The bone anabolic therapy.

Teriparatide (TPTD), the amino-terminal parathyroid hormone recombinant peptide [PTH (1­34)], is a drug with a proven anabolic action on the bone, effective in preventing vertebral and non-vertebral fragility fractures. Recent publications have investigated in great detail the TPTD action on the cortical bone, highlighting the increased strength in the critical zone of the hip with high risk of fracture in osteoporotic patients Poole (PLoS ONE 6:e16190, 2011). In November 2002, TPTD was approved by the FDA for use in post-menopausal women and men with osteoporosis at high risk of fracture and in patients with glucocorticoid-induced osteoporosis and, since then, has been used to treat more than 1 million patients worldwide (J Bone Miner Res 27(12):2429-2437, 2012). The unchanged safety profile and the well-known mechanism of action of this drug have led doctors to explore the use of TPTD in other conditions such as delayed fracture healing, non-union, osteonecrosis of the jaw, etc. The positive reports that have resulted from these studies are helping to hypothesize a new perspective on the wider use of this drug, but warrant further clinical investigation to consolidate these results.

Factor analysis of metabolic syndrome components in severely obese girls and boys.

AIMS AND METHODS: Factor analysis is a multivariate correlation technique frequently employed to characterise the aggregation of abnormalities underlying the metabolic syndrome (MS), but scarcely used in obese adolescents. Aim of the study was to investigate the clustering of anthropometric and metabolic variables related to the MS in 487 obese pubertal adolescents (140 boys, 347 girls) in the range of age 11-18 yr employing the factor analysis with exploratory approach. RESULTS: Principal component analysis reduced 11 correlated physiological variables to 4 uncorrelated factors that explained 68.7% of the variance in the original parameters in boys, and 68.4% in girls. In boys, these factors were: obesity/ hypertension, insulin resistance, dyslipidemia, and hyperglycemia, with elements related to obesity and fat distribution loaded also in dyslipidemia and insulin resistance. In girls no commonalities were detected, but elements of dyslipidemia and insulin resistance were loaded in a single factor, whereas elements of obesity and hypertension were loaded in separate factors. CONCLUSIONS: The identification of 4 independent factors suggests a multiple physiological origin of the MS also in youngsters. The measures of adiposity were correlated with development of hypertension, insulin resistance, and dyslipidemic phenomena in boys only, whereas in girls anthropometric measures were not correlated with any tested component of the MS, possibly disclosing the protective effect of female sex hormones in the juvenile age span.

Prevalence and risk factors of metabolic syndrome in Brazilian and Italian obese adolescents: a comparison study.

BACKGROUND: Metabolic syndrome (MS) prevalence between different populations in obese adolescents is scanty to date. OBJECTIVE: To compare the MS prevalence and related risk factors in Brazilian and Italian obese adolescents. METHODS: A total of 509 adolescents (110 Brazilian, 399 Italian), aged 15-19 years. Anthropometric characteristics, triglycerides (TG), total, low-density lipoprotein (LDL)-, high-density lipoprotein (HDL)-cholesterol, fasting plasma glucose (FPG), insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and blood pressure were measured. RESULTS: Age, body mass index (BMI) and BMI z-score were not significantly different between the two subgroups. BMI z-score, TG, FPG, HOMA-IR and systolic blood pressure (SBP) were significantly higher in boys than in girls both in Brazilian and Italian adolescents, while HDL-cholesterol levels were lower in boys than in girls. No significant differences were observed in BMI, LDL and total-cholesterol and DBP in two genders and groups. Insulin, FPG, HOMA-IR and TG were significantly higher, while LDL-cholesterol and SBP were significantly lower in Brazilian than in Italian subjects, both in males and females. HDL and total-cholesterol and diastolic blood pressure (DBP) were not significantly different between the two subgroups and genders. MS prevalence was higher in Brazilian than in Italian obese boys (34.8 vs. 23.6%, p < 0.001) and girls (15.6 vs. 12.5%, p < 0.01). The most frequently altered parameter was HOMA-IR both in subjects with MS (100% in Brazilian and 81.8% in Italian) and without MS (42.9% and 11.7%). CONCLUSION: Metabolic syndrome represents a worldwide emerging health problem in different ethnical populations, the alterations of the risk factors related to MS (different in their prevalence between different subgroups) being strictly linked to the degree of obesity.

