The putative proton-coupled organic cation antiporter is involved in uptake of triptans into human brain capillary endothelial cells.

BACKGROUND: Triptans are anti-migraine drugs with a potential central site of action. However, it is not known to what extent triptans cross the blood-brain barrier (BBB). The aim of this study was therefore to determine if triptans pass the brain capillary endothelium and investigate the possible underlying mechanisms with focus on the involvement of the putative proton-coupled organic cation (H+/OC) antiporter. Additionally, we evaluated whether triptans interacted with the efflux transporter, P-glycoprotein (P-gp). METHODS: We investigated the cellular uptake characteristics of the prototypical H+/OC antiporter substrates, pyrilamine and oxycodone, and seven different triptans in the human brain microvascular endothelial cell line, hCMEC/D3. Triptan interactions with P-gp were studied using the IPEC-J2 MDR1 cell line. Lastly, in vivo neuropharmacokinetic assessment of the unbound brain-to-plasma disposition of eletriptan was conducted in wild type and mdr1a/1b knockout mice. RESULTS: We demonstrated that most triptans were able to inhibit uptake of the H+/OC antiporter substrate, pyrilamine, with eletriptan emerging as the strongest inhibitor. Eletriptan, almotriptan, and sumatriptan exhibited a pH-dependent uptake into hCMEC/D3 cells. Eletriptan demonstrated saturable uptake kinetics with an apparent Km of 89 ± 38 µM and a Jmax of 2.2 ± 0.7 nmol·min-1·mg protein-1 (n = 3). Bidirectional transport experiments across IPEC-J2 MDR1 monolayers showed that eletriptan is transported by P-gp, thus indicating that eletriptan is both a substrate of the H+/OC antiporter and P-gp. This was further confirmed in vivo, where the unbound brain-to-unbound plasma concentration ratio (Kp,uu) was 0.04 in wild type mice while the ratio rose to 1.32 in mdr1a/1b knockout mice. CONCLUSIONS: We have demonstrated that the triptan family of compounds possesses affinity for the H+/OC antiporter proposing that the putative H+/OC antiporter plays a role in the BBB transport of triptans, particularly eletriptan. Our in vivo studies indicate that eletriptan is subjected to simultaneous brain uptake and efflux, possibly facilitated by the putative H+/OC antiporter and P-gp, respectively. Our findings offer novel insights into the potential central site of action involved in migraine treatment with triptans and highlight the significance of potential transporter related drug-drug interactions.

Atypical cervical radiculopathy presenting with brachioradial pruritus: illustrative cases.

BACKGROUND: Brachioradial pruritus (BRP) is a rare form of chronic dysesthesia characterized by persistent itching, burning, or tingling commonly involving the dorsolateral upper extremities. Although the exact pathophysiology remains unclear, the condition may be a manifestation of atypical cervical radiculopathy. OBSERVATIONS: The authors describe two patients with BRP, a 44-year-old female and a 51-year-old male, both of whom benefited from surgical intervention for atypical cervical radiculopathy, while also highlighting their presentation, diagnostic testing, treatment, and outcomes. LESSONS: The cases demonstrate the potential relationship between cervical spondylosis and BRP while examining the role of surgical intervention as a treatment option.

Characterization of an iPSC-based barrier model for blood-brain barrier investigations using the SBAD0201 stem cell line.

BACKGROUND: Blood-brain barrier (BBB) models based on primary murine, bovine, and porcine brain capillary endothelial cell cultures have long been regarded as robust models with appropriate properties to examine the functional transport of small molecules. However, species differences sometimes complicate translating results from these models to human settings. During the last decade, brain capillary endothelial-like cells (BCECs) have been generated from stem cell sources to model the human BBB in vitro. The aim of the present study was to establish and characterize a human BBB model using human induced pluripotent stem cell (hiPSC)-derived BCECs from the hIPSC line SBAD0201. METHODS: The model was evaluated using transcriptomics, proteomics, immunocytochemistry, transendothelial electrical resistance (TEER) measurements, and, finally, transport assays to assess the functionality of selected transporters and receptor (GLUT-1, LAT-1, P-gp and LRP-1). RESULTS: The resulting BBB model displayed an average TEER of 5474 ± 167 Ω·cm2 and cell monolayer formation with claudin-5, ZO-1, and occludin expression in the tight junction zones. The cell monolayers expressed the typical BBB markers VE-cadherin, VWF, and PECAM-1. Transcriptomics and quantitative targeted absolute proteomics analyses revealed that solute carrier (SLC) transporters were found in high abundance, while the expression of efflux transporters was relatively low. Transport assays using GLUT-1, LAT-1, and LRP-1 substrates and inhibitors confirmed the functional activities of these transporters and receptors in the model. A transport assay suggested that P-gp was not functionally expressed in the model, albeit antibody staining revealed that P-gp was localized at the luminal membrane. CONCLUSIONS: In conclusion, the novel SBAD0201-derived BBB model formed tight monolayers and was proven useful for studies investigating GLUT-1, LAT-1, and LRP-1 mediated transport across the BBB. However, the model did not express functional P-gp and thus is not suitable for the performance of drug efflux P-gp reletated studies.

