Primary aldosteronism is a natural model for chronic aldosterone excess in humans and associated with symptoms of anxiety and depression. Cognitive deficits are inherent to the symptomatology of depression and anxiety disorders. Mineralocorticoid receptors and aldosterone appear to play a role in memory. Aldosterone was additionally supposed to be a risk factor for cognitive decline in patients with essential hypertension. The objective of this study was to investigate possible effects of chronically high aldosterone concentrations on cognitive function. A range of cognitive dimensions were assessed in 19 patients (9 males, 10 females); mean age 47.1 (12.5) under standardized treatment and several rating scales for anxiety, depression, quality of life and sleep were administered. Cognitive parameters were compared to standard norms from a large, healthy standardization sample. Patients showed increased levels of anxiety and depression without meeting diagnostic criteria for a disorder. Besides a numerically lower attention score, patients did not show any significant differences in the cognitive dimensions. Anxiety and depression were negatively correlated with quantitative performance in males. In females, a negative correlation between sleep disturbances and abstract reasoning and a positive correlation with quantitative performance were found. Our data showed no specific effect of chronic aldosterone in the tested cognitive parameters overall at least in younger patients, but they indicate sexually dimorphic regulation processes.
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Lukas Engler, Christian Adolf, Daniel A Heinrich, Anna-Katharine Brem, Anna Riester, Anna Franke, Felix Beuschlein, Martin Reincke, Axel Steiger and Heike Künzel
Xiao-jun Zhou, Lin Ding, Jia-xin Liu, Le-qun Su, Jian-jun Dong and Lin Liao
To investigate the difference in the efficacy among dipeptidyl peptidase-4 (DPP-4) inhibitors in Chinese adults with newly diagnosed diabetes.
Materials and methods
In a multicenter, randomized study, we enrolled adults who were either treatment naive or off prior anti-hyperglycemic therapy for at least 3 months. Eligible patients had hemoglobin A1c (HbA1c) concentrations of 6.5–9.5%. Three hundred patients had been randomly allocated to sitagliptin 100 mg, once daily; vildagliptin 50 mg, twice daily and saxagliptin 5 mg, once daily for 12 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c at week 12. This study was completed and registered with ClinicalTrials.gov, number NCT 01703637.
Totally 277 patients were enrolled in the final analysis, and 93 patients received sitagliptin, 94 received vildagliptin and 90 received saxagliptin. Compared with baseline, adjusted mean differences in change from baseline HbA1c at week 12 were −0.50% (95% CI: −0.20 to −0.90), −0.65% (95% CI: −0.40 to −1.40), −0.70 (95% CI: −0.50 to −1.00) for sitagliptin, vildagliptin and saxagliptin group, respectively. The overall HbA1c-lowering effect was similar for all three selected DPP-4 inhibitors after adjustment for age and baseline HbA1c. Notably, in secondary outcome analysis, patients in vildagliptin group showed a significant decrease in total cholesterol levels, compared with participants in sitagliptin and saxagliptin groups. No significant between-group difference was shown in adverse events (AE).
The overall HbA1c-lowering effect and incidence of AE were similar for sitagliptin, vildagliptin and saxagliptin in Chinese adults with newly diagnosed diabetes.
Giulia Bresciani, Angeliki Ditsiou, Chiara Cilibrasi, Viviana Vella, Federico Rea, Marco Schiavon, Giorgio Cavallesco, Georgios Giamas, Maria Zatelli and Teresa Gagliano
Broncho-Pulmonary Neuroendocrine Neoplasms (BP-NENs) are neoplasms orphan of an efficient therapy. Available medical treatments derived from clinical trials are not specific for the management of this malignancy. Sunitinib is a multi-receptor tyrosine-kinases (RTKs) inhibitor that has already shown its efficacy in NENs but there are not available data about its action in BP-NENs. Therefore, our aim was to understand the effects of RTKs inhibition promoted by Sunitinib in order to evaluate new putative targets useful in malignancy treatment. Since our results underlined a role for EGFR and IGF1R in modulating Sunitinib antiproliferative action, we investigated the effects of Erlotinib, an EGFR inhibitor, and Linsitinib, an IGF1R inhibitor, in order to understand their function in regulating cells behaviour. Cell viability and caspase activation were evaluated on two immortalized human BP-NEN cell lines and primary cultures. Our results showed that after treatment with Sunitinib and/or IGF1, EGF and VEGF, the antiproliferative effect of Sunitinib was counteracted by EGF and IGF1 but not by VEGF. Therefore, we evaluated with alpha-screen technology the phosphorylated EGFR and IGF1R levels in primary cultures treated with Sunitinib and/or EGF and IGF1. Results showed a decrease of p-IGF1R after treatment with Sunitinib and an increase after co-treatment with IGF1. Then, we assessed cell viability and caspase activation on BP-NEN cell lines after treatment with Linsitinib and/or Erlotinib. Results demonstrate that these two agents have a stronger antiproliferative effect compared to Sunitinib. In conclusion, our results suggest that IGF1R and EGF1R could represent putative molecular targets in BP-NENs treatment.