Endocrine arterial hypertension: diagnostic approach in clinical practice.

Endocrine arterial hypertension (EAH) a condition in which hormone excess results in clinically significant hypertension is a rare cause of hypertension. However in the last years its prevalence has increased, mostly due to the improvement of diagnostic work-up. In clinical practice, hypertensive subjects with suspicion of EAH currently undergo hormonal screening of the renin-aldosterone and catecholamines and glucocorticoids excess. This paper reviews current understanding for earlier recognition of the main forms of EAH and discusses screening laboratory methods and localization techniques that have enhanced the clinician's ability to make the diagnosis of EAH. Primary aldosteronism (PA) has recently been recognised as the most frequent cause of EAH. The aldosterone to renin ratio (ARR) is a highly recommended screening test for PA. When ARR is increased, confirmatory tests as saline infusion or fludrocortisone suppression are required. Differential diagnosis of PA requires adrenal gland imaging by computed tomography (CT) or magnetic resonance imaging (MRI), biochemical testing of the aldosterone response to posture, and selective adrenal venous sampling to differentiate unilateral aldosterone-producing adenoma from bilateral hyperplasia. Hypertension is frequently found in endogenous Cushing's Syndrome (CS). Twenty-four-hour urinary free cortisol measurement is the gold standard for the diagnosis of CS, but it must be confirmed by the overnight dexamethasone suppression test. CT and MRI are the primary imaging studies to perform, while scintigraphy is a useful confirmatory method. The most specific and sensitive diagnostic test for catecholamine-producing neoplasms is determination of urinary metanephrine levels; the neoplasms can be located by CT, MRI and metaiodo-benzylguanidine scintigraphy.

Pulse hypertension: a new component of the metabolic syndrome in elderly women?

The classification of arterial hypertension (HT) to define metabolic syndrome (MS) is unclear in that different cutoffs of blood pressure (BP) have been proposed. We evaluated the categorization of HT most qualified to define MS in relationship with coronary heart disease (CHD) mortality at a population level. A total of 3257 subjects aged > or =65 years were followed up for 12 years. MS was defined according to the criteria of the National Education Cholesterol Program using three different categories of HT: MS-1 (systolic blood pressure (SBP) > or =130 and diastolic blood pressure (DBP) > or =85 mm Hg), MS-2 (SBP > or =130 or DBP > or =85 mm Hg) and MS-3 (pulse pressure (PP) > or =75 mm Hg in men and > or =80 mm Hg in women). Gender-specific adjusted hazard ratio (HR) with 95% confidence intervals (CI) for CHD mortality was derived from Cox analysis in the three MS groups, both including and excluding antihypertensive treatment. In women with MS untreated for HT, the risk of CHD mortality was always significantly higher than in those without MS, independent of categorization; the HR of MS was 1.73 (CI 1.12-2.67) using MS-1, 1.75 (CI 1.10-2.83) using MS-2 and 2.39 (CI 3.71-1.31) using MS-3. In women with MS treated for HT, the HR of CHD mortality was significantly increased only in the MS-3 group (1.92, CI 1.1-2.88). MS did not predict CHD in men. In conclusion, MS can predict CHD mortality in elderly women with untreated HT but not in those with treated HT; in the latter, PP is the most predictive BP value.

Apoptosis in the skeletal muscle of patients with heart failure: investigation of clinical and biochemical changes.

