Bilateral pedicle screw fixation provides superior biomechanical stability in transforaminal lumbar interbody fusion: a finite element study.

BACKGROUND CONTEXT: Transforaminal lumbar interbody fusion (TLIF) is increasingly popular for the surgical treatment of degenerative lumbar disease. The optimal construct for segmental stability remains unknown. PURPOSE: To compare the stability of fusion constructs using standard (C) and crescent-shaped (CC) polyetheretherketone TLIF cages with unilateral (UPS) or bilateral (BPS) posterior instrumentation. STUDY DESIGN: Five TLIF fusion constructs were compared using finite element (FE) analysis. METHODS: A previously validated L3-L5 FE model was modified to simulate decompression and fusion at L4-L5. This model was used to analyze the biomechanics of various unilateral and bilateral TLIF constructs. The inferior surface of the L5 vertebra remained immobilized throughout the load simulation, and a bending moment of 10 Nm was applied on the L3 vertebra to recreate flexion, extension, lateral bending, and axial rotation. Various biomechanical parameters were evaluated for intact and implanted models in all loading planes. RESULTS: All reconstructive conditions displayed decreased motion at L4-L5. Bilateral posterior fixation conferred greater stability when compared with unilateral fixation in left lateral bending. More than 50% of intact motion remained in the left lateral bending with unilateral posterior fixation compared with less than 10% when bilateral pedicle screw fixation was used. Posterior implant stresses for unilateral fixation were six times greater in flexion and up to four times greater in left lateral bending compared with bilateral fixation. No effects on segmental stability or posterior implant stresses were found. An obliquely-placed, single standard cage generated the lowest cage-end plate stress. CONCLUSIONS: Transforaminal lumbar interbody fusion augmentation with bilateral posterior fixation increases fusion construct stability and decreases posterior instrumentation stress. The shape or number of interbody implants does not appear to impact the segmental stability when bilateral pedicle screws are used. Increased posterior instrumentation stresses were observed in all loading modes with unilateral pedicle screw/rod fixation, which may theoretically accelerate implant loosening or increase the risk of construct failure.

Regulation of CCL2 expression by an upstream TALE homeodomain protein-binding site that synergizes with the site created by the A-2578G SNP.

CC Chemokine Ligand 2 (CCL2) is a potent chemoattractant produced by macrophages and activated astrocytes during periods of inflammation within the central nervous system. Increased CCL2 expression is correlated with disease progression and severity, as observed in pulmonary tuberculosis, HCV-related liver disease, and HIV-associated dementia. The CCL2 distal promoter contains an A/G polymorphism at position -2578 and the homozygous -2578 G/G genotype is associated with increased CCL2 production and inflammation. However, the mechanisms that contribute to the phenotypic differences in CCL2 expression are poorly understood. We previously demonstrated that the -2578 G polymorphism creates a TALE homeodomain protein binding site (TALE binding site) for PREP1/PBX2 transcription factors. In this study, we identified the presence of an additional TALE binding site 22 bp upstream of the site created by the -2578 G polymorphism and demonstrated the synergistic effects of the two sites on the activation of the CCL2 promoter. Using chromatin immunoprecipitation (ChIP) assays, we demonstrated increased binding of the TALE proteins PREP1 and PBX2 to the -2578 G allele, and binding of IRF1 to both the A and G alleles. The presence of TALE binding sites that form inverted repeats within the -2578 G allele results in increased transcriptional activation of the CCL2 distal promoter while the presence of only the upstream TALE binding site within the -2578 A allele exerts repression of promoter activity.

Sequence variation in the CC-chemokine ligand 2 promoter of pigtailed macaques is not associated with the incidence or severity of neuropathology in a simian immunodeficiency virus model of human immunodeficiency virus central nervous system disease.

Increased expression of CC-chemokine ligand 2 (CCL2) in the cerebrospinal fluid (CSF) and brain is consistently observed in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) central nervous system (CNS) disease. The molecular basis for the correlation between increased expression of CCL2 and HIV neuropathogenesis has been linked to a polymorphism at -2578 in the promoter of human CCL2, which was reported to influence the rate of progression to acquired immunodeficiency syndrome (AIDS) and the predisposition of HIV-infected individuals to develop HIV-associated dementia. However, because the rate of neurological deterioration essentially parallels the progression of immunosuppression, it is inherently difficult to uncouple the influence of this polymorphism on increased progression to AIDS from increased propensity to develop CNS complications. To further investigate the correlation between CCL2 and HIV/SIV CNS disease, the authors sequenced the CCL2 promoter of 29 pigtailed macaques examined in their accelerated and consistent SIV model in which all infected macaques develop AIDS but only 69% developed moderate/severe CNS lesions. Sequence analysis identified 39 sites of nucleotide variation in the pigtailed macaque CCL2 promoter/enhancer regions, with the resulting consensus sequence aligning with 94.7% homology to the human CCL2 promoter. After genetic analyses, no variation was found to correlate with the incidence or severity of CNS lesions or with levels of CCL2 in plasma or CSF. These findings suggest that the determinants of neuropathogenesis in this SIV model are distinct from variation in these regions of the CCL2 promoter.

Naip5 affects host susceptibility to the intracellular pathogen Legionella pneumophila.

BACKGROUND: Legionella pneumophila is a gram-negative bacterial pathogen that is the cause of Legionnaires' Disease. Legionella produces disease because it can replicate inside a specialized compartment of host macrophages. Macrophages isolated from various inbred mice exhibit large differences in permissiveness for intracellular replication of Legionella. A locus affecting this host-resistance phenotype, Lgn1, has been mapped to chromosome 13, but the responsible gene has not been identified. RESULTS: Here, we report that Naip5 (also known as Birc1e) influences susceptibility to Legionella. Naip5 encodes a protein that is homologous to plant innate immunity (so-called "resistance") proteins and has been implicated in signaling pathways related to apoptosis regulation. Detailed recombination mapping and analysis of expression implicates Naip5 in the Legionella permissiveness differences among mouse strains. A bacterial artificial chromosome (BAC) transgenic line expressing a nonpermissive allele of Naip5 exhibits a reduction in macrophage Legionella permissiveness. In addition, morpholino-based antisense inhibition of Naip5 causes an increase in the Legionella permissiveness of macrophages. CONCLUSIONS: We conclude that polymorphisms in Naip5 are involved in the permissiveness differences of mouse macrophages for intracellular Legionella replication. We speculate that Naip5 is a functional mammalian homolog of plant "resistance" proteins that monitor for, and initiate host response to, the presence of secreted bacterial virulence proteins.