Percutaneous Vertebroplasty and Kyphoplasty for Pathologic Vertebral Fractures in the Medicare Population: Safer and Less Expensive than Open Surgery

PurposeTo compare cost and outcomes of surgical and percutaneous treatments of pathologic vertebral fractures.Materials and MethodsStandard Medicare 5% anonymized inpatient files (1999–2009) were retrospectively reviewed. Patients with a diagnosis of vertebral fracture without spinal cord injury and primary or metastatic bony malignancy were divided into percutaneous or surgical groups based on whether they received vertebroplasty/kyphoplasty or surgical treatment. Patients who had no intervention or both interventions were excluded. Cost, length of stay, and type of discharge were examined while controlling for demographic and comorbidity variables.ResultsA total of 451 patients were included; 52% received percutaneous treatment and 48% received surgery. Patients treated percutaneously were older (P<.001) and more likely to be female (P=.04). Percutaneous therapy predicted $14,862 less Medicare cost and $13,565 less overall cost (P<.001 for both), and 4.1 fewer inpatient days (P<.001). Patients who underwent surgery had higher odds of death (odds ratio=3.38, P=.016), discharge to a rehabilitation facility (odds ratio=3.3, P=.003), and transfer to another inpatient facility (odds ratio=8.53, P<.001), and lower odds of discharge to home (odds ratio=0.42, P<.001) and hospice (odds ratio=0.08, P=.002).ConclusionsIn a Medicare population with bony malignancy and vertebral fractures, percutaneous therapy predicted significantly reduced cost and length of stay versus surgery. Patients who underwent percutaneous therapy were significantly less likely to die, be transferred, or be discharged to rehabilitation facilities, and were more likely to be discharged to home or hospice.     

A full-length recombinant Plasmodium falciparum PfRH5 protein induces inhibitory antibodies that are effective across common PfRH5 genetic variants

The lack of an effective licensed vaccine remains one of the most significant gaps in the portfolio of tools being developed to eliminate Plasmodium falciparum malaria. Vaccines targeting erythrocyte invasion – an essential step for both parasite development and malaria pathogenesis – have faced the particular challenge of genetic diversity. Immunity-driven balancing selection pressure on parasite invasion proteins often results in the presence of multiple, antigenically distinct, variants within a population, leading to variant-specific immune responses. Such variation makes it difficult to design a vaccine that covers the full range of diversity, and could potentially facilitate the evolution of vaccine-resistant parasite strains. In this study, we investigate the effect of genetic diversity on invasion inhibition by antibodies to a high priority P. falciparum invasion candidate antigen, P. falciparum Reticulocyte Binding Protein Homologue 5 (PfRH5). Previous work has shown that virally delivered PfRH5 can induce antibodies that protect against a wide range of genetic variants. Here, we show that a full-length recombinant PfRH5 protein expressed in mammalian cells is biochemically active, as judged by saturable binding to its receptor, basigin, and is able to induce antibodies that strongly inhibit P. falciparum growth and invasion. Whole genome sequencing of 290 clinical P. falciparum isolates from across the world identifies only five non-synonymous PfRH5 SNPs that are present at frequencies of 10% or more in at least one geographical region. Antibodies raised against the 3D7 variant of PfRH5 were able to inhibit nine different P. falciparum strains, which between them included all of the five most common PfRH5 SNPs in this dataset, with no evidence for strain-specific immunity. We conclude that protein-based PfRH5 vaccines are an urgent priority for human efficacy trials.     

Monoclonal antibodies for prophylactic and therapeutic use against viral infections

Neutralizing antibodies play an essential part in antiviral immunity and are instrumental in preventing or modulating viral diseases. Polyclonal antibody preparations are increasingly being replaced by highly potent monoclonal antibodies (mAbs). Cocktails of mAbs and bispecific constructs can be used to simultaneously target multiple viral epitopes and to overcome issues of neutralization escape. Advances in antibody engineering have led to a large array of novel mAb formats, while deeper insight into the biology of several viruses and increasing knowledge of their neutralizing epitopes has extended the list of potential targets. In addition, progress in developing inexpensive production platforms will make antiviral mAbs more widely available and affordable.     

Structure of the processive rubber oxygenase RoxA from Xanthomonas sp

Rubber oxygenase A (RoxA) is one of only two known enzymes able to catalyze the oxidative cleavage of latex for biodegradation. RoxA acts as a processive dioxygenase to yield the predominant product 12-oxo-4,8-dimethyl-trideca-4,8-diene-1-al (ODTD), a tri-isoprene unit. Here we present a structural analysis of RoxA from Xanthomonas sp. strain 35Y at a resolution of 1.8 Å. The enzyme is a 75-kDa diheme c-type cytochrome with an unusually low degree of secondary structure. Analysis of the heme group arrangement and peptide chain topology of RoxA confirmed a distant kinship with diheme peroxidases of the CcpA family, but the proteins are functionally distinct, and the extracellular RoxA has evolved to have twice the molecular mass by successively accumulating extensions of peripheral loops. RoxA incorporates both oxygen atoms of its cosubstrate dioxygen into the rubber cleavage product ODTD, and we show that RoxA is isolated with O₂ stably bound to the active site heme iron. Activation and cleavage of O₂ require binding of polyisoprene, and thus the substrate needs to use hydrophobic access channels to reach the deeply buried active site of RoxA. The location and nature of these channels support a processive mechanism of latex cleavage.     

Platelet-derived growth factor triggers PKA-mediated signalling by a redox-dependent mechanism in rat renal mesangial cells

Inflammatory glomerular kidney diseases are often accompanied with a massive production of reactive oxygen species (ROS) that affect the function of the glomerular filtration barrier and contribute to mesangiolysis via the induction of cell death in mesangial cells. Intriguingly, ROS also trigger fine-tuned signalling processes that affect gene expression and cell proliferation or migration. To define such redox-driven signalling devices, a proteomics approach was performed to identify the formation of protein complexes induced by ROS. To this end, protein lysates of human podocytes were treated with or without hydrogen peroxide (250 μM). Thereafter cell lysates were subjected to diagonal 2D gel electrophoresis and putative redox-affected proteins were analysed by MS/MS analysis. Among others, the regulatory subunit of protein kinase A (PKA) could be identified that forms homodimers under oxidative conditions. To evaluate whether ROS dependent dimerization of PKA also occurs in a more physiological setting, rat mesangial cells were treated with platelet-derived growth factor-BB (PDGF-BB) to induce ROS formation. This regimen resulted in a redox dependent dimerization of the R-subunits of PKA. To demonstrate whether PDGF-BB induced ROS formation affects PKA dependent pathways, the effects of PDGF-BB on phosphorylation of serine 157 of vasodilator stimulated protein (VASP) a classical target of PKA were analysed. Interestingly PDGF-BB induced VASP phosphorylation in a ROS dependent manner but independent of changes in cAMP levels. Taken together, we demonstrate a redox-mediated activation of PKA by PDGF-BB thus highlighting a physiological role of ROS as regulator of PKA activity in rat mesangial cells.