Global longitudinal strain for prediction of mortality in ST-segment elevation myocardial infarction and aortic stenosis patients: two sides of the same coin.

OBJECTIVE: Global longitudinal strain (GLS) predicts major adverse events in ST-segment elevation myocardial infarction (STEMI) and aortic stenosis (AS). Different cut-off values and different end-points have been proposed for prognostic stratification. We aimed to verify whether a single GLS cut-off value can be used to identify increased risk of all-cause death in STEMI and AS. PATIENTS AND METHODS: One-hundred- seventeen successfully treated first STEMI (age 63.8±12.5 yrs, 70% men) and 64 AS (age 80.3±6.9 yrs, 44% men) patients, undergoing echocardiography before discharge and before AS treatment, respectively, were retrospectively analyzed. GLS was analyzed, together with pulmonary artery systolic pressure (PASP), Killip class and Genereux stage. End-point was all-cause death at 6-month follow-up. RESULTS: All-cause death occurred in 4 (3.4%) STEMI and 5 (7.8%) AS patients (p=ns). AS patients who died had GLS similar to died STEMI patients (9.7±2.1 vs. 11.3±1.7, p=ns). GLS cut-off ≤12% predicted death with 89% sensitivity and 70% specificity (AUC 0.84, p=0.001): STEMI and AS patients with GLS ≤12% had worse survival than STEMI and AS patients with GLS >12% (log-rank p=0.001). At multivariate Cox regression analysis, lower GLS values independently predicted death (HR 0.667, 95% CI 0.451-0.986, p=0.042), and the prediction model was improved when GLS was added to old age, significant comorbidities, PASP and Killip/Genereux stage (χ2 6.691 vs. 1.364, p=0.010). CONCLUSIONS: Died patients with STEMI and AS show similar values of GLS. A unique cut-off value of GLS can reliably be used to stratify the risk of all-cause death at 6-month follow-up in both two clinical settings.

High serum osteopontin levels are associated with prevalent fractures and worse lipid profile in post-menopausal women with type 2 diabetes.

PURPOSE: Patients with type 2 diabetes (T2DM) have increased fracture risk. Osteopontin (OPN) is a protein involved in bone remodeling and inflammation. The aim of this study was to evaluate the association of OPN with fracture prevalence and with metabolic parameters in post-menopausal women with T2DM. METHODS: Sixty-four post-menopausal women with T2DM (age 67.0 ± 7.8 years, diabetes duration 8.9 ± 6.7 years), enrolled in a previous study, were followed up (3.6 ± 0.9 years). Previous fragility fractures were recorded. The FRAX score (without BMD) was calculated and biochemical parameters (plasma glucose, HbA1c, lipid profile and renal function) were assessed. Serum 25OH-vitamin D, calcium, PTH and OPN were evaluated at baseline. The association between OPN and fracture prevalence at baseline was evaluated by a logistic model. RESULTS: OPN levels were higher in patients with previous fractures (n.25) than in patients without previous fractures at baseline (n.39) (p = 0.006). The odds of having fractures at baseline increased by 6.7 (1.9-31.4, 95% CI, p = 0.007) for each increase of 1 ng/ml in OPN levels, after adjustment for vitamin D and HbA1c levels. Fracture incidence was 4.7%. Higher OPN associated with a decrease in HDL-cholesterol (p = 0.048), after adjustment for age, basal HDL-cholesterol, basal and follow-up HbA1c and follow-up duration. 25OH-vitamin D associated with an increase in FRAX-estimated probability of hip fracture at follow-up (p = 0.029), after adjustment for age, 25OH-vitamin D and time. CONCLUSIONS: In post-menopausal women with T2DM, OPN might be a useful marker of fracture and worse lipid profile.

Long-term effect of testosterone replacement therapy on bone in hypogonadal men with Klinefelter Syndrome.