Subcellular trafficking and transcytosis efficacy of different receptor types for therapeutic antibody delivery at the blood‒brain barrier.

Here, we report an experimental setup to benchmark different receptors for targeted therapeutic antibody delivery at the blood-brain barrier. We used brain capillary endothelial-like cells derived from induced pluripotent stem cells (hiPSC-BECs) as a model system and compared them to colon epithelial Caco-2 cells. This approach helped to identify favourable receptors for transport into the cell layer itself or for directing transport for transcytosis across the cell layer. The sorting receptors transferrin receptor and sortilin were shown to be efficient as antibody cargo receptors for intracellular delivery to the cell layer. In contrast, the cell surface receptors CD133 and podocalyxin were identified as static and inefficient receptors for delivering cargo antibodies. Similar to in vivo studies, the hiPSC-BECs maintained detectable transcytotic transport via transferrin receptor, while transcytosis was restricted using sortilin as a cargo receptor. Based on these findings, we propose the application of sortilin as a cargo receptor for delivering therapeutic antibodies into the brain microvascular endothelium.

Hypoxia increases expression of selected blood-brain barrier transporters GLUT-1, P-gp, SLC7A5 and TFRC, while maintaining barrier integrity, in brain capillary endothelial monolayers.

BACKGROUND: Brain capillary endothelial cells (BCECs) experience hypoxic conditions during early brain development. The newly formed capillaries are tight and functional before astrocytes and pericytes join the capillaries and establish the neurovascular unit. Brain endothelial cell phenotype markers P-gp (ABCB1), LAT-1(SLC7A5), GLUT-1(SLC2A1), and TFR(TFRC) have all been described to be hypoxia sensitive. Therefore, we hypothesized that monolayers of BCECs, cultured under hypoxic conditions, would show an increase in LAT-1, GLUT-1 and TFR expression and display tight endothelial barriers. METHODS AND RESULTS: Primary bovine BCECs were cultured under normoxic and hypoxic conditions. Chronic hypoxia induced HIF-1α stabilization and translocation to the nucleus, as judged by immunocytochemistry and confocal laser scanning imaging. Endothelial cell morphology, claudin-5 and ZO-1 localization and barrier integrity were unaffected by hypoxia, indicating that the tight junctions in the BBB model were not compromised. SLC7A5, SLC2A1, and TFRC-mRNA levels were increased in hypoxic cultures, while ABCB1 remained unchanged as shown by real-time qPCR. P-gp, TfR and GLUT-1 were found to be significantly increased at protein levels. An increase in uptake of [3H]-glucose was demonstrated, while a non-significant increase in the efflux ratio of the P-gp substrate [3H]-digoxin was observed in hypoxic cells. No changes were observed in functional LAT-1 as judged by uptake studies of [3H]-leucine. Stabilization of HIF-1α under normoxic conditions with desferrioxamine (DFO) mimicked the effects of hypoxia on endothelial cells. Furthermore, low concentrations of DFO caused an increase in transendothelial electrical resistance (TEER), suggesting that a slight activation of the HIF-1α system may actually increase brain endothelial monolayer tightness. Moreover, exposure of confluent monolayers to hypoxia resulted in markedly increase in TEER after 24 and 48 h, which corresponded to a higher transcript level of CLDN5. CONCLUSIONS: Our findings collectively suggest that hypoxic conditions increase some BBB transporters' expression via HIF-1α stabilization, without compromising monolayer integrity. This may in part explain why brain capillaries show early maturation, in terms of barrier tightness and protein expression, during embryogenesis, and provides a novel methodological tool for optimal brain endothelial culture.

