Tidal Expiratory Flow Limitation at Rest as a Functional Marker of Pulmonary Emphysema in Moderate-to-Severe COPD

Background: Tidal expiratory flow limitation (EFL) is a step of paramount importance in the functional decline in COPD. Among mechanisms contributing to EFL, loss of airway-parenchymal interdependence could mostly be involved. Aim: To assess if EFL is a functional marker more frequently linked to prevalent pulmonary emphysema rather than to prevalent chronic bronchiolitis in COPD patients with moderate-to-severe airflow obstruction. Methods: Forty consecutive stable COPD patients with FEV₁ between 59 and 30% of predicted were functionally evaluated by measuring spirometry, maximal flow-volume curve and lung diffusion capacity (DL_CO) and coefficient of diffusion (K_CO). EFL was assessed by the negative expiratory pressure (NEP) method both in sitting and supine position. Chronic dyspnea was also scored by modified Medical Research Council (mMRC) scale. Results: In sitting position 13 patients (33%) were flow limited (FL) and 27 were non-flow limited (NFL). Only FEV₁/FVC, FEV₁ and MEF_25–75% were different between FL and NFL patients (p < 0.01). In supine position, however, among NFL patients in sitting position those who developed EFL, had significantly lower values of DL_CO and K_CO (p < 0.05) and higher mMRC score (p < 0.01), but similar values of FEV₁ as compared to those who did not have EFL. Conclusions: In COPD EFL in sitting position is highly dependent by the severity of airflow obstruction. In contrast, the occurrence of EFL in supine position is associated with worse DL_CO and K_CO and greater chronic dyspnea, reflecting a prevalent emphysematous phenotype in moderate-to-severe COPD patients.     

Spatial-temporal variation of parasites in Cnemidophorus ocellifer (Teiidae) and Tropidurus hispidus and Tropidurus semitaeniatus (Tropiduridae) from Caatinga areas in northeastern Brazil

Parasites are natural regulators of their host populations. Despite this, little is known about variations in parasite composition (spatially or temporally) in environments subjected to water-related periodic stress such as the arid and semiarid regions. The objective of this study was to evaluate the spatial-temporal variation in endoparasite species’ abundance and richness in populations of Neotropical Cnemidophorus ocellifer, Tropidurus hispidus, and Tropidurus semitaeniatus lizards in the semiarid northeast of Brazil. The location influenced the abundance of parasites in all analyzed lizard species, while season (dry and rainy) only influenced the total abundance for T. hispidus. In all seasons, males significantly showed more endoparasites than females in all lizard species, although for T. hispidus, this difference was only found in the dry season. Seasonal variations affect the abundance patterns of parasites. Likely, variables include environmental variations such as humidity and temperature, which influence the development of endoparasite eggs when outside of the host. Further, the activity of the intermediate hosts and the parasites of heteroxenous life cycles could be affected by an environmental condition. The variation in the abundance of parasites between the sampling areas could be a reflection of variations in climate and physiochemical conditions. Also, it could be due to differences in the quality of the environment in which each host population lives.     

