From microvasculature to fibroblasts: Contribution of anti-endothelial cell antibodies in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and internal organ fibrosis, caused by microvascular dysfunction. In recent years, the hypothesis that anti-endothelial cell antibodies (AECA) play a key role in microvascular damage seems to be increasingly convincing. In fact, AECA can induce antibody-dependent cellular apoptosis and stimulate the microvasculature to release pro-inflammatory and pro-fibrotic cytokines. Human-microvascular-endothelial-cells (MVECs) were stimulated with SSc sera (with and without AECA) and with sera from healthy donors. The conditioned MVEC culture media were then added to fibroblast cultures obtained from control skin (CTR), non-affected skin of SSc patients (NA), and affected skin of the same sclerodermic (SSc) patients, respectively. AECA contributed to the MVEC increased release of endothelin-1 (ET-1) in the culture medium and to MVEC apoptosis. Fibroblast (CTR, NA, and SSc) proliferation was increased after treatment with AECA-positive conditioned media, compared to AECA-negative and control conditioned media. Furthermore, both AECA-positive (in major contribution) and AECA-negative conditioned media were responsible for alpha-smooth-muscle-actin (αSMA) over-expression in all fibroblast cultures, compared to control conditioned media. Fibroblast type I collagen synthesis was upregulated by both SSc conditioned media (with and without AECA). Finally, the synthesis of fibroblast transforming-growth-factor-beta (TGF-ß) was statistically higher in AECA-positive conditioned media, compared to AECA-negative and control conditioned media. These findings support the concept that AECA may mediate the crosstalk between endothelial damage and dermal-fibroblast activation in SSc.

The association of body composition and sex hormones with quantitative ultrasound parameters at the calcaneus and phalanxes in elderly women.

We investigated the associations of body composition and sex hormones with quantitative ultrasound (QUS) parameters carried out at different skeletal sites. In 897 postmenopausal women (64.1 ± 6.6 years) we measured QUS at the calcaneus (stiffness) by Achilles-GE and at phalanxes (amplitude-dependent speed of sound [AD-SOS], bone transmission time [BTT], and ultrasound bone profile index [UBPI]) by Bone Profiler-IGEA. In all subjects we measured fat mass (FM), lean mass (LM), android fat, and gynoid fat by DXA. In all subjects we also assessed serum testosterone (T), estradiol (E(2)), sex-hormone binding globulin, free estrogen index (FEI), free androgen index, 25-hydroxyvitamin D (25OHD), bone alkaline phosphatase (B-ALP), and type I collagen ß carboxy telopeptide. Both E(2) and FEI showed weak but significant correlations with stiffness and QUS parameters at phalanxes. No significant relationships were found between T and QUS. BMI and LM were positively correlated with stiffness (r = 0.14 and r = 0.17, respectively), whereas BMI and FM showed negative correlations with AD-SOS, BTT, and UBPI. 25OHD showed positive relationships with stiffness and QUS at phalanxes. In multivariate models LM and age were associated with stiffness whereas E(2) and age were significant predictors of BTT. AD-SOS was negatively associated with FM, B-ALP, and age but positively with E(2) and 25OHD. In postmenopausal women QUS parameters at the calcaneus and at phalanxes are significantly, but diversely, associated with body composition, sex hormones, 25OHD, and bone turnover markers.

Bone ultrasonography at phalanxes in patients with Rett syndrome: a 3-year longitudinal study.

Osteopenia is a frequent and early complication of Rett syndrome. This study aimed to evaluate the usefulness of Quantitative Ultrasonography (QUS) at phalanxes in the assessment and monitoring of bone status in Rett patients. We studied 109 girls (10.1+/-6.1 years; range 3-25 years) and 101 age-matched controls. Serum calcium (Ca), bone alkaline phosphatase (B-ALP), parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD) and QUS parameters at phalanxes by Bone Profiler-IGEA (amplitude dependent speed of sound: AD-SoS and bone transmission time: BTT) were measured. At baseline both QUS parameters and 25OHD levels were significantly lower in Rett patients than in controls. Serum 25OHD was inversely correlated with serum PTH and BTT Z-score and BTT Z-score was significantly lower (p<0.05) in the girls with a 25OHD serum levels

Changes in bone turnover and in bone mass in women with breast cancer switched from tamoxifen to exemestane.

