Search

Polypharmacy is very common in older patients and may be associated with drug-drug interactions. Hepatic cytochrome P450 (notably 3A4 subtype, CYP3A4) is a key enzyme which metabolizes most drugs; P-glycoprotein (P-gp) is a transporter which significantly influences distribution and bioavailability of many drugs. In this study, we assess the prevalence and patterns of potential interactions observed in an hospitalized older cohort (Registro Politerapia Societa Italiana di Medicina Interna) exposed to at least two interacting drugs involving CYP3A4 and P-gp at admission, during hospitalization and at discharge. Individuals aged 65 and older (N-4039; mean age 79.2; male 48.1%), hospitalized between 2010 and 2016, were selected. The most common combinations of interacting drugs (relative frequency > 5%) and socio-demographic and clinical factors associated with the interactions were reported. The prevalence of interactions for CYP3A4 was 7.9% on admission, 10.3% during the stay and 10.7% at discharge; the corresponding figures for P-gp interactions were 2.2%, 3.8% and 3.8%. The most frequent interactions were amiodarone-statin for CYP3A4 and atorvastatin-verapamil-diltiazem for P-gp. The prevalence of some interactions, mainly those involving cardiovascular drugs, decreased at discharge, whereas that of others, e.g. those involving neuropsychiatric drugs, increased. The strongest factor associated with interactions was polypharmacy (OR 6.7, 95% CI 5.0–9.2). In conclusion, hospital admission is associated with an increased prevalence, but also a changing pattern of interactions concerning CYP3A4 and P-gp in elderly. Educational strategies and appropriate use of dedicated software seem desirable to limit drug interactions and the inherent risk of adverse events in older patients.

BACKGROUND: Atrial fibrillation is the most common cardiac arrhythmia, and no current therapy is ideal for control of this condition. Experimental studies suggest that angiotensin II-receptor blockers (ARBs) can influence atrial remodeling, and some clinical studies suggest that they may prevent atrial fibrillation. METHODS: We conducted a large, randomized, prospective, placebo-controlled, multicenter trial to test whether the ARB valsartan could reduce the recurrence of atrial fibrillation. We enrolled patients who were in sinus rhythm but had had either two or more documented episodes of atrial fibrillation in the previous 6 months or successful cardioversion for atrial fibrillation in the previous 2 weeks. To be eligible, patients also had to have underlying cardiovascular disease, diabetes, or left atrial enlargement. Patients were randomly assigned to receive valsartan or placebo. The two primary end points were the time to a first recurrence of atrial fibrillation and the proportion of patients who had more than one recurrence of atrial fibrillation over the course of 1 year. RESULTS: A total of 1442 patients were enrolled in the study. Atrial fibrillation recurred in 371 of the 722 patients (51.4%) in the valsartan group, as compared with 375 of 720 (52.1%) in the placebo group (adjusted hazard ratio, 0.97; 96% confidence interval [CI], 0.83 to 1.14; P = 0.73). More than one episode of atrial fibrillation occurred in 194 of 722 patients (26.9%) in the valsartan group and in 201 of 720 (27.9%) in the placebo group (adjusted odds ratio, 0.89; 99% CI, 0.64 to 1.23; P = 0.34). The results were similar in all predefined subgroups of patients, including those who were not receiving angiotensin-converting-enzyme inhibitors. CONCLUSIONS: Treatment with valsartan was not associated with a reduction in the incidence of recurrent atrial fibrillation. (ClinicalTrials.gov number, NCT00376272.) Copyright © 2009 Massachusetts Medical Society.

International audience; INTRODUCTION: Tuberculosis-related morbidity and mortality remain important. Emergence and diffusion of multidrug-resistance tuberculosis (MDR-TB) is a global public health concern. Cases of MDR-TB in children are a sentinel event indicating the spread of a mycobacterial strain within a community. Latent TB precedes MDR-TB and screening and follow-up of contact individuals are key points of TB infection control. METHODS: We performed the case-investigation of 20 adult cases of MDR-TB managed in our institution. RESULTS: Forty-six pediatric contact individuals were identified. A high proportion of these children were lost to follow-up (80% at 12 months), showing that monitoring this reservoir population with migrant history is challenging. Five (11%) children presented a secondary infection: one child was diagnosed with active TB infection (positive tuberculin skin test associated with abnormalities on chest computer tomography [CT] scan). Four children were diagnosed with latent TB infection (isolated positive tuberculin skin test with normal CT scan). Two of these children received a treatment adjusted to the strain of the index case. DISCUSSION: In the setting of emerging MDR-TB, tuberculin skin test may be likely replaced by specific interferon-gamma release assays (IGRA), independent of prior BCG vaccination. In addition, chest CT scan is preferred to chest X-ray to detect TB lesions. The management of latent TB infection is controversial: immediate treatment with second-line anti-TB drugs adapted to the index case strain or, consistently with WHO guidelines, a simple follow-up with subsequent treatment in case of active TB.; IntroductionMalgré une incidence en lente décroissance, la morbi-mortalité de la tuberculose (TB) reste importante. L’émergence et la diffusion de souches multi-résistantes (MR) constituent actuellement un problème mondial majeur de santé publique. Les cas pédiatriques de TB-MR sont un évènement sentinelle indiquant une circulation de souches au sein d’une communauté. L’infection tuberculeuse latente (ITL) précède les cas de TB-MR. La détection et le suivi des sujets contacts sont des axes clés de la lutte anti-TB.MéthodesAutour de 20 cas adultes atteints de TB-MR pris en charge dans notre institution 46 enfants contacts ont été recensés.RésultatsDurant le suivi, le nombre d’enfants perdus de vue était élevé (80 % à 1 an) attestant de la difficulté de suivre une jeune population « réservoir » issue de l’immigration. Le taux d’incidence d’une infection tuberculeuse secondaire était de 11 % : un enfant a développé une TB-maladie (virage tuberculinique associé à des anomalies tomodensitométriques thoraciques) ; quatre enfants ont développé une ITL (virage tuberculinique à tomodensitométrie thoracique normale). Deux enfants ont reçu un traitement adapté à la souche du cas index (préventif ou curatif).DiscussionDans ce contexte d’émergence de la TB-MR, la substitution de l’IDR par les tests de libération d’interféron (TLI), aussi sensibles et plus spécifiques (indépendants du BCG), semble pertinente. De même, la TDM thoracique optimise la détection de lésions infra-radiographiques. La stratégie de traitement de l’ITL en post-exposition d’une TB-MR avec une combinaison adaptée à la souche du cas index est débattue au profit d’une stratégie proposée par l’OMS de surveillance prolongée avec traitement curatif d’une TB active le cas échéant.

The hypoxia-regulated alternative TrkAIII splice variant expressed by human neuroblastomas exhibits oncogenic potential, driven by in-frame exon 6 and 7 alternative splicing, leading to omission of the receptor extracellular immunoglobulin C(1) domain and several N-glycosylation sites. Here, we show that the TrkAIII oncogene promotes genetic instability by interacting with and exhibiting catalytic activity at the centrosome. This function depends upon intracellular TrkAIII accumulation and spontaneous interphase-restricted activation, in cytoplasmic tyrosine kinase (tk) domain orientation, predominantly within structures that closely associate with the fully assembled endoplasmic reticulum intermediate compartment and Golgi network. This facilitates TrkAIII tk-mediated binding of gamma-tubulin, which is regulated by endogenous protein tyrosine phosphatases and geldanamycin-sensitive interaction with Hsp90, paving the way for TrkAIII recruitment to the centrosome. At the centrosome, TrkAIII differentially phosphorylates several centrosome-associated components, increases centrosome interaction with polo kinase 4, and decreases centrosome interaction with separase, the net results of which are centrosome amplification and increased genetic instability. The data characterize TrkAIII as a novel internal membrane-associated centrosome kinase, unveiling an important alternative mechanism to "classical" cell surface oncogenic receptor tk signaling through which stress-regulated alternative TrkAIII splicing influences the oncogenic process.

