Asymmetric C7 pedicle subtraction osteotomy for correction of rigid cervical coronal imbalance secondary to post-traumatic heterotopic ossification: a case report, description of a novel surgical technique, and literature review.

PURPOSE: Deformities of the cervical spine are uncommon in the coronal plane. In this report, a unique case of a 31-year-old male with a fixed, 30° left coronal deformity due to heterotopic ossification 3 years status post poly-trauma was treated with an asymmetric C7 pedicle subtraction osteotomy (PSO). METHODS: Case report. RESULTS: Pre-operatively, the patient had a fixed 45-degree left tilt of his neck and radiographs demonstrated a rigid 30° scoliosis, 7 cm coronal imbalance, and 4 cm negative sagittal balance, diffuse bridging bone between the spinous processes and the facet joints of C5 to T1 bilaterally. An asymmetric C7 PSO with C2-T3 posterior spinal fusion was completed without complication. There was residual 9° coronal deformity, 2.9 cm left coronal imbalance, and 2.3 cm sagittal imbalance. He had a marked improvement in his function, as assessed by the SF-36 physical component score (pre-op 31.1; post-op 44.7) and mental component score (pre-op 46.0; post-op 66.8). Post-operatively, neck disability index scores also improved (pre-op 38; post-op 16). Although the patient passed away from a drug overdose 14 months post-operatively, he did not report neck pain, he had not sought evaluation from another physician for his neck, and he had not undergone a subsequent neck operation before his passing. CONCLUSION: In this one patient, an asymmetric C7 PSO was performed safely. While it was effective in addressing a fixed cervical coronal imbalance, its efficacy and safety profile should be confirmed in larger cohorts.

Selective activation of lectin-like oxidized low-density lipoprotein receptor-1 mediates C-reactive protein-evoked endothelial vasodilator dysfunction in coronary arterioles.

RATIONALE: Studies in cultured endothelium implicate that lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) or Fcγ receptor II (CD32) contributes to the proatherogenic effects of C-reactive protein (CRP). However, the identity of the receptors linking to deleterious actions of CRP in vasomotor regulation remains unknown. OBJECTIVE: We tested the hypothesis that LOX-1 contributes to adverse effects of CRP on endothelium-dependent vasomotor function in resistance arterioles. METHODS AND RESULTS: Porcine coronary arterioles were isolated for vasoreactivity study, dihydroethidium fluorescence staining of superoxide, immunohistochemical localization of receptors, immunoprecipitation of receptor/CRP interaction, and protein blot. Intraluminal treatment of pressurized arterioles with a pathophysiological level of CRP (7 µg/mL; 60 minutes) attenuated endothelium-dependent nitric oxide-mediated and prostacyclin-mediated dilations to serotonin and arachidonic acid, respectively. LOX-1 and CD32 were detected in the endothelium of arterioles. Blockade of LOX-1 with either pharmacological antagonist κ-carrageenan or anti-LOX-1 antibody prevented the detrimental effect of CRP on vasodilator function, whereas anti-CD32 antibody treatment was ineffective. Denudation of endothelium and blockade of LOX-1 but not CD32 prevented CRP-induced elevation of superoxide in the vessel wall. CRP was coimmunoprecipitated with LOX-1 and CD32 from CRP-treated arterioles. Similarly, LOX-1 and CD32 blockade prevented CRP-induced arteriolar expression of plasminogen activator inhibitor-1, a thrombogenic protein. CONCLUSIONS: CRP elicits endothelium-dependent oxidative stress and compromises nitric oxide-mediated and prostacyclin-mediated vasomotor function via LOX-1 activation. In contrast, both LOX-1 and CD32 mediate plasminogen activator inhibitor-1 upregulation in arterioles by CRP. Thus, activation of LOX-1 and CD32 may contribute to vasomotor dysfunction and proatherogenic actions of CRP, respectively.

C-reactive protein impairs coronary arteriolar dilation to prostacyclin synthase activation: role of peroxynitrite.

