Staphylococcus aureus and Acinetobacter baumannii Inhibit Osseointegration of Orthopedic Implants.

Bacterial infections routinely cause inflammation and thereby impair osseointegration of orthopedic implants. Acinetobacter spp., which cause osteomyelitis following trauma, on or off the battlefield, were, however, reported to cause neither osteomyelitis nor osteolysis in rodents.

Mapping of common rib fracture patterns and the subscapular flail chest associated with operative scapula fractures.

Background: Rib fractures occur in approximately 10% of trauma patients and are associated with more than 50% of patients with scapula fractures. This study investigates the location and patterns of rib fractures and flail chest occurring in patients with operatively treated scapula fractures. Novel frequency mapping techniques of rib fracture patterns in patients who also injure the closely associated scapula can yield insight into surgical approaches and fixation strategies for complex, multiple injuries patients.

Radiographic correlation of clinical shoulder deformity and patient perception following scapula fracture.

Background: Interest in operative management of scapular fractures is increasing based upon defined radiographic displacement criteria and growing awareness that certain extra-articular fractures will not do well and result in dysfunction and deformity (slumped shoulder). We intend to quantify clinical deformity, analyze correlations of these novel measures with defined radiographic measures of fracture displacement and with the patients' reported perception of their deformity.

Methods: Prospectively enrolled patients underwent standardized questioning regarding their perception of the deformity.

Injury mechanism, epidemiology, and Hospital trends of scapula fractures: A 10-year retrospective study of the National Trauma Data Bank.

Background: This 10 year retrospective study of the NTDB is the first to describe trends in scapula fracture diagnosis frequency, epidemiology, injury mechanisms and the type of hospital where the condition is treated.

Methods: Demographics, ISS scores, hospital data, mechanism of injury, complications, and hospital length of stay were recorded for patients with diagnosed scapula fractures (ICD-9, 811.0) recorded in the NTDB, v7.

Five to Ten-Year Outcomes of Operatively Treated Scapular Fractures.

Background: The purpose of this study was to assess the 5 to 10-year clinical and patient-reported functional outcomes after open reduction and internal fixation (ORIF) of intra-articular and extra-articular scapular fractures.

Methods: We conducted a retrospective review of prospectively collected data on 106 patients who underwent ORIF of a scapular fracture at a single level-I trauma center between January 2005 and December 2010. Eight patients were excluded from the study because they had either severe neurologic injury or an isolated process fracture, and 66 patients (37 with an isolated extra-articular fracture and 29 with an intra-articular fracture) participated in the 5 to 10-year follow-up, yielding a follow-up rate of 67%.

Particle-Induced Osteolysis Is Mediated by TIRAP/Mal in Vitro and in Vivo: Dependence on Adherent Pathogen-Associated Molecular Patterns.

Background: Proinflammatory signaling by toll-like receptors (TLRs) likely contributes to biologic responses to wear particles causing aseptic loosening. We recently reported associations with aseptic loosening in patients with polymorphisms in the locus encoding an adapter protein specific for TLR-2 and TLR-4 known as toll/interleukin-1 receptor domain-containing adapter protein/MyD88 adapter-like (TIRAP/Mal). To directly examine the contribution of TIRAP/Mal, we tested the hypothesis that TIRAP/Mal deficiency reduces the activity of wear particles.

γδT cells are prevalent in the proximal aorta and drive nascent atherosclerotic lesion progression and neutrophilia in hypercholesterolemic mice.

Unique innate immunity-linked γδT cells have been seen in early human artery lesions, but their role in lesion development has received little attention. Here we investigated whether γδT cells modulate atherogenesis in apolipoprotein E-deficient (ApoE KO) mice. We found that γδT cell numbers were markedly increased in the proximal aorta of ApoE-deficient vs.

Surface contaminants inhibit osseointegration in a novel murine model.

Surface contaminants, such as bacterial debris and manufacturing residues, may remain on orthopedic implants after sterilization procedures and affect osseointegration. The goals of this study were to develop a murine model of osseointegration in order to determine whether removing surface contaminants enhances osseointegration. To develop the murine model, titanium alloy implants were implanted into a unicortical pilot hole in the mid-diaphysis of the femur and osseointegration was measured over a five week time course.

