Development of Consensus-Based Best Practice Guidelines for the Peri- and Post-operative Care of Pediatric Patients with Spinal Deformity and Programmable Implanted Devices.

STUDY DESIGN: Modified Delphi consensus study. OBJECTIVE: To develop consensus-based best practices for the care of pediatric patients who have implanted programmable devices (IPDs) and require spinal deformity surgery. SUMMARY OF BACKGROUND DATA: Implanted programmable devices (IPDs) are often present in patients with neuromuscular or syndromic scoliosis who require spine surgery. Guidelines for monitoring and interrogating these devices during the peri-operative period are not available. METHODS: A panel was assembled consisting of 25 experts (i.e., spinal deformity surgeons, neurosurgeons, neuro-electrophysiologists, cardiologists, and otolaryngologists). Initial postulates were based on literature review and results from a prior survey. Postulates addressed the following IPDs: vagal nerve stimulators (VNS), programmable ventriculo-peritoneal shunts (VPS), intrathecal baclofen pumps (ITBP), cardiac pacemakers and implantable cardioverter-defibrillators (ICD), deep brain stimulators (DBS), and cochlear implants. Cardiologist and otolaryngologists participants responded only to postulates on cardiac pacemakers or cochlear implants, respectively. Consensus was defined as ≥80% agreement, items that did not reach consensus were revised and included in subsequent rounds. A total of three survey rounds and one virtual meeting were conducted. RESULTS: Consensus was reached on 39 total postulates across six IPD types. Postulates addressed general spine surgery considerations, use of intraoperative monitoring and cautery, use of magnetically-controlled growing rods (MCGRs), and use of an external remote controller to lengthen MCGRs. Across IPD types, consensus for the final postulates ranged from 94.4-100%. Overall, experts agreed that MCGRs can be surgically inserted and lengthened in patients with a variety of IPDs and provided guidance for the use of intraoperative monitoring and cautery, which varied between IPD types. CONCLUSION: Spinal deformity correction surgery often benefits from the use of intraoperative monitoring, monopolar and bipolar cautery, and MCGRs. Final postulates from this study can inform the peri- and post-operative practices of spinal deformity surgeons who treat patients with both scoliosis and IPDs. LEVEL OF EVIDENCE: V- Expert opinion.

Cranial vault remodeling for sagittal craniosynostosis in older children.

OBJECT Sagittal craniosynostosis is the most common form of craniosynostosis and is commonly treated within the first year of life. Optimal treatment of patients older than 1 year of age is not well characterized. The authors reviewed cases of sagittal craniosynostosis involving patients who were treated surgically at their institution when they were older than 1 year in order to determine the rate of intracranial hypertension (ICH), potential to develop nonhealing cranial defects, and the need for various surgical procedures to treat the more mature phenotype. METHODS A retrospective chart review was conducted of all cases in the Children's Hospital of Pittsburgh Neurosurgery Database involving patients who underwent cranial vault remodeling for scaphocephaly after 1 year of age between October 2000 and December 2010. RESULTS Ten patients were identified who met the inclusion criteria. Five patients underwent anterior two-thirds cranial vault remodeling procedures, 3 patients underwent posterior vault remodeling, and 2 patients underwent 2-staged total vault remodeling. All patients had improved head shapes, and mean cephalic indices improved from 65.4 to 69.1 (p = 0.05). Six patients exhibited signs of ICH. No patients with more than 3 months of follow-up exhibited palpable calvarial defects. CONCLUSIONS Patients with sagittal synostosis treated after 1 year of age demonstrate increased rates of ICH, warranting diligent evaluations and surveillance to detect it; rarely develop clinically significant cranial defects if appropriate bone grafting is performed at the time of surgery; and achieve acceptable improvements in head shape.

Musculoskeletal Pain Outcomes Pre- and Post Intrathecal Baclofen Pump Implant in Children With Cerebral Palsy: A Prospective Cohort Study.

OBJECTIVE: To characterize musculoskeletal pain intensity, duration, frequency, and interference with activities of daily living in children with cerebral palsy (CP) before and after intrathecal baclofen pump placement. DESIGN: Prospective cohort study. SETTING: Children's tertiary hospital. PARTICIPANTS: Participants were children with CP (N=32; 53% male; mean age, 9.9y; age range, 4-17y). The majority of participants had a CP diagnosis of quadriplegia (76%) and relied on wheeled mobility (91%). INTERVENTIONS: Assessments were completed pre- and post intrathecal baclofen pump implant. MAIN OUTCOME MEASURES: Because of considerable patient heterogeneity, both pain measures (Brief Pain Inventory, Dalhousie Pain Interview) were completed by proxy (parent) report at the time of the procedure and approximately 6 months after intrathecal baclofen (ITB) pump placement. RESULTS: Prior to implant, 31% of participants were living with constant pain, which reduced to 6% post ITB implant (P<.001). Based on Wilcoxon signed rank tests, pain duration significantly decreased post ITB pump implant (P<.01). CONCLUSIONS: This prospective analysis supports the anecdotal and retrospective evidence that musculoskeletal pain decreases in CP following ITB pump implant. The greatest effect appears to be on the duration of pain experience. Pain did not decrease for all individuals, and it would be worth further investigation to better understand the relation between patient characteristics and pain outcomes.

