Aromatase inhibitors, efficacy and metabolic risk in the treatment of postmenopausal women with early breast cancer

The third-generation aromatase inhibitors (AIs), letrozole, anastrozole and exemestane, are becoming the first choice endocrine drugs for post-menopausal women with breast cancer, since they present greater efficacy when compared with tamoxifen in both adjuvant and metastatic setting. In particular, several large and well designed trials have suggested an important role for AIs in the adjuvant treatment of postmenopausal women with estrogen-receptor positive breast cancer either in the upfront, sequential or extended adjuvant mode. Overall, AIs are associated with a small but significant improvement in disease free survival. The expanding use of AIs in the treatment of early breast cancer means that individual patients will be exposed to the agents for longer durations, making it increasingly important to establish their long-term safety. This review focused on the effects of AIs on bone metabolism, serum lipids and cardiovascular risk. AIs have adverse effects on bone turnover with a reduction of bone mineral density and an increase in the rate of fragility fractures. With respect to tamoxifen AIs present lower thrombotic risk and a less favorable impact on lipid profile, whereas the true effects on cardiovascular risk still remain to be clarified. An adequate monitoring of bone mineral density (BMD) and lipid profile could be recommended for post-menopausal women candidate to AIs

Bisphosphonates, atherosclerosis and vascular calcification: Update and systematic review of clinical studies

Background: Epidemiologic and clinical data have suggested the existence of a biologic linkage between the bone system and the vascular system. Bisphosphonates (BPs) are effective inhibitors of bone resorption and are currently considered the drugs of choice for the preven­tion and treatment of osteoporosis and related fractures. Data from several publications have suggested that BPs may also be effective in reducing the atherosclerotic process and vascular calcification, but the results of these studies are contrasting. This review aimed to allow a better understanding of the relationships between BPs and atherosclerosis in humans. Materials and methods: Electronic databases of Pubmed-Medline, Cochrane Library and SCOPUS from inception to June 30, 2016 were searched. The full texts of the articles potentially eligible were carefully assessed and reviewed. Finally, 20 studies were found to be eligible and were included in the systematic review. All included studies were published between 2000 and 2014. Results: In several studies, etidronate limited the progression of aortic and coronary calcification in hemodialysis patients, whereas the nitrogen-containing-BPs given orally did not significantly reduce vascular calcifications in patients with chronic kidney disease, kidney trasplant or in those with osteoporosis. Nitrogen-containing-BPs present favorable effects both on vessel wall thickness and on arterial elasticity due to both a reduction in serum lipids and the interaction of BPs with the bone tissue, with the consequent release of bone turnover markers and cytokines into the bloodstream. Conclusion: To sum up, the BPs seem to have the potential of influencing atherosclerosis and calcium homeostasis at the level of vascular walls with several possible mechanisms which may differ according to the type, potency, dosage and administration route of BPs. Additional studies are needed to specifically address the mechanism by which BP use could influence cardiovascular morbidity and mortality

An alarming deterioration of neurological status

This clinical case should make us reflect on the potential dangers of lithium, often too readily prescribed by non expert physicians to elderly, and often poorly compliant, patients. There also needs to be very close monitoring of plasma lithium levels, in addition to paying attention to clinical signs, such as a persistent polyuria or hyperosmolarity, because these could be important early warning signs. It is therefore useful to reiterate that, in case of lithium intoxication with altered neurological status despite improvement blood tests, it is necessary to consider pontine or extra-pontine myelinolysis as a rare but possible complicatio

Solution Structure of Cox11, a Novel Type of β-Immunoglobulin-like Fold Involved in CuB Site Formation of Cytochrome c Oxidase

Cytochrome c oxidase assembly process involves many accessory proteins including Cox11, which is a copper-binding protein required for Cu incorporation into the Cu(B) site of cytochrome c oxidase. In a genome wide search, a number of Cox11 homologs are found in all of the eukaryotes with complete genomes and in several Gram-negative bacteria. All of them possess a highly homologous soluble domain and contain an N-terminal fragment that anchors the protein to the membrane. An anchor-free construct of 164 amino acids was obtained from Sinorhizobium meliloti, and the first structure of this class of proteins is reported here. The apoform has an immunoglobulin-like fold with a novel type of beta-strand organization. The copper binding motif composed of two highly conserved cysteines is located on one side of the beta-barrel structure. The apoprotein is monomeric in the presence of dithiothreitol, whereas it dimerizes in the absence of the reductant. When copper(I) binds, NMR and extended x-ray absorption fine structure (EXAFS) data indicate a dimeric protein state with two thiolates bridging two copper(I) ions. The present results advance the knowledge on the poorly understood molecular aspects of cytochrome c oxidase assembly

