Economic Recession and Emergence of an HIV-1 Outbreak among Drug Injectors in Athens Metropolitan Area: A Longitudinal Study

Background

During 2011, a dramatic increase (1600%) of reported HIV-1 infections among injecting drug users (IDUs) was noted in Athens, Greece. We herein assess the potential causal pathways associated with this outbreak.

Methods

Our study employed high resolution HIV-1 phylogenetic and phylogeographic analyses. We examined also longitudinal data of ecological variables such as the annual growth of gross domestic product (GDP) of Greece in association with HIV-1 and HCV sentinel prevalence in IDUs, unemployment and homelessness rates and HIV transmission networks in Athens IDUs before and during economic recession (2008–2012).

Results

IDU isolates sampled in 2011 and 2012 suggested transmission networks in 94.6% and 92.7% of the cases in striking contrast with the sporadic networking (5%) during 1998–2009. The geographic origin of most HIV-1 isolates was consistent with the recently documented migratory waves in Greece. The decline in GDP was inversely correlated with annual prevalence rates of HIV and HCV and with unemployment and homelessness rates in IDUs (all p<0.001). The slope of anti-HCV prevalence in the sentinel populations of IDUs and in “new” drug injectors was found 120 and 1.9-fold (p = 0.007, p = 0.08 respectively) higher in 2008–2012 (economic recession) compared with 2002–2006. The median (25th, 75th) size of transmission networks were 34 (12, 58) and 2 (2, 2) (p = 0.057) in 2008–2012 and 1998–2007, respectively. The coverage of harm reduction services was low throughout the study period.

Conclusions

Scaling-up harm reduction services and addressing social and structural factors related to the current economic crisis should be urgently considered in environments where HIV-1 outbreaks may occur.     

Quantitative Phosphoproteome Analysis Unveils LAT as a Modulator of CD3ζ and ZAP-70 Tyrosine Phosphorylation

Signaling through the T cell receptor (TCR) initiates adaptive immunity and its perturbation may results in autoimmunity. The plasma membrane scaffolding protein LAT acts as a central organizer of the TCR signaling machinery to activate many functional pathways. LAT-deficient mice develop an autoimmune syndrome but the mechanism of this pathology is unknown. In this work we have compared global dynamics of TCR signaling by MS-based quantitative phosphoproteomics in LAT-sufficient and LAT-defective Jurkat T cells. Surprisingly, we found that many TCR-induced phosphorylation events persist in the absence of LAT, despite ERK and PLCγ1 phosphorylation being repressed. Most importantly, the absence of LAT resulted in augmented and persistent tyrosine phosphorylation of CD3ζ and ZAP70. This indicates that LAT signaling hub is also implicated in negative feedback signals to modulate upstream phosphorylation events. Phosphorylation kinetics data resulting from this investigation is documented in a database (phosphoTCR) accessible online. The MS data have been deposited to the ProteomeXchange with identifier PXD000341.     

Meander: visually exploring the structural variome using space-filling curves

The introduction of next generation sequencing methods in genome studies has made it possible to shift research from a gene-centric approach to a genome wide view. Although methods and tools to detect single nucleotide polymorphisms are becoming more mature, methods to identify and visualize structural variation (SV) are still in their infancy. Most genome browsers can only compare a given sequence to a reference genome; therefore, direct comparison of multiple individuals still remains a challenge. Therefore, the implementation of efficient approaches to explore and visualize SVs and directly compare two or more individuals is desirable. In this article, we present a visualization approach that uses space-filling Hilbert curves to explore SVs based on both read-depth and pair-end information. An interactive open-source Java application, called Meander, implements the proposed methodology, and its functionality is demonstrated using two cases. With Meander, users can explore variations at different levels of resolution and simultaneously compare up to four different individuals against a common reference. The application was developed using Java version 1.6 and Processing.org and can be run on any platform. It can be found at http://homes.esat.kuleuven.be/~bioiuser/meander.     

Early Miocene herpetofaunas from the Greek localities of Aliveri and Karydia – bridging a gap in the knowledge of amphibians and reptiles from the early Neogene of southeastern Europe

Abstract

We here describe new remains of amphibians and reptiles from the early Miocene (MN 4) of two different Greek localities, Aliveri and Karydia. The newly described material consists of urodelans, alytids, indeterminate anurans, turtles, crocodylians, lacertids, indeterminate scincomorphs, anguids, colubrids, viperids, and indeterminate snakes. The presence of the frog Latonia cf. gigantea in Greece is documented for the first time. Additionally, the presence of viperids in Aliveri implies a much wider distribution for these snakes during the early Miocene of Europe. Of special interest is the presence of a peculiar colubrid that seems to possess a hitherto unknown vertebral structure, which is herein defined as the ‘paracentral ridge’. Although incomplete, the new material has important taxonomic and biogeographic implications, as it enhances our understanding of southeastern European herpetofaunas from the early Miocene, a time period that was characterised by major dispersal and extinction events and climatic change that affected the whole continent.     