Highly cationic cell-penetrating peptides affect the barrier integrity and facilitates mannitol permeation in a human stem cell-based blood-brain barrier model.

The blood-brain barrier (BBB) allows passive permeation of only a limited number of, primarily lipophilic, low-molecular weight drugs that obey the so-called "rule of CNS likeness". Therefore, novel strategies to facilitate drug delivery across the BBB are needed. Cell-penetrating peptides (CPPs) enable delivery of various therapeutic cargoes into cells and may potentially serve as shuttles for delivery of brain-specific drugs across the BBB. The CPPs Tat47-57 and penetratin are prototypical cationic CPPs, whereas apidaecin and oncocin belong to the group of proline-rich cationic antimicrobial peptides displaying CPP-like properties. The aim of the present study was to investigate the potential of Tat47-57, penetratin, apidaecin, and oncocin for interaction with and permeation of the BBB in vitro. We also studied whether the CPPs facilitated permeation of the paracellular flux marker mannitol as well as the transcellular flux marker propranolol. The peptides were labelled with the fluorophore 6-TAMRA (T) for visualization and quantification purposes. CPP membrane-adherence, membrane-embedding, and cellular uptake as well as barrier-permeation were evaluated in murine brain capillary endothelial cells (bEND3) and human induced pluripotent stem cell-derived (Bioni-010c) brain capillary endothelial-like monolayers. The cationic and the proline-rich cationic CPPs were taken up into the Bioni-010c monolayers. T-Tat47-57, T-apidaecin, and T-oncocin also permeated Bioni-010c monolayers, whereas T-penetratin did not. However, both T-Tat47-57 and T-penetratin affected the barrier integrity to a degree that facilitated permeation of 14C-mannitol. These results may therefore pave the way for future CPP-mediated brain delivery of small drugs that do not obey the "rule of CNS likeness".

Screening novel CNS drug candidates for P-glycoprotein interactions using the cell line iP-gp: In vitro efflux ratios from iP-gp and MDCK-MDR1 monolayers compared to brain distribution data from mice.

Drug efflux by P-glycoprotein (P-gp, ABCB1) is considered as a major obstacle for brain drug delivery for small molecules. P-gp-expressing cell monolayers are used for screening of new drug candidates during early states of drug development. It is, however, uncertain how well the in vitro studies can predict the in vivo P-gp mediated efflux at the blood-brain barrier (BBB). We previously developed a novel cell line of porcine origin, the iP-gp cell line, with high transepithelial resistance and functional expression of human P-gp. The aim of the present study was to evaluate the applicability of the cell line for screening of P-gp interactions of novel drug candidates. For this purpose, bidirectional fluxes of 14 drug candidates were measured in iP-gp cells and in MDCK-MDR1 cells, and compared with pharmacokinetic data obtained in male C57BL/6 mice. The iP-gp cells formed extremely tight monolayers (>15 000 Ω∙cm2) as compared to the MDCK- MDR1 cells (>250 Ω∙cm2) and displayed lower Papp,a-b values. The efflux ratios obtained with iP-gp and MDCK-MDR1 monolayers correlated with Kp,uu,brain values from the in vivo studies, where compounds with the lowest Kp,uu,brain generally displayed the highest efflux ratios. 12 of the tested compounds displayed a poor BBB penetration in mice as judged by Kp,uu less than 1. Of these compounds, nine compounds were categorized as P-gp substrates in the iP-gp screening, whereas analysis of data estimated in MDCK-MDR1 cells indicated four compounds as potential substrates. The results suggest that the iP-gp cell model may be a sensitive and useful screening tool for drug screening purposes to identify possible substrates of human P-glycoprotein.

Real-time navigation guidance with intraoperative CT imaging for pedicle screw placement using an augmented reality head-mounted display: a proof-of-concept study.