Recently the third generation aromatase inhibitors have proved their efficacy and tolerability compared with tamoxifen in the adjuvant treatment of women with hormone responsive early breast cancer. However, there is some concern about the possible negative impact of these drugs on bone. The aim of the study was to evaluate the effects of the steroidal aromatase inactivator exemestane on bone turnover markers and on bone mineral density (BMD). Seventy postmenopausal women (62.0+/-8.9 years) with completely resected breast cancer and who were disease-free following 2-3 years on tamoxifen were randomly assigned to continue tamoxifen (n=36) or switch to exemestane (n=34). Sixty-one patients completed the 2-year study period. Bone alkaline phosphatase (B-ALP) and the carboxy-terminal telopeptide of type I collagen (CTX) were measured at baseline and after 3, 6, 9, 12, 18 and 24 months. BMD at lumbar spine (BMD-LS), at femoral neck (BMD-FN), at total hip (BMD-T) and at whole body (BMD-WB) were measured at 6-monthly intervals. Exemestane-treated women showed significant (p<0.01) increases with respect to baseline in both B-ALP and CTX. The difference between the 2 groups reached the statistical significance at month 6 for CTX (p<0.05) and at month 9 for B-ALP (p<0.01). Moreover, the exemestane-treated women showed an early decrease in PTH serum levels (-20.4%, p<0.01 at month 6). In the E group, the percentage changes were -2.37 (p<0.05) BMD-LS, -1.24 (p<0.05) BMD-FN, -1.1 (n.s.) BMD-T, -1.03 (n.s.) BMD-WB at month 12 and -2.99 (p<0.01) BMD-LS, -1.92 (p<0.01) BMD-FN, -2.01 (p<0.05) BMD-T, -1.3 (n.s.) BMD-WB at month 24. The tamoxifen group did not show significant changes in BMD. The differences between the two groups were significant at all skeletal sites except BMD-WB. Our data suggest that switching postmenopausal women from tamoxifen to exemestane causes a marked increase in bone turnover markers with a consequent reduction in BMD. These findings could be due to both the direct effect of exemestane and to the loss of the protective effect of tamoxifen. Therefore, the postmenopausal women switched from tamoxifen to exemestane should be monitored for bone loss especially if other risk factors for osteoporosis are present.

Malignant hypercalcemia in vulvar cancer.

Humoral hypercalcemia of malignancy (HHM) is a common paraneoplastic syndrome, most often associated with squamous cell carcinoma of the lung, esophagus, kidneys and breast, but rarely with vulval cancer. In most patients, HHM is associated with over-production of a peptide analogue of parathormone (parathyroid hormone-related protein, PTHrP). The case of a 70-year-old patient with massive squamous cell epithelioma of the vulva complicated by HHM is reported. To our knowledge, this is the first documented case with high serum concentrations of PTHrP and immunohistochemical confirmation of PTHrP production by neoplastic cells.

Effect of simvastatin treatment on bone mineral density and bone turnover in hypercholesterolemic postmenopausal women: a 1-year longitudinal study.

Although several studies have reported a lower risk of osteoporotic fracture in hypercholesterolemic patients treated with statins, so far longitudinal studies on the effects of statins on bone are lacking. The aim of the present study was to evaluate bone mineral density (BMD) and bone turnover changes induced by 1-year simvastatin treatment on postmenopausal women. Thirty consecutive postmenopausal hypercholesterolemic women (61.2 +/- 4.9 years) were treated for 12 months with 40 mg/day simvastatin and 30 normocholesterolemic age-matched postmenopausal women provided control data. In all subjects, at baseline and at 3-month intervals, serum lipids, calcium, phosphate, total and bone alkaline phosphatase (Bone-ALP), and carboxy-terminal fragment of type I collagen (CTx) were measured in a fasting blood sample. At baseline and after 6 and 12 months BMD was measured at lumbar spine (BMD-LS) and at femur (BMD-Ftot) and at femoral neck (BMD-Fn) by DXA. In the simvastatin-treated group Bone-ALP showed a significant increase (P < 0.05) with respect to baseline from the sixth month, whereas serum CTx showed a weak and nonsignificant increase over the study period. In treated women BMD-LS, BMD-Fn, and BMD-Ftot increased respectively by 1.1, 0.9, and 0.4% at Month 6; and by 2.8, 1.0, and 0.8% at Month 12. In controls BMD-LS, BMD-Fn, and BMD-Ftot at the end of the study period decreased by 1.6, 1.4, and 1.2%, respectively. The difference between controls and simvastatin-treated patients was significant (P < 0.05) for both BMD-LS and BMD-Fn only at Month 12. In conclusion our results, although obtained from a small sample of postmenopausal hypercholesterolemic women, suggest a probable positive effect of simvastatin on bone formation and BMD.

