Influence of shape-memory stent grafts on local aortic compliance

The effect of repair techniques on the biomechanics of the aorta is poorly understood, resulting in significant levels of postoperative complications for patients worldwide. This study presents a computational analysis of the influence of Nitinol-based devices on the biomechanical performance of a healthy patient-specific human aorta. Simulations reveal that Nitinol stent-grafts stretch the artery wall so that collagen is stretched to a straightened high-stiffness configuration. The high-compliance regime (HCR) associated with low diastolic lumen pressure is eliminated, and the artery operates in a low-compliance regime (LCR) throughout the entire cardiac cycle. The slope of the lumen pressure–area curve for the LCR post-implantation is almost identical to that of the native vessel during systole. This negligible change from the native LCR slope occurs because the stent-graft increases its diameter from the crimped configuration during deployment so that it reaches a low-stiffness unloading plateau. The effective radial stiffness of the implant along this unloading plateau is negligible compared to the stiffness of the artery wall. Provided the Nitinol device unloads sufficiently during deployment to the unloading plateau, the degree of oversizing has a negligible effect on the pressure–area response of the vessel, as each device exerts approximately the same radial force, the slope of which is negligible compared to the LCR slope of the native artery. We show that 10% oversizing based on the observed diastolic diameter in the mid descending thoracic aorta results in a complete loss of contact between the device and the wall during systole, which could lead to an endoleak and stent migration. 20% oversizing reaches the Dacron enforced area limit (DEAL) during the pulse pressure and results in an effective zero-compliance in the later portion of systole.

     

Increased urinary protein excretion in the "normal" range is associated with increased renin-angiotensin system activity

Increased levels of albuminuria and proteinuria, both linked to augmented renin-angiotensin system (RAS) activity, are associated with adverse kidney and cardiovascular events. However, the relationship between variations in urinary albumin excretion (UAE) and total protein excretion (UTPE) in the normal range and RAS activity is unclear. We examined the association between UAE and UTPE and the hemodynamic response to angiotensin II (ANG II) challenge, a well-accepted indirect measure of RAS activity, in healthy individuals with normal UAE and UTPE. Forty subjects (15 men, 25 women; age 38 ± 2 yr; UAE, 3.32 ± 0.55 mg/day; UTPE, 56.8 ± 3.6 mg/day) were studied in high-salt balance. Blood pressure (BP), arterial stiffness determined by applanation tonometry, and circulating RAS components were measured at baseline and in response to graded ANG II infusion. The primary outcome was the BP response to ANG II challenge at 30 and 60 min. UAE was associated with a blunted diastolic BP response to ANG II infusion (30 min, P = 0.005; 60 min, P = 0.17), a relationship which remained even after adjustment (30 min, P < 0.001; 60 min, P = 0.035). Similar results were observed with UTPE (30 min, P = 0.031; 60 min, P = 0.001), even after multivariate analysis (30 min, P = 0.008; 60 min, P = 0.001). Neither UAE nor UTPE was associated with systolic BP, circulating RAS components, or arterial stiffness responses to ANG II challenge. Among healthy individuals with UAE and UTPE in the normal range, increased levels of these measures were independently associated with a blunted diastolic BP response to ANG II, indicating increased vascular RAS activity, which is known to be deleterious to both renal and cardiac function.     

A Plasmodium falciparum copper-binding membrane protein with copper transport motifs

Formerly known as a hypoendemic malaria country, the Republic of Djibouti declared the goal of pre-eliminating malaria in 2006. The aim of the present study was to evaluate the prevalence of Plasmodium falciparum, Plasmodium vivax and mixed infections in the Djiboutian population by using serological tools and to identify potential determinants of the disease and hotspots of malaria transmission within the country. The prevalence of P. falciparum and P. vivax within the districts of the capital city and the rest of the Republic of Djibouti were assessed using 13 and 2 serological markers, respectively. The relationship between the immune humeral response to P. falciparum and P. vivax and variables such as age, gender, wealth status, urbanism, educational level, distance to rivers/lakes, living area, having fever in the last month, and staying in a malaria-endemic country more than one year was estimated and analysed by questionnaires administered to 1910 Djiboutians. Multivariate ordinal logistic regression models of the immune humeral response were obtained for P. falciparum and P. vivax. The P. falciparum and P. vivax seroprevalence rates were 31.5%, CI95% [29.4-33.7] and 17.5%, CI95% [15.8-19.3], respectively. Protective effects against P. falciparum and P. vivax were female gender, educational level, and never having visited a malaria-endemic area for more than one year. For P. falciparum only, a protective effect was observed for not having a fever in the last month, living more than 1.5 km away from lakes and rivers, and younger ages. This is the first study that assessed the seroprevalence of P. vivax in the Republic of Djibouti. It is necessary to improve knowledge of this pathogen in order to create an effective elimination programme. As supported by recent observations on the subject, the Republic of Djibouti has probably demonstrated a real decrease in the transmission of P. falciparum in the past seven years, which should encourage authorities to improve efforts toward elimination.     