A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document

The European Union (EU) Council Recommendation on rare diseases urged the member states to implement national and EU collaborative actions to improve the health care of rare disease patients. Following this recommendation, the European Commission launched a tender on newborn screening (NBS) to report on current practices of laboratory testing, form a network of experts and provide guidance on how to further implement NBS screening in a responsible way, the latter of which was provided in an Expert Opinion document. After consultation of experts from EU member states, (potential) candidate member states and European Free Trade Association countries, in a consensus meeting in June 2011, 70 expert opinions were finalized. They included the need to develop case definitions for all disorders screened for to facilitate assessment and international outcome studies. Decision whether a screening program should be performed can be based on screening criteria updated from the traditional Wilson and Jungner (1968) criteria, relating to disease, treatment, test and cost. The interest of the child should be central in the assessment of pros and cons. A European NBS body should assess evidence on (new) screening candidate disorders. For rare conditions, best level evidence should be used. The health system should ensure treatment to cases diagnosed by screening, controlled and revised by follow-up outcome studies. Screening methodology should aim to avoid unintended findings, such as mild forms and carrier status information, as much as possible. Activities to improve NBS in Europe, such as training and scientific evaluation, could benefit from collaboration at EU level and beyond.The European Union (EU) Council Recommendation¹ on Rare Diseases (9 June 2009)² identified rare diseases (ie, a life-threatening or chronically debilitating condition affecting not more than five in 10 000 persons in the community) as a public health concern and highlighted the need for public health actions, promoting the development of research on rare disorders and the improvement of the health care of rare disease patients. Following this recommendation, the European Commission launched a tender on neonatal screening (=newborn screening, NBS) in July 2009 (http://ec.europa.eu/eahc/health/tenders_H09C2.html) in order to (1) report on the practices of neonatal screening for rare disorders implemented in all the member states, including number of centers, estimate the number of infants screened and the number of disorders included in the NBS, as well as reasons for the selection of these disorders, (2) to identify types of medical management and follow-up implemented in the member states, (3) to establish a network of experts analyzing the information and formulating a final opinion containing recommendations on best practices, and recommending a core panel of NBS conditions that could be included in all MS practices, and (4) to develop a decision-making matrix that could be used by member states'' programs to systematically expand (or contract) screening mandates.The focus of the tender activities was on NBS by using laboratory testing techniques (blood spot screening). All reports are available on the internet (http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64).To get some insight into the current practices (points 1 and 2 above), an online survey was compiled and filled out by EU member states, (potential) member states and European Free Trade Association countries – in total 40 countries. Apart from the final report, available on the internet, the current practices are summarized in two journal articles: the first publication addresses the steps in screening programmes from blood spot to screening result³ and the second publication addresses the steps from screening laboratory results to treatment, follow-up and quality assurance.⁴As a third part of the activity and work methodology requested by the tender specifications, a European Union Network of Experts on Newborn Screening (EUNENBS) had to be constituted. Criteria for the inclusion of experts in EUNENBS (http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64) include that all member states'' authorities should be represented in the network. Each countries'' competent authorities were invited to identify their experts to represent the country at the workshops in 2010 and 2011. Further experts represent European professional and scientific organizations involved in NBS, the representative of the US Secretary''s Advisory Committee on Heritable Disorders in Newborns and Children, additional fields of expertise (eg, ethics) and patient organizations. The list of EUNENBS members is available as Appendix 1 of the Expert Opinion document (http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64). Most EUNENBS members have a background in health policy making, health technology assessment (HTA) and/or coordinating screening programs, many are involved in the service delivery of NBS in pediatrics, laboratory medicine and genetics. The task of EUNENBS was to supervise the work of the tender and participate in the revision of the tender deliverables, including the Expert Opinion document. The EUNENBS members have provided informally their input and advice without implying any obligation or commitment of their national authorities or organizations. Working documents were prepared reviewing most relevant scientific literature on the development of NBS policy and submitted to EUNENBS to stimulate the discussion during its meeting held on 6–7 December 2010, where the future of NBS was discussed in a workshop. Conclusions were integrated in a draft of the Expert Opinion document that was circulated by e-mail on 9 March 2011 to the membership of EUNENBS and to European Union Committee of Experts on Rare Diseases members from the Candidate and European Economic Area/European Free Trade Association countries inviting comments. This consultation ended on 6 April 2011. The preparation of the second draft, integrating the suggestions received, took place until 6 May 2011. Before the consensus meeting on 20 and 21 June 2011 in Luxembourg, the document was circulated for a second consultation, which took place from 11 to 27 May 2011, and amended considering the comments received. The Expert Opinion document was endorsed by the Boards of the International Society for Neonatal Screening and the European Society of Human Genetics in August and October 2011.Experiences from other countries have served as useful sources, although their applicability may need to be checked against information from EU countries and agreement needs to be sought with EUNENBS. This article presents the 70 Expert Opinions, resulting from the debate among the EUNENBS members with respect to the elements that are part of a system to evaluate the quality and ethical aspects of neonatal screening in the light of available literature, as well as the proposal for a decision matrix. We furthermore provide a brief discussion.     

uPA‐uPAR molecular complex is involved in cell signaling during neuronal migration and neuritogenesis

