Comparative Efficacy of Lamivudine and Emtricitabine: A Systematic Review and Meta-Analysis of Randomized Trials

Introduction

Lamivudine and emtricitabine are considered equivalent by several guidelines, but evidence of comparable efficacy is conflicting.

Methods

We searched two databases up to June 30 2013 to identify randomized and quasi-randomized trials in which lamivudine and emtricitabine were used as part of combination antiretroviral therapy for treatment-naïve or experienced HIV-positive adult patients. We only included trials where partner drugs in the regimen were identical or could be considered to be comparable. We allowed for comparisons between tenofovir and abacavir provided the study population did not begin treatment with a viral load >100,000 copies/ml.

Results

12 trials contributed 15 different randomized comparisons providing data on 2251 patients receiving lamivudine and 2662 patients receiving emtricitabine. Treatment success was not significantly different in any of the 12 trials. In the three trials that directly compared lamivudine and emtricitabine, the relative risk for achieving treatment success was non-significant (RR 1.03 95%CI 0.96-1.10). For all trials combined, the pooled relative risk for treatment success was not significantly different (RR 1.00, 95%CI 0.97–1.02). No heterogeneity was observed (I ² = 0). Similarly, there was no difference in the pooled relative risk for treatment failure (RR 1.08, 95%CI 0.94–1.22, I ² = 3.4%).

Conclusions

The findings of this systematic review suggest that lamivudine and emtricitabine are clinically equivalent.     

Dendrimers Target the Ischemic Lesion in Rodent and Primate Models of Nonarteritic Anterior Ischemic Optic Neuropathy

IntroductionPolyamidoamine dendrimer nanoparticles (~ 4 nanometers) are inert polymers that can be linked to biologically active compounds. These dendrimers selectively target and accumulate in inflammatory cells upon systemic administration. Dendrimer-linked compounds enable sustained release of therapeutic compounds directly at the site of damage. The purpose of this study was to determine if dendrimers can be used to target the optic nerve (ON) ischemic lesion in our rodent and nonhuman primate models of nonarteritic anterior ischemic optic neuropathy (NAION), a disease affecting >10,000 individuals in the US annually, and for which there currently is no effective treatment.MethodsNAION was induced in male Long-Evans rats (rNAION) and in one adult male rhesus monkey (pNAION) using previously described procedures. Dendrimers were covalently linked to near-infrared cyanine-5 fluorescent dye (D-Cy5) and injected both intravitreally and systemically (in the rats) or just systemically (in the monkey) to evaluate D-Cy5 tissue accumulation in the eye and optic nerve following induction of NAION.ResultsFollowing NAION induction, Cy-5 dendrimers selectively accumulated in astrocytes and circulating macrophages. Systemic dendrimer administration provided the best penetration of the ON lesion site when injected shortly after induction. Systemic administration 1 day post-induction in the pNAION model gave localization similar to that seen in the rats.ConclusionsDendrimers selectively target the ischemic ON lesion after induction of both rNAION and pNAION. Systemic nanoparticle-linked therapeutics thus may provide a powerful, targeted and safe approach to NAION treatment by providing sustained and focused treatment of the cells directly affected by ischemia.     

A trans-specific polymorphism in ZC3HAV1 is maintained by long-standing balancing selection and may confer susceptibility to multiple sclerosis

The human ZC3HAV1 gene encodes an antiviral protein. The longest splicing isoform of ZC3HAV1 contains a C-terminal PARP-like domain, which has evolved under positive selection in primates. We analyzed the evolutionary history of this same domain in humans and in Pan troglodytes. We identified two variants that segregate in both humans and chimpanzees; one of them (rs3735007) does not occur at a hypermutable site and accounts for a nonsynonymous substitution (Thr851Ile). The probability that the two trans-specific polymorphisms have occurred independently in the two lineages was estimated to be low (P = 0.0054), suggesting that at least one of them has arisen before speciation and has been maintained by selection. Population genetic analyses in humans indicated that the region surrounding the shared variants displays strong evidences of long-standing balancing selection. Selection signatures were also observed in a chimpanzee population sample. Inspection of 1000 Genomes data confirmed these findings but indicated that search for selection signatures using low-coverage whole-genome data may need masking of repetitive sequences. A case-control study of more than 1,000 individuals from mainland Italy indicated that the Thr851Ile SNP is significantly associated with susceptibility to multiple sclerosis (MS) (odds ratio [OR] = 1.47, 95% confidence intervals [CI]: 1.08-1.99, P = 0.011). This finding was confirmed in a larger sample of 4,416 Sardinians cases/controls (OR = 1.18, 95% CI: 1.037-1.344, P = 0.011), but not in a population from Belgium. We provide one of the first instances of human/chimpanzee trans-specific coding variant located outside the major histocompatibility complex region. The selective pressure is likely to be virus driven; in modern populations, this variant associates with susceptibility to MS, possibly via the interaction with environmental factors.     

