Role of comprehensive geriatric assessment in low surgical risk older patients with aortic stenosis.

BACKGROUND: Among elderly with severe aortic stenosis (AS), Comprehensive Geriatric Assessment (CGA) originally contributed to address to transcatheter aortic valve implantation (TAVI) patients not suitable to surgical aortic valve replacement(SAVR). Nevertheless, TAVI has recently been proposed also in lower surgical risk patients. AIMS: To evaluate predictors of TAVI procedure and clinical outcomes among these patients. METHODS: For each patient ≥ 65 years with severe AS referring to our Cardiac Surgery Division, CGA was performed, including functional and cognitive status, comorbidity burden, frailty, nutritional status, gait speed, hand-grip strength and number of medications. Surgical risk was evaluated according to the Society of Thoracic Surgeons (STS) score (low-risk < 4%). Post-procedural outcomes (30-day survival and post-procedural complications) were obtained by medical records and a one-year follow-up assessed survival, and functional and cognitive performance. RESULTS: Among 154 subjects (mean age 82.9 years), 52 were at low-risk according to STS score. 32 patients were addressed to TAVI, 20 to SAVR. Variables significantly associated with TAVI-approach were lower gait speed (p 0.030) and higher number of medications (p 0.015). Short and long-term outcomes did not differ between groups. DISCUSSION: Among CGA variables, gait speed and number of medications were associated with the decision to perform TAVI instead of SAVR, even in patients at low surgical risk. 30-day and one-year survival and one-year functional and cognitive decline were similar between groups, despite a relevant prevalence of frailty in the TAVI group. CONCLUSIONS: We suggest that gait speed and number of medications should be considered in selecting appropriate candidates to TAVI among low surgical risk patients.

Direct-acting antivirals in hepatitis C virus (HCV)-infected and HCV/HIV-coinfected patients: real-life safety and efficacy.

OBJECTIVES: Clinical trials of all-oral direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection reported high response rates in HCV/HIV coinfection, similar to those obtained in HCV monoinfection. We evaluated the safety and efficacy of these regimens in a clinical practice setting. METHODS: In this prospective observational study, all the HCV-monoinfected and HCV/HIV-coinfected patients undergoing HCV treatment with all-oral DAA regimens in a routine clinical setting from December 2014 to December 2015 were included in the analysis. Sustained virological response 12 weeks after the end of therapy (SVR12) and reported adverse events (AEs) were evaluated. Resistance-associated variants (RAVs) were analysed in a subgroup of patients at baseline and at the time of viral rebound in those with virological failure. RESULTS: One-hundred and nine patients (51 HCV-infected and 58 HCV/HIV-coinfected) were enrolled in the study. Sixty per cent had cirrhosis and 52% were pegylated interferon and ribavirin (pegIFN/RBV)-experienced. Thirty-six per cent received ombitasvir + paritaprevir/ritonavir + dasabuvir, 25% sofosbuvir + daclatasvir, 16% sofosbuvir + simeprevir, 17% sofosbuvir + ribavirin and 6% sofosbuvir + ledipasvir; ribavirin was used in 57% of subjects. The SVR12 rate was 91% and 96% in HIV-infected and uninfected patients, respectively (P = 0.44). The 4-week HCV viral decline was similar in the two groups. RAVs were found at baseline in 23 of 49 patients and did not affect SVR12. No predictors of SVR12 were identified in our cohort. CONCLUSIONS: Treatment with all-oral DAA combinations of patients infected with HCV and with HCV/HIV under real-life conditions led to high and similar rates of SVR12. Moreover, the historical factors associated with a sustained virological response to pegIFN/RBV were not predictive of the response to all-oral DAAs.

Activation of Protein C in Human Trophoblasts in Culture and Downregulation of Trophoblast Endothelial Protein C Receptor by TNF-α.

In mice, trophoblasts are equipped with a potent anticoagulant mechanism, the protein C pathway. In human placenta, no functional studies of the protein C pathway are available. Human first-trimester trophoblasts (CK(++) HLA-G(+/-) Vim(-)) were isolated and kept in culture for a maximum of 48 hours. Activation of protein C on trophoblasts was at least as efficient as in endothelial cells (4.43 × 10 (-) (7) nmol/L/min/cell). Endothelial protein C receptor (EPCR) was expressed in syncytiotrophoblasts and extravillous trophoblasts. Downregulation of the messenger RNA of trophoblast EPCR occurred when trophoblasts were challenged with tumor necrosis factor α, and it could be prevented by unfractionated heparin but not by low-molecular-weight heparin at therapeutic doses. In conclusion, there is a functional protein C pathway on human first-trimester trophoblasts which can be modulated by inflammation. This finding has implications for the pathogenesis and prevention of placenta-mediated obstetric complications.