Endothelium-derived vasodilators, i.e., nitric oxide (NO), prostacyclin (PGI(2)) and prostaglandin E(2) (PGE(2)), play important roles in maintaining cardiovascular homeostasis. C-reactive protein (CRP), a biomarker of inflammation and cardiovascular disease, has been shown to inhibit NO-mediated vasodilation. The goal of this study was to determine whether CRP also affects endothelial arachidonic acid (AA)-prostanoid pathways for vasomotor regulation. Porcine coronary arterioles were isolated and pressurized for vasomotor study, as well as for molecular and biochemical analysis. AA elicited endothelium-dependent vasodilation and PGI(2) release. PGI(2) synthase (PGI(2)-S) inhibitor trans-2-phenyl cyclopropylamine blocked vasodilation to AA but not to serotonin (endothelium-dependent NO-mediated vasodilator). Intraluminal administration of a pathophysiological level of CRP (7 microg/mL, 60 min) attenuated vasodilations to serotonin and AA but not to nitroprusside, exogenous PGI(2), or hydrogen peroxide (endothelium-dependent PGE(2) activator). CRP also reduced basal NO production, caused tyrosine nitration of endothelial PGI(2)-S, and inhibited AA-stimulated PGI(2) release from arterioles. Peroxynitrite scavenger urate failed to restore serotonin dilation, but preserved AA-stimulated PGI(2) release/dilation and prevented PGI(2)-S nitration. NO synthase inhibitor L-NAME and superoxide scavenger TEMPOL also protected AA-induced vasodilation. Collectively, our results suggest that CRP stimulates superoxide production and the subsequent formation of peroxynitrite from basal released NO compromises PGI(2) synthesis, and thus endothelium-dependent PGI(2)-mediated dilation, by inhibiting PGI(2)-S activity through tyrosine nitration. By impairing PGI(2)-S function, and thus PGI(2) release, CRP could promote endothelial dysfunction and participate in the development of coronary artery disease.

C-reactive protein inhibits endothelium-dependent NO-mediated dilation in coronary arterioles by activating p38 kinase and NAD(P)H oxidase.

OBJECTIVE: Elevated levels of C-reactive protein (CRP), a proinflammatory marker, are associated with reduced systemic endothelium-dependent NO-mediated dilation in patients with coronary artery disease; however, the direct effect of CRP on coronary microvascular reactivity remains unknown. Herein, we examined whether CRP can modulate endothelium-dependent NO-mediated dilation of coronary arterioles and whether proinflammatory signaling pathways such as stress-activated protein kinases (p38 and c-Jun N-terminal kinase [JNK]) and oxidative stress are involved in the CRP-mediated effect. METHODS AND RESULTS: Porcine coronary arterioles were isolated and pressurized without flow for in vitro study. Intraluminal treatment with a clinically relevant concentration of CRP (7 microg/mL; 1 hour) significantly attenuated the NO release and vasodilation to serotonin. Further incubation with the NO precursor l-arginine (3 mmol/L) partially restored serotonin-induced vasodilation. In the presence of superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), NAD(P)H oxidase inhibitor apocynin, or p38 kinase (an upstream activator of NAD(P)H oxidase) inhibitor SB203850, but not xanthine oxidase inhibitor allopurinol or JNK inhibitor SP600125, the detrimental effect of CRP on serotonin-induced dilation was prevented. Dihydroethidium staining showed that CRP produced SB203850- and TEMPOL-sensitive superoxide production in the arteriolar endothelium. CRP treatment of coronary arterioles significantly increased NAD(P)H oxidase activity. CONCLUSIONS: CRP inhibits endothelium-dependent NO-mediated dilation in coronary arterioles by producing superoxide from NAD(P)H oxidase via p38 kinase activation. By impairing endothelium-dependent NO-mediated vasoreactivity, CRP could facilitate the initiation of numerous cardiovascular diseases.

Does Transforaminal Lumbar Interbody Fusion Have Advantages over Posterolateral Lumbar Fusion for Degenerative Spondylolisthesis?