Circulating levels of immunoreactive peptides and steroid hormones in bronchogenic carcinoma.

Plasma levels of immunoreactive parathormone (iPTH), immunoreactive calcitonin (iCT) and prostaglandins (PGE2) were measured by RIA in 115 patients with bronchogenic carcinoma. In 37 of these cases the following hormones were also assayed: adrenocorticotropic hormone (ACTH), cortisol, plasma renin activity (PRA), aldosterone, prolactin, human growth hormone (HGH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH) human chorionic gonadotropin (HCG), progesterone (P), androstenedione (A), testosterone (T), estradiol (E2) and dehydroepiandrosterone sulphate (DHAS). High serum levels of many hormone-like substances and hormones were found and the levels of certain hormones varied in some cases according to the clinical evolution of the disease and the response to therapy.

Acute antihypertensive, diuretic and metabolic effects of etozolin and chlorthalidone.

Etozolin, a new diuretic agent, has shown a dose-dependent diuretic and saluretic effect in both experimental and clinical studies. Etoxolin, when compared to furosemide or thiazides, exerts a similar effect on urinary excretion of water and Na+, but induces a lower urinary K+ and Cl- excretion and a smaller activation of the renin-angiotensin-aldosterone system. Furthermore, the E series of the prostaglandin system seems to play a role in the mechanism of action of the drug. Seven uncomplicated hypertensive patients were included in this double blind, placebo controlled study, according to a latin square design. Each patient received three single oral doses of etozolin (200 mg, 400 mg, 600 mg), of chlorthalidone (25 mg, 50 mg, 75 mg) and one dose of placebo. Etozolin and chlorthalidone caused a similar, dose-dependent antihypertensive and diuretic effect. However, several haemodynamic and metabolic differences were observed between the two drugs. Etozolin, unlike chlorthalidone, caused no increase of heart rate, no decrease of serum K+ levels and a marked rise plasma PGE2. Moreover, etozolin caused a significantly smaller decrease of serum Na levels compared to chlorthalidone, and a significantly lower increase of supine and standing PRA, of plasma aldosterone and of the urinary excretion of Na and K. These results confirm that the acute antihypertensive and diuretic activity of etozolin occur with little involvement of the RAA system and with a significant but still unclear activation of the prostaglandin system.

Evaluation of plasma levels of renin-aldosterone and blood pressure in women over 35 years treated with new oral contraceptives.

Increases in blood pressure and weight are consequences of increased fluid retention following oral contraceptives administration. Hypertension and weight increase are particularly frequent in women over 35 years of age. The aim of the present study was to evaluate the clinical and hormonal effects of a new extra-low dose oral contraceptive [15 microg ethinyl estradiol (EE) and 60 microg gestodene (GSD)] on the renin-aldosterone system in a group of women aged 35-39 years treated for 3 months compared with a formulation containing the same hormones at a higher dose. Eighteen healthy women, age 35-39 years, were divided into two groups. The first group (10 women) used Arianna, Schering, 15 microg EE/60 microg GSD (EE15/GSD60); the second group (8 women) used Fedra, Schering, 20 microg EE/75 microg GSD (EE20/GSD75). Blood samples were obtained before the study and after 3 months of contraceptive use for assay of renin and aldosterone. Blood pressure was also measured on both occasions. No significant changes in plasma renin activity (PRA) or plasma concentrations of aldosterone were observed between the two groups after 3 months of contraceptive use. The mean increase in body weight after 3 months of contraceptive use was 350 +/- 100 g for EE20/GSD75 and 300 +/- 50 g for EE15/GSD60. There was a mean increase of 4 mm Hg for systolic pressure and 2 mm Hg for diastolic pressure in women on EE20/GSD75 and corresponding increases of 3 and 2 mm Hg in women on EE15/GSD60. The changes were not significant in any case. The results of the present study show that the formulations were well tolerated and provided good control of the menstrual cycle in all 18 women. The contraceptive formulations EE20/GSD75 and EE15/GSD60 have no clinical impact on blood pressure, PRA, or aldosterone in this age group.