PURPOSE: To assess different aspects of bone damage in untreated adult patients with Klinefelter Syndrome (KS) before and during testosterone replacement therapy (TRT). METHODS: Fifteen untreated hypogonadal men with KS and 26 control subjects (C) matched for age and BMI were recruited. Sex hormone levels were measured in all subjects. Lumbar spine (LS) and femoral (neck: FN and total hip: TH) bone mineral density (BMD), trabecular bone score (TBS), hip structure analysis (HSA) and fat measures (percentage of fat mass, android/gynoid ratio and visceral adipose tissue) were evaluated by DEXA. In KS patients, blood analysis and DEXA measurements were assessed at baseline and repeated yearly for three years during TRT. RESULTS: Fat measures were significantly higher in KS than C (p < 0.01). In contrast, mean LS, FN and TH BMD were significantly reduced in KS compared to C (p < 0.01), while there was no difference in TBS. HSA revealed a significantly lower cortical thickness and significantly higher buckling ratio in KS compared to C at all femoral sites (p < 0.01). In KS patients, TRT significantly increased BMD at LS only, but did not improve TBS and HSA parameters. Fat measures were inversely associated with TBS values, and TRT did not influence this relationship. CONCLUSIONS: In untreated hypogonadal men with KS, lumbar and femoral BMD was reduced, and femoral bone quality was impaired. Adiposity seemed to have a detrimental effect on lumbar bone microarchitecture, as indirectly evaluated by TBS. However, TRT failed to remedy these negative effects on bone.

Desencadenantes migrañosos y habituación del potencial evocado visual. Definiendo subgrupos de pacientes / Migraine triggers and habituation of visual evoked potentials. Defining subset of patient

Identificar subgrupos específicos de pacientes dentro del espectro clínico de la migraña podría ayudar a personalizar el tratamiento de la misma. Definir perfiles de pacientes según su relación entre las características clínicas y los biomarcadores neurofisiológicos sería de suma importancia y es en gran medida un ámbito inexplorado. Los ataques de migraña pueden ser desencadenados por distintos factores, entre los cuales el estrés, los cambios hormonales, el ayuno y la falta de sueño son los mayormente asociados. Los desencadenantes de la migraña no forman parte de los criterios diagnósticos, pero pueden caracterizar subgrupos de pacientes. La deficiente habituación a los estímulos visuales repetidos es una característica neurofisiológica comúnmente encontrada en las cohortes de migraña, sin embargo, no se puede demostrar en todos los pacientes y no se ha reproducido en todos los estudios. Se puede suponer que los pacientes con diferentes perfiles de habituación pueden diferir por rasgos fenotípicos, como los desencadenantes de las crisis. Por ello nos propusimos estudiar qué asociación existe entre los desencadenantes del ataque de migraña y la habituación de los potenciales evocados visuales (PEV). (AU)

Identifying specific subsets of patients within the widespread clinical spectrum of migraine could help in developing a beneficial migraine treatment approach. The possibility of such categorization combining clinical features with accessible para-clinical tests remains quasi unexplored. Migraine attacks can be triggered by different factors, among which stress, hormonal changes, fasting, and lack of sleep are the most frequently referenced.1 Migraine triggers are not part of the diagnostic criteria for migraine, but they may characterize subgroups of patients. Also, deficient habituation to repeated stimulations is a neurophysiological feature commonly found in migraine cohorts, however it cannot be demonstrated in all patients and has not been reproduced in all studies. One may thus assume that patients with different habituation profiles might differ by phenotypic features, such as attack triggers. Therefore, we analyzed the visual evoked potentials habituation (VEP)4 profile in relation to the report of migraine triggers during a head-to-head, semi-structured interview, which preceded the neurophysiological recordings. (AU)

Persistence with denosumab therapy in women affected by osteoporosis with fragility fractures: a multicenter observational real practice study in Italy.