Yun Hu, Na Li, Peng Jiang, Liang Cheng, Bo Ding, Xiao-Mei Liu, Ke He, Yun-Qing Zhu, Bing-li Liu, Xin Cao, Hong Zhou and Xiao-Ming Mao
Thyroid nodules are usually accompanied by elevated thyroglobulin (Tg) level and autoimmune thyroid diseases (AITDs). However, the relationship between Tg and AITDs is not fully understood. Dysfunction of regulatory T cells (Tregs) plays an important role in the development of AITDs. We aimed to evaluate the effects of Tg on the function of Tregs in patients with thyroid nodules.
Tg levels and the functions of Tregs in peripheral blood and thyroid tissues of patients with thyroid nodules from Nanjing First Hospital were evaluated. The effects of Tg on the function of Tregs from healthy donors were also assessed in vitro. The function of Tregs was defined as an inhibitory effect of Tregs on the effector T cell (CD4+ CD25− T cell) proliferation rate.
The level of Tg in peripheral blood correlated negatively with the inhibitory function of Tregs (R = 0.398, P = 0.03), and Tregs function declined significantly in the high Tg group (Tg >77 μg/L) compared with the normal Tg group (11.4 ± 3.9% vs 27.5 ± 3.5%, P < 0.05). Compared with peripheral blood, the function of Tregs in thyroid declined significantly (P < 0.01), but the proportion of FOXP3+ Tregs in thyroid increased (P < 0.01). High concentration of Tg (100 μg/mL) inhibited the function of Tregs and downregulated FOXP3, TGF-β and IL-10 mRNA expression in Tregs in vitro.
Elevated Tg level could impair the function of Tregs, which might increase the risk of AITDs in patient with thyroid nodules.
Stephanie Burger-Stritt, Linda Bachmann, Max Kurlbaum and Stefanie Hahner
Patients with adrenal insufficiency (AI) need to adapt their glucocorticoid replacement under stressful conditions to prevent adrenal crisis (AC). Prednisone (PN) suppositories are used for emergency treatment. Pharmacokinetics of 100 mg PN suppositories after vaginal or rectal administration was evaluated.
Single-center, open-label, sequence-randomized, cross-over, bioequivalence study.
Twelve females with primary AI were included. Comparison of pharmacokinetics after vaginal and rectal administration of 100 mg PN suppositories. Main outcome measures: bioequivalence (Cmax: maximum plasma concentration of prednisolone; AUC0 –360: area under the plasma concentration curve of prednisolone from administration to 360 min), adrenocorticotropin (ACTH) levels, safety and tolerability. Comparison of ACTH-suppressive effect with subcutaneous and intramuscular administration of 100 mg hydrocortisone.
Vaginal administration of PN suppositories was not bioequivalent to rectal administration: Cmax and AUC0–360 were significantly lower after vaginal compared to rectal administration: 22 ng/mL (109%) vs 161 ng/mL (28%), P < 0.001; 4390 ng/mL * min (116%) vs 40,302 ng/mL * min (26%), P < 0.001; (mean (coefficient of variation), respectively). A suppression of ACTH by >50% of baseline values was observed 149 min (32%) after rectal PN administration; after vaginal PN administration, the maximum decrease within 360 min was only 44%. Adverse events were more frequent after vaginal administration and mainly attributable to the glucocorticoid deficit due to inadequate vaginal absorption. The ACTH-suppressive effect was more pronounced after parenteral hydrocortisone compared to rectal or vaginal PN.