Background: In the development of the central nervous system (CNS), neuronal migration and neuritogenesis are crucial processes for establishing functional neural circuits. This relies on the regulation exerted by several signaling molecules, which play important roles in axonal growth and guidance. The urokinase‐type plasminogen activator (uPA)—in association with its receptor—triggers extracellular matrix proteolysis and other cellular processes through the activation of intracellular signaling pathways. Even though the uPA‐uPAR complex is well characterized in nonneuronal systems, little is known about its signaling role during CNS development. Results : In response to uPA, neuronal migration and neuritogenesis are promoted in a dose‐dependent manner. After stimulation, uPAR interacts with α₅‐ and β₁‐integrin subunits, which may constitute an αβ‐heterodimer that acts as a uPA‐uPAR coreceptor favoring the activation of multiple kinases. This interaction may be responsible for the uPA‐promoted phosphorylation of focal adhesion kinase (FAK) and its relocation toward growth cones, triggering cytoskeletal reorganization which, in turn, induces morphological changes related to neuronal migration and neuritogenesis. Conclusions : uPA has a key role during CNS development. In association with its receptor, it orchestrates both proteolytic and nonproteolytic events that govern the proper formation of neural networks. Developmental Dynamics 243:676–689, 2014. © 2014 Wiley Periodicals, Inc.     

Preclinical Study of a Biodegradable Polymer-based Stent with Abluminal Sirolimus Release

Background

Bioabsorbable polymer stents with drug elution only on the abluminal surface may be safer than durable polymer drug-eluting stents.

Objective

To report the experimental findings with the Inspiron^TM stent - a bioabsorbable polymer-coated stent with sirolimus release from the abluminal surface only, recently approved for clinical use.

Methods

45 stents were implanted in the coronary arteries of 15 pigs. On day 28 after implantation, angiographic, intracoronary ultrasonographic and histomorphological data were collected. Five groups were analyzed: Group I (nine bare-metal stents); Group II (nine coated with bioabsorbable polymer on the luminal and abluminal surfaces); Group III (eight stents coated with bioabsorbable polymer on the abluminal surface); Group IV (nine stents with bioabsorbable polymer and sirolimus on the luminal and abluminal surfaces); and Group V (ten stents with bioabsorbable polymer and sirolimus only on the abluminal surface).

Results

The following results were observed for Groups I, II, III, IV and V, respectively: percentage stenosis of 29 ± 20; 36 ± 14; 33 ± 19; 22 ± 13 and 26 ± 15 (p = 0.443); late lumen loss (in mm) of 1.02 ± 0.60; 1.24 ± 0.48; 1.11 ± 0.54; 0.72 ± 0.44 and 0.78 ± 0.39 (p = 0.253); neointimal area (in mm²) of 2.60 ± 1.99; 2.74 ± 1.51; 2.74 ± 1.30; 1.30 ± 1.14 and 0.97 ± 0.84 (p = 0.001; Groups IV and V versus Groups I, II and III); and percentage neointimal area of 35 ± 25; 38 ± 18; 39 ± 19; 19 ± 18 and 15 ± 12 (p = 0.001; Groups IV and V versus Groups I, II and III). Injury and inflammation scores were low and with no differences between the groups.

Conclusion

The Inspiron^TM stent proved to be safe and was able to significantly inhibit the neointimal hyperplasia observed on day 28 after implantation in porcine coronary arteries.     

Determinants of Functional and Structural Properties of Large Arteries in Healthy Individuals

Background

Changes in the properties of large arteries correlate with higher cardiovascular risk. Recent guidelines have included the assessment of those properties to detect subclinical disease. Establishing reference values for the assessment methods as well as determinants of the arterial parameters and their correlations in healthy individuals is important to stratify patients.

Objective

To assess, in healthy adults, the distribution of the values of pulse wave velocity, diameter, intima-media thickness and relative distensibility of the carotid artery, in addition to assessing the demographic and clinical determinants of those parameters and their correlations.

Methods

This study evaluated 210 individuals (54% women; mean age, 44 ± 13 years) with no evidence of cardiovascular disease. The carotid-femoral pulse wave velocity was measured with a Complior^® device. The functional and structural properties of the carotid artery were assessed by using radiofrequency ultrasound.