[Role of aldosterone in essential arterial hypertension complicated by chronic renal insufficiency]. / Ruolo dell'aldosterone nell'ipertensione arteriosa essenziale complicata da insufficienza renale cronica.

The following parameters were studied in a group of patients suffering from essential arterial hypertension complicated by chronic renal insufficiency (CRI), mean age = 64.31 +/- 1.84, with creatinine clearance (CrC) ranging between 30 and 60 ml/min: blood pressure (systolic and diastolic arterial pressure), heart rate, plasmatic renin activity (PRA), plasma levels of aldosterone (ALDO) both in clino- and orthostatism, as well as some metabolic parameters. All parameters were compared with those in a group of age- and sex-matched patients with slight or moderate essential arterial hypertension. Before starting the study all patients completed a wash-out period of one week to annual the effects of other drugs which might interfere with the RAA system. PRA levels were within the norm, whereas plasma levels of ALDO were high both in clino- and orthostatism. ALDO levels were also found to be inversely correlated with those of CrC. From these data it emerges that hyperaldosteronism, as observed in these patients with CRI, is a relatively reliable marker of the extent of CRI and may occur independently of the activation of the RAA system, given that other factors, such as orthostatic stimulation, alterations in the acid-base equilibrium, and the degree of aldosterone hepatic and urinary clearance, contribute to its pathogenesis.

Risk factors for acquiring Helicobacter pylori infection in a group of Tuscan teenagers.

Risk factors for acquiring Helicobacter pylori infection include hygienic, social, and environmental conditions. Some of these conditions usually change over time. We therefore investigated the existence of risk factors in a group of teenagers living in a place with the same environmental characteristics, in which hygienic and crowding conditions have not changed significantly in the last 20 years. A group of 164 students, mostly borne in 1977, attending four different schools, were examined serologically for H. pylori infection and CagA status. The importance of the risk factors for the transmission of the infection were evaluated by the chi2 test. P values <0.05 were considered significant. Twenty-two students (13.4%) were H. pylori seropositive. Students attending teachers' college and high school of arts were infected significantly more often than those attending high school (P = 0.011 and P = 0.012, respectively). Students who smoked and students whose parents had a manual job had an increased risk of acquiring the infection (P = 0.002, and P = 0.036, respectively). Crowding conditions and the presence of domestic animals were close to being statistically significant. Other factors, such as gender, number of bathrooms and bedrooms, sharing the bed with adults as a child, presence of a sexual partner, and a family history of peptic ulcer and gastric cancer, did not increase the risk of infection. The prevalence of seropositivity for CagA was similar in the various risk groups. Manual job of parents and smoking were the most important factors for acquiring H. pylori infection.

[Age-related changes in the renin-angiotensin-aldosterone system and the sympathetic nervous system in patients with essential hypertension]. / Modificazioni del sistema renina-angiotensina-aldosterone e dell'attività simpatica nei pazienti ipertesi essenziali, con il variare dell'età.

The aim of this study was to evaluate age, plasmatic renin activity (PRA), plasma aldosterone levels and the total quantity of urinary catecholamines (TOT. UR. CAT.) in a large population of out-patients suffering from essential arterial hypertension (EAH). A total of 986 patients were examined (540 women and 426 men aged between 15 and 87 years) suffering form slight or moderate EAH (WHO stage 1-2). After a wash-out period of two weeks, systolic and diastolic arterial pressure was measured together with heart rate in clino- and orthostatism. Blood samples were collected to determine PRA and plasma aldosterone, and lastly a 24-hour urine collection was made to measure the total quantity of catecholamines. It emerged that there was a significant increase in systolic pressure, whereas heart rate and PRA diminished significantly when correlated with age; diastolic pressure was also considerably lower, but did not reach statistical significance. Moreover, it was found that there was a significant positive correlation between PRA and TOT. UR. CAT., whereas no correlation was found between age and plasma aldosterone and between blood pressure and the various endocrine parameters examined. These data confirm the changes in the biological, hemodynamic and endocrine profiles observed in elderly hypertensive patients in comparison to young hypertensive patients, and suggests that age may be an important predictive factor of the activity of both the renin-angiotensin and sympathetic nervous system which appear to be closely connected and gradually attenuated by age.