OBJECTIVE: To investigate the contribution of apoptosis in the development of the skeletal myopathy in chronic heart failure. DESIGN: The electrophoretic pattern of myosin heavy chains (MHC), fibre cross sectional area, number of in situ nick end labelling (TUNEL) positive apoptotic myocyte nuclei, and the tissue levels of caspase-3, Bcl-2, and ubiquitin were determined in biopsies taken from the vastus lateralis muscle. The study involved nine patients with severe chronic heart failure caused by ischaemic heart disease and hibernating myocardium and five controls. RESULTS: In chronic heart failure patients the vastus lateralis showed a significant increase of MHC(2a) and MHC(2b) and a greater degree of fibre atrophy, as demonstrated by the decreased cross sectional area. There was also an increased number of TUNEL positive apoptotic myocyte nuclei. Tissue concentrations of Bcl-2 were decreased, while those of caspase-3 and ubiquitin were increased. Peak oxygen consumption (VO(2)) was negatively correlated with the number of TUNEL positive nuclei and the fibre cross sectional area. There was a correlation between the number of apoptotic nuclei and the fibre cross sectional area, but no correlation between myosin heavy chains and number of apoptotic nuclei. CONCLUSIONS: Myocyte apoptosis occurs in the skeletal muscle of patients with chronic heart failure, and its magnitude is associated with the severity of exercise capacity limitation and the degree of muscle atrophy. Muscle atrophy contributes to the limitation of exercise capacity, together with the increased synthesis of fast, more fatiguable myosin heavy chains.

Correlation between high intake of glycyrrhizin and myolysis of the papillary muscles: an experimental in vivo study.

The ingestion of large quantities of glycyrrhizin, whether as a drug or a sweetener, is known, in susceptible subjects, to induce a syndrome similar to hypermineralcorticoidism, with bouts of hypertension, hypokaliaemia and rabdomyolysis, sometimes associated with severe renal failure and hypokaliaemia-induced arrythmias. Glycyrrhizin is also known to isomerize into the glycyrrhetic (or glycyrrhetinic) acids 18alpha- and 18beta-. In previous works, we reported that these metabolites cause bouts of hypertension and reduction in diuresis at low doses in the rat. In particular, the alpha isomer causes significant elimination of the calcium ion in the urine. The present findings confirm that 18alpha-glycyrrhetic acid is more toxic than either glycyrrhizin or the beta isomer. Histopathological study of tissue samples taken from rats treated with the alpha isomer also reveal selective damage to the myocardium with oedema, myolysis, apoptosis and blistering of the sarcoplasm. These effects begin to appear in the course of subchronic treatment, they manifest themselves in acute treatment and correlate closely with the electrocardiographic changes recorded in rats acutely treated with 18alpha-glycyrrhetic acid.

Apoptosis and atrophy in rat slow skeletal muscles in chronic heart failure.

Congestive heart failure is characterized by a skeletal muscle myopathy with muscle bulk loss. The mechanisms responsible for these changes are not clear at present. We have investigated the role of apoptosis in the rat "slow" soleus muscle during the development of heart failure, which was induced by injection of monocrotaline (30 mg/kg). We looked at the time course of apoptosis by studying six animals at each of the following time points: 0, 17, 24, and 30 days. We found a decreased expression of the antiapoptotic protein Bcl-2, which was accompanied by a rise of proapoptotic caspase-3. Ubiquitin levels did not change. DNA nick-end labeling showed an increased number of apoptotic nuclei both in myofibers and interstitial cells when heart failure occurred. At variance with previous observations in the fast-twitch tibialis anterior muscle in the same animals, in which tumor necrosis factor-alpha (TNF-alpha) increased at the time that apoptosis occurred, the magnitude of apoptosis is lower in soleus muscle and there is no appearance of muscle atrophy. In soleus muscle, apoptosis is accompanied by activation of the caspase-3 system. There is no activation of the TNF-alpha- and ubiquitin-dependent protein waste. In conclusion, slow muscles are less prone to develop apoptosis than fast muscles. Muscle atrophy appears earlier in these latter ones.