Regulatory peptides and their analogs are being extensively investigated as radiopharmaceuticals for cancer imaging. In particular, cholecystokinin (CCK) receptors of the subtype B (CCK-BR) have been shown to be overexpressed in certain neuroendocrine tumors including medullary thyroid cancer. Our recent work has focused on new methods to radiolabel the CCK8 peptide with (111)In or (99m)Tc for the purpose of developing radiopharmaceuticals for in vivo CCK-B receptor imaging. Labeling of CCK8 with (111)In was achieved at the N-terminus of the peptide by adding, in solid phase, a glutamate coupled diethylenetriaminepentaacetic acid (DTPA) moiety through a glycine linker, yielding DTPA-Glu-G-CCK8. For labeling with (99m)Tc, the CCK8 peptide was modified at its N-terminus by introducing, in the following order--cysteine, glycine, and a diphenylphosphinopropionyl moiety--giving a 10-residue peptide derivative, Phos-GC-CCK8. A cell culture model was developed for the purpose of evaluating the binding properties of these two ligands. The human epidermoid carcinoma cell line, A431, was transfected with a plasmid containing the full coding sequence of the human CCK-BR under a strong viral promoter, obtaining a number of receptors in the range of 2-5 x 10(6) per cell. Control cells were transfected with vector alone. An animal tumor model utilizing these two cell lines was developed to evaluate the specificity of interaction with the CCK-BR and biodistribution properties of the compounds. CCK-BR positive and control cells were subcutaneously injected in opposite flanks of CD1 female nude mice in order to obtain xenografts differing only in their ability to express CCK-B receptors. High performance liquid chromatography (HPLC) and other chromatographic methods were utilized to assess stability of the radiolabeled compounds after injection. Both (111)In-DTPA-Glu-G-CCK8 and (99m)Tc-Phos-GC-CCK8 showed similar binding affinities for cultured CCK-BR expressing cells, with dissociation constants in the range of 20-40 nM. With the two xenograft approach, we were able to demonstrate specific interaction with the receptor of both CCK analogs in our animal model. The data obtained shows rapid specific localization of both compounds on the CCK-BR overexpressing xenografts. Both tracers show rapid plasma clearance of unbound peptide. Clearance of (111)In-DTPA-Glu-G-CCK8 appears to be preferentially through the kidneys, whereas (99m)Tc-Phos-GC-CCK8 clearance occurs both through kidneys and the hepatobiliary system. Both our labeling approaches appear adequate for clinical use of peptide based radiopharmaceuticals, although (99m)Tc-Phos-GC-CCK8 shows elevated accumulation in the gastrointestinal tract, which causes high background activity.

BACKGROUND: There is a distinct lack of information on the prognosis of asthma in the elderly. METHODS: In order to compare mortality rates of elderly people with and without asthma and to identify mortality risk factors in those with asthma, 1,233 ambulatory patients aged > or = 65 years with a diagnosis of asthma (n = 210) or chronic nonrespiratory conditions (n = 1,023) were enrolled in a multicentric study. Patients underwent baseline spirometry and multidimensional assessment and were then followed up for a mean of 57.9 months (SD 16.9). We compared mortality rates in the two groups and identified predictors of death using multivariable survival analysis. RESULTS: The 5-year mortality rate in people with asthma was 24.3%, compared to 16.3% in control subjects (p < 0.01), but asthma per se did not explain the excess risk of death. The main causes of death among people with and without asthma were cardiovascular diseases (36.4% and 21.3%, respectively), nonneoplastic lung diseases (28.8% vs 5.4%), and neoplasms (7.6% vs 22.6%). In people without asthma, death was associated with age, gender, smoking, cardiovascular diseases, worse performance on a 6-min walking test, cognitive impairment, depression, and worse respiratory function. In people with asthma, only the association between death and age, smoking, and depression was confirmed. At variance with control subjects, in asthmatics we found an inverse correlation between being overweight and death (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.13 to 0.94) and a trend toward a higher mortality rate in people with a body mass index < 22 kg/m(2) (HR, 2.21; 95% CI, 0.94 to 5.18). CONCLUSIONS: Asthma in the elderly was associated with higher mortality rate, although this condition was not an independent risk factor. Causes of death and factors associated with death were somewhat different between people with and without asthma.

To verify whether the use of potentially inappropriate medications (PIMs) is associated with loss of independence in elderly in-patients by promoting adverse drug reactions (ADRs).Prospective observational study.Five hundred six patients aged 65 and older admitted to 11 acute care medical wards.In-hospital loss of one or more activities of daily living (ADLs) and three or more ADLs. PIMs were identified according to diagnosis-independent Beers criteria and ascertained by study physicians based on daily review of medical and nurse records. The relationship between risk factors and outcomes was assessed using logistic regression.Overall, 104 patients (20.6%) were taking at least one PIM at the time of admission (baseline users), and 49 (9.7%) were newly prescribed at least one PIM during their hospital stay. The loss of one or more ADLs occurred in 9.6% of baseline users, 16.3% of new users, and 8.5% of nonusers (P=.21) and that of three or more ADLs in 7.7% of baseline users, 12.2% of new users, and 4.8% of nonusers (P=.10). The lack of association was confirmed after correction for potential confounders, including ADRs. The occurrence of ADRs was strongly associated with both outcomes (odds ratio (OR)=7.80, 95% confidence interval (CI)=3.53-17.3 for the loss ofor =1 ADLs; OR=3.98, 95% CI=1.50-10.5 for the loss ofor =3 ADLs), but PIMs caused only six of 106 ADRs.ADRs to any drugs more than the use of PIMs might be associated with functional decline in elderly hospitalized patients, but because the power of this study was too limited to definitively exclude a direct relationship between PIMs and functional decline, this merits further investigation.

The high prevalence of multiple chronic disorders and polypharmacotherapy expose elderly patient to an increased risk of adverse drug reactions. Aging is associated with relevant morphological and functional changes in the kidney, with consequent changes in the pharmacokinetics of hydrosoluble drugs. Changes in renal function are not always clinically evident, and a concealed renal failure can lead to an increased risk of adverse drug reactions to hydrosoluble drugs. Targeting these at-risk patients could contribute to reduce the risk of adverse drug reactions with relevant cost saving.

Background Adverse drug reactions (ADRs) are common causes of in-hospital complications for elderly people. The purpose of the present study is to verify whether concealed renal insufficiency, that is, reduction of the estimated glomerular filtration rate (GFR) in people with normal serum creatinine levels, is a risk factor for ADRs in elderly hospitalized patients. Methods We used data on 11 687 hospitalized patients enrolled in the Gruppo Italiano di Farmacovigilanza nell’Anziano study. The outcomes of the study were any ADR, ADR to hydrosoluble drugs, and ADR to any other drug during the hospital stay. We compared 3 groups: normal renal function (normal serum creatinine levels and normal estimated GFRs), concealed (normal serum creatinine levels and reduced estimated GFRs), or overt (increased creatinine levels and reduced estimated GFRs) renal insufficiency. The relationship between renal function and ADR was evaluated using contingency tables and multiple regression analysis including potential confounders. Results Concealed renal insufficiency was detected in 1631 (13.9%) patients and was frequently associated with male sex and poor nutritional status. Hydrosoluble drugs were responsible for 301 of the 941 recorded ADRs. After adjusting for potential confounders, both concealed (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.15-1.25) and overt (OR, 2.02; 95% CI, 1.54-2.65) renal failure were associated with ADR to hydrosoluble drugs, but not with ADR to other drugs (OR, 0.83 [95% CI, 0.65-1.08], and OR, 1.01 [95%CI, 0.83-1.23], respectively). Conclusion Older hospitalized patients frequently have impaired renal function despite normal serum creatinine levels and are exposed to an increased risk of ADRs to hydrosoluble drugs.

