Thyroid Cancer Detection in a Routine Clinical Setting: Performance of ACR TI-RADS, FNAC, and Molecular Testing in Prospective Cohort Study.

The aim of our study was to address the potential for improvements in thyroid cancer detection in routine clinical settings using a clinical examination, the American College of Radiology Thyroid Imaging Reporting and Database System (ACR TI-RADS), and fine-needle aspiration cytology (FNAC) concurrently with molecular diagnostics. A prospective cohort study was performed on 178 patients. DNA from FNA samples was used for next-generation sequencing to identify mutations in the genes BRAF, HRAS, KRAS, NRAS, and TERT. RNA was used for real-time PCR to detect fusion genes. The strongest relevant positive predictors for malignancy were the presence of genetic mutations (p < 0.01), followed by FNAC (p < 0.01) and ACR TI-RADS (p < 0.01). Overall, FNAC, ACR TI-RADS, and genetic testing reached a sensitivity of up to 96.1% and a specificity of 88.3%, with a diagnostic odds ratio (DOR) of 183.6. Sensitivity, specificity, and DOR decreased to 75.0%, 88.9%, and 24.0, respectively, for indeterminate (Bethesda III, IV) FNAC results. FNA molecular testing has substantial potential for thyroid malignancy detection and could lead to improvements in our approaches to patients. However, clinical examination, ACR TI-RADS, and FNAC remained relevant factors.

Regulated upon activation, normal T cell expressed and secreted (RANTES) levels in the peripheral blood of patients with Alzheimer's disease.

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.

Preliminary evidence of altered steroidogenesis in women with Alzheimer's disease: Have the patients "OLDER" adrenal zona reticularis?

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 3ß-hydroxy-5α/ß-reduced C19 steroids to their neuroinhibitory and antiinflammatory GABAergic 3α-hydroxy- counterparts and showed higher levels of the 3α-hydroxy-5α/ß-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/ß-reduced C21 steroids but reduced levels of both 5α/ß-reduced C21 steroids, which implied that the alternative "backdoor" pathway might include both 5α- and 5ß-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.

[(TTTTA), polymorphism in the promoter of the CYP11A1 gene in the pathogenesis of polycystic ovary syndrome]. / Promotorový polymorfismus (TTTTA)n genu CYP11A1 v patogenezi syndromu polycystických ovarií.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrinopathy which is characterized by ovarian androgen excess. PCOS has a strong genetic component but the pathogenetic mechanisms responsible for hyperandrogenemia are still unknown. The CYP11A1 encodes the cholesterol side-chain cleavage enzyme that catalyzes the first and rate-limiting step of steroidogenesis. A promoter polymorphism (TTTTA)n CYP11A1 has been reported to be related to the risk of PCOS but the results were controversial. METHODS AND RESULTS: We determined this polymorphism in a cohort of 256 PCOS and 109 healthy control women. Using two models (dominant model for allele with 4 repeats and dominant model for long alleles, i.e. 7 and more repeats) we did not find either the difference in allele and genotype distribution between PCOS and controls or the influence of polymorphism on serum testosterone and androstendione levels. However, the PCOS carriers of long alleles had lower FSH, total- and LDL-cholesterol compared to the carriers of short alleles (p = 0.007; p = 0.02; p = 0.02, ANOVA). In controls, the non-carriers of allele with 4 repeats had significantly higher DHEA-S (p = 0.02, ANOVA) levels than the carriers of allele with 4 repeats. CONCLUSIONS: Despite of some associations found, it seems that the promoter variability of CYP11A1 does not play a key role in the pathogenesis of PCOS.

Beta cell function and insulin sensitivity in women with polycystic ovary syndrome: influence of the family history of type 2 diabetes mellitus.

