Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study.

BACKGROUND: Hypertension can be controlled adequately with existing drugs such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Nevertheless, treatment success is often restricted by patients not adhering to treatment. Immunisation against angiotensin II could solve this problem. We investigated the safety and efficacy of CYT006-AngQb-a vaccine based on a virus-like particle-that targets angiotensin II to reduce ambulatory blood pressure. METHODS: In this multicentre, double-blind, randomised, placebo-controlled phase IIa trial, 72 patients with mild-to-moderate hypertension were randomly assigned with a computer-generated randomisation list to receive subcutaneous injections of either 100 mug CYT006-AngQb (n=24), 300 mug CYT006-AngQb (24), or placebo (24), at weeks 0, 4, and 12. 24-h ambulatory blood pressure was measured before treatment and at week 14. The primary outcomes were safety and tolerability. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00500786. FINDINGS: Two patients in the 100 mug group, three in the 300 mug group, and none in the placebo group discontinued study treatment. All patients were included in safety analyses; efficacy analyses did not include the five dropouts, for whom no data were available at week 14. Five serious adverse events were reported (two in the 100 mug group, two in the 300 mug group, and one in the placebo group); none were deemed to be treatment related. Most side-effects were mild, transient reactions at the injection site. Mild, transient influenza-like symptoms were seen in three patients in the 100 mug group, seven in the 300 mug group, and none in the placebo group. In the 300 mug group, there was a reduction from baseline in mean ambulatory daytime blood pressure at week 14 by -9.0/-4.0 mm Hg compared with placebo (p=0.015 for systolic and 0.064 for diastolic). The 300 mug dose reduced the early morning blood-pressure surge compared with placebo (change at 0800 h -25/-13 mm Hg; p<0.0001 for systolic, p=0.0035 for diastolic). INTERPRETATION: Immunisation with CYT006-AngQb was associated with no serious adverse events; most observed adverse events were consistent with local or systemic responses similar to those seen with other vaccines. The 300 mug dose reduced blood pressure in patients with mild-to-moderate hypertension during the daytime, especially in the early morning. FUNDING: Cytos Biotechnology AG.

Multivariate QST-FST comparisons: a neutrality test for the evolution of the g matrix in structured populations.

Neutrality tests in quantitative genetics provide a statistical framework for the detection of selection on polygenic traits in wild populations. However, the existing method based on comparisons of divergence at neutral markers and quantitative traits (Q(st)-F(st)) suffers from several limitations that hinder a clear interpretation of the results with typical empirical designs. In this article, we propose a multivariate extension of this neutrality test based on empirical estimates of the among-populations (D) and within-populations (G) covariance matrices by MANOVA. A simple pattern is expected under neutrality: D = 2F(st)/(1 - F(st))G, so that neutrality implies both proportionality of the two matrices and a specific value of the proportionality coefficient. This pattern is tested using Flury's framework for matrix comparison [common principal-component (CPC) analysis], a well-known tool in G matrix evolution studies. We show the importance of using a Bartlett adjustment of the test for the small sample sizes typically found in empirical studies. We propose a dual test: (i) that the proportionality coefficient is not different from its neutral expectation [2F(st)/(1 - F(st))] and (ii) that the MANOVA estimates of mean square matrices between and among populations are proportional. These two tests combined provide a more stringent test for neutrality than the classic Q(st)-F(st) comparison and avoid several statistical problems. Extensive simulations of realistic empirical designs suggest that these tests correctly detect the expected pattern under neutrality and have enough power to efficiently detect mild to strong selection (homogeneous, heterogeneous, or mixed) when it is occurring on a set of traits. This method also provides a rigorous and quantitative framework for disentangling the effects of different selection regimes and of drift on the evolution of the G matrix. We discuss practical requirements for the proper application of our test in empirical studies and potential extensions.

Seroepidemiology of Herpes Simplex virus type 1 and 2 in Western and Southern Switzerland in adults aged 25-74 in 1992-93: a population-based study.