To assess differences, if any, in the pattern of disability measured using basic activities of daily living (BADL) and instrumental activities of daily living (IADL) in COPD and congestive heart failure (CHF), using diabetes mellitus as a reference noncardiorespiratory disabling condition.Multicenter survey.General medicine or geriatric wards in tertiary hospitals throughout Italy.Patients admitted because of CHF (n = 432), COPD (n = 305), and diabetes mellitus (n = 534).Construct validity of self-reported preadmission BADL-IADL was assessed for each group by main component analysis. The three populations had a comparable average degree of dependency in BADL-IADL. In both CHF and diabetes mellitus patients, three components cumulatively explained most of variance in BADL-IADL: the BADL, 10 IADL, and 4 housework-related IADL. In COPD, a four-factor solution was generated, with factor 4 having loading with IADL items assessing mobility and outdoor moving, and factor 3 with selected IADL requiring both physical and mental capabilities such as managing money, taking medicine, and traveling. Correlates of dependency in IADL related to factor 4 in COPD were older age, cognitive impairment, widowhood, and comorbidity. Both factors 3 and 4 were associated with longer stay (factor 3: 13.9 +/- 9.5 days vs 11.5 +/- 7.6 days, p0.05; factor 4: 14.2 +/- 8.8 days vs 11.0 +/- 5.5 days, p0.05) of COPD patients (mean +/- SD).COPD was associated with a distinctive pattern of disability expressed by loss of selected BADL-IADL but not by the crude number of lost BADL-IADL.

An immunoreactive role of lactic acid bacteria established in animals has seldom been investigated in humans. In a large-scale clinical study, children from day-care centers received either yoghurt (Y), milk fermented by yoghurt symbiosis and Lactobacillus casei (DN 114 001) (YC), or gelified milk (GM) as diet supplements during two 30-day supplementation periods separated by one 30-day period without supplementation. Feces samples were collected before, during, and after the 2nd supplementation period. Proteins were extracted in a buffer containing enzymatic inhibitors. IgA levels were assessed and adjusted to the weight of feces samples. Specific IgA to lactic acid bacteria strains (Streptococcus thermophilus 8901A, 8902A; Lactobacillus bulgaricus; Lactobacillus casei) present in Y and YC were assayed in ELISA and adjusted to individual IgA levels. Mean levels of fecal IgA were within reported ranges for pediatric populations of similar age. IgA levels decreased significantly but transiently in children receiving Y, and increased significantly in children receiving GM, but did not vary in the group of children who were given YC. Specific IgA to the 4 strains tested increased significantly during the supplementation period only in the group of children receiving GM, while it was transient and not significant in children receiving YC. No variation was noted in children given Y Specific IgA to lactic acid bacteria can be assayed in feces. Supplementation with fermented milks might induce a mucosal tolerance to environmental flora.

Background Whether cancer is more disabling than other highly prevalent chronic diseases in the elderly is not well understood, and represents the objective of the present study. Methods We used data from the Gruppo Italiano di Farmacovigilanza nell'Anziano (GIFA) study, a large collaborative observational study based in community and university hospitals located throughout Italy. Our series consisted of three groups of patients with non-neoplastic chronic disease (congestive heart failure, CHF, N = 832; diabetes mellitus, N = 939; chronic obstructive pulmonary disease, COPD, N = 399), and three groups of patients with cancer (solid tumors without metastasis, N = 813; solid tumors with metastasis, N = 259; leukemia/lymphoma, N = 326). Functional capabilities were ascertained using the activities of daily living (ADL) scale, and categorical variables for dependency in at least 1 ADL or dependency in 3 or more ADLs were considered in the analysis. Cognitive status was evaluated by the 10-items Hodgkinson Abbreviated Mental Test (AMT). Results Cognitive impairment was more prevalent in patients with CHF (28.0%) or COPD (25.8%) than in those with cancer (solid tumors = 22.9%; leukemia/lymphoma = 19.6%; metastatic cancer = 22.8%). Dependency in at least 1 ADL was highly prevalent in patients with metastatic cancer (31.3% vs. 24% for patients with CHF and 22.4% for those with non-metastatic solid tumors, p < 0.001). In people aged 80 years or more, metastatic cancer was not associated with increased prevalence of physical disability. In multivariable analysis, metastatic cancer was associated with a greater prevalence of physical (OR 2.09, 95%CI 1.51–2.90) but not cognitive impairment (OR 1.34, 95%CI 0.94–1.91) with respect to CHF patients. Finally, diabetes was significantly associated with cognitive impairment (OR 1.40, 95%CI 1.11–1.78). Conclusion Cancer should not be considered as an ineluctable cause of severe cognitive and physical impairment, at least not more than other chronic conditions highly prevalent in older people, such as CHF and diabetes mellitus.

Background: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines have been promulgated to improve the management of chronic obstructive pulmonary disorder (COPD). Objective: To evaluate the extent to which the current therapeutic approach to COPD conforms to GOLD guidelines. Methods: This was a multicentre observational study of elderly COPD patients enrolled for acute care in general medicine or geriatric wards in tertiary hospitals in Italy in April 2002. Our series consisted of 471 patients >64 years of age consecutively admitted for acute exacerbations of COPD to wards participating in the study. Data describing drugs used prior to exacerbation and prescribed at discharge were collected using a standardised protocol. Changes in prescription at discharge were then compared with home therapy. Demographic variables and indices of COPD severity and co-morbidity were tested as potential correlates for the main outcome measure 'variant prescription', i.e. prescription of a drug considered as a third-line treatment (e.g. methylxanthines) or not recommended (e.g. mucolytics) by GOLD guidelines. The correlation was assessed first by univariate analysis and then by logistic regression analysis. Results: At discharge, prescription of short-acting β2-adrenoceptor agonists had decreased from 26.3% to 14.0%. Conversely, increases in prescription of long-acting β2- adrenoceptor agonists (from 43.1% to 68.4%), inhaled corticosteroids (50.7% to 69.6%) and anticholinergics (17.2% to 22.3%) were seen. The rate of use of methylxanthines was 49.7% before admission and 44.8% at discharge, with previous use being the main correlate of discharge prescription for this class of drugs (odds ratio [OR] = 4.35; 95% CI 2.88, 6.54). The rate of use of mucolytics was 26.3% before admission and 26.8% at discharge, with use of mucolytics prior to admission being the only correlate of discharge prescription (OR = 4.10; 95% CI 2.47, 6.82). Conclusions: Hospitalisation resulted in increased adherence to GOLD guidelines in patients with COPD, but the rate of use of anticholinergics was distinctly low and that of methylxanthines and mucolytics surprisingly high. A carry-over effect (i.e. of therapy prescribed by general practitioners on that prescribed by hospital-based physicians) likely accounts for most of the 'variant prescriptions' seen at discharge from the acute care hospital

Cell membranes are impermeable to most molecules that are not actively imported by living cells, including all macromolecules and even small molecules whose physiochemical properties prevent passive membrane diffusion. However, recently, we have seen the development of increasingly sophisticated methodology for intracellular drug delivery. Cell-penetrating peptides (CPPs), short peptides believed to enter cells by penetrating cell membranes, have attracted great interest in the hope of enhancing gene therapy, vaccine development and drug delivery. Nevertheless, to achieve an efficient intracellular delivery, further strategies to bypass the endocytotic pathway must be investigated. We report on a novel peptide molecule derived from glycoprotein gH of herpes simplex type I virus that is able to traverse the membrane bilayer and to transport a cargo into the cytoplasm with novel properties in comparison with existing CPPs. We use as cargo molecule quantum dots that do not significantly traverse the membrane bilayer on their own. From the Clinical Editor: Cell-penetrating peptides have recently attracted great interest in optimizing gene therapy, vaccine development and drug delivery. In this study, a peptide derived from glycoprotein gH of herpes simplex I is investigated from this standpoint. © 2011 Elsevier Inc.