Study Design Retrospective cohort study. Objective To compare the clinical and radiographic outcomes of transforaminal lumbar interbody fusion (TLIF) and posterolateral lumbar fusion (PLF) in the treatment of degenerative spondylolisthesis. Methods This study compared 24 patients undergoing TLIF and 32 patients undergoing PLF with instrumentation. The clinical outcomes were assessed by visual analog scale (VAS) for low back pain and leg pain, physical component summary (PCS) of the 12-item Short-Form Health Survey, and the Oswestry Disability Index (ODI). Radiographic parameters included slippage of the vertebra, local disk lordosis, the anterior and posterior disk height, lumbar lordosis, and pelvic parameters. Results The improvement of VAS of leg pain was significantly greater in TLIF than in PLF unilaterally (3.4 versus 1.0; p = 0.02). The improvement of VAS of low back pain was significantly greater in TLIF than in PLF (3.8 versus 2.2; p = 0.02). However, there was no significant difference in improvement of ODI or PCS between TLIF and PLF. Reduction of slippage and the postoperative disk height was significantly greater in TLIF than in PLF. There was no significant difference in local disk lordosis, lumbar lordosis, or pelvic parameters. The fusion rate was 96% in TLIF and 84% in PLF (p = 0.3). There was no significant difference in fusion rate, estimated blood loss, adjacent segmental degeneration, or complication rate. Conclusions TLIF was superior to PLF in reduction of slippage and restoring disk height and might provide better improvement of leg pain. However, the health-related outcomes were not significantly different between the two procedures.

Intermediate outcomes of fresh talar osteochondral allografts for treatment of large osteochondral lesions of the talus.

BACKGROUND: Large osteochondral defects of the talus present a treatment challenge. Fresh osteochondral allograft transplantation can be used for large lesions without the donor-site morbidity associated with other procedures such as autologous chondrocyte implantation or osteochondral autograft transfer. The goal of this study was to prospectively evaluate the intermediate outcomes of fresh osteochondral allografting for osteochondral lesions of the talus with use of validated outcome measures. METHODS: Sixteen patients (seventeen ankles) received a fresh osteochondral allograft, and all sixteen were available for follow-up. Data were prospectively collected with use of the Ankle Osteoarthritis Scale (AOS), Short Form-36 (SF-36), and American Academy of Orthopaedic Surgeons (AAOS) Foot and Ankle Module outcome measures. Postoperative American Orthopaedic Foot & Ankle Society (AOFAS) hindfoot scale scores were also collected. All sixteen patients underwent radiographic and computed tomographic (CT) analyses preoperatively, and fifteen patients had these studies postoperatively. RESULTS: The average duration of follow-up was 4.1 years. The latest follow-up CT evaluation identified failure of graft incorporation in two of sixteen ankles. Osteolysis, subchondral cysts, and degenerative changes were found in five, eight, and seven ankles, respectively. Five ankles were considered failures, and two required a reoperation because of ongoing symptoms. The AOS Disability and the AAOS Foot and Ankle Core Scale scores significantly improved, but there was no significant change in the AOS Pain, AAOS Foot and Ankle Shoe Comfort Scale, or SF-36 scores. Overall, ten patients had a good or excellent result; however, persistent symptoms remained in six of these patients. Only four were symptom-free. CONCLUSION: The use of a fresh osteochondral allograft is a reasonable option for the treatment of large talar osteochondral lesions. The high reoperation rate (two of seventeen) and failure rate (five of seventeen) must be taken into consideration when one is choosing this procedure for the management of these lesions.

Expression of VEGF gene isoforms in a rat segmental bone defect model treated with EPCs.

