Search Results

You are looking at 51 - 60 of 67 items for

  • Abstract: anti-androgenic x
  • Abstract: Bisphenol-A x
  • Abstract: Drugs x
  • Refine by Access: All content x
Clear All Modify Search
Open access

Melinda Kertész, Szilárd Kun, Eszter Sélley, Zsuzsanna Nagy, Tamás Kőszegi, and István Wittmann

Background

Type 2 diabetes is characterized, beyond the insulin resistance, by polyhormonal resistance. Thyroid hormonal resistance has not yet been described in this population of patients. Metformin is used to decrease insulin resistance, and at present, it is assumed to influence the effect of triiodothyronine, as well.

Methods

In this open-label, pilot, hypothesis-generating, follow-up study, 21 patients were included; all of them were euthyroid with drug naïve, newly diagnosed type 2 diabetes. Before and after 4 weeks of metformin therapy, fructosamine, homeostasis model assessment for insulin resistance (HOMA-IR), thyroid hormones, T3/T4 ratio, and TSH, as well as blood pressure and heart rate using ambulatory blood pressure monitor were measured. We also conducted an in vitro study to investigate the possible mechanisms of T3 resistance, assessing T3-induced Akt phosphorylation among normal (5 mM) and high (25 mM) glucose levels with or without metformin treatment in a human embryonal kidney cell line.

Results

Metformin decreased the level of T3 (P < 0.001), the ratio of T3/T4 (P = 0.038), fructosamine (P = 0.008) and HOMA-IR (P = 0.022). All these changes were accompanied by an unchanged TSH, T4, triglyceride, plasma glucose, bodyweight, blood pressure, and heart rate. In our in vitro study, T3-induced Akt phosphorylation decreased in cells grown in 25 mM glucose medium compared to those in 5 mM. Metformin could not reverse this effect.

Conclusion

Metformin seems to improve T3 sensitivity in the cardiovascular system in euthyroid, type 2 diabetic patients, the mechanism of which may be supracellular.

Open access

Satoshi Higuchi, Hideki Ota, Yuta Tezuka, Kazumasa Seiji, Hidenobu Takagi, Jongmin Lee, Yi-Wei Lee, Kei Omata, Yoshikiyo Ono, Ryo Morimoto, Masataka Kudo, Fumitoshi Satoh, and Kei Takase

Objectives

This study compared cardiac function, morphology, and tissue characteristics between two common subtypes of primary aldosteronism (PA) using a 3T MR scanner.

Design

A retrospective, single-center, observational study.

Methods

We retrospectively reviewed 143 consecutive patients with PA, who underwent both adrenal venous sampling and cardiac magnetic resonance. We acquired cine, late gadolinium enhancement, and pre- and postcontrast myocardial T1-mapping images.

Results

PA was diagnosed as unilateral aldosterone-producing adenoma (APA) in 70 patients and bilateral hyperaldosteronism (BHA) in 73. The APA group showed significantly higher plasma aldosterone concentration (PAC) and aldosterone to renin rate (ARR) than the BHA group. After controlling for age, sex, antihypertensive drugs, systolic and diastolic blood pressure, and disease duration, the parameters independently associated with APA were: left ventricular end-diastolic volume index (EDVI: adjusted odds ratio (aOR) = 1.06 (95% CI: 1.030–1.096), P < 0.01), end-systolic volume index (ESVI: 1.06 (1.017–1.113), P < 0.01), stroke index (SI: 1.07 (1.020–1.121), P < 0.01), cardiac index (CI: 1.001 (1.000–1.001), P < 0.01), and native T1 (1.01 (1.000–1.019), P = 0.038). Weak positive correlations were found between PAC and EDVI (R = 0.28, P < 0.01), ESVI (0.26, P < 0.01), and SI (0.18, P = 0.03); and between ARR and EDVI (0.25, P < 0.01), ESVI (0.24, P < 0.01), and native T1 (0.17, P = 0.047).

Conclusions

APA is associated with greater LV volumetric parameters and higher native T1 values, suggesting a higher risk of volume overload and myocardial damage.

Open access

Matilde Calanchini, Michael Tadman, Jesper Krogh, Andrea Fabbri, Ashley Grossman, and Brian Shine

Background

The 24-h urinary output of 5-hydroxyindoleacetic acid (5-HIAA) is used to monitor disease progression and treatment responses of neuroendocrine neoplasms (NENs). Several conditions are required for 5-HIAA assay, involving urine collection/preservation and food/drug restrictions.