We aimed to examine biomechanical and neuroautonomic adaptation to blood volume displacement induced by tilt test in patients with previous inferoapical/inferolateral (IA-IL) or basal/apical septal (BS-AS) myocardial infarction (MI). Twenty-four patients with heart failure (HF) and previous IA-IL MI and 30 patients with HF and previous BS-AS MI were enrolled. All patients underwent head-up tilt test, radionuclide ventricular function monitoring (VEST), sympathovagal balance evaluation, and chronotropic 25-dose isoproterenol infusion test (CD25). Physiopathological reactions to stress-tests were assessed in both groups. Follow-up lasted 36 mo. IA-IL patients showed lower stroke volume (SV), cardiac output (CO), and left ventricle ejection fraction (LVEF) compared with BS-AS. End-diastolic volume decreased in IA-IL group (F = 3.1, P = 0.043) more than in BS-AS group during tilt test. The time trend of end-systolic volume, SV, CO, LVEF, and peak filling rate were similar in the two groups. Norepinephrine (IA-IL supine→tilting 499.5 (SD:28.8)→719.3 (SD:41.5) pg/mL vs. BS-AS supine→tilting 533.9 (SD:33.3)→768.8 (SD:47.9) pg/mL; P < 0.001) and epinephrine plasma concentrations (IA-IL supine→ tilting 125.7 (SD:9.8)→193.7 (SD:9.6) pg/mL vs. BS-AS supine→ tilting 118.8 (SD:8.9)→191.7 (SD:10.2) pg/mL; P < 0.001) increased in both groups. Low-to-high frequencies ratio significantly increased in IA-IL and decreased in BS-AS patients. CD25 was similar in IA-IL and BS-AS patients (IA-IL = 4.6 (SD:0.94), BS-AS = 5.0 (SD:1.06) mg; P = 0.79). CD25 predicted all-cause mortality (hazard ratio 1.48, 95% confidence interval 1.32–1.67; P < 0.0001) after adjusting for age/heart rate. In conclusion, patients with ischemic HF show abnormal biomechanical adaptation to volume displacement and compensatory sympathetic overdrive. The association of reduced b-adrenergic sensitivity and sympathetic denervation in such patients warrants for careful therapeutic choices. NEW & NOTEWORTHY The adaptation to volume displacement induced by tilt test was assessed in patients with heart failure and previous inferoapical/inferolateral or basal/apical septal myocardial infarction. The responsiveness of cardiac muscle to sympathetic nervous system stimulation predicts the mortality in patients with ischemic heart failure and may represent a useful tool for clinicians in the general assessment of this kind of patients.

Peptide nucleic acids (PNAs) have been recently proposed as useful molecules in pharmacogenetic therapy, especially due to the fact that they show a very high stability with respect to DNA and RNA. However, PNAs are not efficient decoy molecules, are characterized by negligible cell internalization and low solubility and are not suitable to be delivered by liposomes. With respect to the biological activity of PNA-based molecules, PDP deserve great consideration, due to the fact that they exhibit high levels of solubility, and are expected to be resistant to proteinases and exonucleases. In this manuscript we determined whether double-stranded molecules based on PNA–DNA chimeras containing NF-κB binding sites, exhibit decoy activity against NF-κB transcription factors. In addition, we determined whether they can be complexed by cationic liposomes. The results obtained demonstrated that hybrids based on PNA–DNA chimeras are powerful decoy molecules against NF-κB p52 transcription factor. In addition, we found that cationic liposomes can be proposed for in vitro delivery to target cells of these decoy molecules. The results presented in this paper are thus of practical importance, since the simplicity and the versatility of the cationic liposome technology have made cationic liposomes useful nonviral gene delivery systems for human gene therapy.

Obesity and high blood pressure (BP) are strongly related and weight loss is mightily associated with a significant BP decrease. The aim of the present meta-analysis was to evaluate and quantify the BP decrease associated with orlistat use in randomized controlled trials. The search included PubMed-Medline, Scopus, Web of Science and Google Scholar databases by up to June 05, 2017, to identify randomized controlled trials investigating the impact of orlistat on blood pressure. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference and 95% confidence interval as summary statistics. Meta-regression and leave-one-out sensitivity analyses were performed to assess the modifiers of treatment response. Our meta-analysis included 27 randomized controlled clinical trials which comprehended overall 8150 subjects (4419 in the orlistat group and 3731 in the control one). We observed a statistically significant decreasing effect of orlistat on both systolic BP (-1.15 mmHg [-2.11, -0.19]) and diastolic BP (-1.07 mmHg [-1.69, -0.45]), regardless of its dosage. Significant associations were found between changes in systolic BP and diastolic BP with treatment duration but not with corresponding baseline BP values. In conclusion, Orlistat use contributes weight loss associated decrease in BP in overweight and obese subjects.

Background The coexistence of asthma and chronic obstructive pulmonary disease (asthma–COPD overlap syndrome: ACOS) is increasingly recognized but data about its prevalence and long-term mortality are needed. Methods Prevalence of ACOS and 15-year mortality rates were assessed in 1065 subjects aged > 65 years, enrolled in the SA.R.A. study, with complete clinical, lung functional and follow-up data. Physical performance, disease-related disability, and health-related quality of life (HRQL) were also evaluated. Results ACOS was found in 11.1% of subjects (29.4% of those previously diagnosed with COPD and 19.7% of those with asthma). ACOS was positively associated with impaired physical performance, functional ability, and HRQL. Individuals with ACOS had higher mortality rates than controls (7.17 per 100 person-years; mortality rate ratio: 1.83). After adjustment for the main confounders, the risk of all-cause mortality remained significantly increased in subjects with ACOS (HR: 1.82), COPD (HR: 2.12), and restriction (HR: 2.41), but not asthma. Conclusions Long-term prognosis of ACOS was similar to COPD, and worse than asthma and healthy controls. ACOS had a significant impact on physical performance, functional ability, and HRQL.

Claudio Sorino,1,2 Salvatore Battaglia,1 Nicola Scichilone,1 Claudio Pedone,3 Raffaele Antonelli-Incalzi,3 Duane Sherrill,4 Vincenzo Bellia11Biomedical Department of Internal and Specialist Medicine, Section of Pulmonology, University of Palermo, Italy; 2Division of Pulmonology, S Anna Hospital, Como, Italy; 3Chair of Geriatrics, University Campus Bio-Medico, Roma, Italy; 4Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USABackground: The choice between lower limit of normal or fixed value of forced expiratory volume in one second/forced vital capacity ratio (FEV1/FVC) < 0.70 as the criterion for confirming airway obstruction is an open issue. In this study, we compared the criteria of lower limit of normal and fixed FEV1/FVC for diagnosis of airway obstruction, with a focus on healthy elderly people.Methods: We selected 367 healthy nonsmoking subjects aged 65–93 years from 1971 participants in the population-based SARA (Salute Respiratoria nell’Anziano, Italian for “Respiratory Health in the Elderly”) study, analyzed their spirometric data, and tested the relationship between spirometric indices and anthropometric variables. The lower limit of normal for FEV1/FVC was calculated as the fifth percentile of the normal distribution for selected subjects.Results: While FEV1 and FVC decreased significantly with aging, the relationship between FEV1/FVC and age was not statistically significant in men or women. The lower limit of normal for FEV1/FVC was 0.65 in men and 0.67 in women. Fifty-five participants (15%) had FEV1/FVC < 0.70 and would have been inappropriately classified as obstructed according to the Global Initiative for Obstructive Lung Disease, American Thoracic Society/European Respiratory Society, and Canadian guidelines on chronic obstructive pulmonary disease. By applying different FEV1/FVC thresholds for the different age groups, as previously proposed in the literature, (0.70 for 80 years) the percentage of patients classified as obstructed decreased to 6%. No subjects older than 80 years had an FEV1/FVC < 0.60.Conclusion: The present results confirm the inadequacy of FEV1/FVC < 0.70 as a diagnostic criterion for airway obstruction after the age of 65 years. FEV1/FVC < 0.65 and