Development of a high-content screening assay panel to accelerate mechanism of action studies for oncology research

Efficient elucidation of the biological mechanism of action of novel compounds remains a major bottleneck in the drug discovery process. To address this need in the area of oncology, we report the development of a multiparametric high-content screening assay panel at the level of single cells to dramatically accelerate understanding the mechanism of action of cell growth-inhibiting compounds on a large scale. Our approach is based on measuring 10 established end points associated with mitochondrial apoptosis, cell cycle disruption, DNA damage, and cellular morphological changes in the same experiment, across three multiparametric assays. The data from all of the measurements taken together are expected to help increase our current understanding of target protein functions, constrain the list of possible targets for compounds identified using phenotypic screens, and identify off-target effects. We have also developed novel data visualization and phenotypic classification approaches for detailed interpretation of individual compound effects and navigation of large collections of multiparametric cellular responses. We expect this general approach to be valuable for drug discovery across multiple therapeutic areas.     

LC/MS-Based Quantitative Proteomic Analysis of Paraffin-Embedded Archival Melanomas Reveals Potential Proteomic Biomarkers Associated with Metastasis

Background

Melanoma metastasis status is highly associated with the overall survival of patients; yet, little is known about proteomic changes during melanoma tumor progression. To better understand the changes in protein expression involved in melanoma progression and metastasis, and to identify potential biomarkers, we conducted a global quantitative proteomic analysis on archival metastatic and primary melanomas.

Methodology and Findings

A total of 16 metastatic and 8 primary cutaneous melanomas were assessed. Proteins were extracted from laser captured microdissected formalin fixed paraffin-embedded archival tissues by liquefying tissue cells. These preparations were analyzed by a LC/MS-based label-free protein quantification method. More than 1500 proteins were identified in the tissue lysates with a peptide ID confidence level of >75%. This approach identified 120 significant changes in protein levels. These proteins were identified from multiple peptides with high confidence identification and were expressed at significantly different levels in metastases as compared with primary melanomas (q-Value<0.05).

Conclusions and Significance

The differentially expressed proteins were classified by biological process or mapped into biological system networks, and several proteins were implicated by these analyses as cancer- or metastasis-related. These proteins represent potential biomarkers for tumor progression. The study successfully identified proteins that are differentially expressed in formalin fixed paraffin-embedded specimens of metastatic and primary melanoma.     

Randomised controlled trial and economic evaluation of a chest pain observation unit compared with routine care

Objectives To measure the effectiveness and cost effectiveness of providing care in a chest pain observation unit compared with routine care for patients with acute, undifferentiated chest pain.Design Cluster randomised controlled trial, with 442 days randomised to the chest pain observation unit or routine care, and cost effectiveness analysis from a health service costing perspective.Setting The emergency department at the Northern General Hospital, Sheffield, United Kingdom.Participants 972 patients with acute, undifferentiated chest pain (479 attending on days when care was delivered in the chest pain observation unit, 493 on days of routine care) followed up until six months after initial attendance.Main outcome measures The proportion of participants admitted to hospital, the proportion with acute coronary syndrome sent home inappropriately, major adverse cardiac events over six months, health utility, hospital reattendance and readmission, and costs per patient to the health service.Results Use of a chest pain observation unit reduced the proportion of patients admitted from 54% to 37% (difference 17%, odds ratio 0.50, 95% confidence interval 0.39 to 0.65, P < 0.001) and the proportion discharged with acute coronary syndrome from 14% to 6% (8%, -7% to 23%, P = 0.264). Rates of cardiac event were unchanged. Care in the chest pain observation unit was associated with improved health utility during follow up (0.0137 quality adjusted life years gained, 95% confidence interval 0.0030 to 0.0254, P = 0.022) and a saving of £78 per patient (-£56 to £210, P = 0.252).Conclusions Care in a chest pain observation unit can improve outcomes and may reduce costs to the health service. It seems to be more effective and more cost effective than routine care.     

Fungal virulence studies come of age

Sophisticated molecular biological research has revealed many virulence attributes in at least four pathogenic fungi, but the future study of fungal virulence requires investigators to distinguish between molecules that directly interact with the host, molecules that regulate these, and molecules that are always required for fungal growth and survival, independent of the host.     

Development of protoporphyrinogen oxidase as an efficient selection marker for Agrobacterium tumefaciens-mediated transformation of maize

In this article, we report the isolation of plant protoporphyrinogen oxidase (PPO) genes and the isolation of herbicide-tolerant mutants. Subsequently, an Arabidopsis double mutant (Y426M + S305L) was used to develop a selectable marker system for Agrobacterium tumefaciens-mediated transformation of maize (Zea mays) and to obtain multiple events tolerant to the PPO family of herbicides. Maize transformants were produced via butafenacil selection using a flexible light regime to increase selection pressure. Butafenacil selection per se did not change transgene copy number distribution relative to other selectable marker systems, but the most tolerant events identified in the greenhouse were more likely to contain multiple copies of the introduced mutant PPO gene. To date, more than 2,500 independent transgenic maize events have been produced using butafenacil selection. The high frequency of A. tumefaciens-mediated transformation via PPO selection enabled us to obtain single-copy transgenic maize lines tolerant to field levels of butafenacil.