OBJECTIVE: Augmented reality (AR) has the potential to improve the accuracy and efficiency of instrumentation placement in spinal fusion surgery, increasing patient safety and outcomes, optimizing ergonomics in the surgical suite, and ultimately lowering procedural costs. The authors sought to describe the use of a commercial prototype Spine AR platform (SpineAR) that provides a commercial AR head-mounted display (ARHMD) user interface for navigation-guided spine surgery incorporating real-time navigation images from intraoperative imaging with a 3D-reconstructed model in the surgeon's field of view, and to assess screw placement accuracy via this method. METHODS: Pedicle screw placement accuracy was assessed and compared with literature-reported data of the freehand (FH) technique. Accuracy with SpineAR was also compared between participants of varying spine surgical experience. Eleven operators without prior experience with AR-assisted pedicle screw placement took part in the study: 5 attending neurosurgeons and 6 trainees (1 neurosurgical fellow, 1 senior orthopedic resident, 3 neurosurgical residents, and 1 medical student). Commercially available 3D-printed lumbar spine models were utilized as surrogates of human anatomy. Among the operators, a total of 192 screws were instrumented bilaterally from L2-5 using SpineAR in 24 lumbar spine models. All but one trainee also inserted 8 screws using the FH method. In addition to accuracy scoring using the Gertzbein-Robbins grading scale, axial trajectory was assessed, and user feedback on experience with SpineAR was collected. RESULTS: Based on the Gertzbein-Robbins grading scale, the overall screw placement accuracy using SpineAR among all users was 98.4% (192 screws). Accuracy for attendings and trainees was 99.1% (112 screws) and 97.5% (80 screws), respectively. Accuracy rates were higher compared with literature-reported lumbar screw placement accuracy using FH for attendings (99.1% vs 94.32%; p = 0.0212) and all users (98.4% vs 94.32%; p = 0.0099). The percentage of total inserted screws with a minimum of 5° medial angulation was 100%. No differences were observed between attendings and trainees or between the two methods. User feedback on SpineAR was generally positive. CONCLUSIONS: Screw placement was feasible and accurate using SpineAR, an ARHMD platform with real-time navigation guidance that provided a favorable surgeon-user experience.

Transendothelial Electrical Resistance Measurement across the Blood-Brain Barrier: A Critical Review of Methods.

The blood-brain barrier (BBB) represents the tightest endothelial barrier within the cardiovascular system characterized by very low ionic permeability. Our aim was to describe the setups, electrodes, and instruments to measure electrical resistance across brain microvessels and culture models of the BBB, as well as critically assess the influence of often neglected physical and technical parameters such as temperature, viscosity, current density generated by different electrode types, surface size, circumference, and porosity of the culture insert membrane. We demonstrate that these physical and technical parameters greatly influence the measurement of transendothelial electrical resistance/resistivity (TEER) across BBB culture models resulting in severalfold differences in TEER values of the same biological model, especially in the low-TEER range. We show that elevated culture medium viscosity significantly increases, while higher membrane porosity decreases TEER values. TEER data measured by chopstick electrodes can be threefold higher than values measured by chamber electrodes due to different electrode size and geometry, resulting in current distribution inhomogeneity. An additional shunt resistance at the circumference of culture inserts results in lower TEER values. A detailed description of setups and technical parameters is crucial for the correct interpretation and comparison of TEER values of BBB models.

A Retrospective Evaluation and Review of Outcomes for Single- and Multilevel ACDF With a Zero-Profile Stand-Alone Cage Device With Integrated Instrumentation.

This study aimed to assess clinical and radiological outcomes associated with zero-profile stand-alone cages with instrumentation used for single- and multilevel anterior cervical discectomy and fusion (ACDF) operations. Many plate-cage ACDF systems have proven to be successful in producing high fusion rates and positive clinical outcomes. However, the anterior plating in traditional systems has been associated with complications such as dysphagia and mechanical accidents. A total of 190 patients underwent single- or multilevel ACDF surgeries with zero-profile polyetheretherketone cages containing integrated titanium instrumentation and screw fixation (one-level, n=31; two-level, n=65; three-level, n=71; four-level, n=23). Demographic information such as age and smoking status as well as postoperative outcomes were collected and analysed. Out of the 190 patients who underwent ACDF surgeries with a zero-profile stand-alone cage, none experienced any conditions or infections, and zero were readmitted postoperatively. Although traditional plate-cage systems yield high fusion rates in ACDF surgeries, zero-profile systems with integrated fixation have showcased impressive clinical and radiographic results in both single- and multilevel operations.

Interspinous Process (ISP) Devices in Comparison to the Use of Traditional Posterior Spinal Instrumentation.