Background: Few studies have examined the role of cardiovascular drugs on acute ischaemic stroke prognosis. Aims: To evaluate the relationship between a favourable outcome in patients with acute ischaemic stroke and specific demographic, clinical and laboratory variables and cardiovascular drug pretreatment. Methods: The 1096 patients enrolled in the GIFA study (who had a main discharge diagnosis of ischaemic stroke) represent the final patient sample used in this analysis. Drugs considered in the analysis included angiotensin converting enzyme (ACE)-inhibitors, angiotensin II receptor blockers, statins, calcium channel blockers, anti-platelet drugs, vitamin K antagonists and heparins. The outcomes analyzed included in-hospital mortality, cognitive function evaluated by the Hodkinson Abbreviated Mental Test (HAMT), and functional status evaluated by activities of daily living (ADL). The definition of a good outcome was no in-hospital mortality, a HAMT score of >= 6 and no ADL impairment. Results: Patients with no in-hospital mortality, a HAMT score of >6 and no ADL impairment were more likely to be younger at baseline and have a lower blood glucose level and a systolic blood pressure (SBP) between 120 and 180 mmHg, a higher plasma total cholesterol level, a lower white blood cell count, and a lower Charlson Index (CI) score, a higher rate of pretreatment with ACE-inhibitors, calcium channel blockers and a lower rate of pretreatment with heparin. Conclusions: Predictors of good outcome, in terms of in-hospital mortality and cognitive and functional performance at discharge, included higher SBP at admission between 120 and 180 mmHg, a SBP plasma total cholesterol levels, a lower CI score, and pretreatment with ACE-inhibitors, calcium channel blockers and anti-platelets. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. Its biological activity is mediated by the binding to the extracellular domain of two tyrosine kinase transmembrane receptors: VEGFR1 and VEGFR2. Deletion studies showed that VEGF binding site resides in the first three domains of VEGFR1 and in domains 2 and 3 of VEGFR2. In particular, the second extracellular domain of VEGFR1 (VEGFR1(D2)) contains most of the VEGF binding requirements. Here, we report an efficient expression protocol and the molecular characterization by spectroscopic techniques of VEGFR1(D2). The protein was expressed in E. coli and refolded from inclusion bodies. The recombinant protein assumes the correct fold as assessed by a combination of biochemical and functional assays as well as by NMR characterization. Furthermore, the recombinant VEGFR1(D2) was analyzed by circular dichroism and fluorescence spectroscopy. The protein obtained by this procedure is suitable for the structural characterization of the complexes with receptor binders and to be used in interaction/screening studies. 2010 Wiley Periodicals, Inc.

SummaryObjectivesTo evaluate the association between pulmonary restriction and mortality in the elderly, taking into account potential confounders not considered in the past (disability, cognitive dysfunction, diabetes, and visceral obesity).DesignLongitudinal study.SettingCommunity-based.ParticipantsTwelve hundred sixty-five patients (51.9% men) aged 65–97 years old from the Salute Respiratoria nell'Anziano (SaRA) Italian multicentric study.MeasurementsParticipants were divided in 4 groups: normal spirometry (NS): FEV1/FVC≥70%, FVC≥80% of predicted; restrictive ventilatory pattern (RVP): FEV1/FVC≥70%, FVC

Cognitive impairment is highly prevalent in chronic obstructive pulmonary disease (COPD) complicated by chronic hypoxemia, but the effect of cognitive training in patients with COPD has not been studied. The aim of the present study was to verify whether cognitive training can preserve cognitive abilities of patients with hypoxemic COPD. Our series consisted of 105 COPD patients with at rest (n = 36) or effort (n = 69) hypoxemia and free from concurrent dementing diseases. Neuropsychologic assessment included a screening test, the Mini Mental State Examination (MMSE), and a standardized confirmatory battery of neuropsychological tests, the Mental Deterioration Battery (MDB). After baseline assessment, patients were randomized to receive standardized multidimensional care (standardization of pharmacological therapy, health education, selection of inhalers according to patient's ability, respiratory rehabilitation, nutritional counseling, oxygen therapy, and control visits) with (n = 53) or without (n = 52) cognitive training aimed at stimulating attention, learning, and logical-deductive thinking. Cognitive performance was reassessed after 1.5, 4, and 6 months. The analysis of variance for repeated measures (ANOVA) having the group membership (study vs. control) as grouping factor was used to assess changes in cognitive performance. Both intervention and control groups showed no significant changes in cognitive performance except for a trend toward improvement in verbal fluency and verbal memory, but cognitive intervention had no significant effect. In conclusion, cognitive training seems ineffective in COPD. However, a multidimensional standardized therapeutic approach, as it was indistinctly provided to all patients, could help to slow or prevent cognitive decline.

Cognitive impairment frequently occurs in elderly COPD patients, but little is known about its prognostic implications. We aimed at evaluating the prognostic role of cognitive impairment in patients with severe COPD.Our series consisted of 149 stable patients (mean [+/- SD] age, 68.7 +/- 8.5 years) with COPD and a Pao(2) of57 mm Hg at rest (n = 97) or at the end of the 6-min walking test (n = 37) who were enrolled in a prospective observational study. After a multidimensional baseline assessment, patients were followed up by telephone calls for a mean duration of 32.5 +/- 9.2 months (minimal follow-up duration, 24 months); 134 patients were successfully tracked. We used multivariable Cox proportional hazard analysis to identify predictors of death among clinical/functional variables that previously were shown to have prognostic implications and among neuropsychological indexes selected on the basis of univariate analysis.We observed 29 deaths over a median follow-up time of 32 months. Only the two following variables were independently associated with the outcome: an abnormal score on the copy with landmark test (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.34 to 6.39); and a 6-min walk distance of300 m (HR, 3.46; 95% CI, 1.15 to 10.5). A Pao(2) of57 mm Hg at rest (HR, 2.19; 95% CI, 0.93 to 5.18) and an FEV(1) of40% predicted (HR, 2.74; 95% CI, 0.99 to 7.57) were nearly significantly associated with the outcome, while Paco(2), body mass index, physical dependence, comorbid diseases, and the impairment of cognitive domains other than drawing impairment were unrelated to the outcome.Drawing impairment is a risk factor for mortality and might improve the assessment of hypoxemic COPD patients.

Haemophilus influenzae type b (Hib) is one of the leading causes of invasive bacterial infection in young children, characterized by inflammation mainly mediated by cytokines and chemokines. One of the most abundant components of the Hib outer membrane is the P2 porin, which has been shown to induce the release of several inflammatory cytokines. Synthetic peptides corresponding to loops L5, L6, and L7 activate JNK and p38 mitogen-activated protein kinase (MAPK) pathways, L7 being the most active peptide. Therefore, sequence-activity relationships and key residues were identified by elongating sequence to different extents, designing cyclic peptides, and performing an alanine scan of L7. The ability of mutant peptides to induce activation of signal transduction pathways and release of TNF-alpha and IL-6 has been determined, and, in conjunction with CD spectra, bioinformatics analysis, and molecular dynamics data, showed that 6 out of 8 amino acids contribute significantly to the overall activity. Molecular dynamics showed that L7 modifications increased loop rigidity and helicity after Gly6 mutation, thus, providing a possible structural explanation for observed loss of bioactivity. This work provides insights into essential molecular details of P2 that may impact on the pathogenesis of Hib infections where interruption of the signaling cascade could represent an attractive therapeutic strategy.