Acute effects of acylated ghrelin on salbutamol-induced metabolic actions in humans.

The aim of this study is to describe a potential modulatory effect of acute acylated ghrelin (AG) administration on the glucose, insulin, and free fatty acids (FFA) responses to salbutamol (SALBU). Six healthy young male volunteers underwent the following four testing sessions in random order at least 7 days apart: (a) acute AG administration (1.0 µg/kg i.v. as bolus at 0'); (b) SALBU infusion (0.06 µg/kg/min i.v. from -15' to +45'); (c) SALBU infusion+AG; and (d) isotonic saline infusion. Blood samples for glucose, insulin, and FFA levels were collected every 15 min. As expected, with respect to saline, SALBU infusion induced a remarkable increase in glucose (10.8±5.6 mmol/l×min; P<0.05), insulin (2436.8±556.9 pmol/l×min; P<0.05), and FFA (18.9±4.5 mmol/l×min; P<0.01) levels. A significant increase in glucose (7.4±3.9 mmol/l×min; P<0.05) and FFA levels (10.0±2.8 mmol/l×min; P<0.01) without significant variations in insulin levels were recorded after AG administration. Interestingly, the hyperglycemic effect of AG appeared to be significantly potentiated during SALBU infusion (26.7±4.8 mmol/l×min; P<0.05). On the other hand, the stimulatory effect of SALBU on insulin and FFA was not significantly modified by AG administration. The results of this study show that acute AG administration has a synergic effect with ß2-adrenergic receptor activation by SALBU on blood glucose increase, suggesting that their pharmacological hyperglycemic action takes place via different mechanisms. On the other hand, AG has a negligible influence on the other pharmacological metabolic effects of SALBU infusion.

Impact of short-term treatment with benzodiazepines and imidazopyridines on glucose metabolism in healthy subjects.

AIM: In the last years there has been a progressive reduction of the average duration of sleep and an increase in the incidence of sleep disturbances. At the same time, an increase of the incidence of the metabolic syndrome has been described, partly attributable to the progressive worsening of dietary habits and the increase in sedentary lifestyle. Recent studies suggest that adequate sleep is essential to maintain good glucose metabolism and sleep disturbances may contribute to the manifestation of the metabolic syndrome. Benzodiazepines (BZ), such as brotizolam, and imidazopyridines, such as zolpidem, are frequently used as hypnotics but their potential impact on glucose metabolism has never been evaluated so far. METHODS: In 12 healthy volunteers [age (mean ± SEM) 38.3 ± 8.1 years; body mass index (BMI) 21.9 ± 0.8 kg/m²] we studied glucose and insulin responses to oral glucose tolerance test (OGTT, 75 g) before and after 15 days treatment with brotizolam 0.25 mg/day or zolpidem 10 mg/day. RESULTS: Brotizolam increased glucose delta area under curve response to the OGTT by 122 % (p < 0.01) and zolpidem by 86 % (p < 0.01) without significant variations of insulin levels, suggesting an impact on insulin sensitivity and/or insulin secretion. CONCLUSIONS: This study suggests that BZ and imidazopyridines have a rapid glucometabolic effect that is detectable as early as after 15 days treatment.

Collagen fibers in the rectus abdominis muscle of cadavers of different age.

PURPOSE: To assess collagen content and types in the rectus abdominis muscle of cadavers of different ages. METHODS: Forty fresh adult male cadavers within 24 h of death were obtained from an Institute of Legal Medicine and divided by age at death into Group 1 (mean age, 23.3 years; range, 18-30 years; n = 20) and Group 2 (mean age, 46.2 years; range, 31-60 years; n = 20). From each cadaver, samples of the rectus abdominis muscle measuring 1 cm(2) were collected 3 cm superiorly and 2 cm inferiorly to the umbilicus. Histological sections were prepared and stained with picrosirius red and Masson's trichrome stain for visualization of total collagen fibers, and immunohistochemical analysis was performed to distinguish types I, II, III, IV and V collagen. RESULTS: No significant differences in total collagen were found between groups by Masson's trichrome staining. However, picrosirius red staining revealed a significantly greater amount and higher concentration of total collagen and types I and III collagen in Group 1 than in Group 2 (P < 0.05). All but type II collagen were detected by immunohistochemistry in both groups. No significant difference in type IV collagen was found between groups. Type V collagen was detected by immunohistochemistry in both groups, but quantification was not possible due to background staining. CONCLUSION: The amounts of types I and III collagen in the rectus abdominis muscle were significantly smaller in older subjects.