BACKGROUND: Persistence is commonly considered a key factor for the successful management of osteoporosis and fragility fractures. Denosumab is the first biologic agent developed for the treatment of osteoporosis with satisfying data regarding the persistence with this therapy. AIM: The purpose of this multicenter observational real practice study was to evaluate the persistence with denosumab treatment in post-menopausal women affected by osteoporosis. MATERIAL/SUBJECTS AND METHODS: Women were recruited in four specialized centers for the management of osteoporosis in North, Center and South of Italy. We included women with a diagnosis of post-menopausal osteoporosis, aged >50 years, able to obtain a prescription according to the Italian reimbursement criteria in force during the study period for anti-osteoporotic pharmacological treatment. They initiated a treatment with subcutaneous denosumab (Prolia®) 60 mg/every 6 months between November 2011 and May 2016. Women who had received aromatase inhibitors were excluded. Patients were assessed at baseline and every 6 months for all treatment length. Persistence data were evaluated for a total of 36 months. RESULTS: Eight hundred seventy women were enrolled; mean aged 70 years, with a mean body mass index of 24.8 ± 4.1 kg/m2. At the Dual-energy X-ray absorptiometry assessment, the mean lumbar spine T-score was -2.76 ± 1.14 standard deviations (SD) and the mean femoral neck T-score was -2.49 ± 0.80 SD. During the study, the total persistence was 91.4%. Total dropouts were 75 (8.6%), higher within the initial 6-month period of treatment. CONCLUSIONS: Persistence to denosumab treatment in our observational real practice study was very high. These results suggest that factors such as frequency of visits, pharmacological schedule, and opportunity to call the doctor might play an important role in the persistence and adherence to treatment to obtain maximum therapeutic effect and avoid further fragility fractures.

Bone damage in type 2 diabetes mellitus.

This review focuses on the mechanisms determining bone fragility in patients with type 2 diabetes mellitus (T2DM). Despite bone mineral density (BMD) is usually normal or more often increased in these patients, fracture incidence is high, probably because of altered bone "quality". The latter seems to depend on several, only partly elucidated, mechanisms, such as the increased skeletal content of advanced glycation end-products causing collagen deterioration, the altered differentiation of bone osteogenic cells, the altered bone turnover and micro-architecture. Disease duration, its severity and metabolic control, the type of therapy, the presence or absence of complications, as like as the other known predictors for falls, are all relevant contributing factors affecting fracture risk in T2DM. In these patients the estimate of fracture risk in the everyday clinical practice may be challenging, due to the lower predictive capacity of both BMD and risk factors-based algorithms (e.g. FRAX).

Effect of a single oral dose of 600,000 IU of cholecalciferol on muscle strength: a study in young women.

BACKGROUND: The effect of a single large oral dose of vitamin D on muscle function in young people with vitamin D deficiency has not been investigated so far. AIM: We evaluated the effect of a single oral dose of 600,000 IU of cholecalciferol on muscle strength. SUBJECTS AND METHODS: Eighteen young women with vitamin D deficiency received a single oral dose of 600,000 IU of cholecalciferol. We evaluated changes in maximal voluntary contraction (MVC) and speed of contraction (S) in response to cholecalciferol by using an hand held dynamometer at 3, 15, 30, 60 and 90 days, compared to baseline. RESULTS: We observed no significant change in MVC and S values, a significant increase of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and a significant decrease in serum parathyroid hormone (PTH) (p<0.001 for all). A significant correlation was found between MVC and S and serum phosphorus (P) after supplementation (p<0.02 and p<0.05, respectively). Conversely, we observed no association between the parameters of muscle strength and 25(OH)D, ionized calcium (Ca2+), PTH and 1,25(OH)2D. CONCLUSIONS: A single dose of 600,000 IU of cholecalciferol does not directly enhance handgrip strength in young women with vitamin D deficiency. More studies are needed on the indirect effect of the hormone on muscle.

Effect of gender and geographic location on the expression of primary hyperparathyroidism.