Aim

To evaluate the correlation between 5-HIAA concentration in a spot urine sample and the output in a 24-h urine collection, and whether spot urine specimens can replace 24-h collection.

Methods

Patients with NENs or symptoms suggestive of NENs were asked to provide a separate spot urine at the end of the 24-h urine collection for 5-HIAA assessment. The upper reference limit for 24-h urinary 5-HIAA was 40 µmol/24 h. 5-HIAA measurements in spot urine samples were corrected for variation in urine flow rate by expressing results as a ratio to creatinine concentration.

Results

We included 136 paired urinary samples for 5-HIAA assessment from 111 patients (100 NENs). The correlation between 5-HIAA values measured in 24-h and spot urines was r = +0.863 (P < 0.001) and r = +0.840 (P < 0.001) including only NEN patients. Using the 24-h urinary 5-HIAA as reference method, the AUC on ROC analysis for spot urinary 5-HIAA was 0.948 (95% CI, 0.914–0.983; P < 0.001), attaining a sensitivity of 83% and specificity of 95% using 5.3 mol/mmol as cut-off for the spot urine. The AUC among NEN patients alone was 0.945 (95% CI, 0.904–0.987; P < 0.001).

Conclusions

The ratio of 5-HIAA to creatinine in a spot urine could replace the measurement of 5-HIAA output in a 24-h urine collection, especially for follow-up of patients with known elevated 5-HIAA levels.

Open access

Marek Niedziela

The term 'hyperthyroidism' refers to a form of thyrotoxicosis due to inappropriate high synthesis and secretion of thyroid hormone(s) by the thyroid. The leading cause of hyperthyroidism in adolescents is Graves’ disease (GD); however, one should also consider other potential causes, such as toxic nodular goitre (single or multinodular), and other rare disorders leading to excessive production and release of thyroid hormones. The term 'thyrotoxicosis' refers to a clinical state resulting from inappropriate high thyroid hormone action in tissues, generally due to inappropriate high tissue thyroid hormone levels. Thyrotoxicosis is a condition with multiple aetiologies, manifestations, and potential modes of therapy. By definition, the extrathyroidal sources of excessive amounts of thyroid hormones, such as iatrogenic thyrotoxicosis, factitious ingestion of thyroid hormone, or struma ovarii, do not include hyperthyroidism. The aetiology of hyperthyroidism/and thyrotoxicosis should be determined. Although the diagnosis is apparent based on the clinical presentation and initial biochemical evaluation, additional diagnostic testing is indicated. This testing should include: (1) measurement of thyroid-stimulating hormone receptor (TSHR) antibodies (TRAb); (2) analysis of thyroidal echogenicity and blood flow on ultrasonography; or (3) determination of radioactive iodine uptake (RAIU). A 123I or 99mTc pertechnetate scan is recommended when the clinical presentation suggests toxic nodular goitre. A question arises regarding whether diagnostic workup and treatment (antithyroid drugs, radioiodine, surgery, and others) should be the same in children and adolescents as in adults, as well as whether there are the same goals of treatment in adolescents as in adults, in female patients vs in male patients, and in reproductive or in postreproductive age. In this aspect, different treatment modalities might be preferred to achieve euthyroidism and to avoid potential risks from the treatment. The vast majority of patients with thyroid disorders require life-long treatment; therefore, the collaboration of different specialists is warranted to achieve these goals and improve patients’ quality of life.

Open access

Martin Zweifel, Beat Thürlimann, Salome Riniker, Patrik Weder, Roger von Moos, Olivia Pagani, Martin Bigler, Karin M Rothgiesser, Christiane Pilop, Hanne Hawle, Peter Brauchli, Coya Tapia, Wolfgang Schoenfeld, Cristiana Sessa, and for the Swiss Group for Clinical Cancer Research (SAKK)

CR1447 (4-hydroxytestosterone, 4-OHT) binds to the androgen receptor and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells in preclinical studies. The objective of this first-in man trial was to evaluate the safety and to determine the dose of CR1447, administered as an ointment, for Phase II. Escalating doses (100, 200, 400 mg) of CR1447 were administered topically on a daily basis to patients with ER-positive/AR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. 14 patients have been treated for a total of 42 cycles. Two patients, one at dose level 100 mg and one at dose level 200 mg, showed early tumour progression and were replaced. Related adverse events were all ≤ grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose-limiting toxicities (DLTs) were seen. Two patients (17%) achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447. 4-OH-androstenedione (4-OHA), a key metabolite of 4-OHT, was undetectable in most of the plasma samples. Urine metabolites of 4-OHT and 4-OHA indicate high exposure of 4-OHT after topical administration. Oestradiol serum concentrations did not increase, confirming preclinical data that CR1447 is not converted to estrogens in vivo. In conclusion, CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400 mg/day.