The fossil turtles of Greece: An overview of taxonomy and distribution

Turtle remains are common in the Miocene-Holocene deposits of Greece, and are a key focus of the growing research interest in Neogene herpetofaunas from the Aegean region. Some of the most important finds include one of Europe's stratigraphically youngest pleurodiran taxa, Nostimochelone lampra, from the Early Miocene of Macedonia, together with arguably the richest record of fossil tortoises from the Eastern Mediterranean. This incorporates the presently oldest definitive representatives of the quintessential genus Testudo sensu stricto from the Late Miocene of Attica and Macedonia, and numerous specimens of the colossal (carapace ∼2 m-length) testudinid Cheirogaster from Late Miocene-Late Pliocene sediments in southern and northern Greece, as well as on the eastern Aegean islands of Samos and Lesvos. Tantalising, but as yet unconfirmed Miocene accounts of the geoemydid Mauremys in Macedonia, and indeterminate emydid-like remains from Euboea, also provide potentially significant range extensions. Although hampered by a historically sparse documentation, the fossil turtles of Greece are a significant resource that record both assemblage changes and the origin of modern lineages.     

Reduction of apoptosis and preservation of mitochondrial integrity under ischemia/reperfusion injury is mediated by estrogen receptor β

Background

Estrogen improves cardiac recovery after ischemia/reperfusion (I/R) by yet incompletely understood mechanisms. Mitochondria play a crucial role in I/R injury through cytochrome c-dependent apoptosis activation. We tested the hypothesis that 17β-estradiol (E2) as well as a specific ERβ agonist improve cardiac recovery through estrogen receptor (ER)β-mediated mechanisms by reducing mitochondria-induced apoptosis and preserving mitochondrial integrity.

Methods

We randomized ovariectomized C57BL/6N mice 24h before I/R to pre-treatment with E2 or a specific ERβ agonist (ERβA). Isolated hearts were perfused for 20min prior to 30min global ischemia followed by 40min reperfusion.

Results

Compared with controls, ERβA and E2 treated groups showed a significant improvement in cardiac recovery, i.e. an increase in left ventricular developed pressure, dP/dtmax and dP/dtmin. ERβA and E2 pre-treatment led to a significant reduction in apoptosis with decreased cytochrome c release from the mitochondria and increased mitochondrial levels of anti-apoptotic Bcl2 and ACAA2. Protein levels of mitochondrial translocase inner membrane (TIM23) and mitochondrial complex I of respiratory chain were increased by ERβA and E2 pre-treatment. Furthermore, we found a significant increase of myosin light chain 2 (MLC2) phosphorylation together with ERK1/2 activation in E2, but not in ERβA treated groups.

Conclusions

Activation of ERβ is essential for the improvement of cardiac recovery after I/R through the inhibition of apoptosis and preservation of mitochondrial integrity and can be a achieved by a specific ERβ agonist. Furthermore, E2 modulates MLC2 activation after I/R independent of ERβ.

     

eGender—from e-Learning to e-Research: a web-based interactive knowledge-sharing platform for sex- and gender-specific medical education

Background

Sex and Gender Medicine is a novel discipline that provides equitable medical care for society and improves outcomes for both male and female patients. The integration of sex- and gender-specific knowledge into medical curricula is limited due to adequate learning material, systematic teacher training and an innovative communication strategy. We aimed at initiating an e-learning and knowledge-sharing platform for Sex and Gender Medicine, the eGender platform (http://egender.charite.de), to ensure that future doctors and health professionals will have adequate knowledge and communication skills on sex and gender differences in order to make informed decisions for their patients.

Methods

The web-based eGender knowledge-sharing platform was designed to support the blended learning pedagogical teaching concept and follows the didactic concept of constructivism. Learning materials developed by Sex and Gender Medicine experts of seven universities have been used as the basis for the new learning tools. The content of these tools is patient-centered and provides add-on information on gender-sensitive aspects of diseases. The structural part of eGender was designed and developed using the open source e-learning platform Moodle. The eGender platform comprises an English and a German version of e-learning modules: one focusing on basic knowledge and seven on specific medical disciplines. Each module consists of several courses corresponding to a disease or symptom complex. Self-organized learning has to be managed by using different learning tools, e.g., texts and audiovisual material, tools for online communication and collaborative work.