Apoptosis of skeletal muscle myofibers and interstitial cells in experimental heart failure.

UNLABELLED: Congestive heart failure (CHF) is characterized by a limb skeletal muscle myopathy with shift from the slow aerobic, fatigue resistant fibers, to the fast, anaerobic ones, and muscle bulk loss. Apoptosis (A) has been recently demonstrated to play a role in several cardiovascular diseases. AIM OF THE STUDY: we have investigated the role of A in the skeletal muscle of the hindlimbs in an experimental model of CHF. ANIMALS AND METHODS: CHF was induced in 7 males 80-100 g Sprague-Dawley rats with 30 mg/kg monocrotaline. Five age and diet matched controls were also studied. The time course of A was also studied in additional animals at day 0, 17, 24 and 30 days. RESULTS: At day 27 the electrophoretic analysis of myosin heavy chains (MHCs) demonstrated in the CHF rats the occurrence of a myopathy, with disappearance of slow MHC1 in the Tibialis Anterior (TA), and a significant shift from the slow to the fast isoforms in the soleus and EDL. With in situ DNA nick-end labelling (TUNEL) we found in the TA of CHF animals a significantly higher number of TUNEL positive nuclei (0.43 +/- 0.24 v 0.08 +/- 0.02, P<0.02 and TUNEL positive myonuclei (0.031 +/- 0.012 v 0.0025 +/- 0.005, P<0.02). The time course of A showed a progressive rise in interstitial and myocyte A, accompanied by a drop in fibers cross-sectional area and muscle weight/body weight, that came out to be significant at 30 days. Western blot showed a lower expression of Bcl-2 at 27 days and a further drop at 30 days in the CHF rats. Double staining for TUNEL and antibody against anti-MHC2a and anti MHC2b + 2x showed that A occurs non-selectively in all the myofiber types. BetaANP and Right Ventricle Mass/Volume (RVM/V) correlated significantly with total apoptotic nuclei. CONCLUSIONS: In CHF myofibers A can lead to muscle atrophy. Endothelial cells A may produce an imbalance in myofibres nutrition with relative ischemia that triggers the preferential synthesis of fast anaerobic myosin as an adaptive mechanism or alternatively induce myofibres death.

[Myosin isoforms in skeletal muscle in patients with chronic heart decompensation: distribution and correlation with with exercise tolerance]. / Le isoforme miosiniche nel muscolo scheletrico del paziente con scompenso cronico di cuore: distribuzione e correlazione con la tolleranza allo sforzo.

Chronic heart failure (CHF) is accompanied by a reduced exercise capacity, and the symptoms can be at least in part explained by qualitative and quantitative changes in the skeletal muscle composition and metabolism. We have correlated the myosin heavy chain (MHC) composition of the gastrocnemius in 20 patients with different degrees of CHF to expiratory gases measured during maximal cardiopulmonary exercise testing, NYHA functional class and echocardiographic parameters. MHC composition was determined electrophoretically in skeletal muscle needle microbiopsies and the percent distribution calculated by laser densitometry. There was no correlation between ejection fraction, left ventricular end-diastolic and end-systolic diameters and MHC composition. The percentage of MHC 1 (slow aerobic isoform) was positively correlated with peak VO2 (r2 = 0.5, p = 0.0004), ventilatory threshold (VT, r2 = 0.33, p = 0.008), and O2 pulse (peak VO2/HR, r2 = 0.40, p = 0.003). There was a negative correlation between MHC 2a and 2b (fast isoforms) and peak VO2 (r2 = 0.38 and 0.37, p = 0.004, respectively), VT (r2 = 0.2, p = 0.05; r2 = 0.34, p = 0.007, respectively) and O2 pulse (r2 = 0.39, p = 0.003; r2 = 0.23, p = 0.03, respectively). NYHA functional class was also negatively correlated with the same parameters (r2 = 0.2, p = 0.01; r2 = 0.4, p = 0.001; r2 = 0.34, p = 0.006, respectively) as well as with MHC 1 (r2 = 0.62, p = 0.0001). A positive correlation was found between NYHA functional class and MHC 2a and 2b (r2 = 0.46, p = 0.001; r2 = 0.41, p = 0.002, respectively). The severity of heart failure is paralleled by a shift of the MHC pattern toward the fast MHC 2b. The correlation between the magnitude of the MHCs shift, from the slow aerobic to the fast type, with both clinical parameters (NYHA functional class) and functional measurements (peak VO2, VT, O2 pulse) of exercise capacity seem to suggest that changes in skeletal muscle composition may play a key role in exercise tolerance in patients with CHF.