BACKGROUND: Genital herpes is one of the most prevalent sexually-transmitted diseases, and accounts for a substantial morbidity. Genital herpes puts newborns at risk for very severe disease and also increases the risk of horizontal HIV transmission. It thus stands as an important public health problem. The recent availability of type-specific gG-based assays detecting IgG against HSV-1 and HSV-2 allows to establish the prevalence of each subtype. Worldwide, few data have been published regarding the seroprevalence in general populations of HSV-2, the major causative agent for genital herpes, while no data exist regarding the Swiss population. METHODS: To evaluate the prevalence of IgG antibodies against HSV-1 and HSV-2 in Switzerland, we used a population-based serum repository from a health examination survey conducted in the Western and Southern area of Switzerland in 1992-93. A total of 3,120 sera were analysed by type-specific gG-based ELISA and seroprevalence was correlated with available volunteers characteristics by logistic regression. RESULTS: Overall, seroprevalence rates were 80.0 +/- 0.9% (SE, 95% CI: 78.1-81.8) for HSV-1 and 19.3 +/- 0.9% (SE, 95% CI: 17.6-21.1) for HSV-2 in adults 35-64 year old. HSV-1 and HSV-2 seroprevalence increased with age, with a peak HSV-2 seroprevalence in elderly gentlemen, possibly a seroarcheological evidence of sexually transmitted disease epidemics during World War II. Risk factors for HSV-2 infection included female sex, marital status other than married, and size of town of residence larger than 1500 inhabitants. Unexpectedly and conversely to HSV-1, HSV-2 seroprevalence increased with educational level. HSV-2 infection was less prevalent among HSV-1 infected individuals when compared to HSV-1 uninfected individuals. This effect was most apparent among women at high risk for HSV-2 infection. CONCLUSIONS: Our data demonstrate that by the early nineties, HSV-2 had spread quite largely in the Swiss population. However, the epidemiology of HSV-2 in Switzerland presents paradoxical characteristics, e.g. positive correlation with education level, that have not been observed elsewhere.

Overlapping, additive and counterregulatory effects of type II and I interferons on myeloid dendritic cell functions.

Dendritic cells (DCs) are central player in immunity by bridging the innate and adaptive arms of the immune system (IS). Interferons (IFNs) are one of the most important factors that regulate both innate and adaptive immunity too. Thus, the understanding of how type II and I IFNs modulate the immune-regulatory properties of DCs is a central issue in immunology. In this paper, we will address this point in the light of the most recent literature, also highlighting the controversial data reported in the field. According to the wide literature available, type II as well as type I IFNs appear, at the same time, to collaborate, to induce additive effects or overlapping functions, as well as to counterregulate each one's effects on DC biology and, in general, the immune response. The knowledge of these effects has important therapeutic implications in the treatment of infectious/autoimmune diseases and cancer and indicates strategies for using IFNs as vaccine adjuvants and in DC-based immune therapeutic approaches.

La transición en la sociedad red en Catalunya. Informe final de investigación (volumen II)

Aquest estudi analitza les pràctiques diàries, els valors socials i les actituds de la població catalana en el procés de transició cap a la societat xarxa. Analitza el comportament de les persones a Internet i fora d'Internet, investigant el paper específic dels usos d'Internet a l'hora d'influenciar pràctiques i actituds. Es basa en les respostes a una enquesta de 3.005 individus, una mostra representativa de la població catalana el 2002. L'enquesta es va fer entre el febrer i el maig del 2002, i es basava en entrevistes cara a cara a partir d'un qüestionari de 179 preguntes. Es van utilitzar fonts secundàries per a situar els resultats catalans, particularment sobre els usos d'Internet, en el context global. L'anàlisi es va completar el 2007 incorporant-hi noves dades secundàries. L'estudi va cobrir pràctiques socials de treball, comunicació, sociabilitat, usos d'espai i temps, usos d'Internet, identitat cultural, pràctica política, associacionisme i formació de projectes d'autonomia. Es van construir diversos models estadístics per a proporcionar una anàlisi causal de cada una d'aquestes àrees d'estudi. El descobriment més significatiu fa referència a la relació entre els usos d'Internet i la construcció d'autonomia per part d'actors socials. Fent servir anàlisis factorial, l'estudi va definir cinc índexs d'autonomia que eren estadísticament independents: autonomia personal, autonomia professional, autonomia comunicativa, autonomia corporal i autonomia sociopolítica. Cada un d'aquests índexs d'autonomia independents estan fortament associats amb la freqüència i la intensitat de l'ús d'Internet, i les relacions observades es mantenen quan es controlen per variables sociodemogràfiques. A partir d'aquest estudi es pot afirmar que Internet és una plataforma important per a la construcció d'autonomia en la societat xarxa. En general, la societat catalana sembla que canviï de manera similar a altres societats en transició, amb l'èmfasi afegit del paper del territori i la família a l'hora d'enfortir les relacions socials, amb la contribució positiva d'Internet a un dens patró d'interacció social.