A systematic literature review was conducted on studies comparing interspinous process (ISP) devices to traditional methods of posterior spinal instrumentation (pedicle screw-rod construct), in terms of indications of use, complications, pain assessment, estimated blood loss, length of hospital stay, reoperation rates, and return to work. The objective was to analyze, evaluate and summarize the current published literature on the proposed efficacy and clinical and surgical long-term outcomes of the ISP device in comparison to the traditional posterior spinal instrumentation (pedicle screw-rod construct). The ISP device is a minimally invasive and less disruptive alternative to traditional methods of posterior spinal instrumentation (pedicle screw-rod construct). However, very few published literature studies to date have reported the comparison of ISPs in terms of efficacy and clinical and surgical outcomes, to traditional posterior spinal instrumentation. A systematic literature review was performed in PubMed and Google Scholar to evaluate the results of published research that meet the defined inclusion and exclusion criteria and to analyze clinical indications and surgical outcomes of the ISP device compared to traditional methods of posterior spinal instrumentation (pedicle screw-rod construct). Inclusion criteria included keywords such as "ISP device, ISP, posterior spinal instrumentation, pedicle screw fixation, bilateral pedicle screws, interbody fusion with posterior spinal instrumentation, lumbar spinal stenosis, and posterior lumbar stability." No exclusion criteria keywords were included in this literature review. ISPs provide a high degree of spinal stability in multiple planes, including a decreased range of motion restriction in flexion-extension, and comparable results to bilateral pedicle screw (BPS) in axial rotation. The use of the ISP device in adjunct with an interbody fusion, ensures less estimated operative blood loss (EBL), shorter operative time, less bony exposure without the need for extensive soft tissue or muscle retraction, a decrease in the rate of pseudoarthrosis, and a shorter length of hospital stay (LOHS) when compared to the traditional posterior instrumentation (pedicle screw-rod construct). Based on the various published literature reviews noted throughout this research paper, it is safe to conclude, that an ISP device that is accompanied by interbody fusion, including posterior approaches posterior lumbar interbody fusion (PLIF) and transforaminal lumbar interbody fusion (TLIF); anterior approaches such as anterior interbody fusion (ALIF), and lateral approaches including direct lateral interbody fusion (DLIF), lateral lumbar interbody fusion (LLIF), extreme lateral interbody fusion (XLIF), is considered a credible and an effective minimally invasive option for the treatment of mild to moderate lumbar stenosis and stable low-grade spondylolisthesis (less than two) when compared to the traditional posterior spinal instrumentation of a pedicle screw-rod construct. Surgeons that are relatively new to the ISP technologies for spinal instrumentation would likely benefit from more clinical and surgical evidence of safety and efficacy in published peer-reviewed medical literature. Further clinical trials are needed to manifest the efficacy of ISPs regarding postoperative outcomes when compared to traditional posterior instrumentation techniques (pedicle screw-rod construct) with adjunct interbody fusions.

Data demonstrating the challenges of determining the kinetic parameters of P-gp mediated transport of low-water soluble substrates.

The presented data are related to the research article entitled "Characterization of the IPEC-J2 MDR1 (iP-gp) cell line as a tool for identification of P-gp substrates" by Ozgur et al. (2017) [1]. This data report describes the challenges of investigating the concentration-dependent transport of P-glycoprotein (P-gp) substrates with relatively low aqueous solubility. Thus, we provide solubility data on two prototypical P-gp substrates, digoxin and rhodamine 123, representing P-gp substrates with a relatively low- and high-aqueous solubility, respectively. We present a hypothetical Michaelis-Menten curve of the P-gp mediated transport of digoxin to demonstrate that the maximal donor concentration, which can be reached in the experimental transport buffer, is too low to yield transport data in the saturable range of the Michaelis-Menten relationship. Furthermore, we present data on the bidirectional transport of digoxin and rhodamine 123 across cell monolayers of the MDCK II MDR1 cell line and iP-pg cell line in the presence of the selective P-gp inhibitor, zosuquidar/LY335979.

Characterization of the IPEC-J2 MDR1 (iP-gp) cell line as a tool for identification of P-gp substrates.