The effects of matrix stiffness and RhoA on the phenotypic plasticity of smooth muscle cells in a 3-D biosynthetic hydrogel system.

Studies using 2-D cultures have shown that the mechanical properties of the extracellular matrix (ECM) influence cell migration, spreading, proliferation, and differentiation; however, cellular mechanosensing in 3-D remains under-explored. To investigate this topic, a unique biomaterial system based on poly(ethylene glycol)-conjugated fibrinogen was adapted to study phenotypic plasticity in smooth muscle cells (SMCs) as a function of ECM mechanics in 3-D. Tuning the compressive modulus between 448 and 5804 Pa modestly regulated SMC cytoskeletal assembly in 3-D, with spread cells in stiff matrices having a slightly higher degree of F-actin bundling after prolonged culture. However, vinculin expression in all 3-D conditions was qualitatively low and was not assembled into the classic focal adhesions typically seen in 2-D cultures. Given the evidence that RhoA-mediated cytoskeletal contractility represents a critical node in mechanosensing, we molecularly upregulated contractility by inducing SMCs to express constitutively active RhoA. In these cells, F-actin bundling and total vinculin expression increased, and focal adhesion-like structures began to emerge, consistent with RhoA's mechanism of action in cells cultured on 2-D substrates. Furthermore, SMC proliferation in 3-D did not depend significantly on matrix stiffness, and was reduced by constitutive activation of RhoA irrespective of ECM mechanical properties. Conversely, the expression of contractile markers globally increased with constitutive RhoA activation and depended on 3-D matrix stiffness only in cells with heightened RhoA activity. Combined, these data suggest that the synergistic effects of ECM mechanics and RhoA activity on SMC phenotype in 3-D are distinct from those in 2-D, and highlight the importance of studying the mechanical role of cell-matrix interactions in tunable 3-D environments.

Risk of cervical spine injury and other complications seen with skull fractures in the setting of mild closed head injury in young children: a retrospective study.

We have reviewed records for patients under 2 years of age who presented at our hospital with mild closed head injuries and nondisplaced skull fractures, specifically to examine methods utilized for spine clearance, associated cervical injuries, involvement and findings of child protective services and delayed complications. Of 42 patients included in the series, none were found to have cervical spine injuries. Child protective services were involved in 12 cases with confirmatory findings and subsequent placement occurring in 2 cases. There were no serious delayed complications in this series of patients. AP and lateral plain films of the cervical spine are nonetheless recommended until larger prospective studies suggest otherwise.

Optical glucose analogs of aminolevulinic acid for fluorescence-guided tumor resection and photodynamic therapy.

PURPOSE: We have developed and tested a novel conjugation of the clinically used prodrug aminolevulinic acid with 2-deoxyglucosamine as a novel probe (ALA-2DG) for fluorescence imaging and photodynamic therapy. PROCEDURES: ALA-2DG was successfully synthesized, and the mechanisms of probe uptake, PpIX synthesis, and photodynamic therapy efficacy were evaluated in vitro and in vivo. RESULTS: ALA-2DG led to PpIX synthesis in tumor cells in vitro and in tumor in vivo. Competitive and inhibitory assays in vitro showed a reduction of this PpIX synthesis that was not observed when cells were incubated with ALA itself, indicating that intracellular uptake of ALA-2DG occurs by GLUT-mediated active transport. Initial photodynamic therapy studies confirmed the efficacy of ALA-2DG as a photodynamic sensitizer. CONCLUSIONS: The in vitro assays suggest that ALA-2DG is taken up by cells via glucose transporters. Initial studies in oral cancer demonstrated the applicability of ALA-2DG for in vivo imaging and its potential as an alternative to ALA-PpIX-based fluorescence diagnostics and photodynamic therapy, providing higher tumor specificity.

PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease.

Parkinson's disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson's and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson's disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson's disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson's disease identifies PGC-1α as a potential therapeutic target for early intervention.

The influence of ascorbic acid, TGF-beta1, and cell-mediated remodeling on the bulk mechanical properties of 3-D PEG-fibrinogen constructs.