OBJECTIVES: Angiogenesis and osteogenesis are essential for bone growth, fracture repair, and bone remodeling. Vascular endothelial growth factor (VEGF) has an important role in bone repair by promoting angiogenesis and osteogenesis. In our previous study, endothelial progenitor cells (EPCs) promoted bone healing in a rat segmental bone defect as confirmed by radiological, histological, biomechanical, and micro-CT evaluations. Although EPCs have demonstrated effectiveness in animal models of fracture healing, the mechanism by which EPCs enhance fracture healing remains unclear. We hypothesized a possible paracrine mechanism of action, where the secretion of growth factors critical to the processes of fracture healing (such as VEGF), is responsible for the positive effects of EPC therapy. The purpose of this study was to evaluate VEGF gene expression after local EPC therapy for a rat segmental bone defect. METHODS: Rat bone marrow-derived EPCs were isolated by the Ficoll-paque gradient centrifuge technique. The EPCs were cultured for 7-10 days in endothelial cell growth medium with supplements and collected for treatment of the rat segmental bone defect. EPCs were identified by immunocytochemistry staining with primary antibodies for CD34, CD133, fetal liver kinase-1, and Von Willebrand factor. A total of 56 rats were studied. A 5-mL segmental bone defect was created in the middle one-third of each femur followed by miniplate fixation. The treatment group received 1 × 10 EPCs locally at the bone defect on a gelfoam scaffold and control animals received the gelfoam scaffold only. Seven control and 7 EPC-treated rats were included in each group at 1, 2, 3, and 10 weeks. The animals were sacrificed at the end of the treatment period, and specimens from the fracture gap area were collected and immediately frozen. Rat VEGF mRNA was measured by reverse-transcriptase-polymerase chain reaction and quantified by VisionWorksLS. All measurements were performed in triplicate. RESULTS: Cultured EPCs at 1 week showed positive staining for CD34, CD133, fetal liver kinase-1, and Von Willebrand factor markers. The EPC group had a greater VEGF expression than the control group at weeks 1, 2, and 3, but not at week 10. Three VEGF isoforms were detected in this rat model: VEGF120, VEGF164, and VEGF188. VEGF120 and VEGF164 levels peaked at 2 weeks, whereas VEGF188 levels peaked at 3 weeks. All 3 VEGF isoform levels were low at 10 weeks. DISCUSSION AND CONCLUSIONS: EPC-based therapy for a segmental bone defect results in increased VEGF expression during the early period of fracture repair. In addition, the specific VEGF isoform may be a key regulator of the bone healing process. These findings demonstrate that EPCs may promote fracture healing by increasing VEGF levels and thus stimulating angiogenesis, a process that is essential for early callus formation and bone regeneration.

Evaluation of a novel poly N-acetyl glucosamine (pGlcNAc) hydrogel for treatment of the degenerating intervertebral disc.

AIMS: The early stages of degenerative disc disease (DDD) primarily affect the disc nucleus pulposus (NP). Tissue-engineered strategies may enhance intervertebral disc (IVD) functionality. The aim of this study was to develop and evaluate a novel deacetylated poly-N-acetyl glucosamine (pGlcNAc) hydrogel characterizing its biochemical effect on human IVD cells as well as material biomechanical properties. MAIN METHODS: A novel deacetylated derivative of a marine diatom-derived glycosaminoglycan was developed into a hydrogel formulation as a potential therapy to treat degenerating IVD NP. In vitro biochemical studies were conducted using primary human disc cell cultures to evaluate cell viability, metabolic activity, proteoglycan and extracellular matrix protein expression. The biomechanical hydration kinetics and viscoelastic behavior of the hydrogel were determined and compared with the behavior of human lumbar NP. KEY FINDINGS: Disc cell viability, metabolic activity, and proteoglycan content of the treated cells were observed to be significantly greater in experimental samples when compared to untreated control groups. RT-PCR and immunohistochemical data corroborated the expression of characteristic NP disc markers, aggrecan and type II collagen in cultured cells. Rheological data demonstrated that the elastic component of the hydrogel dominated the viscous component over a frequency range of 0.1 to 15.85rad/s. Of several formulations evaluated, a sulphated, deactylated derivative of the nanofiber derived pGlcNAc hydrogel demonstrated the most robust biologic effects on cell viability, metabolic activity, and proteoglycan expression. SIGNIFICANCE: This in vitro study using human disc cells demonstrates that a sulphated deacetylated glycosaminoglycan derivative hydrogel possesses promising characteristics motivating further evaluation as a potential therapy for NP degeneration.

Endothelial progenitor cells for fracture healing: a microcomputed tomography and biomechanical analysis.