Myzobdella platensis (Hirundinida: Piscicolidae) is true parasite of blue crabs (Crustacea: Portunidae)

Leeches exhibit a marked scope of diversity, including different kinds of symbiosis. The aim of the present study was to demonstrate through biochemical and histological analysis that a species of piscicolid leech, Myzobdella platensis, is a true parasite of blue crabs, feeding on their hemolymph and using them as a site for cocoon deposition. In a total of 48 blue crabs collected on October 2007 at 3 sites of the S?o Vicente Estuary, 12 specimens were infested with leeches. Callinectes bocourti (n = 7) was the most infested species with leeches and cocoons; it was chosen for biochemical and histological assays. The immunoblotting assays showed a positive reaction of the proteins in the intestinal samples of leeches collected from crabs using antihemocyanin polyclonal antibody of Ampullaria canaliculata. In addition, leech intestinal samples were recognized by antihemolymph polyclonal antibody of nonparasitized blue crabs. Histological sections of leech gut showed hemocytes and a granular matrix similar to those found in crab blood vessels. Collectively, this evidence strongly suggests a parasitic interaction between the leech M. platensis and the blue crab C. bocourti, in which the former utilizes the latter as a site for cocoon deposition and possibly for dispersal similar to that proposed for Myzobdella lugubris in Callinectes sapidus in North America.     

Antibody 2G12 Recognizes Di-Mannose Equivalently in Domain- and Nondomain-Exchanged Forms but Only Binds the HIV-1 Glycan Shield if Domain Exchanged