E-governança i atenció ciutadana : la Generalitat de Catalunya en el context internacional. Informe de recerca (Vol.II)

Aquest estudi té com a objectiu principal analitzar les transformacions que s'esdevenen al voltant de la incorporació d'innovacions tecnològiques de l'entorn de les TIC en els processos d'atenció al ciutadà per part de les administracions públiques. Les transformacions que hem analitzat tenen a veure amb tres dimensions que hem considerat bàsiques. D'una banda, ens hem centrat en els canvis que es produeixen en la forma en què els ciutadans (com a principals, tot i que no únics, usuaris) i l'administració es relacionen entre sí. De l'altra hem analitzat les transformacions que s'esdevenen en el funcionament intern i en la pròpia organització de l'administració arran de les transformacions dels canals de comunicació amb els usuaris. Per últim, hem considerat els canvis en la forma de gestionar (dissenyar, planificar, organitzar i dur a terme) el canvi i la innovació, tenint en compte especialment els rols dels diferents actors (no només públics) que hi participen. La recerca es recolza en un ampli estudi empíric sobre la Generalitat de Catalunya i en un estudi compartiu internacional sobre el Quebec, Emillia-Romagna i Escòcia.

L'escola a la societat xarxa : Internet a l'educació primària i secundària. Informe final de recerca (volum II)

Aquest projecte té la intenció d'identificar i analitzar els efectes de la introducció d'Internet a les escoles catalanes (educació primària i secundària). L'objectiu és posar de manifest la manera com s'utilitza la xarxa en aquest àmbit i en quina mesura contribueix a l'aparició, en els centres educatius, d'una nova cultura adaptada a les necessitats de la societat xarxa. Amb aquest propòsit, aquest projecte desplega les seves línies d'anàlisi per a fer atenció al procés d'incorporació d'Internet, principalment, en tres direccions: la pràctica pedagògica, les formes d'organització i gestió dels centres educatius i la seva vinculació amb la comunitat i el territori. Aquesta investigació ha estat desenvolupada pel grup de recerca ENS (Education and Network Society). Amb una perspectiva comparativa, el treball d'aquest grup vol contribuir, sobre la base de dades empíriques, a interpretar la transformació de l'àmbit educatiu no universitari en els paràmetres que estableix, avui dia, la nostra societat.

La transició a la societat xarxa a Catalunya. Informe final de recerca (volum II)