Vaginal administration of PN suppositories in the available form is not useful for prevention of AC. Pharmacokinetics after rectal use of PN show inferiority compared to available data on parenteral glucocorticoids. In adrenal emergencies, hydrocortisone injection should be the first choice.
Carina Ankarberg-Lindgren, Aneta Gawlik, Berit Kriström, Laura Mazzanti, Elisabeth J Ruijgrok and Theo C J Sas
Transdermal estradiol patches are primarily designed for adult women. No low-dose patches are licensed for pubertal induction in hypogonadal girls. Low doses can be achieved by cutting a matrix patch into smaller pieces. However, the manufacturers do not guarantee stability or utility of cut estradiol patches. The aim of the study was to assess 1-month stability of cut estradiol patches from four different manufacturers in the laboratory at room temperature (+21°C) and at an elevated temperature (+35°C).
Design and methods
Estraderm MX 50 µg, Systen 50 µg and Oesclim 25 µg matrix patches were cut into eight pieces while Estradot 50 µg small patches were cut in half. The cut patches were stored in their respective pouches at +21°C or at +35°C for up to 1 month. The estradiol drug was extracted from the patch by ethyl acetate n-hexane and determined by radioimmunoassay.
Storage at +21°C or +35°C up to 1 month did not reduce the estradiol concentration in Estraderm MX, Systen and Oesclim patches. However, although the estradiol in Estradot patches was not affected by storage at +21°C, at +35°C, estradiol decreased by 57% (±1%) in cut pieces.
Unused Estraderm MX, Systen and Oesclim patch pieces may be stored for at least 1 month at ≤+35°C. Where estradiol patches for children are not available, cut pieces of these or similar patches can be used for pubertal induction. The Estradot patch was too small to properly cut into low doses and not stable in elevated temperatures.
Li Jing and Wang Chengji
Metabolomics was used to explore the effect of exercise intervention in type 2 diabetes. A rat model of type 2 diabetes was induced by an injection of streptozocin (30 mg/kg), after 8 weeks of high-fat diet. The rats were divided into three groups, the control group, the diabetic model group (DM) and the diabetes+exercise group (DME). After exercise for 10 weeks, blood samples were collected to test biomedical indexes, and 24h urine samples were collected for the metabolomics experiment. In the DM group, fasting blood glucose (FBG), both total cholesterol (TC) and total plasma triglycerides (TG) were decreased significantly, compared with those in the DM group. By employing gas chromatography-mass spectrometry (GC/MS), a urinary metabolomics method was used to study the mechanism of exercise on diabetes. Based on principal component analysis, it was found that the DM group and control group were separated into two different clusters. The DME group was located between the DM group and the control group, closer to the control group. Twelve significantly changed metabolites were detected and identified, including 4-methyl phenol, benzoic acid, aminomalonic acid. After exercise, the levels of 7 metabolites were significantly changed, and levels of L-ascorbic acid and aminomalonic acid (related to oxidative stress) were significantly changed compared to normal. The results showed that exercise has anti-hyperglycemic and anti-hyperlipidemic effects. Exercise had an antioxidation function in preventing the occurrence of complications with diabetes mellitus to some extent. This work illustrates the usefulness of metabolomics in the study of mechanisms of exercise treatment．
Andrea Haas, Paul N Hopkins, Nancy Brown, Luminita Pojoga, Jonathan S Williams, Gail K Adler and Gordon H Williams
There is conflicting data on whether variations of physiologic cortisol levels associate with cardiovascular risk. We hypothesize that prior discordant findings are related to problems associated with varying sample size, techniques for assessing cardiovascular risk, and failure to adequately account for environmental factors. We utilized a large sample size, selected the Framingham risk score to compute cardiovascular risk, and performed the study in a highly controlled setting. We had two main objectives: determine whether higher, yet physiologic, cortisol levels associate with increased cardiovascular risk and determine whether caveolin-1 risk allele carriers associate with increased cardiovascular risk. This was a cross-sectional study of 574 individuals who completed a common protocol. Data collection included fasting blood samples, blood pressure measurements, and a 24-hour urine free cortisol collection. 517 of these participants also completed caveolin-1 genotyping. Subjects were classified as belonging to either the low-mode or high-mode urine free cortisol groups, based on the bimodal distribution of urine free cortisol. In multivariate analysis, Framingham risk score was statistically higher in the high-mode cortisol group (10.22 [mean] ± 0.43 [SEM]) compared to the low-mode cortisol group (7.73 ± 0.34), P<0.001. Framingham risk score was also statistically higher in the caveolin-1 risk allele carriers (8.91 ± 0.37) compared to caveolin-1 non-risk allele carriers (7.59 ± 0.48), P=0.034. Overall, the estimated effect on Framingham risk score of carrying the caveolin-1 risk allele was 1.33 ± 0.61, P=0.029. Both urinary cortisol and caveolin-1 risk allele status are independent predictors of Framingham risk score.