Recently, we transfected the porcine intestinal cell line IPEC-J2, with human P-glycoprotein (P-gp, ABCB1). The resulting cell line, iP-gp, has a high expression of functional human P-gp in the apical membrane, and a low expression of nonhuman ATP-binding cassette (ABC) transporters. The aim of the present work was to investigate the usability of iP-gp cell line for determining transepithelial transport kinetics of the prototypical P-gp substrates digoxin and rhodamine 123. The cell line generated tight monolayers after 16days of culture, reflected by high transepithelial electrical resistance values (TEER>15,000Ω·cm2), immunocytochemistry and low fluxes of the paracellular flux marker [14C]-mannitol. Monolayer integrity was not affected the common solvents dimethyl sulfoxide (DMSO), methanol and ethanol in concentrations up to 2% (v/v). Transepithelial fluxes of [3H]-labeled digoxin and rhodamine 123 were measured at varying donor concentrations, and kinetic parameters were estimated. Km and Vmax of P-gp mediated basolateral-to-apical (B-A) flux of rhodamine 123 were estimated to 332±124µM and 111±16pmol·cm-2·min-1 (n=3, total N=6), respectively. Vmax and Km of digoxin B-A flux could not be estimated due to the low aqueous solubility of digoxin. The half maximal inhibitory concentrations (IC50) of the selective P-gp inhibitor, zosuquidar (LY-335979), were estimated to 0.05±0.01µM (n=3, total N=6) and 0.04±0.01µM (n=3, total N=6) in transport experiments with digoxin and rhodamine 123 as substrates, respectively. Bidirectional fluxes of digoxin and rhodamine 123 were measured in transfected Madin Darby canine kidney cells (MDCK II MDR1) and compared with the fluxes obtained with the iP-gp cell monolayers. Efflux ratios were highest in the iP-gp cells, due to a tighter paracellular pathway. In conclusion, both digoxin and rhodamine 123 could be used to obtain IC50 values of inhibition, Ki values were only possible to obtain using rhodamine 123. The observed tightness, robustness towards solvents and the high efflux ratios confirmed that the iP-gp cell line may serve as a useful screening tool for investigations of substrate-P-gp interactions and modulation of P-gp function.

Exciton binding energy and nonhydrogenic Rydberg series in monolayer WS(2).

We have experimentally determined the energies of the ground and first four excited excitonic states of the fundamental optical transition in monolayer WS_{2}, a model system for the growing class of atomically thin two-dimensional semiconductor crystals. From the spectra, we establish a large exciton binding energy of 0.32 eV and a pronounced deviation from the usual hydrogenic Rydberg series of energy levels of the excitonic states. We explain both of these results using a microscopic theory in which the nonlocal nature of the effective dielectric screening modifies the functional form of the Coulomb interaction. These strong but unconventional electron-hole interactions are expected to be ubiquitous in atomically thin materials.

Two-year clinical and radiographic success of minimally invasive lateral transpsoas approach for the treatment of degenerative lumbar conditions.

BACKGROUND: The lateral transpsoas approach to interbody fusion is a less disruptive but direct-visualization approach for anterior/anterolateral fusion of the thoracolumbar spine. Several reports have detailed the technique, the safety of the approach, and the short term clinical benefits. However, no published studies to date have reported the long term clinical and radiographic success of the procedure. MATERIALS AND METHODS: The current study is a retrospective chart review of prospectively collected clinical and radiographic outcomes in 62 patients having undergone the Anterolateral transpsoas procedure at a single institution for anterior column stabilization as treatment for degenerative conditions, including degenerative disk disease, spondylolisthesis, scoliosis, and stenosis. Only patients who were a minimum of 2 years postoperative were included in this evaluation. Clinical outcomes measured included visual analog pain scales (VAS) and Oswestry disability index (ODI). Radiographic outcomes included identification of successful arthrodesis. RESULTS: Sixty-two patients were treated with lateral interbody fusion between 2003 and December 2006. Twenty-six patients (42%) were single-level, 13 (21%) 2-level, and 23 (37%) 3- or more levels. Forty-five (73%) included supplemental posterior pedicle fixation, 4 (6%) lateral fixation, and 13 (21%) were stand-alone. Pain scores (VAS) decreased significantly from preoperative to 2 years follow-up by 37% (P < .0001). Functional scores (ODI) decreased significantly by 39% from preoperative to 2 years follow-up (P < .0001). Clinical success by ODI-change definition was achieved in 71% of patients. Radiographic success was achieved in 91% of patients, with 1 patient with pseudarthrosis requiring posterior revision. CONCLUSION: The lateral transpsoas approach is similar to a traditional anterior lumbar interbody fusion, in that access is obtained through a retroperitoneal, direct-visualization exposure, and a large implant can be placed in the interspace to achieve disk height and alignment correction. The 2 years plus clinical and radiographic success rates are similar to or better than those reported for traditional anterior and posterior approach procedures, which, coupled with significant short-term benefits of minimal morbidity, make the lateral approach a safe and effective treatment option for anterior/anterolateral lumbar fusions.

Nonsyndromic craniosynostosis: current treatment options.

