Alzheimer's disease (AD) is the most common type of dementia, but it is very difficult to diagnose with certainty, so many AD studies have attempted to find early and relevant diagnostic markers. Regulated upon activation, normal T cell expressed and secreted (RANTES, also known as C-C chemokine ligand) is a chemokine involved in the migration of T cells and other lymphoid cells. Changes in RANTES levels and its expression in blood or in cerebrospinal fluid have been reported in some neurodegenerative diseases, such as Parkinson's disease and multiple sclerosis, but also in metabolic diseases in which inflammation plays a role. The aim of this observational study was to assess RANTES levels in peripheral blood as clinical indicators of AD. Plasma levels of RANTES were investigated in 85 AD patients in a relatively early phase of AD (median 8.5 months after diagnosis; 39 men and 46 women; average age 75.7 years), and in 78 control subjects (24 men and 54 women; average age 66 years). We found much higher plasma levels of RANTES in AD patients compared to controls. A negative correlation of RANTES levels with age, disease duration, Fazekas scale score, and the medial temporal lobe atrophy (MTA) score (Scheltens's scale) was found in AD patients, i.e., the higher levels corresponded to earlier stages of the disease. Plasma RANTES levels were not correlated with cognitive scores. In AD patients, RANTES levels were positively correlated with the levels of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α, which is consistent with the well-known fact that AD is associated with inflammatory processes. RANTES levels were also positively correlated with insulin levels in AD patients, with insulin resistance (HOMA-R) and pancreatic beta cell function (HOMA-F). This study evaluated several clinical and metabolic factors that may affect plasma levels of RANTES, but these factors could not explain the increases in RANTES levels observed in AD patients. Plasma levels of RANTES appear to be an interesting peripheral marker for early stages of AD. The study was approved by the Ethics Committee of Institute of Endocrinology, Prague, Czech Republic on July 22, 2011.

• Klíčová slova
• Alzheimer’s disease, RANTES, biomarker, central nervous system, cognitive impairment, inflammation,
• Publikační typ
• časopisecké články MeSH

There is a rise in the incidence of thyroid nodules in pediatric patients. Most of them are benign tissues, but part of them can cause papillary thyroid cancer (PTC). The aim of this study was to detect the mutations in commonly investigated genes as well as in novel PTC-causing genes in thyroid nodules and to correlate the found mutations with clinical and pathological data. The cohort of 113 pediatric samples consisted of 30 benign lesions and 83 PTCs. DNA from samples was used for next-generation sequencing to identify mutations in the following genes: HRAS, KRAS, NRAS, BRAF, IDH1, CHEK2, PPM1D, EIF1AX, EZH1 and for capillary sequencing in case of the TERT promoter. RNA was used for real-time PCR to detect RET/PTC1 and RET/PTC3 rearrangements. Total detection rate of mutations was 5/30 in benign tissues and 35/83 in PTCs. Mutations in RAS genes (HRAS G13R, KRAS G12D, KRAS Q61R, NRAS Q61R) were detected in benign lesions and HRAS Q61R and NRAS Q61K mutations in PTCs. The RET/PTC rearrangement was identified in 18/83 of PTCs and was significantly associated with higher frequency of local and distant metastases. The BRAF V600E mutation was identified in 15/83 of PTCs and significantly correlated with higher age of patients and classical variant of PTC. Germline variants in the genes IDH1, CHEK2 and PPM1D were found. In conclusion, RET/PTC rearrangements and BRAF mutations were associated with different clinical and histopathological features of pediatric PTC. RAS mutations were detected with high frequency in patients with benign nodules; thus, our results suggest that these patients should be followed up intensively.

• Klíčová slova
• benign, mutations, next-generation sequencing, papillary thyroid cancer, pediatric,
• Publikační typ
• časopisecké články MeSH

Alzheimer's disease (AD) is the most common type of dementia, with a prevalence that is rising every year. AD is associated with type 2 diabetes mellitus (T2DM) and insulin resistance, and is therefore sometimes called "type 3 diabetes mellitus". The aim of this study was to examine whether the variants of some candidate genes involved in the development of AD, namely BIN1 (rs744373), CLU (rs11136000), CR1 (rs3818361), and PICALM (rs3851179), are related to several disorders of glucose metabolism-gestational diabetes (GDM), T2DM and impaired glucose tolerance (IGT). Our study included 550 women with former GDM and 717 control women, 392 patients with T2DM and 180 non-diabetic controls, and 117 patients with IGT and 630 controls with normal glucose tolerance. Genotyping analysis was performed using specially-designed TaqMan assays. No significant associations of the genetic variants rs744373 in BIN1, rs11136000 in CLU, or rs3818361 in CR1 were found with GDM, T2DM or IGT, but rs3851179 in PICALM was associated with an increased risk of GDM. The frequency of the AD risk-associated C allele was significantly higher in the GDM group compared to controls: OR 1.21; 95% CI (1.03-1.44). This finding was not apparent in T2DM and IGT; conversely, the C allele of the PICALM SNP was protective for IGT: OR 0.67; 95% CI (0.51-0.89). This study demonstrates an association between PICALM rs3851179 and GDM as well as IGT. However, elucidation of the possible role of this gene in the pathogenesis of GDM requires further independent studies.