Modulating angiogenesis is an attractive goal because many pathological conditions depend on the growth of new vessels. Angiogenesis is mainly regulated by the VEGF, a mitogen specific for endothelial cells. In the last years, many efforts have been pursued to modulate the angiogenic response targeting VEGF and its receptors. Based on the x-ray structure of VEGF bound to the receptor, we designed a peptide, QK, reproducing a region of the VEGF binding interface: the helix region 17–25. NMR conformation analysis of QK revealed that it adopts a helical conformation in water, whereas the peptide corresponding to the α-helix region of VEGF, VEGF15, is unstructured. Biological assays in vitro and on bovine aorta endothelial cells suggested that QK binds to the VEGF receptors and competes with VEGF. VEGF15 did not bind to the receptors indicating that the helical structure is necessary for the biological activity. Furthermore, QK induced endothelial cells proliferation, activated cell signaling dependent on VEGF, and increased the VEGF biological response. QK promoted capillary formation and organization in an in vitro assay on matrigel. These results suggested that the helix region 17–25 of VEGF is involved in VEGF receptor activation. The peptide designed to resemble this region shares numerous biological properties of VEGF, thus suggesting that this region is of potential interest for biomedical applications, and molecules mimicking it could be attractive for therapeutic and diagnostic applications.

The presence of a right bundle branch block (RBBB) is associated with increased mortality. We studied the role of dobutamine stress echocardiography for the prognostic stratification of patients with RBBB. The presence of an abnormal dobutamine stress echocardiography was the strongest predictor of cardiac events and provided incremental prognostic information to clinical and stress test data.

The segment 32-47 of the N-terminal extracellular domain of the type A cholecystokinin receptor, CCKA-R(32-47), was synthesized and structurally characterized in a membrane mimicking environment by CD, NMR and molecular dynamics calculations. The region of CCKA-R(32-47) encompassing residues 39-46 adopted a well-defined secondary structure in the presence of DPC micelles, whereas the conformation of the N-terminal region (segment 32-37) could not be uniquely defined by the NOE derived distance constraints because of local flexibility. The conformation of the binding domain of CCKA-R(32-47) was different from that found for the intact N-terminal receptor tail, CCKA-R(1-47). To assess whether CCKA-R(32-47) was still able to bind the nonsulfated cholecystokinin C-terminal octapeptide, CCK8, a series of titrations was carried out in SDS and DPC micelles, and the binding interaction was followed by fluorescence spectroscopy. These titrations gave no evidence for complex formation, whereas a high binding affinity was found between CCKA- R(1-47) and CCK8. The different affinities for the ligand shown by CCKA-R(32-47) and CCKA-R(1-47) were paralleled by different interaction modes between the receptor segments and the micelles. The interaction of CCKA-R(32-47) with DPC micelles was much weaker than that of CCKA-R(1-47), because the former receptor segment lacks proper stabilizing contacts with the micelle surface. In the case of SDS micelles CCKA-R(32-47) was found to form non-micellar adducts with the detergent that prevented the onset of a functionally significant interaction between the receptor segment and the micelle. It is concluded that tertiary structure interactions brought about by the 1-31 segment play a key role in the stabilization of the membrane bound, biologically active conformation of the N-terminal extracellular tail of the CCKA receptor. Copyright  2003 European Peptide Society and John Wiley & Sons, Ltd.

The interaction between the 1-47 N-terminus fragment of the cholecystokinin receptor and the nonsulfated cholecystokinin octapeptide, CCK8, is monitored by fluorescence emission. Quenching of the fluorescence intensities is observed on binding. Dissociation constants calculated by these data are in the same submicromolar range as found for the binding of linear CCK8 analogues to B-type receptors. Although detailed structural information cannot be obtained, fluorescence emission is more sensitive than other techniques and permits fast detection of receptor-ligand interaction.

Bronchial asthma is one of the most common chronic diseases worldwide, and by definition not expected to recover with aging. However, the concept that asthma can affect older individuals has been largely denied in the past. In clinical practice, asthma that occurs in the most advanced ages is often diagnosed as COPD, thus leading to undertreatment or improper treatment. The heterogeneity of clinical and functional presentation of geriatric asthma, including the partial loss of reversibility and of the allergic component, contributes to this misconception. A large body of evidence has accumulated demonstrating that the prevalence of asthma in the most advanced ages is similar to that in younger ages. The frequent coexistence of comorbid conditions in older patients compared to younger asthmatics, together with age-associated changes of the human lung, may render the management of asthma a complicated task. The article addresses the main issues related to the diagnosis and treatment of asthma in the geriatric age.

Expressing forced expiratory volume in 1 s (FEV1) as % predicted relies on the assumption of proportional variability and generalisability of prediction equations that may be unrealistic, especially for elderly people. We evaluated the prognostic implications of alternative ways of expressing FEV1. We enrolled 318 patients with chronic obstructive pulmonary disease (COPD) and 475 controls in the Salute Respiratoria nell'Anziano (SARA) study. The risk for 5-, 10- and 15-year mortality associated with FEV1 was studied by expressing FEV1 % pred, standardised by height cubed (FEV1 · Ht(-3)) and as a multiple of the sex-specific first percentile (FEV1 quotient (FEV1Q)). In the group with COPD, the incidence rate ratio for the worst versus the best quintile of FEV1Q was 4.65 (95% CI 2.33-10.37), compared to 2.98 (1.53-6.27) for FEV1 % pred and 3.95 (2.01-8.45) for FEV1 · Ht(-3). The corresponding incidence rate ratios at 15 years were 4.52 (2.84-7.43), 3.16 (2.02-5.07) and 3.52 (2.25-5.63), respectively. In the control group, even moderate reduction of FEV1Q was associated with long-term mortality, while FEV1 % pred was not associated with the outcome. FEV1Q may be more informative about prognosis in an elderly population compared to FEV1 % pred.

Background Clinical and epidemiologic evidence on asthma in the elderly is scant. There is evidence that forced expiratory volume in the first second (FEV 1 ), a commonly used indicator of overall pulmonary function, might not be an independent predictor of 5-year mortality in elderly patients with asthma. Objective To investigate the association between FEV 1 expressed using 3 alternative methods and 5-, 10-, and 15-year mortality in a population of elderly patients with asthma. Methods Participants in the Salute Respiratoria nell' Anziano study were included. Asthma was diagnosed at baseline according to spirometric and clinical data. Vital status at 15 years was assessed using death registries. FEV 1 was expressed as percentage of predicted, divided by height cubed, and as a multiple of the sex-specific first percentile. The association between FEV 1 and mortality was evaluated using Cox proportional hazard models. Results Two hundred patients were studied (52% women, mean age 73.1 years, standard deviation 6.2 years). All FEV 1 measurements were associated with mortality at unadjusted analysis. After correction for potential confounders, no association was found between FEV 1 and 5-year mortality. Only FEV 1 as a multiple of the sex-specific first percentile was independently associated with 10-year (hazard ratio 0.35, 95% confidence interval 0.14–0.87) and 15-year (hazard ratio 0.38, 95% confidence interval 0.19–0.79) mortality. Conclusion Although extensively used, FEV 1 expressed as percentage of predicted does not seem to be the best predictor of mortality in elderly patients with asthma. Although no spirometric index can predict 5-year mortality in this population, FEV 1 as a multiple of the sex-specific first percentile should be considered when longer-term prognostic stratification is needed.