AIM: To study the impact of family history (FH) of type 2 diabetes mellitus on beta-cell compensatory mechanism in women with polycystic ovary syndrome (PCOS). SUBJECTS AND METHODS: A total of 70 women with PCOS, 14 with first-degree relative with type 2 diabetes mellitus (T2DM) (FH+), 56 with negative FH of T2DM (FH-) and 72 age and BMI matched control healthy women (CNT) underwent oral glucose tolerance test (OGTT). Insulin resistance was evaluated as oral glucose index (OGIS); insulin and C-peptide secretion as the insulinogenic index in 30th min of OGTT. RESULTS: Fasting blood glucose levels were significantly higher in FH+ than in FH- (p < 0.05). Fasting insulin was higher in FH+ than in CNT (p < 0.05). Fasting C-peptide was significantly higher in both FH- and FH+ than in CNT (p < 0.05 and p < 0.01, respectively). OGIS was lower in FH+ than in FH- or in CNT (p < 0.05). Insulinogenic index calculated from C-peptide values (II-Cp) was lower in FH+ than in CNT (p < 0.05). Adaptation index calculated from the values of OGIS and insulinogenic index was significantly lower in FH+ than in CNT or in FH- (p < 0.0001 and p < 0.01, respectively). CONCLUSIONS: Insulin resistance and defective early-phase insulin secretion is present only in those PCOS-affected subjects who had positive FH of T2DM.

Low-density lipoprotein receptor-related protein-5 C/T polymorphism in exon 18 is associated with C peptide and proinsulin levels in control women and patients with polycystic ovary syndrome.

OBJECTIVE: To assess the previously unstudied potential role of C/T (A1330V) polymorphism of the low-density lipoprotein receptor-related protein-5 gene in insulin sensitivity and secretion in polycystic ovary syndrome. The low-density lipoprotein receptor-related protein-5 gene has been found to play a role in determining insulin secretion in animal models. DESIGN: Case-control study. SETTING: Tertiary outpatient clinic. PATIENT(S): Women with polycystic ovary syndrome (n = 299; age, 27.5 +/- 7.1 y [mean +/- SD]), according to the European Society of Human Reproduction and Embryology criteria, as well as healthy control women (n = 187, age, 28.9 +/- 9.8 y). INTERVENTION(S): Oral glucose tolerance test, blood sampling. MAIN OUTCOME MEASURE(S): Glucose, insulin, C peptide, proinsulin during oral glucose tolerance tests, and lipids. Genotyping of C/T (A1330V) polymorphism by polymerase chain reaction-restriction fragment length polymorphism. RESULT(S): There was no difference in the frequency of genotypes between women with polycystic ovary syndrome (CC/CT/TT: 80.3%, 18.4%, 1.3%) and the control women (79.1%, 19.8%, and 1.1%). Carriers of the T allele had statistically significantly higher basal and stimulated C peptide and proinsulin levels than CC homozygotes, both basally and at the 180th minute. Regarding insulin sensitivity, there was no difference between T carriers and CC homozygotes. CONCLUSION(S): Polymorphism of C/T in the low-density lipoprotein receptor-related protein-5 gene is associated with C-peptide and proinsulin secretion but does not influence insulin sensitivity in either healthy women or women with polycystic ovary syndrome.

Role of D327N sex hormone-binding globulin gene polymorphism in the pathogenesis of polycystic ovary syndrome.

SHBG (sex hormone-binding globulin) is a transport protein specific for dihydrotestosterone, testosterone and estradiol. The missense mutation in exon 8 (GAC-->AAC) causing the amino acid exchange Asp-->Asn in codon 327 (D327N) correlates according to the published data with increased SHBG levels. We studied possible association of this polymorphism with polycystic ovary syndrome (PCOS) and anthropometric and biochemical parameters in 248 PCOS patients and 109 healthy control women. The D327N polymorphism (wild-type and variant allele) was detected using PCR-RFLP method (restriction enzyme Bbs-I). For statistical evaluation chi(2) test, Mann-Whitney test, ANCOVA, ANOVA (NCSS 2004, Statgraphics Plus v.5.1, USA) were used. There was no significant difference in genotype distribution between PCOS and controls (chi(2)=1.03, p=0.59). Moreover, we did not find an association of the variant allele with plasma SHBG level, steroid hormones, or screened parameters of lipid and glucose metabolism. In conclusion, the D327N polymorphism of the SHBG gene does not influence susceptibility to PCOS.

Determinants of circulating adiponectin in women with polycystic ovary syndrome.