Aquest estudi analitza les pràctiques diàries, els valors socials i les actituds de la població catalana en el procés de transició cap a la societat xarxa. Analitza el comportament de les persones a Internet i fora d'Internet, investigant el paper específic dels usos d'Internet a l'hora d'influenciar pràctiques i actituds. Es basa en les respostes a una enquesta de 3.005 individus, una mostra representativa de la població catalana el 2002. L'enquesta es va fer entre el febrer i el maig del 2002, i es basava en entrevistes cara a cara a partir d'un qüestionari de 179 preguntes. Es van utilitzar fonts secundàries per a situar els resultats catalans, particularment sobre els usos d'Internet, en el context global. L'anàlisi es va completar el 2007 incorporant-hi noves dades secundàries. L'estudi va cobrir pràctiques socials de treball, comunicació, sociabilitat, usos d'espai i temps, usos d'Internet, identitat cultural, pràctica política, associacionisme i formació de projectes d'autonomia. Es van construir diversos models estadístics per a proporcionar una anàlisi causal de cada una d'aquestes àrees d'estudi. El descobriment més significatiu fa referència a la relació entre els usos d'Internet i la construcció d'autonomia per part d'actors socials. Fent servir anàlisis factorial, l'estudi va definir cinc índexs d'autonomia que eren estadísticament independents: autonomia personal, autonomia professional, autonomia comunicativa, autonomia corporal i autonomia sociopolítica. Cada un d'aquests índexs d'autonomia independents estan fortament associats amb la freqüència i la intensitat de l'ús d'Internet, i les relacions observades es mantenen quan es controlen per variables sociodemogràfiques. A partir d'aquest estudi es pot afirmar que Internet és una plataforma important per a la construcció d'autonomia en la societat xarxa. En general, la societat catalana sembla que canviï de manera similar a altres societats en transició, amb l'èmfasi afegit del paper del territori i la família a l'hora d'enfortir les relacions socials, amb la contribució positiva d'Internet a un dens patró d'interacció social.

Appropriate end-points for right results in the age of antiangiogenic agents: Future options for phase II trials in patients with recurrent glioblastoma.

The progression-free survival rate at 6months (PFS-6) has long been considered the best end-point for assessing the efficacy of new agents in phase II trials in patients with recurrent glioblastoma. However, due to the introduction of antiangiogenic agents in this setting, and their intrinsic propensity to alter neuroradiological disease assessment by producing pseudoregression, any end-point based on neuroradiological modifications should be reconsidered. Further, statistically significant effects on progression-free survival (PFS) only should not automatically be considered reliable evidence of meaningful clinical benefit. In this context, because of its direct and unquestionable clinical relevance, overall survival (OS) represents the gold standard end-point for measuring clinical efficacy, despite the disadvantage that it is influenced by subsequent therapies and usually takes longer time to be evaluated. Therefore, while awaiting novel imaging criteria for response evaluation and/or new imaging tools to distinguish between 'true' and 'pseudo'-responses to antiangiogenic agents, the measurement of OS or OS rates should be considered primary end-points, also in phase II trials with these agents.

Diagnostic accuracy of the Eurotest for dementia: a naturalistic, multicenter phase II study

BACKGROUND Available screening tests for dementia are of limited usefulness because they are influenced by the patient's culture and educational level. The Eurotest, an instrument based on the knowledge and handling of money, was designed to overcome these limitations. The objective of this study was to evaluate the diagnostic accuracy of the Eurotest in identifying dementia in customary clinical practice. METHODS A cross-sectional, multi-center, naturalistic phase II study was conducted. The Eurotest was administered to consecutive patients, older than 60 years, in general neurology clinics. The patients' condition was classified as dementia or no dementia according to DSM-IV diagnostic criteria. We calculated sensitivity (Sn), specificity (Sp) and area under the ROC curves (aROC) with 95% confidence intervals. The influence of social and educational factors on scores was evaluated with multiple linear regression analysis, and the influence of these factors on diagnostic accuracy was evaluated with logistic regression. RESULTS Sixteen neurologists recruited a total of 516 participants: 101 with dementia, 380 without dementia, and 35 who were excluded. Of the 481 participants who took the Eurotest, 38.7% were totally or functionally illiterate and 45.5% had received no formal education. Mean time needed to administer the test was 8.2+/-2.0 minutes. The best cut-off point was 20/21, with Sn = 0.91 (0.84-0.96), Sp = 0.82 (0.77-0.85), and aROC = 0.93 (0.91-0.95). Neither the scores on the Eurotest nor its diagnostic accuracy were influenced by social or educational factors. CONCLUSION This naturalistic and pragmatic study shows that the Eurotest is a rapid, simple and useful screening instrument, which is free from educational influences, and has appropriate internal and external validity.