The GH-releasing effect of acylated ghrelin in normal subjects is refractory to GH acute auto-feedback but is inhibited after short-term GH administration inducing IGF1 increase.

OBJECTIVE: GH secretion is regulated by an interplay between GH-releasing hormone (GHRH), somatostatin (SST), and other central and peripheral signals. Acylated ghrelin (AG) amplifies GH pulsatility acting, at least partially, independently from GHRH and SST. The GH response to GHRH is inhibited by recombinant human GH (rhGH), likely due to a SST-mediated negative GH auto-feedback. The effect of exogenous rhGH on the GH-releasing effect of AG has never been tested. DESIGN AND METHODS: In six healthy volunteers, we studied the GH response to acute AG administration (1.0 µg/kg i.v.) during saline or rhGH infusion (4.0 µg/kg per h i.v.) or after 4-day rhGH (10.0 µg/kg s.c.) administration. RESULTS: Compared with saline, rhGH infusion increased GH levels (P<0.01). During saline, acute i.v. AG induced a marked increase (P<0.01) in GH levels similar to those observed after AG administration during rhGH infusion. During s.c. rhGH, IGF1 levels rose from day 0 to day 5 (P<0.01). After 4-day s.c. rhGH, i.v. AG increased (P<0.01) GH levels, though significantly (P<0.05) less than on day 0. CONCLUSIONS: The marked somatotroph-releasing effect of AG is refractory to a direct GH auto-feedback whereas is markedly inhibited after 4-day rhGH administration, suggesting the possibility of a selective IGF1-mediated inhibitory feedback.

Extracellular glycosaminoglycan changes in healthy and overgrown gingiva fibroblasts after cyclosporin A and cytokine treatments.

BACKGROUND: It has been demonstrated that cyclosporin A (CyA) blocks the immune system, acts on cytoskeleton and stimulates the production of extracellular matrix (ECM) and transforming growth factor-beta1 (TGF-beta1). This cytokine, such as transforming growth factor-alpha (TGF-alpha), induces deposition of glycosaminoglycans (GAG), proteoglycans and collagen fibres in the ECM. METHODS: In this work, we examined the effect induced by CyA, TGF-beta1 and TGF-alpha on cultures of healthy and overgrown human gingival fibroblasts in order to evaluate the glycosaminoglycan, cytoskeletal changes and the behaviour of fibroblasts after concanavalin A (Con A) treatment. Moreover, we examined gingival biopsies by Alcian blue histochemical staining and electron transmission microscopy. RESULTS: Total and extracellular sulphated GAG in overgrown gingiva specimens and in derived fibroblast cultures treated with CyA and cytokines were significantly higher than controls. The action of cytokines was increased (P < or = 0.01) compared with CyA with a greater effect of TGF-alpha in comparison with TGF-beta1; the electron microscopy showed ECM accumulation. The agglutinations showed the heterogeneity of fibroblast populations. CONCLUSIONS: Stimulation with Con A showed that the fibroblast population had cell surface heterogeneity, and could respond in a different way to both CyA and cytokine stimulus. Moreover, increased synthesis of GAG in overgrown gingiva compared with synthesis in normal fibroblasts before CyA treatment suggests a possible genetic origin of damage. As not all CyA-treated patients develop gingival overgrowth, a genetic predisposition may explain the different responses of gingival fibroblast populations.

[Preliminary study of the chemical characteristics of water inside and outside the area of Cassino]. / Studio preliminare sulle caratteristiche chimiche delle acque interne ed esterne dell'area di Cassino.

Quality and control of waters, particularly phreatic waters, is a strong need of a modern society and in particular of all administrations that is entitled to care for its citizen's health. The current legislation although not very strict, or at least not as strict and careful as it should be and definitely less than that of the World Health Organization (WHO), has recently constrained thresholds for maximum concentrations of chemical species dissolved into waters (anions, cations and heavy metals). Comparisons between data from water analyses collected in Cassino area and these thresholds have shown that these waters resulted of very good quality and they are not related to any source of inorganic pollution. Tap water should be preferred to mineral water usually in stores. Economically they are at least one thousands times cheaper and often can be considered of better quality.

Different modes of assisted ventilation in patients with acute respiratory failure.