Efficacy and Tolerability of a Nutraceutical Combination (Red Yeast Rice, Policosanols, and Berberine) in Patients with Low-Moderate Risk Hypercholesterolemia: A Double-Blind, Placebo-Controlled Study

Background: Statins are at the forefront of strategies to manage hypercholesterolemia. However 10% to 15% of patients are intolerant to any statin drugs, even at low daily doses and almost one-third of statin users discontinue therapy within 1 year. Some nutraceuticals are prescribed as lipid-lowering substances, but doubts remain about their efficacy and tolerability. Objectives: We aimed to investigate the efficacy and the safety of a nutraceutical combination consisting mainly of 200 mg red yeast rice extract (equivalent to 3 mg monacolins), 500 mg berberine, and 10 mg policosanols (MBP-NC) in patients with low-moderate risk hypercholesterolemia. Methods: In this single centre, randomized, double-blind, placebo-controlled study 60 consecutive outpatients (29 men and 31 women; age range = 18-60 years), with newly diagnosed primary hypercholesterolemia not previously treated, after a run-in period of 3 weeks on a stable hypolipidic diet, were randomized to receive a pill of MBP-NC (n = 30) or placebo (n = 30) once a day after dinner, in addition to the hypolipidic diet. The efficacy and the tolerability of the proposed nutraceutical treatment were fully assessed after 4, 12, and 24 weeks of treatment. Results: In the MBP-NC group both total cholesterol and LDL-C already showed a significant reduction at Week 4 (-30.3% ± 33.9% and -29.4% ± 35.3%, respectively) that remained substantially unchanged at Week 12 (-26.7% ± 33.1% and -25.6% ± 31.5%, respectively) and at Week 24 (-24.6% ± 32.1% and -23.7% ± 32.6%, respectively). The between-groups differences were significant at all time points for both total cholesterol and LDL-C. There were no significant changes in HDL-C, fasting glucose, and triglyceride serum levels in either group. MBP-NC was also safe and well tolerated. Conclusions: In patients with low- to moderate-risk hypercholesterolemia a nutraceutical combination in association with a hypolipidic diet significantly reduced total cholesterol and LDL-C levels and may favor the reaching the recommended cholesterol targets

Short and long-term effects of continuous versus intermittent loop diuretics treatment in acute heart failure with renal dysfunction

Intravenous loop diuretics are still the cornerstone of therapy in acute decompensated heart failure, however, the optimal dosage and administration strategies remain poorly defined particularly in patients with an associated renal dysfunction. This is a single-center, pilot, randomized trial involving patients with acute HF and renal dysfunction. Patients were assigned to receive continuous furosemide infusion (cIV) or bolus injections of furosemide (iIV). Primary end points were the evaluation of urine output volumes, renal function, and b-type natriuretic peptide (BNP) levels during treatment time. Secondary end point included: weight loss, length of hospitalization, differences in plasma electrolytes, need for additional treatment, and evaluation of cardiac events during follow-up period. 57 patients were included in the study. The cIV group showed an increase in urine output (2,505 ± 796 vs 2140 ± 468 ml/day, p < 0.04) and a more significant decrease of BNP levels in respect to the iIV group (679.6 ± 397 vs 949 ± 548 pg/ml, p < 0.04). We observed a significant increase in creatinine levels (1.78 ± 0.5 vs 1.41 ± 0.3 mg/dl, p < 0.01), and a reduction of the estimated glomerular filtration rate in cIV (44.8 ± 6.1 vs 46.7 ± 6.1 ml/min, p < 0.05). We observed a significant difference in eGFR (p = 0.01), creatinine (p = 0.02) and BNP levels (p = 0.03) from baseline to the end of treatment in both groups. A significant increase of in-hospital additional treatment as well as length of hospitalization was observed in cIV. Finally, cIV revealed a higher rate of adverse events during the follow-up period (p < 0.03). cIV appears to provide a more efficient diuresis and BNP level reduction during hospitalization, however, it was associated with increased rate of worsening renal function during hospitalization. cIV also appears related to a longer hospitalization and an increased number of adverse events during follow-up. For all of these reasons, a larger multi-center study is required to determine whether high-dose diuretics are responsible for worsening renal function and to define the best modality of administratio

Glucagon-like Peptide-1 Receptor Agonists and Diabetic Osteopathy: Another Positive Effect of Incretines? A 12 Months Longitudinal Study