Human beta-defensins (hBDs) are crucial peptides for the innate immune response and are thus prime candidates as therapeutic agents directed against infective diseases. Based on the properties of wild-type hBD1 and hBD3 and of previously synthesized analogs (1C, 3I, and 3N), we have designed a new analog, 3NI, and investigated its potential as an antimicrobial drug. Specifically, we evaluated the antimicrobial activities of 3NI versus those of hBD1, hBD3, 1C, 3I, and 3N. Our results show that 3NI exerted greater antibacterial activity against Pseudomonas aeruginosa , Escherichia coli , and Enterococcus faecalis than did hBD1 and hBD3, even with elevated salt concentrations. Moreover, its antiviral activity against herpes simplex virus 1 was greater than that of hBD1 and similar to that of hBD3. Subsequently, we investigated the cytotoxic effects of all peptides in three human epithelial carcinoma cell lines: A549 from lung, CaCo-2 from colon, and Capan-1 from pancreas. None of the analogs significantly reduced cell viability versus wild-type hBD1 and hBD3. They did not induce genotoxicity or cause an increase in the number of apoptotic cells. Using confocal microscopy, we also investigated the localization of the peptides during their incubation with epithelial cells and found that they were distributed on the cell surface, from which they were internalized. Finally, we show that hBD1 and hBD3 are characterized by high resistance to serum degradation. In conclusion, the new analog 3NI seems to be a promising anti-infective agent, particularly given its high salt resistance—a feature that is relevant in diseases such as cystic fibrosis.

This study analyzed the relations and time-related changes in eligibility for cardiac resynchronization therapy and prophylactic defibrillator implantation in 161 potential candidates for heart transplantation. Although up to 62% of patients who fulfilled the severity criteria for heart transplantation were eligible for either device, this percentage increased as clinical/instrumental parameters of heart failure severity worsened.

Peptide Nucleic Acids (PNAs), nucleic acid analogues showing high stability to enzyme degradation and strong affinity and specificity of binding toward DNA and RNA are widely investigated as tools to interfere in gene expression. Several studies have been focused on PNA analogues with modifications on the backbone and bases in the attempt to overcome solubility, uptake and aggregation issues. γ PNAs, PNA derivatives having a substituent in the γ position of the backbone show interesting properties in terms of secondary structure and affinity of binding toward complementary nucleic acids. In this paper we illustrate our results obtained on new analogues, bearing a sulphate in the γ position of the backbone, developed to be more DNA-like in terms of polarity and charge. The synthesis of monomers and oligomers is described. NMR studies on the conformational properties of monomers and studies on the secondary structure of single strands and triplexes are reported. Furthermore the hybrid stability and the effect of mismatches on the stability have also been investigated. Finally, the ability of the new analogue to work as antigene, interfering with the transcription of the ErbB2 gene on a human cell line overexpressing ErbB2 (SKBR3), assessed by FACS and qPCR, is described. © 2012 Avitabile et al.

Erythrocyte sedimentation rate (ESR) might represent a less expensive alternative to C-reactive protein (CRP) as a marker of systemic inflammation in stable chronic obstructive pulmonary disease (COPD). We tried to verify this hypothesis in 223 consecutive outpatients aged 65 years or more with stable COPD enrolled in a multicenter observational study. Patients were grouped according to normal/increased ESR/CRP values and groups were compared with regard to clinical and laboratory characteristics. Correlations between CRP, ESR and selected variables of interest were assessed by Spearman's ζ-test and multivariate linear regression analysis. CRP was weakly and inversely correlated with the forced expiratory volume in the first second (FEV1%) (Spearman's ζ = -0.15; p < 0.027), while ESR was not (Spearman's ζ = -0.05; p = 0.411). The highest prevalence of anemia and hypoalbuminemia and the lowest FEV1% were recorded in high ESR-high CRP group. For anemia B = 14.180 ± 3.521 (± S.E.M.); p = 0.001 and hypoalbuminemia B = 10.241 ± 3.790; p = 0.007 qualified as significant independent correlates of ESR values, while only FEV1 remained significantly associated with CRP values (B = -0.570 ± 0.258; p = 0.028). In conclusion, CRP, but not ESR, shows a weak correlation with COPD severity, while anemia and hypoalbuminemia are main correlates of high ESR. Neither ESR, nor CRP qualify as reliable markers of COPD severity and seem to reflect the effects of different determinants.

BACKGROUND: The ratio of forced expiratory volume in 1 s and forced expiratory volume in 6 s (FEV1/FEV6) has been proposed as an alternative for FEV1/forced vital capacity (FVC) to diagnose obstructive diseases with less effort during spirometry; however, its prognostic value is unknown. We evaluated whether FEV1/FEV6 is a significant predictor of mortality in elderly subjects and compared its prognostic value with that of FEV1/FVC and FEV1. METHODS: One thousand nine hundred and seventy-one subjects, aged >65 years, participated in the population-based SA.R.A. study. During the baseline exam, a multidimensional assessment included spirometry. Vital status was determined during 6 years of follow-up. Association of all-cause, cardio-pulmonary (CP) and non-CP mortality with a low FEV1/FEV6, FEV1/FVC and FEV1 was evaluated. RESULTS: Among subjects with both survival data and acceptable spirometry including FEV6, all-cause unadjusted mortality rates were 7.00 and 2.46 per 100 person-years in subjects with FEV1/FEV6 less than and greater than or equal to lower limit of normal (LLN), respectively (mortality rate ratio: 2.84, 95%CI: 2.12-3.84). After adjustment for age, gender, FVC, smoke exposure and main comorbidities, the risk of all-cause mortality remained significantly increased in subjects with FEV1/FEV6

Chronic obstructive pulmonary disease (COPD) and ageing may contribute to malnutrition. We aimed to explore whether COPD and ageing determine malnutrition in different manners. 460 stable COPD outpatients (376 males and 84 females) from the Extrapulmonary Consequences of COPD in the Elderly (ECCE) study database were investigated (age 75.0±5.9 yrs; forced expiratory volume in 1 s 54.7±18.3% predicted). Nutritional status was evaluated using the Mini Nutritional Assessment® (MNA) questionnaire. From the MNA, three scores exploring the domains of the nutritional status were calculated: body composition, energy intake and body functionality scores. Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages were negatively correlated with five MNA items exploring mobility, patient ’ s perception of own nutrition and health status, and arm and calf circumferences (lowest Spearman’s rho (r s ) = -0.011; highest p = 0.039). GOLD stages were independently correlated with body composition and body functionality scores (model r 2 = 0.073). Age was negatively correlated with four MNA items exploring loss of appetite, fluid intake, mobility and autonomy in daily life (lowest r s = -0.013; highest p = 0.030). Age was independently correlated with body functionality score (model r 2 = 0.037). Severe COPD and ageing are independent and probably concurrent conditions leading to malnutrition. The MNA questionnaire allows a valuable insight into the complexity of components of nutritional status and may provide useful clues for treatment strategies.

Angiogenesis is a fundamental process underlining physiological and pathological conditions. It is mainly regulated by the vascular endothelial growth factor (VEGF) and its receptors, which are the main targets of molecules able to modulate the angiogenic response. Pharmaceutical therapies based on antiangiogenic drugs represent a promising approach for the treatment of several socially important diseases. We report the biological and structural characterization of a VEGF receptor binder peptide designed on the N-terminal helix of VEGF. The reported experimental evidence shows that the peptide assumes in water a well-defined helical conformation and indicates that this peptide is a VEGF receptor antagonist and possesses antiangiogenic biological activity. In particular, it inhibits VEGF stimulated endothelial cell proliferation, activation, and survival, as well as angiogenesis and tumor progression in vivo. This peptide is a candidate for the development of novel peptide-based drugs for the treatment of diseases associated with excessive VEGF-dependent angiogenesis. © 2011 American Chemical Society.

Apurinic/apyrimidinic endonuclease 1 (APE1), an essential protein in mammals, is involved in base excision DNA repair (BER) and in regulation of gene expression, acting as a redox co-activator of several transcription factors. Recent findings highlight a novel role for APE1 in RNA metabolism, which is modulated by nucleophosmin (NPM1). The results reported in this article show that five lysine residues (K24, K25, K27, K31 and K32), located in the APE1 N-terminal unstructured domain, are involved in the interaction of APE1 with both RNA and NPM1, thus supporting a competitive binding mechanism. Data from kinetic experiments demonstrate that the APE1 N-terminal domain also serves as a device for fine regulation of protein catalytic activity on abasic DNA. Interestingly, some of these critical lysine residues undergo acetylation in vivo. These results suggest that protein-protein interactions and/or post-translational modifications involving APE1 N-terminal domain may play important in vivo roles, in better coordinating and fine-tuning protein BER activity and function on RNA metabolism.