Results

The means of the following parameters were: pulse wave velocity, 8.7 ± 1.5 m/s; diameter, 6,707.9 ± 861.6 μm; intima-media thickness, 601 ± 131 μm; relative distensibility, 5.3 ± 2.1%. No significant difference related to sex or ethnicity was observed. On multiple linear logistic regression, the factors independently related to the vascular parameters were: pulse wave velocity, to age (p < 0.01) and triglycerides (p = 0.02); intima-media thickness, to age (p < 0.01); diameter, to creatinine (p = 0.03) and age (p = 0.02); relative distensibility, to age (p < 0.01) and systolic and diastolic blood pressures (p = 0.02 and p = 0.01, respectively). Pulse wave velocity showed a positive correlation with intima media thickness (p < 0.01) and with relative distensibility (p < 0.01), while diameter showed a positive correlation with distensibility (p = 0.03).

Conclusion

In healthy individuals, age was the major factor related to aortic stiffness, while age and diastolic blood pressure related to the carotid functional measure. The carotid artery structure was directly related to aortic stiffness, which was inversely related to the carotid artery functional property.     

Mortality related to coagulase-negative staphylococcal bacteremia in febrile neutropenia: A cohort study

BACKGROUND:

Coagulase-negative staphylococci (CoNS) are currently the most common isolates recovered from the blood of patients with cancer and febrile neutropenia (FN).

OBJECTIVES:

To assess the mortality associated with bloodstream infections (BSIs) caused by CoNS in cancer patients with FN.

METHODS:

A prospective cohort study was conducted in a single tertiary hospital from October 2009 to August 2011. Follow-ups were performed on all of the adult patients who were admitted to the hematology ward with cancer and FN. Bacteremia caused by CoNS was defined as two positive results of two independent cultures. Twenty-eight days after the onset of FN, the mortality rates of the patients with BSIs caused by CoNS were compared with those of patients with BSIs caused by other pathogens.

RESULTS:

A total of 169 subjects were evaluated. During the study period, 78 patients with BSIs were documented. Twenty-three BSIs (29.4%) were a result of CoNS. CoNS-induced bacteremia resulted in lower 28-day mortality compared with bacteremia caused by other pathogens (4.3% versus 32.7%; log-rank P=0.009). In a Cox proportional hazards regression analysis, BSIs caused by CoNS were independently associated with lower mortality (HR 0.09 [95% CI 0.01 to 0.74]).

CONCLUSIONS:

In adult patients with cancer and FN, BSIs caused by CoNS were associated with lower mortality compared with BSIs caused by other pathogens.     

Lateral habenula and the rostromedial tegmental nucleus innervate neurochemically distinct subdivisions of the dorsal raphe nucleus in the rat

The lateral habenula (LHb) is an epithalamic structure differentiated in a medial (LHbM) and a lateral division (LHbL). Together with the rostromedial tegmental nucleus (RMTg), the LHb has been implicated in the processing of aversive stimuli and inhibitory control of monoamine nuclei. The inhibitory LHb influence on midbrain dopamine neurons has been shown to be mainly mediated by the RMTg, a mostly GABAergic nucleus that receives a dominant input from the LHbL. Interestingly, the RMTg also projects to the dorsal raphe nucleus (DR), which also receives direct LHb projections. To compare the organization and transmitter phenotype of LHb projections to the DR, direct and indirect via the RMTg, we first placed injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin into the LHb or the RMTg. We then confirmed our findings by retrograde tracing and investigated a possible GABAergic phenotype of DR‐projecting RMTg neurons by combining retrograde tracing with in situ hybridization for GAD67. We found only moderate direct LHb projections to the DR, which mainly emerged from the LHbM and were predominantly directed to the serotonin‐rich caudal DR. In contrast, RMTg projections to the DR were more robust, emerged from RMTg neurons enriched in GAD67 mRNA, and were focally directed to a distinctive DR subdivision immunohistochemically characterized as poor in serotonin and enriched in presumptive glutamatergic neurons. Thus, besides its well‐acknowledged role as a GABAergic control center for the ventral tegmental area (VTA)–nigra complex, our findings indicate that the RMTg is also a major GABAergic relay between the LHb and the DR. J. Comp. Neurol. 522:1454–1484, 2014. © 2013 Wiley Periodicals, Inc.