The aim of the present study was to verify that the patient/ventilator interaction is similar, regardless of the mode of assisted mechanical ventilation (i.e. pressure- or volume-limited) used, if tidal volume (VT) and peak inspiratory flow (PIF) are matched. Therefore, the authors compared the effects of three different modes of assisted ventilation on the work of breathing (WOB) and gas exchange in patients with acute respiratory failure. For Protocol 1, in seven patients, the authors compared pressure support, assist pressure control and assist control (with square and decelerating wave inspiratory flow pattern) set to deliver the same VT and PIF. For Protocol 2, in another 10 patients, the authors compared pressure support and assist control with high (0.8 L x s(-1)) and low (0.6 L x s(-1)) PIFs set to deliver the same VT. In Protocol 1, there was no difference in WOB and gas exchange between the three modes of assisted ventilation tested. In Protocol 2, the decrease of PIFs during assist control significantly increased WOB. In conclusion, different modes of assisted ventilation similarly reduce work of breathing and provide adequate gas exchange at fixed tidal volume and peak inspiratory flow only. During assist control, tidal volume and peak inspiratory flow (set by the physician) are the main determinants of the patient/ventilator interaction.

Effects of different continuous positive airway pressure devices and periodic hyperinflations on respiratory function.

OBJECTIVE: To compare the effect on respiratory function of different continuous positive airway pressure systems and periodic hyperinflations in patients with respiratory failure. DESIGN: Prospective SETTING: Hospital intensive care unit. PATIENTS: Sixteen intubated patients (eight men and eight women, age 54 +/- 18 yrs, PaO2/FiO2 277 +/- 58 torr, positive end-expiratory pressure 6.2 +/- 2.0 cm H2O). INTERVENTIONS: We evaluated continuous flow positive airway pressure systems with high or low flow plus a reservoir bag equipped with spring-loaded mechanical or underwater seal positive end-expiratory pressure valve and a continuous positive airway pressure by a Servo 300 C ventilator with or without periodic hyperinflations (three assisted breaths per minute with constant inspiratory pressure of 30 cm H2O over positive end-expiratory pressure). MEASUREMENTS AND MAIN RESULTS: We measured the respiratory pattern, work of breathing, dyspnea sensation, end-expiratory lung volume, and gas exchange. We found the following: a) Work of breathing and gas exchange were comparable between continuous flow systems; b) the ventilator continuous positive airway pressure was not different compared with continuous flow systems; and c) continuous positive airway pressure with periodic hyperinflations reduced work of breathing (10.7 +/- 9.5 vs. 6.3 +/- 5.7 J/min, p <.05) and dyspnea sensation (1.6 +/- 1.2 vs. 1.1 +/- 0.8 cm, p <.05) increased end-expiratory lung volume (1.6 +/- 0.8 vs. 2.0 +/- 0.9 L, p <.05) and PaO2 (100 +/- 21 vs. 120 +/- 25 torr, p <.05) compared with ventilator continuous positive airway pressure. CONCLUSIONS: The continuous flow positive airway pressure systems tested are equally efficient; a ventilator can provide satisfactory continuous positive airway pressure; and the use of periodic hyperinflations during continuous positive airway pressure can improve respiratory function and reduce the work of breathing.

[Synthesis and pharmacologic study of new esters of naproxen with derivatives of N-oxyethylpiperazine]. / Sintesi e studio farmacologico di nuovi esteri del naproxen con derivati dell'N-ossietilpiperazina.

The preparation of naproxen esters with N,N'-dioxyethylpiperazine and derivatives of N-oxyethylpiperazine with various substituents on the nitrogen is described. Study of analgesic-antiinflammatory properties in comparison with a reference compounds has shown that in most of the new compounds analgesic activity (phenylquinone) is preserved whereas antiinflammatory activity (carrageenin) is generally reduced. The diester with N,N'-dioxyethylpiperazine (MG 28136) proved most interesting, showing clear pharmacological activity and very low toxicity.

Pantetheine and pantethine esters with hypolipidemic nicotinic acid derivatives.

We prepared several esters of pantetheine and pantethine, respectively, with 3-pyridineacetic acid and with 3-(3-pyridinemethoxycarbonyl)propionic acid, and we tested these products for their capacity to lower serum non-esterified fatty acids and triglycerides in normal animals. Among the products thus tested, the tetraester of pantethine with 3-(3-pyridinemethoxycarbonyl)propionic acid (MG 28362) displayed marked hypolipidemic activity, the action being of uncommonly long duration.