The broadly neutralizing anti-human immunodeficiency virus type 1 (HIV-1) antibody 2G12 targets the high-mannose cluster on the glycan shield of HIV-1. 2G12 has a unique V_H domain-exchanged structure, with a multivalent binding surface that includes two primary glycan binding sites. The high-mannose cluster is an attractive target for HIV-1 vaccine design, but so far, no carbohydrate immunogen has elicited 2G12-like antibodies. Important questions remain as to how this domain exchange arose in 2G12 and how this unusual event conferred unexpected reactivity against the glycan shield of HIV-1. In order to address these questions, we generated a nondomain-exchanged variant of 2G12 to produce a conventional Y/T-shaped antibody through a single amino acid substitution (2G12 I19R) and showed that, as for the 2G12 wild type (2G12 WT), this antibody is able to recognize the same Manα1,2Man motif on recombinant gp120, Candida albicans, and synthetic glycoconjugates. However, the nondomain-exchanged variant of 2G12 is unable to bind the cluster of mannose moieties on the surface of HIV-1. Crystallographic analysis of 2G12 I19R in complex with Manα1,2Man revealed an adaptable hinge between V_H and C_H1 that enables the V_H and V_L domains to assemble in such a way that the configuration of the primary binding site and its interaction with disaccharide are remarkably similar in the nondomain-exchanged and domain-exchanged forms. Together with data that suggest that very few substitutions are required for domain exchange, the results suggest potential mechanisms for the evolution of domain-exchanged antibodies and immunization strategies for eliciting such antibodies.The broadly neutralizing anti-human immunodeficiency virus type 1 (HIV-1) human monoclonal antibody 2G12 recognizes a highly conserved cluster of oligomannose residues on the glycan shield of the HIV-1 envelope glycoprotein gp120 (9, 10, 36, 39, 44, 45). The antibody binds terminal Manα1,2Man-linked sugars of high-mannose glycans (Man_8-9GlcNAc₂) with nanomolar affinity using a unique domain-exchanged structure in which the variable domains of the heavy chains swap to form a multivalent binding surface that includes two conventional antigen-combining sites and a third potential noncanonical binding site at the novel V_H/V_H′ interface (10). gp120 is one of the most heavily glycosylated proteins identified to date, with approximately 50% of its mass arising from host-derived N-linked glycans (24). These glycans play an important role in shielding the virus from the host immune system (34). Carbohydrates are generally poorly immunogenic, and the dense covering of glycans is often referred to as the “silent face” (52). The oligomannose glycans on gp120 in particular are closely packed, forming a tight cluster, and the unique domain-exchanged structure of 2G12 has been proposed as a means to recognize this cluster (10).The attraction of 2G12 as a template for HIV-1 vaccine design has recently been highlighted in a study that showed the antibody can protect macaques against simian-human immunodeficiency virus (SHIV) challenge at remarkably low serum neutralizing titers (18, 30, 43). When using 2G12 as a template for design of a carbohydrate immunogen, some important considerations must be taken into account. First, 2G12 is unusual in its specificity (targeting host cell-derived glycan motifs presented in a “nonself” arrangement), and although the 2G12 epitope is common to many HIV-1 envelopes, 2G12-like antibodies are rarely elicited (5, 38). Second, due to inherently weak carbohydrate-protein interactions (49, 50), it can be assumed that in order for a carbohydrate-specific antibody to achieve the affinity required to neutralize HIV-1, the avidity of the interaction must be enhanced by both Fab arms of the IgG-contacting glycan motifs simultaneously on the HIV-1 envelope. Third, the unique domain-exchanged structure of 2G12 has not been described for any other antibody (10). These considerations raise a number of questions. Which antigen or sequence of antigens elicited 2G12? Is domain exchange the only solution for recognition of highly clustered oligomannoses? If so, can domain exchange be elicited by immunization with clustered oligomannose motifs (38)?Efforts to design immunogens that elicit responses to the glycan shield of HIV-1 and neutralize the virus have to date been unsuccessful (2, 3, 14, 20, 21, 28, 29, 32, 46-48). Immunogen design strategies that mimic the 2G12 epitope have focused on both chemical and biochemical methods to generate multivalent and clustered displays of both high-mannose sugars (Man_8-9GlcNAc₂) (13, 15, 20, 21, 27-29, 32, 47) and truncated versions of such sugars (Man₉ and Man₄ linked via a 5-carbon linker) (3, 46). These constructs typically bind 2G12 with a lower affinity (on the order of 1 to 3 logs) than recombinant gp120. Although mannose-specific antibodies have been elicited by these immunogens, no HIV-1-neutralizing activities have been described. In a study by Luallen et al., antibodies against recombinant gp120 were generated by immunization with yeast cells that had been mutated to display only Man₈GlcNAc₂ glycans (27, 29). However, no neutralization activity against the corresponding pseudovirus was noted. It was proposed that this was due to either the low abundance of the gp120-specific antibodies in the serum or the antibodies elicited being against carbohydrate epitopes that differed from the 2G12 epitope (27, 29).To gain a better understanding of the importance of domain exchange for glycan recognition and how 2G12 may have been induced, we analyzed the binding characteristics of a nondomain-exchanged (conventional Y/T-shaped) 2G12 variant antibody. This variant was generated by a single point mutation, I19R, that disrupts the V_H/V_H′ interface. We show that the mutant is still able to recognize the Manα1,2Man motif arrayed on yeast, synthetic glycoconjugates, and recombinant gp120 in enzyme-linked immunosorbent assay (ELISA) format but is unable to recognize the discrete, dense mannose clusters found on the surface of the HIV-1 envelope (as measured by neutralization activity and binding to HIV-1-transfected cells). We further show that a major conformational change in the elbow region between V_H and C_H1 in this nondomain-exchanged variant of 2G12 allows the variable domains to assemble in similar orientations with respect to each other, as in the 2G12 wild type (WT), with an identical primary binding site, although with dramatically different orientations with respect to the constant domains. Thus, we conclude that 2G12 recognizes Manα1,2Man motifs in an identical manner in both conventional and domain-exchanged configurations, and the 2G12 specificity for Manα1,2Man likely first arose in a conventional IgG predecessor of 2G12. Subsequent domain exchange was the key event that then enabled high-affinity recognition of the tight oligomannose clusters on HIV-1.     

