Joel S. Beckett

Olive oil polyphenol oleuropein inhibits smooth muscle cell proliferation.

OBJECTIVES The Mediterranean diet, with a high content of olive oil, is associated with a reduced risk of coronary artery disease. The aim of this study was to determine the effect of oleuropein, one of the polyphenols in olive oil, on vascular smooth muscle cell (SMC) proliferation in vitro. DESIGN This was an experimental study. MATERIALS AND METHODS Bovine vascular SMCs were cultured in the presence of 100 μM of oleuropein. On days 1, 3 and 5, cell number was counted. Cell cycle analysis was performed by flow cytometry. Cell cycle regulators were assessed by immunoblotting. RESULTS Cell proliferation in the presence of oleuropein was significantly inhibited by 92%. Cell cycle analysis revealed that oleuropein treatment blocked cells in the G1-S phase compared with the non-treated group. Among G1 phase regulators, retinoblastoma protein, cyclinD, p21 and p27 were not affected by oleuropein, but extracellular signal-regulated kinase 1/2 (ERK1/2) activation was inhibited. Growth of SMC treated with 100 μM of the mitogen-activated protein (MAP) kinase/ERK kinase 1 (MEK1) inhibitor PD98059 was also significantly inhibited by 70%. CONCLUSIONS Oleuropein inhibited SMC proliferation through a cell cycle block between the G1 and the S phases, which may be regulated by ERK1/2. These results suggest a mechanism by which olive oil consumption may have beneficial effects on cardiovascular mortality by inhibiting SMC proliferation.

A Divergent Approach to the Diastereoselective Synthesis of Several Ant-Associated Iridoids

The ant-associated iridoids nepetalactol, actinidine, dolichodial, isoiridomyrmecin, and dihydronepetalactone were prepared from citronellal using a divergent approach. Key features include a three-step synthesis of the individual antipodes of actinidine by a novel tandem cycloaddition/pyridine formation and a facile diastereoselective synthesis of both enantiomers of dolichodial.

Bilateral orbital dysmorphology in unicoronal synostosis.

Background: Orbital dysmorphology is believed to cause ipsilateral ocular abnormalities in unicoronal synostosis. Recently, there has been increasing evidence of visual problems in the contralateral eye. The purpose of this study was to explore morphology of both the ipsilateral and contralateral unicoronal synostosis orbit. Methods: Demographic data and computed tomographic information were recorded. Three-dimensional computed tomographic renderings were created digitally and analyzed (SurgiCase). Craniometric analysis was conducted for orbital volume, horizontal and vertical orbital cone angle, orbital depth, and corneal projection. Results: Twenty-one unicoronal synostosis infants and 10 matched controls were examined. The orbital volume ratio between ipsilateral and contralateral sides was 93.8 ± 5.3 in unicoronal synostosis infants and 99.3 ± 2.1 (p = 0.001) in the control group. The horizontal orbital cone angle of the contralateral eye was significantly greater than that of both the ipsilateral side (p < 0.0001) and the control orbits (p = 0.0011, p = 0.0004). The vertical cone angle of the ipsilateral eye was significantly greater than that of the ipsilateral (p < 0.0001) and control orbits (p = 0.0326, p = 0.0030). There was no difference in orbital depth between ipsilateral and contralateral orbits. The ipsilateral globe projected 27 percent farther past the orbital aperture than the contralateral side. There was no difference between right and left orbits of a control in any analysis. Conclusions: In addition to ipsilateral orbital deformity, the contralateral orbit is highly dysmorphic. As orbital asymmetry may underlie visual abnormalities, future reconstructive efforts may necessitate bilateral correction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Altered brain connectivity in sagittal craniosynostosis