PI3Kγ deletion reduces variability in the in vivo osteolytic response induced by orthopaedic wear particles.

Orthopedic wear particles activate a number of intracellular signaling pathways associated with inflammation in macrophages and we have previously shown that the phosphoinositol-3-kinase (PI3K)/Akt pathway is one of the signal transduction pathways that mediates the in vitro activation of macrophages by orthopedic wear particles. Since PI3Kγ is primarily responsible for PI3K activity during inflammation, we hypothesized that PI3Kγ mediates particle-induced osteolysis in vivo. Our results do not strongly support the hypothesis that PI3Kγ regulates the overall amount of particle-induced osteolysis in the murine calvarial model.

Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice.

Objective: Atherosclerosis encompasses a conspicuously maladaptive inflammatory response that might involve innate immunity. Here, we compared the role of Toll-like receptor 4 (TLR4) with that of TLR2 in intimal foam cell accumulation and inflammation in apolipoprotein E (ApoE) knockout (KO) mice in vivo and determined potential mechanisms of upstream activation and downstream action.

Methods And Results: We measured lipid accumulation and gene expression in the lesion-prone lesser curvature of the aortic arch.

Bacterial pathogen-associated molecular patterns stimulate biological activity of orthopaedic wear particles by activating cognate Toll-like receptors.

Aseptic loosening of orthopaedic implants is induced by wear particles generated from the polymeric and metallic components of the implants. Substantial evidence suggests that activation of Toll-like receptors (TLRs) may contribute to the biological activity of the wear particles. Although pathogen-associated molecular patterns (PAMPs) produced by Gram-positive bacteria are likely to be more common in patients with aseptic loosening, prior studies have focused on LPS, a TLR4-specific PAMP produced by Gram-negative bacteria.

Prolyl hydroxylase 2 deficiency limits proliferation of vascular smooth muscle cells by hypoxia-inducible factor-1{alpha}-dependent mechanisms.

Arterial O(2) levels are thought to modulate vascular smooth muscle cell (VSMC) proliferation and vascular remodeling, but the mechanisms involved are poorly understood. Here, we tested the hypothesis that PHD2, a prolyl hydroxylase domain (PHD)-containing O(2) sensor, modulates growth factor-induced proliferative responses of human pulmonary artery SMC (HPASMC). We found that both PHD1 and PHD2 were robustly expressed by HPASMC, and inhibiting prolyl hydroxylase activity pharmacologically by using the nonselective dioxygenase inhibitor dimethyloxalylglycine (DMOG) inhibited proliferation and cyclin A expression induced by PDGF-AB or FGF-2.

Endogenous interleukin-1 alpha promotes a proliferative and proinflammatory phenotype in human vascular smooth muscle cells.

During vascular disease and following injury, vascular smooth muscle cells (VSMC) proliferate and produce inflammation-promoting cytokines and chemokines. Similar phenotypic changes can be elicited in vitro by activation of Toll-like receptors (TLR) within VSMC. TLR-activated VSMC also produce IL-1 alpha, but it is unknown whether endogenous IL-1 alpha stimulates VSMC in an autocrine manner.

Comparison of the roles of IL-1, IL-6, and TNFalpha in cell culture and murine models of aseptic loosening.

Pro-inflammatory cytokines, such as IL-1, IL-6, and TNF, are considered to be major mediators of osteolysis and ultimately aseptic loosening. This study demonstrated that synergistic interactions among these cytokines are required for the in vitro stimulation of osteoclast differentiation by titanium particles. In contrast, genetic knock out of these cytokines or their receptors does not protect murine calvaria from osteolysis induced by titanium particles.

The balance between endotoxin accumulation and clearance during particle-induced osteolysis in murine calvaria.

Bacterial endotoxin may contribute to aseptic loosening of orthopedic implants even in the absence of clinical or microbiological evidence of infection. One potential source of endotoxin during aseptic loosening is systemically circulating endotoxin, derived from intestinal flora, minor infections, or dental procedures, that may bind to wear particles. The current study demonstrates that systemically derived endotoxin accumulates when 'endotoxin-free' titanium and polyethylene particles are implanted on murine calvaria.

Toll-like receptor 3 signaling evokes a proinflammatory and proliferative phenotype in human vascular smooth muscle cells.

