothalamo-pituitary-adrenal axis were recruited to undergo the LDT in standard conditions. Control group consists of 30 patients (22 women and 8 men, aged 758 years, mean 38.4±10.6 years) evaluated in whom for suspicion of primary AI as suggested by LDT was confirmed by supplemental investigations (elevated ACTH levels, positive autoantibodies against 21-hydroxylase, mutational analysis of corresponding genes). Results: The mean peak FP level at 30min (FP30) of the subjects was 675±85nmol/L (95% CI=659 to 691nmol/L), thus reference values expressed as mean±2 SD were 505845nmol/L. There was a significant negative correlation between basal FP values (FP0) (434±105nmol/L) and the absolute FP incremental (FP1) response varying from 52 to 553nmol/L (median 230nmol/L) (r=0.71; P<0.001). FP30 was higher in elderly subjects (n=27) in comparison to younger subjects (n=25) (689±88nmol/L vs. 642±63nmol/L, u=2.11, P<0.05) due to higher FP1 (274±116nmol/L vs. 175±112nmol/L; u=4.02, P<0.01); FP30 levels in obese subjects (n=27) did not differ from those with normal BMI (n=33) (694±100nmol/L vs. 667±65nmol/L, u=1.31, P>0.05). We did not find any correlation between body weight or body surface area and FP0, FP30 or FP1. Post-stimulation FP30 levels in the control group varied from 0 to 354nmol/L with median 64nmol/L (25th percentile 10nmol/L; 75 th percentile 165nmol/L) and were entirely distinctive from those of the subjects without adrenal impairment (P<0.001). Conclusions: Taking the mean 2 SD result as a threshold, FP value of 500nmol/L can be consider as cut-off at 30min in the LDT for defining the intact adrenocortical function, independently of age and body weight, body surface area. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart - New York.
Stanik J.,Slovak Academy of Sciences |
Stanik J.,Comenius University |
Dusatkova P.,Charles University |
Cinek O.,Charles University |
And 11 more authors.
Diabetologia | Year: 2014
Aims/hypothesis: MODY is mainly characterised by an early onset of diabetes and a positive family history of diabetes with an autosomal dominant mode of inheritance. However, de novo mutations have been reported anecdotally. The aim of this study was to systematically revisit a large collection of MODY patients to determine the minimum prevalence of de novo mutations in the most prevalent MODY genes (i.e. GCK, HNF1A, HNF4A). Methods: Analysis of 922 patients from two national MODY centres (Slovakia and the Czech Republic) identified 150 probands (16%) who came from pedigrees that did not fulfil the criterion of two generations with diabetes but did fulfil the remaining criteria. The GCK, HNF1A and HNF4A genes were analysed by direct sequencing. Results: Mutations in GCK, HNF1A or HNF4A genes were detected in 58 of 150 individuals. Parents of 28 probands were unavailable for further analysis, and in 19 probands the mutation was inherited from an asymptomatic parent. In 11 probands the mutations arose de novo. Conclusions/interpretation: In our cohort of MODY patients from two national centres the de novo mutations in GCK, HNF1A and HNF4A were present in 7.3% of the 150 families without a history of diabetes and 1.2% of all of the referrals for MODY testing. This is the largest collection of de novo MODY mutations to date, and our findings indicate a much higher frequency of de novo mutations than previously assumed. Therefore, genetic testing of MODY could be considered for carefully selected individuals without a family history of diabetes. © 2013 Springer-Verlag Berlin Heidelberg.
Javor J.,Comenius University |
Ferencik S.,University of Duisburg - Essen |
Bucova M.,Comenius University |
Stuchlikova M.,Comenius University |
And 5 more authors.
Archivum Immunologiae et Therapiae Experimentalis | Year: 2010
Numerous cytokines have been shown to participate in the pathogenesis of type 1 diabetes (T1D). As gene polymorphisms can influence cytokine production or function, they may potentially contribute to genetic predisposition to the disease. The aim of this study was therefore to investigate the role of 22 single nucleotide polymorphisms (SNPs) in 13 cytokine and cytokine receptor genes in genetic susceptibility to T1D. Polymerase chain reaction with sequence-specific primers was used to genotype cytokine SNPs and HLA-DRB1 alleles in 151 diabetics and 140 healthy individuals of Slovak origin. Univariate analysis showed that transforming growth factor (TGF)-β1 codon 10 TT homozygotes were significantly more susceptible to developing T1D than C allele carriers (P c = 0.0066, OR = 2.46). Furthermore, tumor necrosis factor (TNF)-α -308 A allele carriers were also significantly overrepresented among the diabetics (P c = 0.0031, OR = 2.62); however, the association of the -308 A allele with T1D might be due to its strong linkage disequilibrium with the susceptibility allele HLA-DRB1*0301. An association was also found with interleukin (IL)-6 -174 G/C and nt565 G/A SNPs; however, its significance was lost when statistical correction was applied. These data suggest that the TGF-β1 codon 10 SNP is among numerous genetic variations with small individual effects on T1D development. Moreover, a possible role of TNF-α and IL-6 SNPs cannot be ruled out, although their association with T1D was due to strong LD with the HLA class II susceptibility allele or did not withstand statistical correction, respectively. © 2010 L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland.