Sandrine Visentin, Gérard Michel, Claire Oudin, Béatrice Cousin, Bénédicte Gaborit, Inès Abdesselam, Marie Maraninchi, Marion Nowicki, René Valéro, Maxime Guye, Monique Bernard, Pascal Auquier, Hervé Chambost, Marie-Christine Alessi and Sophie Béliard
The number of long-term survivors of childhood acute leukemia (AL) is substantially growing. These patients are at high risk for metabolic syndrome (MS), especially those who received total body irradiation (TBI). The consequences of children’s irradiation on adipose tissue (AT) development in adulthood are currently unknown. The objective of this study is to assess the impact of TBI on AT of childhood AL survivors.
We compared the morphological and functional characteristics of AT among survivors of childhood AL who developed MS and received (n = 12) or not received (n = 12) TBI.
Body fat distribution and ectopic fat stores (abdominal visceral and liver fat) were evaluated by DEXA, MRI and 1H-spectroscopy. Functional characteristics of subcutaneous AT were investigated by studying gene expression and pre-adipocyte differentiation in culture.
Patients who have received TBI exhibited a lower BMI (minus 5 kg/m2) and a lower waist circumference (minus 14 cm), especially irradiated women. Despite the lower quantity of intra-abdominal AT, irradiated patient displayed a nearly two-fold greater content of liver fat when compared to non-irradiated patient (17 vs 9%, P = 0.008). These lipodystrophic-like features are supplemented by molecular abnormalities in subcutaneous AT of irradiated patients: decrease of gene expression of SREBP1 (minus 39%, P = 0.01) and CIDEA (minus 36%, P = 0.004) and a clear alteration of pre-adipocyte differentiation.
These results strongly support the direct effect of irradiation on AT, especially in women, leading to specific nonalcoholic fatty liver disease, despite lower BMI. A long-term appropriate follow-up is necessary for these patients.
Elena Izkhakov, Joseph Meyerovitch, Micha Barchana, Yacov Shacham, Naftali Stern and Lital Keinan-Boker
Thyroid cancer (TC) survivors may be at risk of subsequent cardiovascular and cerebrovascular (CaV&CeV) morbidity. The 2009 American Thyroid Association (ATA) guidelines recommended less aggressive treatment for low-risk TC patients. The aim of this study was to assess the atherosclerotic CaV&CeV outcome of Israeli TC survivors compared to individuals with no thyroid disease, and the atherosclerotic CaV&CeV outcome before (2000–2008) and after (2009–2011) implementation of the 2009 ATA guidelines.
All members of the largest Israeli healthcare organization who were diagnosed with TC from 1/2000 to 12/2014 (study group) and age- and sex-matched members with no thyroid disease (controls) were included. Adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated using Cox proportional hazards models.
The mean follow-up was 7.6 ± 4.2 and 7.8 ± 4.1 years for the study (n = 5,677, 79% women) and control (n = 23,962) groups, respectively. The former had an increased risk of new atherosclerotic CaV&CeV events (adjusted HR 1.26, 95% CI 1.15–1.39). The 5-year incidence of CaV&CeV was lower (adjusted HR 0.49, 95% CI 0.38–0.62) from 2009 to 2011 compared to 2000 to 2008, but remained higher in the study group than in the control group (adjusted HR 1.5, 95% CI 1.14–1.69).
This large Israeli population-based cohort study showed greater atherosclerotic CaV&CeV morbidity in TC survivors compared to individuals with no thyroid diseases. There was a trend toward a decreased 5-year incidence of atherosclerotic CaV&CeV events among TC survivors following the implementation of the 2009 ATA guidelines, but it remained higher compared to the general population.