Diabetic osteopathy is a frequent complication in patients with type 2 diabetes mellitus (T2DM). The association between T2DM and increased fracture risk has led to study the impact of new antidiabetic drugs on bone metabolism. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin mimetic drugs which have many pleiotropic properties. The relationship between GLP-1RAs and bone is very complex: while in vitro and animal studies have demonstrated a protective effect on bone, human studies are scarce. We led a 12 months longitudinal study evaluating bone changes in 65 patients withT2DM for whom a therapy with GLP-1RAs had been planned. Fifty-four T2DM patients completed the 12-month study period; of them, 30 had been treated with weekly dulaglutide and 24 with weekly semaglutide. One-year therapy with GLP-1RAs resulted in a significant reduction in weight and BMI. Bone mineral density (BMD), bone metabolism, trabecular bone score (TBS), adiponectin, and myostatin were evaluated before and after 12 months of GLP-1RAs therapy. After 12 months of therapy bone turnover markers and adiponectin showed a significant increase, while myostatin values showed a modest but significant reduction. BMD-LS by DXA presented a significant reduction while the reduction in BMD-LS by REMS was not significant and TBS values showed a marginal increase. Both DXA and REMS techniques showed a modest but significant reduction in femoral BMD. In conclusion, the use of GLP-1RAs for 12 months preserves bone quality and reactivates bone turnover. Further studies are needed to confirm whether GLP-1RAs could represent a useful therapeutic option for patients with T2DM and osteoporosis

Radiofrequency echographic multispectrometry (REMS): an innovative technique for the assessment of bone status in young women with anorexia nervosa

Purpose Reduced bone mineral density (BMD) and increase risk of fragility fracture are common complication of anorexia nervosa (AN). BMD by dual-energy X-ray absorptiometry (DXA) present several limits in subjects with AN. This study aimed to evaluate the usefulness of the new Radiofrequency echographic multispectrometry (REMS) technique in the assessment of bone status in young women with AN. Methods In a cohort of 50 subjects with restrictive AN and in 30 healthy controls, we measured BMD at the lumbar spine (LS-BMD), at femoral neck (FN-BMD) and total hip (TH-BMD) using both DXA and REMS technique. Results BMD evaluated by DXA and REMS technique at all measurement sites were all significantly (p &lt; 0.01) lower in subjects suffering from AN subjects than in controls. Good correlations were detected between BMD by DXA and BMD by REMS measurements at LS (r = 0.64, p &lt; 0.01) at FN (r = 0.86, p &lt; 0.01) and at TH (r = 0.84, p &lt; 0.01) in subjects suffering from AN. Moreover, Bland-Altman analysis confirmed the good agreement between the two techniques. The subjects suffering from AN with previous vertebral fragility fractures presented lower values of both BMD-LS and BMD-TH by DXA and by REMS with respect to those without fractures; however, the difference was significant only for BMD-TH by REMS (p &lt; 0.05). Conclusions Our data suggest that REMS technique due to its characteristic of precision and reproducibility may represent an important tool for the evaluation of the changes in bone status in AN young women, especially during the fertile age and in case of pregnancy and breastfeeding. © 2022, The Author(s)

Multispectral, Thermographic and Spectroradiometric Analyses Unravel Bio-Stimulatory Effects of Wood Distillate in Field-Grown Chickpea (Cicer arietinum L.)

Wood distillate (WD) has recently emerged as a promising bio-stimulant for sustainable legume crop production, owing to its ability to enhance seed yield and quality. However, no studies exist on the effects of WD on chickpea plants at pre-harvesting stages, hindering the farmers' ability to acquire valuable knowledge on the early action of WD on the plants' status and preventing the establishment of proactive measures to optimize WD use in agriculture. In this study, two multispectral, thermographic and spectroradiometric surveys, along with in-situ measurements of specific plant biometric traits, were conducted across the reproductive stage of field-grown chickpea in order to evaluate the early involvement of WD on plant health. The acquired multispectral images were used to calculate the Normalized Difference Vegetation Index (NDVI), revealing a notable similar to 35% increase in NDVI scores of WD-treated plants at the onset of physiological maturity, and indicating an improved plant status compared to the control (water-treated) plants. Moreover, control and WD-treated plants exhibited distinct spectral signatures across the visible, near-infrared (NIR) and short-wave infrared (SWIR) spectra, suggesting potential changes in their photosynthetic capacity, structural properties and water content both at the leaf and at the pod level. Furthermore, WD-treated plants showed a 25% increase in pod production, particularly at the beginning of seed maturity, suggesting that enhancements in plant status were also reflected in higher pod yields. These results point to a beneficial effect of WD on plant health during the preliminary stages of seed formation and indicate that a combination of both multispectral and spectroradiometric analyses can provide critical insights on the status of chickpea crops at pre-harvesting stages. In addition, these findings emphasize the importance of analyzing pre-harvesting stages to gain insights into the early involvement of WD in promoting plant health and, ultimately, in predicting final crop yields