PURPOSE: Local treatment of segmental bone defects with ex vivo expanded endothelial progenitor cells (EPCs) has been shown to increase osteogenesis and callus formation in rat femur diaphyseal defects. The purpose of this study was to evaluate the effects of local EPC therapy on the microarchitecture and biomechanical properties of a segmental bone defect in a rat model. METHODS: Five-millimeter segmental defects were created in the femora of 14 Fisher 344 rats and stabilized with miniplates. The treatment group (n = 7) received 1 × 10(6) EPCs, seeded on a Gelfoam scaffold, locally at the site of the bone defect, and control animals (n = 7) received Gelfoam and saline only. Animals were euthanized 10 weeks after the procedure and new bone formation was assessed with radiographs, microcomputed tomography and biomechanical testing. RESULTS: Radiographically, all the animals in the EPC-treated group healed with bridging callus formation, whereas animals in the control group developed nonunion of the defect. Microcomputed tomography assessment demonstrated significantly superior bone formation in the EPC-treated group versus the control group for all parameters tested (P = 0.013-0.000). Biomechanical testing revealed that the EPC-treated group had significantly higher torsional strength (P = 0.000) and stiffness (P = 0.000) when compared with the control group. CONCLUSION: The results of this study suggest that local EPC therapy significantly enhances fracture healing in a segmental defect model in a rat femur. EPC therapy results in superior radiographic bone formation and healing when compared with appropriate controls.

Sodium azide dilates coronary arterioles via activation of inward rectifier K+ channels and Na+-K+-ATPase.

Sodium azide (NaN(3)), a potent vasodilator, causes severe hypotension on accidental exposure. Although NaN(3) has been shown to increase coronary blood flow, the direct effect of NaN(3) on coronary resistance vessels and the mechanism of the NaN(3)-induced response remain to be established. To address these issues without confounding influences from systemic parameters, subepicardial coronary arterioles were isolated from porcine hearts for in vitro study. Arterioles developed basal tone at 60 cmH(2)O intraluminal pressure and dilated acutely, in a concentration-dependent manner, to NaN(3) (0.1 microM to 50 microM). The NaN(3) response was not altered by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester or endothelial removal. Neither inhibition of phosphoinositol 3-kinase and tyrosine kinases nor blockade of ATP-sensitive, Ca(2+)-activated, and voltage-dependent K(+) channels affected NaN(3)-induced dilation. However, the vasomotor action of NaN(3) was significantly attenuated in a similar manner by the inward rectifier K(+) (K(IR)) channel inhibitor Ba(2+), the Na(+)-K(+) ATPase inhibitor ouabain, or the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ). Ba(2+), in combination with either ouabain or ODQ, nearly abolished the vasodilatory response. However, there was no additive inhibition by combining ouabain and ODQ. The NaN(3)-mediated vasodilation was also attenuated by morin, an inhibitor of phosphatidylinositolphosphate (PIP) kinase, which can regulate K(IR) channel activity. With the use of whole cell patch-clamp methods, NaN(3) acutely enhanced Ba(2+)-sensitive K(IR) current in isolated coronary arteriolar smooth muscle cells. Collectively, this study demonstrates that NaN(3), at clinically toxic concentrations, dilates coronary resistance vessels via activation of both K(IR) channels and guanylyl cyclase/Na(+)-K(+)-ATPase in the vascular smooth muscle. The K(IR) channels appear to be modulated by PIP kinase.

Regulation of nitric oxide consumption by hypoxic red blood cells.

The homeostasis of nitric oxide (NO) is attained through a balance between its production and consumption. Shifts in NO bioavailability have been linked to a variety of diseases. Although the regulation of NO production has been well documented, its consumption is largely thought to be unregulated. Here, we have demonstrated that under hypoxic conditions, NO accelerates its own consumption by increasing its entry into RBCs. When RBCs were exposed to NO (1:400 NO/heme ratio) under hypoxic conditions to form HbFe(II)NO, the consumption rate of NO increased significantly. This increase in NO consumption converted the bioactivity of serotonin from a vasodilator to a vasoconstrictor in isolated coronary arterioles. We identified HbFe(II)NO as a potential mediator of accelerated NO consumption. Accelerated NO consumption by HbFe(II)NO-bearing RBCs may contribute to hypoxic pulmonary vasoconstriction and the rebound effect seen on termination of NO inhalation therapy. Furthermore, accelerated NO consumption may exacerbate ischemia-mediated vasospasm and nitrate tolerance. Finally, this phenomenon may be an evolved mechanism to stabilize the vasculature in sepsis.