Open access

Monia Cito, Silvia Pellegrini, Lorenzo Piemonti, and Valeria Sordi

The experience in the field of islet transplantation shows that it is possible to replace β cells in a patient with type 1 diabetes (T1D), but this cell therapy is limited by the scarcity of organ donors and by the danger associated to the immunosuppressive drugs. Stem cell therapy is becoming a concrete opportunity to treat various diseases. In particular, for a disease like T1D, caused by the loss of a single specific cell type that does not need to be transplanted back in its originating site to perform its function, a stem cell-based cell replacement therapy seems to be the ideal cure. New and infinite sources of β cells are strongly required. In this review, we make an overview of the most promising and advanced β cell production strategies. Particular hope is placed in pluripotent stem cells (PSC), both embryonic (ESC) and induced pluripotent stem cells (iPSC). The first phase 1/2 clinical trials with ESC-derived pancreatic progenitor cells are ongoing in the United States and Canada, but a successful strategy for the use of PSC in patients with diabetes has still to overcome several important hurdles. Another promising strategy of generation of new β cells is the transdifferentiation of adult cells, both intra-pancreatic, such as alpha, exocrine and ductal cells or extra-pancreatic, in particular liver cells. Finally, new advances in gene editing technologies have given impetus to research on the production of human organs in chimeric animals and on in situ reprogramming of adult cells through in vivo target gene activation.

Open access

Lili Liu, Zhuo Shao, Ying Xia, Jiabi Qin, Yang Xiao, Zhiguang Zhou, and Zubing Mei

Objective

Combined treatment with an incretin-based drug, such as a glucagon-like peptide 1 receptor agonist (GLP-1 RA) or a dipeptidyl peptidase-4 (DPP-4) inhibitor, and basal insulin is a new strategy for improving glucose control in type 1 diabetes mellitus (T1DM). We performed a meta-analysis to assess the effect of this combined treatment on glycaemic control, insulin dose, severe hypoglycaemia, weight gain and gastrointestinal side effects in T1DM patients.

Methods

We searched PubMed, EMBASE and the Cochrane Library for relevant studies published before July 16, 2018. The primary outcome was glycosylated haemoglobin (HbA1c). Secondary outcomes included total daily insulin dose, body weight, severe hypoglycaemia and gastrointestinal side effects.

Results

Nine randomized controlled trials (RCTs) involving 2389 patients were ultimately included in the meta-analysis. The pooled data suggested that incretin-based therapy was associated with a reduction in HbA1c levels (weighted mean difference (WMD) −0.17%, 95% confidence interval (CI) −0.24 to −0.11, P < 0.001), total daily insulin dose (WMD −5.53 IU/day, 95% CI −8.89 to −2.17, P = 0.001) and body weight (WMD −3.24 kg, 95% CI −4.43 to −2.04, P < 0.001). Incretins did not increase the risk of severe hypoglycaemia (odds ratio (OR) 0.83, 95% CI 0.60–1.16, P = 0.287) but increased the occurrence of gastrointestinal side effects (OR 3.46, 95% CI 2.20–5.45, P < 0.001).

Conclusions

In T1DM patients, GLP-1 RAs, but not DPP-4 inhibitors, combined with insulin appear to be an effective therapy but may increase the occurrence of gastrointestinal side effects.

Open access

Anastasia P Athanasoulia-Kaspar, Matthias K Auer, Günter K Stalla, and Mira Jakovcevski

Objective

Patients with non-functioning pituitary adenomas exhibit high morbidity and mortality rates. Growth hormone deficiency and high doses of glucocorticoid substitution therapy have been identified as corresponding risk factors. Interestingly, high levels of endogenous cortisol in, e.g., patients with post-traumatic stress disorder or patients with Cushing’s disease have been linked to shorter telomere length. Telomeres are noncoding DNA regions located at the end of chromosomes consisting of repetitive DNA sequences which shorten with aging and hereby determine cell survival. Therefore, telomere length can serve as a predictor for the onset of disease and mortality in some endocrine disorders (e.g., Cushing’s disease).

Design/methods

Here, we examine telomere length from blood in patients (n = 115) with non-functioning pituitary adenomas (NFPA) in a cross-sectional case–control (n = 106, age-, gender-matched) study using qPCR. Linear regression models were used to identify independent predictors of telomere length.