Human beta-defensins (hBDs) are antimicrobial peptides of human innate immunity. The antibacterial activities of hBDs 1, 2, and 4 but not the activity of hBD3 are impaired by high salt levels. We have designed and synthesized seven novel hBD analogs, constituted by different domains of hBD1 (which is constitutively expressed in humans) and of hBD3 (which is induced by microorganisms and inflammatory factors in humans), that would maintain and potentially increase the wild-type antimicrobial activities and be salt resistant. We have compared the antibacterial, antiviral, and chemotactic activities of the analogs with those of hBD1 and hBD3. We show that the hBD1 internal region and the hBD3 C-terminal region are critical for antibacterial activity also at high salt concentrations, whereas deletion of the N-terminal region of hBD3 results in an increase in antibacterial activity. All analogs inhibited herpes simplex virus; antiviral activity was enhanced by the hBD1 internal region and the hBD3 C-terminal region. Wild-type and analog peptides were chemotactic for granulocytes and monocytes, irrespective of the salt concentrations. These new peptides may have therapeutic potential.

Objectives: The deciphering of intracellular signaling pathways that are activated by the interaction between viral fusion peptides and cellular membranes are important for the understanding of both viral replication strategies and host defense mechanisms. Methods: Fusion peptides of several enveloped viruses belonging to different virus families were prepared by standard 9-fluorenylmethoxycarbonyl polyamine solid-phase synthesis and used to stimulate U937 cells in vitro to analyze the phosphorylation patterns of the signaling pathways (PKC, Src, Akt, and MAPK pathways). Immunoprecipitation and Western blotting were carried out by using phosphospecific antibodies. All samples were also assayed for the presence of IL-10 and IFN-β by ELISA and activation of nuclear factors (AP-1 and NF-ĸB). Results: We have demonstrated that hydrophobic domains of fusion proteins are able to induce several transduction pathways that lead to cytokine (IFN-β and IL-10) production, an event that appears to be dependent on early activation of AP-1 and NF-ĸB. Conclusions: The results obtained on the signaling activity of fusion peptides from different viruses enabled us to shed some light on the complex mechanism of viral entry and more precisely we focused on the exact signaling event induced by hydrophobic domains characteristic of fusion peptides interacting with the cell membrane.

BACKGROUND AND OBJECTIVE: The Saint George Respiratory Questionnaire (SGRQ) is widely used as a measure of health-related quality of life (HRQL) in patients with COPD. This study tested whether the SGRQ predicts the survival of patients with COPD. METHODS: The study recruited 238 patients with COPD who were participants in the multicentre Salute Respiratoria nell'Anziano (Sa.R.A.) study. Patients' sociodemographic, clinical and functional characteristics were assessed and the association between the SGRQ and mortality, corrected for potential confounders, was estimated. RESULTS: The mean age of study participants was 72.6 years. Over the 5-year observation period there were 88 deaths. After adjustment for potential confounders, the SGRQ score was associated with an increased risk of dying (hazard ratio (HR): 1.22 for four-point increments; 95% confidence interval (CI): 1.02-1.45). There was no association between mortality and the Symptoms subscale (corrected HR: 1.13; 95% CI: 0.96-1.32), whereas each four-point increment of the Activity (HR: 1.20; 95% CI: 1.00-1.43) and Impact (HR: 1.38; 95% CI: 1.03-1.83) subscale scores were associated with increased mortality. Higher FEV(1) relative to predicted (HR: 0.73 for each 5% increment; 95% CI: 0.58-0.91) and better performance at the 6-min walking test relative to predicted (HR: 0.93 for each 5% increment; 95% CI: 0.89-0.97) were associated with lower mortality. CONCLUSIONS: In elderly COPD patients, the SGRQ can improve prognostic models based on classical indicators of disease severity.

We studied 54 patients with hypoxemic chronic obstructive pulmonary disease (COPD). The Mini Mental State Examination and the Mental Deterioration Battery were used for neuropsychological assessment. Heart rate variability (HRV) was assessed based on 24-h Holter ECG recording. Mann-Whitney test was used to compare HRV parameters of patients performing normally or abnormally on individual neuropsychological tasks. Spearman's rho was used to investigate the correlations between HRV parameters and neuropsychological scores, indexes of health status or COPD severity. Patients with defective performance at copying drawings with landmarks (CDL) test (N = 23) had lower very low frequency (VLF) power with respect to patients with normal performance (N = 31) (24 h: median 213; interquartile range 120-282 vs. 309; 188-431 ms2, p = 0.043; daytime: 202; 111-292 vs. 342; 194-397 ms2, p = 0.039). The CDL score correlated with the VLF power (24 h: rho = 0.27, p = 0.049; daytime: rho = 0.30, p = 0.028), and the normalized low frequency/high frequency (LF/HF) ratio (24 h: rho = 0.27, p = 0.05; daytime: rho = 0.33, p = 0.015). Sympathetic modulation decreased for increasing severity of COPD. In conclusion, drawing impairment correlates with depressed sympathetic modulation in patients with COPD, and both might be indexes of COPD severity.

PED (Phosphoprotein Enriched in Diabetes) is an ubiquitously expressed 15 kDa cytosolic protein with recognized multiple functions. It has been demonstrated that PED has broad anti-apoptotic properties1,2 and, by altering insulin secretion, has a proven implication in diabetes3. In cultured cells and in transgenic mice, PED overexpression induces insulin-resistance and impairs glucose tolerance. Recent evidence indicates that increased interaction of PED with Phospholipase D1 (hPLD1) is a key event leading to these abnormalities in vivo and that this interaction is mediated by a C-terminal domain of PLD1 comprising residues 712–1070, D44. To further study this interaction, we prepared the recombinant proteins/sub-domains and after purification and preliminary characterization by CD, we measured the KDby SPR. Furthermore, following an approach of protein fragmentation and peptide fractionation we have been able to identify regions on PED that are involved in the...

Background The association between bronchial obstruction severity and mortality in Chronic Obstructive Pulmonary Disease (COPD) is well established, but it is unknown whether disease-specific health status measures and multidimensional assessment (MDA) have comparable prognostic value. Methods We analyzed data coming from the Salute Respiratoria nell'Anziano (Respiratory Health in the Elderly – SaRA) study, enrolling elderly people attending outpatient clinics for respiratory and non-respiratory problems. From this population we selected 449 patients with bronchial obstruction (77.3% men, mean age 73.1). We classified patients' health status using tertiles of the Saint George Respiratory Questionnaire (SGRQ) and a MDA including functional (the 6' walking test, WT), cognitive (Mini-Mental State Examination, MMSE) and affective status (Geriatric Depression Scale, GDS). The agreement of the classification methods was calculated using the kappa statistic, and survival associated with group membership was evaluated using survival analysis. Results Pulmonary function, expressed by the FEV1, worsened with increasing SGRQ or MDA scores. Cognitive function was not associated with the SGRQ, while physical performance and mood status were impaired only in the highest tertile of SGRQ. A poor agreement was found between the two classification systems tested (k = 0.194). Compared to people in the first tertile of SGRQ score, those in the second tertile had a sex-adjusted HR of 1.22 (0.75 – 1.98) and those in the third tertile of 2.90 (1.92 – 4.40). The corresponding figures of the MDA were 1.49 (95% CI 1.02 – 2.18) and 2.01 (95% CI: 1.31 – 3.08). After adjustment for severity of obstruction, only a SGRQ in the upper tertile was associated with mortality (HR: 1.86; 95% CI: 1.14 – 3.02). Conclusion In elderly outpatients with mild-moderate COPD, a disease-specific health status index seems to be a better predictor of death compared to a MDA.