New insights in the male anatomy,spermatophore formation,and sperm structure in Atyidae: The red cherry shrimp Neocaridina davidi

This study aims to analyze the functional anatomy of the male reproductive system in Neocaridina davidi, a very popular ornamental species of caridean shrimp. Mature males were cold‐anaesthetized and their reproductive systems were dissected for histological and histochemical analysis, while the spermatozoa and spermatophore wall ultrastructure were analyzed under transmission electron microscopy. The male reproductive system consisted of two coiled testes, which were continuous with the vasa deferentia. Testes were positioned on the dorsal side of the cephalothorax above the hepatopancreas, and comprised seminiferous tubules where spermatogenesis occurred. Each vas deferens (VD) was a long tube dorsolaterally positioned with respect to the hepatopancreas, and increased in diameter at the distal end. Three regions could be recognized in the VD: proximal, middle, and distal. The proximal region had a cylindrical epithelium with secretory cells. The middle region (or typhlosole) had a dorsal fold (or typhlosole) with a thick columnar epithelium and high secretory activity. The spermatophore was a continuous cord with three acellular layers, which were mainly characterized by the presence of neutral glycoconjugates and proteins. The sperm morphology was distinct from the inverted cup‐shaped spermatozoa observed in the majority of caridean shrimps. The spermatozoa in specimens of N. davidi were spherical in shape, with a cross‐striated, single, short spike, and arranged in clusters of three or four sperm cells. The composition of the spermatophore, and the arrangement and form of the spermatozoa, seem to be unique in comparison to other species of Caridea.     

Mercury Exposure: Protein Biomarkers of Mercury Exposure in Jaraqui Fish from the Amazon Region

Poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132) is a water-soluble organogermanium compound that exerts various physiological effects, including anti-inflammatory activity and pain relief. In water, Ge-132 is hydrolyzed to 3-(trihydroxygermyl)propanoic acid (THGP), which in turn is capable of interacting with cis-diol compounds through its trihydroxy group, indicating that this compound could also interact with diol-containing nucleic acid constituents. In this study, we evaluated the ability of THGP to interact with nucleosides or nucleotides via nuclear magnetic resonance (NMR) analysis. In addition, we evaluated the effect of added THGP on the enzymatic activity of adenosine deaminase (ADA) when using adenosine or 2′-deoxyadenosine as a substrate. In solution, THGP indeed formed complexes with nucleotides or nucleosides through their cis-diol group. Moreover, the ability of THGP to form complexes with nucleotides was influenced by the number of phosphate groups present on the ribose moiety. Notably, THGP also inhibited the catalysis of adenosine by ADA in a concentration-dependent manner. Thus, interactions between THGP and important biological nucleic acid constituents might be implicated in the physiological effects of Ge-132.     

The space-time distribution of the mRNA of the nuclear proteins c-myc and P-53 in the development of the clawed toad studied by hybridization in situ]

We studied distribution of mRNA for nuclear protooncogene c-myc and nuclear protein P-53 in mature oocytes and embryos of Xenopus laevis from the stage of fertilization up to the stage of hatching by in situ hybridization with histological sections. mRNA for c-myc was present in all cells of the embryo at all studied developmental stages. Between the stage of fertilization and up to the late blastula, mRNA concentration for c-myc decreased progressively in all embryonic cells. During gastrulation a local increase in the concentration of this messenger was found in dorsal mesoderm and ectoderm. At the stage of neurula increased concentration of mRNA for c-myc was observed in all cells of the embryo but the hybridization signal increased particularly distinctly in cells of the neural tube. In studies of P-53 mRNA distribution hybridization signal was detected only in brain cells after stage 20 of development (after closure of the neural folds) and up to the stage of hatching.     

FLO11-based model for air-liquid interfacial biofilm formation by Saccharomyces cerevisiae

Sardinian wine strains of Saccharomyces cerevisiae used to make sherry-like wines form a biofilm at the air-liquid interface at the end of ethanolic fermentation, when grape sugar is depleted and further growth becomes dependent on access to oxygen. Here, we show that FLO11, which encodes a hydrophobic cell wall glycoprotein, is required for the air-liquid interfacial biofilm and that biofilm cells have a buoyant density greater than the suspending medium. We propose a model for biofilm formation based on an increase in cell surface hydrophobicity occurring at the diauxic shift. This increase leads to formation of multicellular aggregates that effectively entrap carbon dioxide, providing buoyancy. A visible biofilm appears when a sufficient number of hydrophobic cell aggregates are carried to and grow on the liquid surface.