BACKGROUND AND AIM: Adiponectin is regarded as a possible link between adiposity and insulin resistance. Ghrelin and leptin are considered as signals of energy status. We evaluated the relationships between these peptides, androgens and insulin sensitivity in women affected by polycystic ovary syndrome. METHODS: Thirty-six women with PCOS were examined with euglycemic hyperinsulinemic clamp (to determine M/I, index of insulin sensitivity). Leptin, ghrelin, adiponectin, androgens, and SHBG were determined. Statistics was done using correlation analysis and backward stepwise multiple regression. RESULTS: The positive correlation of adiponectin with testosterone remains significant even after adjustment for BMI (p = 0.01), M/I (p = 0.009) and for both M/I and BMI (p = 0.02). In multiple regression with testosterone, M/I, leptin and ghrelin as independent variables, the model including testosterone (p = 0.03) and ghrelin (p = 0.002) explained 49% of the variability (p < 0.0012) of adiponectin. CONCLUSIONS: Both adiponectin and ghrelin can be involved in the pathophysiology of PCOS but their relation must be delineated further.

Association of insulin gene VNTR polymorphism with polycystic ovary syndrome.

Variability in the number of tandem repeats of the insulin gene (INS VNTR) is known to influence several phenotypes, including polycystic ovary syndrome (PCOS), diabetes mellitus type 1, diabetes mellitus type 2, and birth weight. The presence of the class III allele of INS VNTR has been reported to be protective in diabetes mellitus type 1, but in contrary it increases the disease risk of PCOS and diabetes mellitus type 2. PCOS is a very common endocrinopathy in women of reproductive age. The etiology of PCOS is uncertain, but family history of this syndrome suggests a major genetic cause. The aim of this pilot study was to investigate the possible association of INS VNTR polymorphism with PCOS in Czech women. In PCOS, significantly higher WHR, BMI, G(0), G(180), I(30), Cp(0), Cp(30), Cp(60), AUC-I, AUC-Cp, and insulinogenic index and significantly lower AUC-G/AUC-I were found. No significant differences in INS VNTR genotype, phenotype, or allele frequencies were found between PCOS and controls. In spite of several differences in anthropometric and biochemical parameters (abdominal fat localization, increased beta-cell function, and lower insulin sensitivity in PCOS women), no effect of INS VNTR polymorphism was found on insulin secretion, insulin action, or any other screened parameter.

Insulin sensitivity and beta-cell function in women with polycystic ovary syndrome.

OBJECTIVE: To evaluate insulin sensitivity (IS) and beta-cell function (beta F) in lean and obese women with polycystic ovary syndrome (PCOS), either separately or by using a disposition index (DI). RESEARCH DESIGN AND METHODS: A total of 64 women with PCOS and 20 healthy women were examined by anthropometry, oral glucose tolerance tests (OGTTs), and insulin tolerance tests. Statistical analysis used one-way ANOVA, Kruskal-Wallis, and Mann-Whitney U tests, as appropriate. RESULTS: A significantly higher waist-to-hip ratio (P < 0.0001) was found in both lean and obese women with PCOS. Higher basal blood glucose (P < 0.004) and blood glucose values at 3 h of OGTT (P < 0.008) were found in lean and obese PCOS subjects in comparison with control subjects. Insulin resistance by homeostasis model assessment (P < 0.007) was significantly higher in obese PCOS than in control or lean PCOS subjects. Early-phase insulin secretion (insulinogenic index [Delta I/Delta G(30-0), where I is insulin and G is glucose]; P < 0.0007) was significantly higher in both lean and obese PCOS subjects than in healthy women. All tested combinations of parameters of IS and beta F (DIs) followed a physiological hyperbolic relationship. Significantly lower values of the fasting state-derived DIs were found (all P < 0.05) in obese PCOS subjects. Significantly higher values of all of these indexes derived from nonfasting values were found in lean PCOS as compared with control and obese PCOS subjects (all P < 10(-3)). CONCLUSIONS: Increased beta F was found even in lean individuals with PCOS. Insulin hypersecretion is thus probably connected to the pathogenesis of PCOS.