• Klíčová slova
• Alzheimer’s disease, Gestational diabetes mellitus, Glucose metabolism, Impaired glucose tolerance, Polymorphisms, Type 2 diabetes mellitus,
• MeSH
• adaptorové proteiny signální transdukční krev   genetika   MeSH
• alely MeSH
• Alzheimerova nemoc komplikace   genetika   MeSH
• běloši genetika   MeSH
• diabetes mellitus 2. typu genetika   MeSH
• dospělí MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• genetická variace MeSH
• genetické asociační studie metody   MeSH
• gestační diabetes genetika   metabolismus   MeSH
• jaderné proteiny krev   genetika   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• klusterin krev   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• monomerní proteiny vytvářející klathrin krev   genetika   MeSH
• nádorové supresorové proteiny krev   genetika   MeSH
• odds ratio MeSH
• porucha glukózové tolerance genetika   metabolismus   MeSH
• receptory komplementu 3b krev   genetika   MeSH
• rizikové faktory MeSH
• senioři MeSH
• těhotenství MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• BIN1 protein, human MeSH Prohlížeč
• CLU protein, human MeSH Prohlížeč
• CR1 protein, human MeSH Prohlížeč
• jaderné proteiny MeSH
• klusterin MeSH
• monomerní proteiny vytvářející klathrin MeSH
• nádorové supresorové proteiny MeSH
• PICALM protein, human MeSH Prohlížeč
• receptory komplementu 3b MeSH

Alzheimer's disease (AD) represents more than half of total dementias. Various factors including altered steroid biosynthesis may participate in its pathophysiology. We investigated how the circulating steroids (measured by GC-MS and RIA) may be altered in the presence of AD. Sixteen women with AD and 22 age- and BMI-corresponding controls aged over 65 years were enrolled in the study. The steroid levels (47 steroids and steroid polar conjugates) and their ratios in AD female patients indicated increased CYP11A1 activity, weakened activity of the CYP17A1C17,20 lyase metabolic step and attenuated sulfotransferase SULT2A1 activity at higher activity of the CYP17A1 17-hydroxylase step. The patients showed diminished HSD3B2 activity for C21 steroids, abated conversion of 17-hydroxyprogesterone to cortisol, and significantly elevated cortisol. The women with AD had also attenuated steroid 7α-hydroxylation forming immunoprotective Δ(5)-C19 steroids, attenuated aromatase activity forming estradiol that induces autoimmunity and a shift from the 3β-hydroxy-5α/β-reduced C19 steroids to their neuroinhibitory and antiinflammatory GABAergic 3α-hydroxy- counterparts and showed higher levels of the 3α-hydroxy-5α/β-reduced C21 steroids and pregnenolone sulfate (improves cognitive abilities but may be both protective and excitotoxic). Our preliminary data indicated functioning of alternative "backdoor" pathway in women with AD showing higher levels of both 5α/β-reduced C21 steroids but reduced levels of both 5α/β-reduced C21 steroids, which implied that the alternative "backdoor" pathway might include both 5α- and 5β-reduced steroids. Our study suggested relationships between AD status in women based on the age of subjects and levels of 10 steroids measured by GC-MS.

• Klíčová slova
• Alzheimer’s disease, GC–MS, Multivariate statistics, RIA, Steroid metabolome, Women,
• MeSH
• Alzheimerova nemoc krev   metabolismus   MeSH
• hormony krev   MeSH
• lidé MeSH
• oxidoreduktasy metabolismus   MeSH
• plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
• progesteronreduktasa metabolismus   MeSH
• senioři MeSH
• sulfotransferasy metabolismus   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• zona reticularis metabolismus   MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3 beta-hydroxysteroid dehydrogenase type II MeSH Prohlížeč
• 3-oxo-5 beta-steroid delta 4-dehydrogenase MeSH Prohlížeč
• alcohol sulfotransferase MeSH Prohlížeč
• hormony MeSH
• oxidoreduktasy MeSH
• progesteronreduktasa MeSH
• sulfotransferasy MeSH
• systém (enzymů) cytochromů P-450 MeSH