Results

More than 90 users from Europe registered for the eGender Medicine learning modules. The most frequently accessed module was “Gender Medicine—Basics” and the users favored discussion forums. These e-learning modules fulfill the quality criteria for higher education and are used within the elective Master Module “Gender Medicine—Basics” implemented into the accredited Master of Public Health at Charité—Berlin.

Conclusions

The eGender platform is a flexible and user-friendly electronical knowledge-sharing platform providing evidence-based high-quality learning material used by a growing number of registered users. The eGender Medicine learning modules could be key in the reform of medical curricula to integrate Sex and Gender Medicine into the education of health professionals.

     

Brugia malayi Antigen (BmA) Inhibits HIV-1 Trans-Infection but Neither BmA nor ES-62 Alter HIV-1 Infectivity of DC Induced CD4+ Th-Cells

One of the hallmarks of HIV-1 disease is the association of heightened CD4⁺ T-cell activation with HIV-1 replication. Parasitic helminths including filarial nematodes have evolved numerous and complex mechanisms to skew, dampen and evade human immune responses suggesting that HIV-1 infection may be modulated in co-infected individuals. Here we studied the effects of two filarial nematode products, adult worm antigen from Brugia malayi (BmA) and excretory-secretory product 62 (ES-62) from Acanthocheilonema viteae on HIV-1 infection in vitro. Neither BmA nor ES-62 influenced HIV-1 replication in CD4⁺ enriched T-cells, with either a CCR5- or CXCR4-using virus. BmA, but not ES-62, had the capacity to bind the C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) thereby inhibiting HIV-1 trans-infection of CD4⁺ enriched T-cells. As for their effect on DCs, neither BmA nor ES-62 could enhance or inhibit DC maturation as determined by CD83, CD86 and HLA-DR expression, or the production of IL-6, IL-10, IL-12 and TNF-α. As expected, due to the unaltered DC phenotype, no differences were found in CD4⁺ T helper (Th) cell phenotypes induced by DCs treated with either BmA or ES-62. Moreover, the HIV-1 susceptibility of the Th-cell populations induced by BmA or ES-62 exposed DCs was unaffected for both CCR5- and CXCR4-using HIV-1 viruses. In conclusion, although BmA has the potential capacity to interfere with HIV-1 transmission or initial viral dissemination through preventing the virus from interacting with DCs, no differences in the Th-cell polarizing capacity of DCs exposed to BmA or ES-62 were observed. Neither antigenic source demonstrated beneficial or detrimental effects on the HIV-1 susceptibility of CD4⁺ Th-cells induced by exposed DCs.     

A Predictive Model for Selecting Patients with HCV Genotype 3 Chronic Infection with a High Probability of Sustained Virological Response to Peginterferon Alfa-2a/Ribavirin

Background

Access to direct-acting antiviral agents (DAAs) is restricted in some settings; thus, the European Association for the Study of the Liver recommends dual peginterferon/ribavirin (PegIFN/RBV) therapy wherever DAAs are unavailable. HCV genotype (GT) 3 infection is now the most difficult genotype to eradicate and PegIFN/RBV remains an effective option. The goal of this study was to devise a simple predictive score to identify GT3 patients with a high probability of achieving a sustained virologic response (SVR) with PegIFN alfa-2a/RBV therapy.

Methods

Relationships between baseline characteristics and SVR were explored by multiple logistic regression models and used to develop a simple scoring system to predict SVR using data from 1239 treatment-naive GT3 patients who received PegIFN alfa-2a/RBV for 24 weeks in two large observational cohort studies.

Results

The score was validated using a database of 473 patients. Scores were assigned for six factors as follows: age (years) (≤40: 2 points; >40 but ≤55: 1); bodyweight (kg) (<70: 2; ≥70 but <90: 1); no cirrhosis/transition to cirrhosis (2); ALT ≤2.5 x ULN (1); platelets (10⁹/L) (>200: 2; ≥100 but <200: 1); HCV RNA (<400,000 IU/mL: 1). The points are summed to arrive at a score ranging from 0‒10 where higher scores indicate higher chances of SVR; 141, 123, 203, 249, 232, and 218 patients had total scores of 0‒4, 5, 6, 7, 8, and 9–10, respectively, among whom SVR rates were 45%, 62%, 72%, 76%, 84%, and 89%. Among 622 patients who had scores of 6‒10 and HCV RNA <50 IU/mL by treatment week 4 the SVR rate was 86% (532/622).

Conclusions

A simple baseline scoring system involving age, bodyweight, cirrhosis status, ALT level, platelet count and HCV RNA level can be used to identify treatment-naive Caucasian patients with HCV GT3 infection with a high probability of SVR with PegIFN alfa-2a/RBV therapy.