Feasibility of intrathecal therapeutic injections in spinal muscular atrophy patients via a percutaneous transsacral hiatus route: An initial neuroimaging morphometric study.

INTRODUCTION/AIMS: Standard fluoroscopic lumbar puncture (LP) can be impossible in patients with severe spinal deformities from spinal muscular atrophy (SMA) who require intrathecal nusinersen therapy. There usually exists a straight trajectory in the lower sacral canal (SC) that could allow image-guided percutaneous transsacral hiatus puncture of the lumbosacral dural sac. In this study we determine whether sacra are comparatively straighter in SMA patients (SMAps) vs healthy controls (HCs), which may facilitate unhindered transsacral hiatus spinal needle insertion for intrathecal nusinersen therapy. METHODS: We retrospectively analyzed lumbosacral spine computed tomograms (CTs) or CT-myelogram images of 38 SMAps and age- and sex-matched HCs. We digitally measured ventrodorsal sacral curvatures, SC surface areas, dural sac termination levels, and distances from sacral hiatus to the most caudad aspects of dural sacs ("needle distance"). RESULTS: Mean ages of HCs and SMAps were 32.7 and 31.7 years, respectively, with dural sacs terminating at similar levels. Mean values for morphometrics were: (a) midsagittal SC surface area for HCs = 701.2 mm2 , and for SMAps = 601.5 mm2 (not statistically significant [ns]); (b) using a "line method," sacral curvature for HCs = 61.9°, and SMAp = 35.7° (P = .0009), and was similar when using an "angle summation method"; (c) width of sacral hiatus for HCs = 14.9 mm, and SMAps = 15.0 mm (ns); and (d) "needle distance" for HCs = 54.7 mm, and SMAps = 49.9 mm (ns). DISCUSSION: SMAps have significantly straighter sacra compared with HCs, which theoretically renders them more amenable to percutaneous transsacral hiatus puncture of the dural sac.

Feasibility of percutaneous dural sac puncture via a posterior trans-sacral foraminal conduit approach: a CT morphometric analysis.

We assess the theoretical feasibility of percutaneous posterior sacral foramen (pSF) needle puncture of the sacral dural sac (DS) by studying the three-dimensional imaging anatomy of pSFs relative to the sacral canal (SC). On CT images of 40 healthy subjects, we retrospectively studied sacral alae passageways from SC to pSFs in all three planes to determine if an imaginary spinal needle could theoretically traverse S1 or S2 pSFs in a straight path toward DS. If not straight, we measured multiplane angulations and morphometrics of this route. We found no straight connections between S1 or S2 pSFs and SC. Instead, there were bilateral spatially complex dorsoventral M-shaped "foraminal conduits" (FCs; common, ventral, and dorsal) from SC to anterior SFs and pSFs that would prevent percutaneous straight needle puncture of the DS. This detailed knowledge of the sacral FCs will be useful for accurate imaging interpretation and interventional procedures on the sacrum.

Caudolenticular gray bridges of the brain: A magnetic resonance imaging study.

The caudolenticular (or transcapsular) gray bridges (CLGBs) connect the caudate nucleus (CN) and putamen across the internal capsule. The CLGBs function as the main efferent terminus from premotor and supplementary motor area cortex to the basal ganglia (BG). We conjectured if inherent variations in numbers and sizes of CLGBs could contribute to abnormal cortical-subcortical connectivity in Parkinson's disease (PD), a neurodegenerative disorder featuring a hindrance of BG processing. However, there are no literature accounts of normative anatomy and morphometry of CLGBs. We therefore retrospectively analyzed axial and coronal 3T fast spoiled gradient-echo magnetic resonance images (MRIs) of 34 healthy individuals for bilateral CLGBs symmetry, their numbers, dimensions of thickest and longest bridge, and axial surface areas of CN head and putamen. We calculated Evans' index (EI) to account for any brain atrophy. We statistically tested associations between sex or age and measured dependent variables, and linear correlations between all measured variables (significance at p < 0.05). Study subjects were F:M = 23:11 with mean age 49.9 years. All EI's were normal (<0.3). All but three CLGBs were bilaterally symmetrical with a mean 7.4 CLGBs per side. Mean CLGBs thickness and lengths were 1.0 and 4.6 mm, respectively; CN head and putamen areas were 205 and 382.0 mm2 , respectively. Females had thicker CLGBs (p = 0.02) but we found no significant interactions between sex or age and measured dependent variables, and no correlations between CN head or putamen areas and CLGBs dimensions. These normative MRI dimensions of the CLGBs will help guide future studies on the possible role of CLGBs morphometry in PD predisposition.