[Normalization of the prolactin values during alfa-interferon therapy: the considerations with a female patient with anti-HCV-positive chronic hepatitis and prolactin-secreting hypophyseal microadenoma]. / Normalizzazione dei valori di prolattina in corso di terapia con alfa-interferon: considerazioni su una paziente affetta da epatite cronica anti-HCV positiva e microadenoma ipofisario prolattino-secernente.

We report the case of a 45-year-old woman suffering from anti-hepatitis C virus (HCV) positive chronic active hepatitis and amenorrhea-galactorrhea syndrome due to a prolactin-secreting pituitary microadenoma. She was repeatedly given alpha-interferon for hepatitis, and a concomitant normalization of plasma prolactin levels, with disappearance of the related symptoms, was observed during the treatment. Further experience is needed in order to verify the therapeutical effectiveness of alpha-interferon on prolactin-secreting tumors.

[Treatment of diastolic dysfunction of the left ventricle]. / La terapia della disfunzione diastolica del ventricolo sinistro.

Numerous studies have already recognized the importance of diastole in the pathogenesis of congestive heart failure. Non-invasive evaluations are based particularly on echo-Doppler, on radionuclide angiography and on cine-nuclear magnetic resonance: they have enabled an accurate evaluation of diastolic function and dysfunction, although invasive hemodynamic study maintains a gold standard position. All these methods of study have consented the identification of 3 basic components (anatomic and functional): active relaxation, passive elastic relaxation, atrial function. The Authors have identified the causes of diastolic failure with a particular attention to the various components of diastole. They have analyzed the implication of therapy on the basis of a clear understanding of the etiology, pathogenesis and pathophysiology of the underlying cardiac disease.

[Acute hemodynamic effects of nicardipine in patients with chronic congestive heart failure]. / Effetti emodinamici acuti della nicardipina in pazienti affetti da insufficienza cardiaca congestizia cronica.

We evaluated haemodynamic parameters in 13 patients suffering from chronic heart failure (CHF) in III and IV NYHA class. They were 10 males and 3 females, average age 57 +/- 11 years. Haemodynamic monitoring was made at basal condition and for 40 min after the administration of nicardipine (10 mg iv). We observed that mean arterial pressure and systemic vascular resistances (SVR) showed an important decrease (respectively -10.8%, p less than 0.001 and -22%, p less than 0.001); total pulmonary resistances (TPR) also decreased (-16.6%, p less than 0.001), while mean pulmonary pressure did not show significant reduction. Cardiac index increased with the highest value at the fifteenth minute (-11.7%, p less than 0.01). Pulmonary wedge pressure (PWP) did not show statistic variations, and heart rate too. Cardiac index (CI) did not rise in 3 patients with clinical worsening during the monitoring (patients non responders) (CI increase was less than 15%); while in 10 patients CI increased more than 15% (patients responders). Patients non responders did not show any decrease of TPR and only a transitory reduction of SVR; patients responders showed an important decrease of TPR, SVR, PWP. We observed that at baseline, the difference between the 2 groups was based on the value of TPR and PWP. We conclude that nicardipine is an efficient drug in patients affected by CHF without severe hemodynamic failure.