No abstract

Thyroid hormones are essential for normal skeletal development and normal bone metabolism in adults but can have detrimental effects on bone structures in states of thyroid dysfunction. Untreated severe hyperthyroidism influences the degree of bone mass and increases the probability of high bone turnover osteoporosis. Subclinical hyperthyroidism, defined as low thyrotropin (TSH) and free hormones within the reference range, is a subtler disease, often asymptomatic, and the diagnosis is incidentally made during screening exams. However, more recent data suggest that this clinical condition may affect bone metabolism resulting in decreased bone mineral density (BMD) and increased risk of fracture, particularly in postmenopausal women. The main causes of exogenous subclinical hyperthyroidism are inappropriate replacement dose of thyroxin and TSH suppressive L-thyroxine doses in the therapy of benign thyroid nodules and thyroid carcinoma. Available data similarly suggest that a long-term TSH suppressive dose of thyroxin may decrease BMD and may induce an increased risk of fracture. These effects are particularly observed in postmenopausal women but are less evident in premenopausal women. Overt hypothyroidism is known to lower bone turnover by reducing both osteoclastic bone resorption and osteoblastic activity. These changes in bone metabolism would result in an increase in bone mineralization. At the moment, there are no clear data that demonstrate any relationship between BMD in adults and hypothyroidism. Despite these clinical evidences, the cellular and molecular actions of thyroid hormones on bone structures are not complete clear.

hyperpolarising factor. EETs are synthesised from arachidonic acids by cytochrome P450 enzymes, and soluble epoxide hydrolase (SEH) inhibition may up-regulate EETs. EETs signaling may be implicated in cardiovascular risk groups. The effects of two agonists in stimulating EETs release were compared, and the best agonist was chosen to investigate this pathway in cardiovascular patient groups, and to confirm target engagement in a first in human clinical trial of a novel SEH inhibitor. Methods: Healthy volunteers (12 male, 12 female) underwent 4 forearm venous occlusion plethysmography studies to compare the effects of intraarterial bradykinin and acetylcholine co-infused with saline, fluconazole (cytochrome P450 inhibitor), L-monomethylarginine (nitric oxide synthase inhibitor) plus aspirin (cyclo-oxygenase inhibitor) (LNMMA+ASA), or with all three inhibitors (Triple). Data were analysed by repeated measures analysis of variance. MeanAESEM are presented. Results: Fluconazole had no effect on basal tone (pZ0.25). Bradykinin and acetylcholine both caused dose related vasodilatation (p<0.0001 vs. p<0.001). Fluconazole inhibited bradykinin-induced flow, but not acetylcholine (p<0.0001 vs. pZ0.86). LNMMA+ASA inhibited bradykinin and acetylcholine induced vasodilatation (p<0.0001 vs. p<0.0001). There was no additive effect with triple inhibition. At top agonist doses, fluconazole inhibited bradykinin-induced flow, but not acetylcholine (-18.84AE5.08% vs. 3.36AE9.07%; pZ0.01). LNMMA+ASA inhibited bradykinin and acetylcholine induced flow (-35.74AE7.57% vs. -32.78AE10.60% pZ0.74). There were no gender differences. Conclusions: Basal tone is not dependent on EETs signaling. Bradykinininduced flow is EETs dependent, therefore bradykinin was chosen to probe EETs in cardiovascular patient groups.

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single nucleotide polymorphisms (SNPs) with the lowest p-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI related loci was performed in the AN GWAMA. We detected significant associations (p-values < 5×10−5, Bonferroni corrected p < 0.05) for 9 SNP alleles at 3 independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; poverall: 2.47 × 10−06/pfemales: 3.45 × 10−07/pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet induced obese (DIO) mice as compared to age-matched lean controls. We observed no evidence for associations for the look-up of BMI related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.

The guidelines on hypertension recently published by the European Societies of Hypertension and Cardiology, have acknowledged cognitive function (and its decline) as a hypertension-mediated organ damage. In fact, brain damage can be the only hypertension-mediated organ damage in more than 30% of hypertensive patients, evolving undetected for several years if not appropriately screened; as long as undetected it cannot provide either corrective measures, nor adequate risk stratification of the hypertensive patient. The medical community dealing with older hypertensive patients should have a simple and pragmatic approach to early identify and precisely treat these patients. Both hypertension and cognitive decline are undeniably growing pandemics in developed or epidemiologically transitioning societies. Furthermore, there is a clear-cut connection between exposure to the increased blood pressure and development of cognitive decline. Therefore, a group of experts in the field from the European Society of Hypertension and from the European Geriatric Medicine Society gathered together to answer practical clinical questions that often face the physician when dealing with their hypertensive patients in a routine clinical practice. They elaborated a decision-making approach to help standardize such clinical evaluation.