OBJECT Sagittal nonsyndromic craniosynostosis (sNSC) is the most common form of NSC. The condition is associated with a high prevalence (> 50%) of deficits in executive function. The authors employed diffusion tensor imaging (DTI) and functional MRI to evaluate whether hypothesized structural and functional connectivity differences underlie the observed neurocognitive morbidity of sNSC. METHODS Using a 3-T Siemens Trio MRI system, the authors collected DTI and resting-state functional connectivity MRI data in 8 adolescent patients (mean age 12.3 years) with sNSC that had been previously corrected via total vault cranioplasty and 8 control children (mean age 12.3 years) without craniosynostosis. Data were analyzed using the FMRIB Software Library and BioImageSuite. RESULTS Analyses of the DTI data revealed white matter alterations approaching statistical significance in all supratentorial lobes. Statistically significant group differences (sNSC < control group) in mean diffusivity were localized to the right supramarginal gyrus. Analysis of the resting-state seed in relation to whole-brain data revealed significant increases in negative connectivity (anticorrelations) of Brodmann area 8 to the prefrontal cortex (Montreal Neurological Institute [MNI] center of mass coordinates [x, y, z]: -6, 53, 6) and anterior cingulate cortex (MNI coordinates 6, 43, 14) in the sNSC group relative to controls. Furthermore, in the sNSC patients versus controls, the Brodmann area 7, 39, and 40 seed had decreased connectivity to left angular gyrus (MNI coordinates -31, -61, 34), posterior cingulate cortex (MNI coordinates 13, -52, 18), precuneus (MNI coordinates 10, -55, 54), left and right parahippocampus (MNI coordinates -13, -52, 2 and MNI coordinates 11, -50, 2, respectively), lingual (MNI coordinates -11, -86, -10), and fusiform gyri (MNI coordinates -30, -79, -18). Intrinsic connectivity analysis also revealed altered connectivity between central nodes in the default mode network in sNSC relative to controls; the left and right posterior cingulate cortices (MNI coordinates -5, -35, 34 and MNI coordinates 6, -42, 39, respectively) were negatively correlated to right hemisphere precuneus (MNI coordinates 6, -71, 46), while the left ventromedial prefrontal cortex (MNI coordinates 6, 34, -8) was negatively correlated to right middle frontal gyrus (MNI coordinates 40, 4, 33). All group comparisons (sNSC vs controls) were conducted at a whole brain-corrected threshold of p < 0.05. CONCLUSIONS This study demonstrates altered neocortical structural and functional connectivity in sNSC that may, in part or substantially, underlie the neuropsychological deficits commonly reported in this population. Future studies combining analysis of multimodal MRI and clinical characterization data in larger samples of participants are warranted.

A range of condylar hypoplasia exists in Treacher Collins syndrome.

PURPOSE Temporomandibular joint malformation is a complex deformity in Treacher-Collins syndrome (TCS); however, it is not well characterized. This study aimed to better clarify this pathology by volumetrically assessing the mandibular condyle in patients with TCS compared with normal controls and the relative contribution of the condyle to hemimandibular volume. MATERIALS AND METHODS A retrospective, cross-sectional analysis of pediatric patients with TCS and unaffected controls was performed. The study sample was comprised of Treacher Collins patients. The predictor variable in this study was disease status (TCS diagnosis vs control), and the outcome variable was condylar volume. Demographic information was collected, and 3-dimensional computed tomographic data were analyzed by computerized segmentation (Materialise). Volumes were obtained for TCS condyles and compared with age-matched controls using the Student t test. RESULTS Three-dimensional computed tomographic scans were identified in 10 patients with TCS (20 sides) and 14 control subjects (28 sides). The TCS group included 4 female and 6 male patients (age, 0.3 to 213 mo; average age, 66.5 mo). The control cohort included 7 female and 7 male subjects (average age, 68.8 mo). Evaluation of the mandibular condyle showed that patients with TCS had a significantly smaller condylar volume than control patients (TCS, 178.28 ± 182.74 mm(3); control, 863.55 ± 367.20 mm(3); P < .001). Additional intragroup analysis showed no significant differences between the left and right condylar volumes in the TCS group (P = .267). In addition, the condyle for patients with TCS represented a smaller proportion of hemimandibular volume compared with controls (1.37% vs 4.19%, respectively; P < .001). CONCLUSIONS The results of the this study suggest that condylar volumes are significantly smaller in patients with TCS compared with age-matched controls, and the condyle represents a smaller fraction of the total mandibular volume for patients with TCS than in unaffected children. In addition, there is considerable variability of condylar size in patients with TCS. These facts portend treatment decisions because a functional temporomandibular joint is necessary and may need to be reconstructed as a first stage before effective implementation of distraction procedures.

Normalization of brain morphology after surgery in sagittal craniosynostosis

OBJECT Nonsyndromic craniosynostosis (NSC) is associated with significant learning disability later in life. Surgical reconstruction is typically performed before 1 year of age to correct the cranial vault morphology and to allow for normalized brain growth with the goal of improving cognitive function. Yet, no studies have assessed to what extent normalized brain growth is actually achieved. Recent advances in MRI have allowed for automated methods of objectively assessing subtle and pronounced brain morphological differences. The authors used one such technique, deformation-based morphometry (DBM) Jacobian mapping, to determine how previously treated adolescents with sagittal NSC (sNSC) significantly differ in brain anatomy compared with healthy matched controls up to 11.5 years after surgery. METHODS Eight adolescent patients with sNSC, previously treated via whole-vault cranioplasty at a mean age of 7 months, and 8 age- and IQ-matched control subjects without craniosynostosis (mean age for both groups = 12.3 years), underwent functional 3-T MRI. Statistically significant group tissue-volume differences were assessed using DBM, a whole-brain technique that estimates morphological differences between 2 groups at each voxel (p < 0.01). Group-wise Jacobian volume maps were generated using a spacing of 1.5 mm and a resolution of 1.05 × 1.05 × 1.05 mm(3). RESULTS There were no significant areas of volume reduction or expansion in any brain areas in adolescents with sNSC compared with controls at a significance level of p < 0.01. At the more liberal threshold of p < 0.05, two areas of brain expansion extending anteroposteriorly in the right temporooccipital and left frontoparietal regions appeared in patients with sNSC compared with controls. CONCLUSIONS Compared with previous reports on untreated infants with sNSC, adolescents with sNSC in this cohort had few areas of brain dysmorphology many years after surgery. This result suggests that comprehensive cranioplasty performed at an early age offers substantial brain normalization by adolescence, but also that some effects of vault constriction may still persist after treatment. Specifically, few areas of expansion in frontoparietal and temporooccipital regions may persist. Overall, data from this small cohort support the primary goal of surgery in allowing for more normalized brain growth. Larger samples, and correlating degree of normalization with cognitive performance in NSC, are warranted.