Bicikova M.,Institute of Endocrinology |
Hampl R.,Institute of Endocrinology |
Hill M.,Institute of Endocrinology |
Ripova D.,Prague Psychiatric Center |
And 3 more authors.
Neuroendocrinology Letters | Year: 2011
OBJECTIVE: Serum levels of neuro- and immunomodulatory adrenal steroids together with selected hormonal, lipid and other relevant biochemical parameters were investigated to examine the differences between first-episode schizophrenia patients and age-matched healthy subjects, and the effect of treatment with atypical antipsychotics. METHODS: The patient's group consisted of 22 drug-naive patients (13 men and 9 women), diagnosed with schizophrenia according to ICD-10 criteria, before and after six-months treatment with atypical antipsychotics of olanzapine or non-olanzapine type. Biochemical markers included steroids cortisol, dehydroepiandrosterone, its sulfate, 7-hydroxylated metabolites of dehydroepiandrosterone, prolactin, thyrotropin, free thyroxine, autoantibodies against thyroid peroxidase and thyroglobulin, glucose levels, four major lipid parameters, homocysteine and three other aminothiols. Steroids, prolactin and thyroid parameters were determined by radioimmunoassays, the other markers by standard biochemical methods. RESULTS: Significantly lower dehydroepiandrosterone sulfate and of 7α-hydroxy- dehydroepiandrosterone levels than in controls were found in male patients. In the female group, the only difference in steroid spectra was significantly higher cortisolemia in the patients. The patients had also higher titres of autoantibodies against thyroid peroxidase. Compared to controls, the patients displayed worse lipid spectra, and higher homocysteinemia. Medication did not lead to significant changes in the parameters, with the exception of expected increase in prolactin levels in non-olanzapine treated subgroups. CONCLUSION: Lower levels of 7α-hydroxydehydroepiandrosterone, abundant especially in brain, determined for the first time in schizophrenia patients, are in agreement with recent opinion of their neuroprotective and immunoprotective role. High levels of autoantibodies against thyroid peroxidase in the patients support the autoimmunity hypothesis of schizophrenia. © 2011 Neuroendocrinology Letters.
Podoba J.,Slovak Medical University |
Racova K.,Institute of Laboratory Medicine |
Urbankova H.,National Institute of Endocrinology and Diabetology |
Srbecky M.,Slovak Academy of Sciences
Endocrine Regulations | Year: 2016
Objective. Prophylaxis of iodine deficiency-related disorders with iodized salt in Slovakia was introduced in 1951. This prophylactic measure yielded remarkably good results. Endemic goiter and endemic cretinism disappeared. Sufficient iodine intake, mainly in children and adolescents, was confirmed in several local and international studies carried out in the period 1991–95. Unfortunately, since seventies, there has been no institution which would have dealt with iodine prophylaxis in such an extent as this important measure of Slovak preventive medicine would require. Neither systematic monitoring of iodine intake nor systematic population epidemiological studies have been carried out. We do not have any data on the iodine intake in pregnant women, the most vulnerable population group in relation to the iodine deficiency. During the period June 2014 – October 2015, we examined iodine excretion in 426 probands from three regions of Slovakia with an emphasis on the pregnant women. Results. Iodine intake was found to be sufficient, even more than adequate, in all age groups of Slovak population. The only population group with iodine intake borderline or very mild iodine deficiency are pregnant women. Conclusions: 1/ Iodine nutrition in Slovakia is generally sufficient, even oversteps the requirement, with the exception of pregnant women. Iodine intake in pregnant women should be fortified by iodine containing multivitamin preparations. 2/ We recommend to include the examination of urinary iodine into the screening of thyropathies in early pregnancy. 3/ It is not enough to implement the iodine deficiency-related disorders prevention programs, it is also necessary to stabilize such programs over time and balance the benefits with possible side effects of this program. © 2016, Institute of Experimental Endocrinology. All rights reserved.