Results

We show that patients with NFPA exhibited shorter telomeres than controls. No significant association of indices of growth hormone deficiency (IGF-1-level-SDS, years of unsubstituted growth hormone deficiency etc.) with telomere length was detected. Interestingly, linear regression analysis showed that hydrocortisone replacement dosage in patients with adrenal insufficiency (n = 52) was a significant predictor for shorter telomere length (β = 0.377; P = 0.018) independent of potential confounders (gender, age, BMI, arterial hypertension, systolic blood pressure, number of antihypertensive drugs, total leukocyte count, waist-to-hip ratio, waist circumference, diabetes mellitus type 2, HbA1c, current statin use). Median split analysis revealed that higher hydrocortisone intake (>20 mg) was associated with significantly shorter telomeres.

Conclusion

These observations strengthen the importance of adjusted glucocorticoid treatment in NFPA patients with respect to morbidity and mortality rates.

Open access

Eva Olga Melin, Magnus Hillman, and Mona Landin-Olsson

Objective

To explore associations between high midnight salivary cortisol (MSC) secretion and high blood pressure (BP) in type 1 diabetes (T1D).

Methods

Cross-sectional study of 196 adult patients with T1D (54% men). Associations between high MSC (≥9.3 nmol/L) and high systolic BP (>130 mmHg), and high diastolic BP (>80 mmHg) were explored for all patients, users and non-users of antihypertensive drugs (AHD). Adjustments were performed for age, sex, diabetes-related variables, p-creatinine, smoking, physical inactivity, depression and medication.

Results

The prevalence of high MSC differed between patients with high and low systolic BP in all 196 patients: 39 vs 13% (P = 0.001); in 60 users of AHD: 37 vs 12% (P = 0.039), and in 136 non-users of AHD: 43 vs 13% (P = 0.012). Significant associations with high systolic BP were for all patients: physical inactivity (adjusted odds ratio (AOR) 6.5), high MSC (AOR 3.9), abdominal obesity (AOR 3.7), AHD (AOR 2.9), age (per year) (AOR 1.07), and p-creatinine (per µmol/L) (AOR 1.03); for 60 users of AHD: high MSC (AOR 4.1) and age (per year) (AOR 1.11); for 136 non-users of AHD: abdominal obesity (AOR 27.4), physical inactivity (AOR 14.7), male sex (AOR 9.0), smoking (AOR 7.9), and age (per year) (AOR 1.08). High MSC was not associated with high DBP.

Conclusions

In adult patients with T1D, high systolic BP was associated with physical inactivity, high MSC secretion, abdominal obesity, p-creatinine, age, and AHD, the latter indicating treatment failure.

Open access

Riying Liang, Meijun Wang, Chang Fu, Hua Liang, Hongrong Deng, Ying Tan, Fen Xu, and Mengyin Cai

Background:

Obesity is associated with the development and progression of chronic kidney disease. Emerging evidence suggests that glucagon-like peptide-1 receptor agonist could reduce renal damage and albuminuria. Sirtuin 1 (SIRT1) was considered as a crucial regulator in metabolism-related kidney disease. Herein, the role of SIRT1 in liraglutide-ameliorated high-fat diet (HFD)-induced kidney injury was illustrated.

Methods:

Male C57BL/6 mice were fed HFD for 20 weeks to induce kidney injury that was then treated with liraglutide for 8 weeks to estimate its protective effect on the kidney. Also, the mechanism of the drug in SV40 MES 13 (SV40) mouse mesangial cells was elucidated.

Results:

Liraglutide treatment ameliorated HFD-induced metabolic disorders, including hyperglycemia, increasing body weight, and insulin resistance. In addition, kidney weight, urine albumin-to-creatinine, and kidney morphological changes such as vacuolated tubules, glomerulomegaly, thickened glomerular basement membrane, and tubulointerstitial fibrosis were also significantly ameliorated. Furthermore, apoptotic cells and apoptosis markers were downregulated in the kidney of liraglutide-treated mice. In addition, the expression of SIRT1 protein was upregulated, whereas thioredoxin-interacting protein (TXNIP), which serves as a mediator of oxidative stress and apoptosis in metabolism disease, was downregulated by liraglutide. In SV40 cells, the effect of liraglutide on reversing the upregulation of cleaved caspase-3 induced by high glucose (30 mM) was hampered when SIRT1 was knocked down; also, the downregulation of TXNIP by liraglutide was blocked.

Conclusions:

Liraglutide might have a beneficial effect on metabolism-related kidney damage by inhibiting apoptosis via activation of SIRT1 and suppression of TXNIP pathway.