The significance and etiology of abnormal skull shape have been under investigation since ancient times. Nonsyndromic, or isolated, craniosynostosis predominates and is defined as suture fusion that creates functional impairments related to local effects of the fusion. The purpose of this article is to present our current approach to patients with nonsyndromic craniosynostosis, outlining the place of both open, conventional approaches and newer, minimally invasive, endoscopic assisted craniosynostosis correction.

Intraoperative ultrasound using phase inversion harmonic imaging: first experiences.

OBJECTIVE: To study the feasibility of intraoperative ultrasound using the phase inversion harmonic imaging (PIHI) technique. METHODS: Eight patients with intracranial middle cerebral artery aneurysms and five patients with arteriovenous malformations were studied after written informed consent. A first ultrasound study was performed through the intact dura mater after cranial trepanation to assess the pathology, its feeding artery, and downstream segments. A second ultrasound study was performed immediately after intervention to monitor the success of the procedure. All patients were studied using a Siemens Sonoline Antares ultrasound machine (Siemens Medical Solutions USA, Inc., Malvern, PA) before and after intravenous administration of an ultrasound contrast agent (Optison; GE Healthcare, Milwaukee, WI). Other than conventional brightness mode, PIHI is sensitive to the nonlinear acoustic response of tissue, and especially to ultrasound contrast agent microbubbles. The latter enables contrast-specific vascular imaging. RESULTS: PIHI provided anatomically detailed information. In combination with an ultrasound contrast agent, angiography-like views of the vascular pathologies, including their surrounding vessels, could be obtained. Flow velocities in afferent and downstream vascular segments, as well as inside the pathology, could be assessed. Flow dynamics inside the aneurysm sac or the arteriovenous malformation could be studied in real-time. Postintervention, contrast-enhanced PIHI could be used to immediately monitor the success of the surgical procedure. CONCLUSION: PIHI enables intraoperative visualization and morphological assessment of neurovascular pathologies, such as middle cerebral artery aneurysms or arteriovenous malformations. In combination with an ultrasound contrast agent, the flow dynamics of these lesions can be displayed in real-time.

Automated intraoperative EMG testing during percutaneous pedicle screw placement.

BACKGROUND: EMG screw testing has been shown to be sensitive and reliable in open spinal instrumentation cases. However, there is little evidence to show its applicability to percutaneous screw placement. PURPOSE: To demonstrate the utility of EMG testing in percutaneous techniques, where lack of direct visualization poses an added risk to nerve injury. STUDY DESIGN: Summary of intraoperative EMG results during percutaneous pedicle screw placement. METHODS: Percutaneous pedicle screws were placed in twenty patients (22 levels, 88 pedicles). The initial fluoroscopically-guided k-wires and the subsequent taps were insulated and stimulated via an automated EMG system. Low threshold values prompted repositioning of the pedicle trajectory. RESULTS: Four (5%) k-wires induced EMG thresholds less than 10mA, prompting repositioning. One was repositioned without improvement, but with improvement upon tapping. One k-wire with very low threshold (3mA) was repositioned with an improved result (13mA). In 78 pedicles (89%) the tap threshold was greater than the k-wire. CONCLUSIONS: EMG testing helps to identify suboptimal screw trajectories, allowing for early adjustment and confirmation of improved placement. Tapping often improved thresholds, perhaps by compressing the bone and creating a denser, more insulative pedicle wall. EMG testing may improve the safety of percutaneous screw techniques, where the pedicle cannot be visually inspected.

Extreme Lateral Interbody Fusion (XLIF): a novel surgical technique for anterior lumbar interbody fusion.

BACKGROUND: Minimally disruptive approaches to the anterior lumbar spine continue to evolve in a quest to reduce approach-related morbidity. A lateral retroperitoneal, trans-psoas approach to the anterior disc space allows for complete discectomy, distraction, and interbody fusion without the need for an approach surgeon. PURPOSE: To demonstrate the feasibility of a minimally disruptive lateral retroperitoneal approach and the advantages to patient recovery. METHODS/RESULTS: The extreme lateral approach (Extreme Lateral Interbody Fusion [XLIF]) is described in a step-wise manner. There have been no complications thus far in the author's first 13 patients. CONCLUSIONS: The XLIF approach allows for anterior access to the disc space without an approach surgeon or the complications of an anterior intra-abdominal procedure. Longer-term follow-up and data analysis are under way, but initial findings are encouraging.