Towards a real-time vision-based navigation system for a small-class UUV

This paper deals with the problem of navigation for an unmanned underwater vehicle (UUV) through image mosaicking. It represents a first step towards a real-time vision-based navigation system for a small-class low-cost UUV. We propose a navigation system composed by: (i) an image mosaicking module which provides velocity estimates; and (ii) an extended Kalman filter based on the hydrodynamic equation of motion, previously identified for this particular UUV. The obtained system is able to estimate the position and velocity of the robot. Moreover, it is able to deal with visual occlusions that usually appear when the sea bottom does not have enough visual features to solve the correspondence problem in a certain area of the trajectory

Homology modeling and metabolism prediction of human carboxylesterase-2 using docking analyses by GriDock: a parallelized tool based on AutoDock 4.0.

Metabolic problems lead to numerous failures during clinical trials, and much effort is now devoted to developing in silico models predicting metabolic stability and metabolites. Such models are well known for cytochromes P450 and some transferases, whereas less has been done to predict the activity of human hydrolases. The present study was undertaken to develop a computational approach able to predict the hydrolysis of novel esters by human carboxylesterase hCES2. The study involved first a homology modeling of the hCES2 protein based on the model of hCES1 since the two proteins share a high degree of homology (congruent with 73%). A set of 40 known substrates of hCES2 was taken from the literature; the ligands were docked in both their neutral and ionized forms using GriDock, a parallel tool based on the AutoDock4.0 engine which can perform efficient and easy virtual screening analyses of large molecular databases exploiting multi-core architectures. Useful statistical models (e.g., r (2) = 0.91 for substrates in their unprotonated state) were calculated by correlating experimental pK(m) values with distance between the carbon atom of the substrate's ester group and the hydroxy function of Ser228. Additional parameters in the equations accounted for hydrophobic and electrostatic interactions between substrates and contributing residues. The negatively charged residues in the hCES2 cavity explained the preference of the enzyme for neutral substrates and, more generally, suggested that ligands which interact too strongly by ionic bonds (e.g., ACE inhibitors) cannot be good CES2 substrates because they are trapped in the cavity in unproductive modes and behave as inhibitors. The effects of protonation on substrate recognition and the contrasting behavior of substrates and products were finally investigated by MD simulations of some CES2 complexes.

Identification of Mycobacterium tuberculosis complex based on amplification and sequencing of the oxyR pseudogene from stored Ziehl-Neelsen-stained sputum smears in Brazil

A cross-sectional analysis of stored Ziehl-Neelsen (ZN)-stained sputum smear slides (SSS) obtained from two public tuberculosis referral laboratories located in Juiz de Fora, Minas Gerais, was carried out to distinguish Mycobacterium bovis from other members of the Mycobacterium tuberculosis complex (MTC). A two-step approach was used to distinguish M. bovis from other members of MTC: (i) oxyR pseudogene amplification to detect MTC and, subsequently, (ii) allele-specific sequencing based on the polymorphism at position 285 of this gene. The oxyR pseudogene was successfully amplified in 100 of 177 (56.5%) SSS available from 99 individuals. No molecular profile of M. bovis was found. Multivariate analysis indicated that acid-fast bacilli (AFB) results and the source laboratory were associated (p < 0.05) with oxyR pseudogene amplification. SSS that were AFB++ SSS showed more oxyR pseudogene amplification than those with AFB0, possibly due to the amount of DNA. One of the two source laboratories presented a greater chance of oxyR pseudogene amplification, suggesting that differences in sputum conservation between laboratories could have influenced the preservation of DNA. This study provides evidence that stored ZN-SSS can be used for the molecular detection of MTC.