Inflammation plays a key role in atherogenesis, perhaps promoted by bacterial and viral products present within the artery wall. Vascular smooth muscle cells (VSMC) can express certain bacterially responsive Toll-like receptors (TLR), which promote a proinflammatory and proliferative VSMC phenotype when activated, but it is unknown whether virally activated TLR can regulate VSMC phenotype. Here we tested the role in VSMC of TLR3, which is activated by double-stranded (dsRNA), a molecular signature of viruses.

Polyethylene and titanium particles induce osteolysis by similar, lymphocyte-independent, mechanisms.

Periprosthetic osteolysis is a major clinical problem that limits the long-term survival of total joint arthroplasties. Osteolysis is induced by implant-derived wear particles, primarily from the polyethylene bearing surfaces. This study examined two hypotheses.

Roles of the melanocortin-4 receptor in antipyretic and hyperthermic actions of centrally administered alpha-MSH.

Activation of central melanocortin receptors (MCR) inhibits fever but can also stimulate thermogenesis, and the mechanisms involved are unknown. To determine whether the long-recognized antipyretic effect of exogenous alpha-MSH is mediated by the melanocortin-4 receptor (MC4R), and what thermoeffector systems are involved, we tested the effects of intracerebroventricular (i.c.

The central melanocortin system and fever.

Fever is a phylogenetically ancient response that is mounted upon exposure of the host to pathogens or inflammatory agents. Melanocortin agonists act centrally to inhibit fever by acting at receptors, including the melanocortin-4 receptor, which is prominently expressed in key hypothalamic thermoregulatory centers. Furthermore, endogenous melanocortins act centrally as physiological modulators of fever, recruited during the febrile response to restrain its intensity.

Central serotonin and melanocortin pathways regulating energy homeostasis.

It is now established that the hypothalamus is essential in coordinating endocrine, autonomic, and behavioral responses to changes in energy availability. However, the interaction of key peptides, neuropeptides, and neurotransmitters systems within the hypothalamus has yet to be delineated. Recently, we investigated the mechanisms through which central serotonergic (5-hydroxytryptamine, 5-HT) systems recruit leptin-responsive hypothalamic pathways, such as the melanocortin systems, to affect energy balance.

Activation of central melanocortin-4 receptor suppresses lipopolysaccharide-induced fever in rats.

Activation of central melanocortin receptors (MCR) inhibits fever, but the identity of the MCR subtype(s) mediating this antipyretic effect is unknown. To determine whether selective central melanocortin receptor-4 (MC4R) activation produces antipyretic effects, the MC4R selective agonist MRLOB-0001 (CO-His-d-Phe-Arg-Trp-Dab-NH(2)) was administered intracerebroventricularly to rats treated with Escherichia coli lipopolysaccharide (LPS, 30 microg/kg ip). Treatment with MRLOB-0001 (150 ng icv) did not lower core body temperature (T(c)) in afebrile rats but did suppress LPS-induced increases in T(c) and associated decreases in tail skin temperature (T(sk)), an indicator of vasomotor thermoeffector function.

Alpha-melanocyte stimulating hormone suppresses intracerebral tumor necrosis factor-alpha and interleukin-1beta gene expression following transient cerebral ischemia in mice.

Following stroke, an intracerebral inflammatory response develops that may contribute to postischemic central nervous system injury. This study's objective was to determine whether the anti-inflammatory neuropeptide alpha-melanocyte stimulating hormone (MSH) can suppress postischemic activation of intracerebral tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) gene expression. Ipsilateral TNF-alpha levels were increased in cerebrocortical territory of the middle cerebral artery (MCA) following transient unilateral MCA occlusion (MCAO) and reperfusion in mice, and systemic alpha-MSH treatment (0.

Activation of central melanocortin pathways by fenfluramine.

D-fenfluramine (d-FEN) was once widely prescribed and was among the most effective weight loss drugs, but was withdrawn from clinical use because of reports of cardiac complications in a subset of patients. Discerning the neurobiology underlying the anorexic action of d-FEN may facilitate the development of new drugs to prevent and treat obesity. Through a combination of functional neuroanatomy, feeding, and electrophysiology studies in rodents, we show that d-FEN-induced anorexia requires activation of central nervous system melanocortin pathways.