BACKGROUND: The effect of gender on the expression of primary hyperparathyroidism (PHPT) is not well characterized. AIM: We therefore evaluated two Caucasian populations (US and Italian) of men and women with PHPT, matched for age and body mass index (BMI), in a cross-sectional retrospective observational study. METHODS: We studied 74 US (23 men) and 126 Italian (42 men) patients evaluating main biochemical indices of the disease and bone mineral density (BMD) at the spine and proximal femur. RESULTS: Mean serum calcium levels were higher both in Italian men compared to women (11.7 ± 1.22 mg/dl and 11.1 ± 0.83, p<0.01) and in Italian compared to US patients (11.3 ± 1.01 and 10.8 ± 0.58, p<0.001), with similar results for the serum ionized calcium. Mean serum PTH levels were not different either between the genders or between the countries. After controlling for BMI, the mean BMD at both the femoral neck and total hip in females US patients was significantly higher compared with Italian female patients. CONCLUSION: Despite similar levels of circulating PTH, Italian patients have more pronounced effects of the disease as assessed by serum calcium and a more significant cortical involvement in women as assessed by BMD.

Transradial approach in the catheterization laboratory: pros/cons and suggestions for successful implementation.

In the last decade the radial access use in the catheterization laboratory has sensibly grown up worldwide. From an initial sporadic use as alternative but challenging vascular approach, radial artery is today utilized by default for percutaneous procedures in many centers. The tangible interest in the transradial approach is also testified by increasing presence of specific sessions in the main interventional meetings and by continuous development of dedicated catheters and ancillary devices by manufacturers. In this review we describe the anatomical characteristics and the technical aspects related to transradial procedure underlying its pros/cons in opposition to femoral access. We also point up practical instructions trying to resolve the main concerns related to an extensive use of radial approach in catheterization laboratory, such as increased operator's discomfort, higher radiation exposure, safety and feasibility for complex high-risk procedures.

Chronic constipation in hypercalcemic patients with primary hyperparathyroidism.

BACKGROUND: Chronic constipation (C), among gastrointestinal symptoms, is commonly associated with primary hyperparathyroidism (PHPT) and probably attributable to hypercalcemia. OBJECTIVE OF THE STUDY: To evaluate in patients affected with PHPT the prevalence of C utilizing a validated questionnaire and the current prevalence of C compared to that observed in the past and to evaluate the relationship between C and the severity of PHPT. METHODS: 55 outpatients affected with PHPT, admitted to our Department of Internal Medicine and Medical Specialities in the years (2006-2009) were studied (group 1: 50 postmenopausal women and 5 men, mean age 61.9 +/- 9.4 years), together with 55 sex and age matched controls (group 2). Also considered were a group of PHPT patients observed, in the same ambulatory, during the years '70-'80 (group 3). A questionnaire, Rome II criteria, was administered and used to define C, whereas only anamneses were used to define C in group 3. RESULTS: The prevalence of C in patients with PHPT was 21.8% in group 1 vs 12.7% in group 2 (n.s.) and 32.7% in group 3. There is a decreasing trend in the prevalence of C in patients with PHPT as observed from 1970-89 to 2006-2009 (p < 0.05). The reduction of C was associated together with a significant reduction in the serum calcium level (p < 0.001). The presence of C vs its absence in patients with PHPT is characterized by higher values of calcemia (p < 0.001), ionized calcium (p < 0.001), and parathyroid hormone (p = 0.019). CONCLUSION: The actual prevalence of C in patients with PHPT is not significantly different from that found in the control group and is decreasing with respect to the past years. Moreover, C seems to be associated with the severity of the disease rather than with the diagnosis of PHPT per se.

Serum sclerostin levels decline in post-menopausal women with osteoporosis following treatment with intermittent parathyroid hormone.