Two-dimensional cell culture studies have shown that matrix rigidity can influence cell function, but little is known about how matrix physical properties, and their changes with time, influence cell function in 3-D. Biosynthetic hydrogels based on PEGylated fibrinogen permit the initial decoupling of matrix chemical and mechanical properties, and are thus potentially attractive for addressing this question. However, the mechanical stability of these gels due to passive hydrolysis and cell-mediated remodeling has not previously been addressed. Here, we show that the bulk mechanical properties of acellular PEG-fibrinogen hydrogels significantly decrease over time in PBS regardless of matrix cross-linking density in 7 days. To compensate, smooth muscle cells (SMCs) were encapsulated and stimulated to produce their own matrix using ascorbic acid or TGF-beta1. Ascorbic acid treatment improved the mechanical properties of the constructs after 14 days in less cross-linked matrices, but TGF-beta1 did not. The increase in matrix modulus of the constructs was not due to an increase in type I collagen deposition, which remained low and pericellular regardless of cross-link density or the soluble factor applied. Instead, ascorbic acid, but not TGF-beta1, preferentially enhanced the contractile SMC phenotype in the less cross-linked gels. Inhibition of contractility reduced cell spreading and the expression of contractile markers, and eliminated any beneficial increase in matrix modulus induced by cell-generated contraction of the gels. Together, these data show that PEG-fibrinogen hydrogels are susceptible to both hydrolysis and proteolysis, and suggest that some soluble factors may stimulate matrix remodeling by modulating SMC phenotype instead of inducing ECM synthesis in a 3-D matrix.

Three-tesla high-field applications.

The authors believe that 3-T intraoperative MRI (iMRI) is likely to become the standard of care for a wide range of neurosurgical procedures. Although 3-T high-field image acquisition does pose challenges, the advantages of this field strength, such as superior visualization of soft tissue and clear delineation of any residual tumor tissue, are clearly optimized using this equipment. Additionally, the use of 3-T high-field scanning offers functional options, such as brain activation studies and complex vascular imaging, that are unavailable with low- and midfield iMRI systems. The authors believe that the cost and effort necessary to acquire and establish a 3-T high-field iMRI program represent the natural progression for image-guided neurosurgery.

ECM compliance regulates osteogenesis by influencing MAPK signaling downstream of RhoA and ROCK.

The compliance of the extracellular matrix (ECM) regulates osteogenic differentiation by modulating extracellular signal-regulated kinase (ERK) activity. However, the molecular mechanism linking ECM compliance to the ERK-mitogen-activated protein kinase (MAPK) pathway remains unclear. Furthermore, RhoA has been widely implicated in integrin-mediated signaling and mechanotransduction. We studied the relationship between RhoA and ERK-MAPK signaling to determine their roles in the regulation of osteogenesis by ECM compliance. Inhibition of RhoA and ROCK in MC3T3-E1 pre-osteoblasts cultured on substrates of varying compliance reduced ERK activity, whereas constitutively active RhoA enhanced it. The expression of RUNX2, a potent osteogenic transcription factor, was increased on stiffer matrices and correlated with elevated ERK activity. Inhibition of RhoA, ROCK, or the MAPK pathway diminished RUNX2 activity and delayed the onset of osteogenesis as shown by altered osteocalcin (OCN) and bone sialoprotein (BSP) gene expression, alkaline phosphatase (ALP) activity, and matrix mineralization. These data establish that one possible mechanism by which ECM rigidity regulates osteogenic differentiation involves MAPK activation downstream of the RhoA-ROCK signaling pathway.

Identification of a novel membrane-associated gene product that suppresses toxicity of a TrfA peptide from plasmid RK2 and its relationship to the DnaA host initiation protein.

The toxicity of a peptide derived from the amino-terminal portion of 33-kDa TrfA, one of the initiation proteins encoded by the broad-host-range plasmid RK2, was suppressed by a host protein related to DnaA, the initiation protein of Escherichia coli. The newly identified 28.4-kDa protein, termed a DnaA paralog (Dp) because it is similar to a region of DnaA but likely has a different function in initiation of plasmid RK2 replication, interacts physically with the 33-kDa TrfA initiation protein, including the initiation-active monomeric form. The Dp has a cellular distribution similar to that of the 33-kDa TrfA initiation protein, being found primarily in the inner membrane fraction, with lesser amounts detected in the outer membrane fraction and almost none in the soluble fraction of E. coli. Maintenance and inner membrane-associated replication of plasmid RK2 were enhanced in a Dp knockout strain and inhibited in strains containing extra copies of the Dp gene or in membrane extracts to which a tagged form of Dp was added. Recently, the Dp was independently shown to help prevent overinitiation in E. coli and was termed Hda (S. Kato and T. Katayama, EMBO J. 20:4253-4262, 2001).