Does an elevated bony ridge along the course of the metopic suture equal metopic synostosis? Implications for management.

AbstractMetopic synostosis represents an increasingly prevalent form of nonsyndromic craniosynostosis. Premature fusion of the metopic suture classically results in trigonocephaly, hypotelorism, temporal narrowing, and a pronounced midline forehead ridge. However, as varying degrees of skull deformity exist, there is confusion regarding the appropriate management for an infant with a metopic ridge. We report on a 2-month-old infant with clinical manifestations of metopic synostosis but with a patent metopic suture documented on computed tomography scan. We examine the implications for management related to fusion of the suture, age of the patient, and severity of the head deformity.

Computerized Assessment of Superior Semicircular Canal Dehiscence Size Using Advanced Morphological Imaging Operators

Abstract Superior semicircular canal dehiscence (SSCD) describes a pathological aperture at the level of the arcuate eminence. Techniques for quantifying defect size are described with most studies using two‐dimensional lengths that underestimate the pathology. The objective of this study is to describe a novel method of measurement that combines manual segmentation of high‐resolution computed tomography (HRCT) images of the temporal bone and a morphological skeletonization transform to calculate dehiscence volume. Images were imported into a freely available image segmentation tool: ITK‐SNAP (version 3.4.0; available at: http://www.itksnap.org/) software. Coronal and sagittal planes were used to outline the dehiscence in all slices demonstrating the defect using the paintbrush tool. A morphological skeletonization transform derived a single‐pixel thick representation of the original delineation. This “sheet” of voxels overlaid the dehiscence. Volume was calculated by counting the number of nonzero image voxels within this “sheet” and multiplying this number by the volume (mm3) of each voxel. A total of 70 cases of SSCD were identified. Overall, mean volume was 0.88 mm3 (standard deviation: 0.57, range: 0.11‐2.27). We present a novel technique for measuring SSCD, which we believe provides a more accurate representation of the pathology, and has the potential to standardize measurement of SSCD.

Olive Oil Polyphenols Differentially Inhibit Smooth Muscle Cell Proliferation through a G1/S Cell Cycle Block Regulated by ERK1/2.

We hypothesized that polyphenols contained in olive oil play a role in reducing the risk of atherosclerosis. The aim of this study was to determine if the polyphenols in olive oil, oleuropein (Ole), hydroxytyrosol (HT), and tyrosol (Tyr) could inhibit smooth muscle cell (SMC) proliferation through its influence on cell cycle regulation. Bovine vascular SMC were cultured in the presence of Ole, HT, or Tyr at concentration of 1, 10, or 100 μmol/L. On days 1, 3, and 5, numbers of cells were counted. Cell cycle analysis was performed by flow cytometry on day 1 after SMC were stained with propidium iodide. Cell populations grown in the presence of Ole or HT at 100 μmol/L concentration were significantly inhibited after 5 days of exposure. Tyr had a similar tendency but it did not attain significance. Cell cycle analysis revealed that 66% of cells were in G1 phase in Ole group, compared with 48% in control group. To examine the cell cycle block between G1 and S phases, we performed Western blotting and found that ERK1/2 activation was inhibited by Ole or HT. We conclude that olive oil polyphenols could inhibit SMC proliferation through a cell cycle block between G1 and S phases which may be regulated by ERK1/2. These results demonstrate a mechanism by which olive oil consumption may be atheroprotective by inhibiting SMC proliferation.

Coil embolization through the Marathon microcatheter: Advantages and pitfalls:

Due to technical limitations, small, distal, and tortuous intracranial pathology is sometimes out of reach of the current armamentarium of microcatheters designed for intracranial coil embolization. The Marathon microcatheter (Medtronic, Minneapolis, Minnesota, USA), designed specifically for the delivery of Onyx, is longer and more flexible than most coil delivery catheters. We report on nine patients (three with arteriovenous fistula, three with arteriovenous malformation, two with intracranial aneurysm, and one with tumor) where Marathon was used to deliver commercially available platinum coils. We also conducted laboratory compatibility testing and conclude that the Marathon can be used as a coil delivery catheter for Barricade coils (Blockade Medical, Irvine, California, USA) with diameter less than 0.012 in.