Effects of intravenous zoledronate and ibandronate on carotid intima-media thickness, lipids and FGF-23 in postmenopausal osteoporotic women.

OBJECTIVE: Osteoporosis and atherosclerosis are interconnected entities and share also some pathophysiological mechanisms. Moreover, recent literature data have supported the hypothesis that bisphosphonates (BPs) may have some antiatherogenic actions. This study aimed to evaluate the effects of one year with zoledronate or ibandronate given intravenously on lipid profile and on carotid artery intima-media thickness (CA-IMT). METHODS: Sixty postmenopausal osteoporotic women (mean age: 66.6±7.8years) were randomly assigned to 1-year treatment with zoledronate 5mg i.v. annually or ibandronate 3mg i.v. every 3 months. In all patients at baseline and after 12months we measured CA-IMT, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), 25-hydroxyvitamin D (25OHD), bone alkaline phosphatase (B-ALP), type I collagen ß carboxy telopeptide (ßCTX), osteocalcin (OC), fibroblast growth factor 23 (FGF-23) and sclerostin. RESULTS: The osteoporotic women treated with zoledronate showed a greater reduction in CA-IMT than those treated with ibandronate. HDL-C and HDL-C/LDL-C ratio showed a significant (p<0.01) increase in the 2 groups, whereas, LDL-C showed a reduction in the two groups which, however, reached statistical significance (p<0.05) only in the zoledronate group. FGF-23 serum levels showed a similar and significant decrease in both the women treated with zoledronate and in those treated with ibandronate. At the end of the study period sclerostin serum levels showed a higher increase in the patients treated with zoledronate than in those treated with ibandronate. CONCLUSION: In osteoporotic women both zoledronate and ibandronate given intravenously resulted in an increase in HDL-C/LDL-C ratio and a reduction of CA-IMT which was significant only for zoledronate. Further prospective studies are needed to clarify whether the change in FGF-23 and sclerostin levels is a marker or a potential mechanism of the action of BPs at a vascular level.

The relationship between serum ghrelin and body composition with bone mineral density and QUS parameters in subjects with Rett syndrome.

Several studies have reported that females with Rett's syndrome frequently have marked decreases in bone mineral density (BMD). However, the pathogenesis of impaired bone status in RTT girls remains controversial. This study aimed to investigate whether ghrelin, an orexigenic peptide secreted by the stomach, was associated with body composition parameters, bone mineral density and quantitative ultrasound (QUS) in girls with Rett's syndrome. In 123 Rett girls (13.6±8.2 years) and in 55 similar age range controls we evaluated ghrelin serum levels, 25OHD, quantitative ultrasound parameters at phalanxes by Bone Profiler-IGEA (amplitude dependent speed of sound: AD-SoS and bone transmission time: BTT), total body bone mineral density (BMD-WB) by Hologic QDR 4500. Whole body mineral content (BMC-WB), BMC-WB/height, fat mass (FM), fat percentage and lean mass (LM) were determined by using the same DXA device. We found that serum ghrelin levels were significantly higher in the Rett patients with respect to the control group (p<0.05). In Rett girls ghrelin serum levels were inversely correlated with both age (R(2)=0.17, p<0.001) and BMI (R(2)=0.14, p<0.001). Moreover, in Rett subjects the values of BMD-WB, BMC-WB, BMC-WB/height and QUS parameters were significantly lower than in control subjects. Fat mass and lean mass were lower in Rett subjects than in controls, but the difference reached the statistical significance only for lean mass. In Rett girls ghrelin serum levels were not predictors of bone status. Instead, we found that in Rett subjects, lean mass, age and 25OHD were significant independent predictors of BMC-WB/h, whereas both age and height were independent predictors of BMD-WB. Moreover, AD-SoS was predicted by age, fat percentage and height; while BTT was predicted only by height. In conclusion, our findings indicate that ghrelin levels were higher in Rett girls with respect to healthy controls, and negatively associated with both DXA and QUS parameters. However, in our study ghrelin was not found to be an independent predictor of bone mass, so supporting the hypothesis that ghrelin is elevated in Rett subjects in a compensatory manner.