OBJECTIVE: This study was carried out in order to evaluate the effect of 18-month treatment with PTH (1-34) or PTH (1-84) on serum sclerostin levels in humans. SUBJECTS AND METHODS: We investigated 10 women with severe osteoporosis, previously treated with alendronate and 20 untreated osteoporotic women. Subjects with severe osteoporosis were randomly divided into 2 groups of 5 patients each; the first group was treated with 20 µg of PTH (1-34) and the second one with 100 µg of PTH (1-84) according to an open-label design. Fasting blood samples were collected at baseline and at 2, 4, and 24 h after hormone administration. The same protocol was followed at month 1, 6, 12, 18. Serum sclerostin levels were measured at each time point by a sandwich-type enzyme-linked immunosorbent assay. RESULTS: Basal serum sclerostin levels were not significantly different between patients previously treated with alendronate and those never treated. No significant acute change of serum sclerostin levels was observed after PTH administration. Fitting a mixed effect regression model, we found a significant time effect (p=0.0012) using the sclerostin level as the response variable and the month of drug administration as a single covariate. Treatment with both PTH molecules induced a monthly mean reduction of sclerostin levels of 0.1956 pmol/l. CONCLUSIONS: Our results indicate that long-term therapy with PTH (1-34) or PTH (1-84) in women with osteoporosis previously treated with alendronate is associated with a reduction in circulating sclerostin levels. This is a putative mechanism through which PTH performs its anabolic action.

Vertebral morphometry by dual-energy X-ray absorptiometry (DXA) for osteoporotic vertebral fractures assessment (VFA).

PURPOSE: This study was done to evaluate the diagnostic accuracy of dual-energy X-ray absorptiometry (DXA) compared with conventional radiography for identifying vertebral fractures. MATERIALS AND METHODS: A total of 930 postmenopausal women underwent conventional radiography and DXA imaging of the spine. The images were evaluated by two expert skeletal radiologists using the semiquantitative (SQ) method for conventional radiography and the morphometric vertebral fracture assessment (VFA) for DXA. RESULTS: The SQ method for radiography (SQ-Rx) analysed 99.1% of vertebrae, identifying 442 vertebral fractures; VFA analysed 97.5% vertebrae, detecting 420 vertebral fractures. Agreement between SQ-Rx and VFA reached 98.76%, and the κ-score was 0.96 [95% confidence interval (CI), 0.95-0.98]. Assessing the grading of vertebral fractures, agreement reached 97.5% and the κ-score was 0.841 (95% CI, 0.821-0.891). Considering SQ-Rx method as "gold standard", VFA had a sensitivity of 97.85 % and a specificity of 99.81%. The negative (NPV) and positive (PPV) predictive value for VFA were 99.83 % and 98.15%, respectively. Fractures were identified in 251 (27 %) and 242 (26 %) of patients on SQ-Rx and VFA, respectively. On a per-patient basis, the agreement between the two methods was 97% and the κ-score was 0.95 (95% CI, 0.920-0.968). The diagnostic parameters for VFA were 97.23% sensitivity, 98.86% specificity, 97.60% PPV and 98.84% NPV. CONCLUSIONS: This study demonstrated that VFA with DXA may reach a high level of accuracy for diagnosing vertebral fractures, suggesting that VFA should be introduced in the screening of individuals with a risk of osteoporosis and in the follow-up of osteoporotic patients receiving treatment.

Sporadic and hereditary primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, particularly frequent in post-menopausal women. It is characterized by hypercalcemia with inappropriately high spontaneous plasma PTH. Singlegland adenoma is the most common cause (75- 85%). PHPT is usually a sporadic disease but in approximately <5% of cases, a familial hyperparathyroid syndrome is diagnosed. Familial hyperparathyroidism is a clinically and genetically heterogeneous group of disorders including: multiple endocrine neoplasia (MEN) type 1, MEN type 2A, MEN4, benign familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, hyperparathyroidism-jaw tumor syndrome, and familial isolated hyperparathyroidism. These syndromes show mendelian inheritance patterns and the main genes for most of them have been defined. The classic form of PHPT, which presents with hypercalcemia, kidney stones, and bone disease, is no longer common. Currently, there is an increasing interest in the subtle manifestations of PHPT, particularly the cardiovascular and neuropsychiatric manifestations. Parathyroidectomy is the definitive cure for PHPT even though patients with the asymptomatic form of the disease can be followed conservatively.