Drugs Associated with Hepatotoxicity and their Reporting Frequency of Liver Adverse Events in VigiBase (TM) Unified List Based on International Collaborative Work

BACKGROUND Challenges exist in the clinical diagnosis of drug-induced liver injury (DILI) and in obtaining information on hepatotoxicity in humans. OBJECTIVE (i) To develop a unified list that combines drugs incriminated in well vetted or adjudicated DILI cases from many recognized sources and drugs that have been subjected to serious regulatory actions due to hepatotoxicity; and (ii) to supplement the drug list with data on reporting frequencies of liver events in the WHO individual case safety report database (VigiBase). DATA SOURCES AND EXTRACTION (i) Drugs identified as causes of DILI at three major DILI registries; (ii) drugs identified as causes of drug-induced acute liver failure (ALF) in six different data sources, including major ALF registries and previously published ALF studies; and (iii) drugs identified as being subjected to serious governmental regulatory actions due to their hepatotoxicity in Europe or the US were collected. The reporting frequency of adverse events was determined using VigiBase, computed as Empirical Bayes Geometric Mean (EBGM) with 90% confidence interval for two customized terms, 'overall liver injury' and 'ALF'. EBGM of >or=2 was considered a disproportional increase in reporting frequency. The identified drugs were then characterized in terms of regional divergence, published case reports, serious regulatory actions, and reporting frequency of 'overall liver injury' and 'ALF' calculated from VigiBase. DATA SYNTHESIS After excluding herbs, supplements and alternative medicines, a total of 385 individual drugs were identified; 319 drugs were identified in the three DILI registries, 107 from the six ALF registries (or studies) and 47 drugs that were subjected to suspension or withdrawal in the US or Europe due to their hepatotoxicity. The identified drugs varied significantly between Spain, the US and Sweden. Of the 319 drugs identified in the DILI registries of adjudicated cases, 93.4% were found in published case reports, 1.9% were suspended or withdrawn due to hepatotoxicity and 25.7% were also identified in the ALF registries/studies. In VigiBase, 30.4% of the 319 drugs were associated with disproportionally higher reporting frequency of 'overall liver injury' and 83.1% were associated with at least one reported case of ALF. CONCLUSIONS This newly developed list of drugs associated with hepatotoxicity and the multifaceted analysis on hepatotoxicity will aid in causality assessment and clinical diagnosis of DILI and will provide a basis for further characterization of hepatotoxicity.

Use of palliative radiotherapy in brain and bone metastases (VARA II study).

INTRODUCTION Metastases are detected in 20% of patients with solid tumours at diagnosis and a further 30% after diagnosis. Radiation therapy (RT) has proven effective in bone (BM) and brain (BrM) metastases. The objective of this study was to analyze the variability of RT utilization rates in clinical practice and the accessibility to medical technology in our region. PATIENTS AND METHODS We reviewed the clinical records and RT treatment sheets of all patients undergoing RT for BM and/or BrM during 2007 in the 12 public hospitals in an autonomous region of Spain. Data were gathered on hospital type, patient type and RT treatment characteristics. Calculation of the rate of RT use was based on the cancer incidence and the number of RT treatments for BM, BrM and all cancer sites. RESULTS Out of the 9319 patients undergoing RT during 2007 for cancer at any site, 1242 (13.3%; inter-hospital range, 26.3%) received RT for BM (n = 744) or BrM (n = 498). These 1242 patients represented 79% of all RT treatments with palliative intent, and the most frequent primary tumours were in lung, breast, prostate or digestive system. No significant difference between BM and BrM groups were observed in: mean age (62 vs. 59 yrs, respectively); gender (approximately 64% male and 36% female in both); performance status (ECOG 0-1 in 70 vs. 71%); or mean distance from hospital (36 vs. 28.6 km) or time from consultation to RT treatment (13 vs. 14.3 days). RT regimens differed among hospitals and between patient groups: 10 × 300 cGy, 5 × 400 cGy and 1x800cGy were applied in 32, 27 and 25%, respectively, of BM patients, whereas 10 × 300cGy was used in 49% of BrM patients. CONCLUSIONS Palliative RT use in BM and BrM is high and close to the expected rate, unlike the global rate of RT application for all cancers in our setting. Differences in RT schedules among hospitals may reflect variability in clinical practice among the medical teams.