[Guidelines on prevention and treatment of vitamin D deficiency. Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS)]. / Linee guida su prevenzione e trattamento dell'ipovitaminosi D con colecalciferolo. SIOMMMS.

The Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS) has elaborated the following guidelines about the definition, prevention and treatment of inadequate vitamin D status. The highlights are presented here. Daily vitamin D allowance ranges from 1,500 IU (healthy adults) to 2,300 IU (elderly with low calcium intake). Since the average Italian diet includes around 300 IU/day, subjects with no effective sun exposure should be supplemented with 1,200-2,000 IU vitamin D per day. The serum 25-hydroxy-vitamin D [25(OH)D] levels represents the most accurate way to assess vitamin D repletion, even though there are still no standardized assay methods. Conditions of "deficiency" and "insufficiency" are defined by the following ranges of 25(OH)D levels: less than 20 ng/ml and 20-30 ng/ml, respectively. In Italy, approximately 50% of young healthy subjects have vitamin D insufficiency during the winter months. The prevalence of deficiency increases with ageing, affecting almost all elderly subjects not on vitamin D supplements. When a condition of deficiency has been identified, a cumulative dose of 300,000-1,000,000 IU, over 1-4 weeks is recommended. In subjects recently treated for deficiency-insufficiency, a maintenance dose of 800-2,000 IU/day (or weekly equivalent) is recommended. In patients on daily doses over 1,000 IU, 25(OH)D levels should be checked regularly (e.g. once every two years). The highest tolerated daily dose has been identified as 4,000 IU/day. Vitamin D supplementation should be carefully monitored in patients at higher risk of vitamin D intoxication (granulomatosis) or with primary hyperparathyroidism. In pregnant women, vitamin D supplements should be given as in non-pregnant women, but bolus administration (i.e.: single dose >25,000 IU) should be avoided.

Relationship between bone metabolism and adipogenesis.

Several findings indicate that adipose tissue and bone have a complex reciprocal relationship. The two cells lineages share a common progenitor, and adipocyte endocrine activity may influence bone metabolism. Recent evidence from animal models suggests that bone cells may contribute regulating energy metabolism.

EuroSCORE as predictor of in-hospital mortality after percutaneous coronary intervention.

OBJECTIVE: To date, no common risk stratification system is available to predict the risk of surgical or percutaneous myocardial revascularisation in patients with coronary artery disease (CAD). Thus, we sought to assess the European System for Cardiac Operative Risk Evaluation (EuroSCORE) validity to predict in-hospital mortality after percutaneous coronary intervention (PCI). DESIGN, SETTING AND PARTICIPANTS: EuroSCORE was prospectively and systematically assessed in 1173 consecutive patients undergoing PCI in a high-volume single centre between April 2005 and October 2006. MAIN OUTCOME MEASURE: The receiver-operating characteristics (ROC) curve was used to describe performance and accuracy of the EuroSCORE risk model for the prediction of in-hospital mortality after PCI. RESULTS: The EuroSCORE model demonstrated an overall relation between EuroSCORE rank and the incidence of in-hospital mortality, showing consistency in predicting patient risk across many subgroups and levels of global risk. At multivariable logistic regression analysis the EuroSCORE value was an independent in-hospital mortality predictor (p = 0.002) together with left main disease (p = 0.005), procedural urgency (p = 0.001), ACC/AHA C type lesion (p = 0.02) and PCI failure (p = 0.01). The area under the ROC curve for the EuroSCORE system was 0.91 (95% CI 0.86 to 0.97), indicating a good ability of the model to discriminate patients at risk of dying during the index hospitalisation. CONCLUSION: The EuroSCORE risk model, already extensively validated for the prediction of early mortality following open-heart surgery, can also be efficiently utilised in the setting of PCI. The introduction of the EuroSCORE assessment in patients with documented CAD may help to improve the revascularisation strategy decision-making process.