Biomimetic nanobubbles for triple-negative breast cancer targeted ultrasound molecular imaging.

Triple-negative breast cancer (TNBC) is a highly heterogeneous breast cancer subtype with poor prognosis. Although anatomical imaging figures prominently for breast lesion screening, TNBC is often misdiagnosed, thus hindering early medical care. Ultrasound (US) molecular imaging using nanobubbles (NBs) capable of targeting tumor cells holds great promise for improved diagnosis and therapy. However, the lack of conventional biomarkers in TNBC impairs the development of current targeted agents. Here, we exploited the homotypic recognition of cancer cells to synthesize the first NBs based on TNBC cancer cell membrane (i.e., NBCCM) as a targeted diagnostic agent. We developed a microfluidic technology to synthesize NBCCM based on the self-assembly property of cell membranes in aqueous solutions. In vitro, optimal NBCCM had a hydrodynamic diameter of 683 ± 162 nm, showed long-lasting US contrast enhancements and homotypic affinity. In vivo, we demonstrated that NBCCM showed increased extravasation and retention in a TNBC mouse model compared to non-targeted NBs by US molecular imaging. Peak intensities and areas under the curves from time-intensity plots showed a significantly enhanced signal from NBCCM compared to non-targeted NBs (2.1-fold, P = 0.004, and, 3.6-fold, P = 0.0009, respectively). Immunofluorescence analysis further validated the presence of NBCCM in the tumor microenvironment. Circumventing the challenge for universal cancer biomarker identification, our approach could enable TNBC targeting regardless of tumor tissue heterogeneity, thus improving diagnosis and potentially gene/drug targeted delivery. Ultimately, our approach could be used to image many cancer types using biomimetic NBs prepared from their respective cancer cell membranes.

Camouflaged Hybrid Cancer Cell-Platelet Fusion Membrane Nanovesicles Deliver Therapeutic MicroRNAs to Presensitize Triple-Negative Breast Cancer to Doxorubicin.

Camouflaged cell-membrane-based nanoparticles have been gaining increasing attention owing to their improved biocompatibility and immunomodulatory properties. Using nanoparticles prepared from the membranes of specific cell types, or fusions derived from different cells membranes, can improve their functional performance in several aspects. Here, we used cell membranes extracted from breast cancer cells and platelets to fabricate a hybrid-membrane vesicle fusion (cancer cell-platelet-fusion-membrane vesicle, CPMV) in which we loaded therapeutic microRNAs (miRNAs) for the treatment of triple-negative breast cancer (TNBC). We used a clinically scalable microfluidic platform for the fusion of cell membranes. The reconstitution process during synthesis allows for efficient loading of miRNAs into CPMVs. We systematically optimized the conditions for preparation of miRNA-loaded CPMVs and demonstrated their property of homing to source cells using in vitro experiments, and by therapeutic evaluation in vivo. In vitro, the CPMVs exhibited significant recognition of their source cells and avoided engulfment by macrophages. After systemic delivery in mice, the CPMVs showed a prolonged circulation time and site-specific accumulation at implanted TNBC-xenografts. The delivered antimiRNAs sensitized TNBCs to doxorubicin, resulting in an improved therapeutic response and survival rate. This strategy has considerable potential for clinical translation to improve personalized therapy for breast cancer and other malignancies.

Ambiguous "olfactory" terms for anatomic spaces adjacent to the cribriform plate: A publication database analysis and quest for uniformity.

A precise nomenclature and terminology is the foundation of communication in Anatomy and related biomedical sciences. The olfactory bulbs and nerves lie above and below the cribriform plate (CP), respectively. Hence, many anatomical landmarks in this region have names adopting the term "olfactory" as qualifiers. Ambiguous use of these "olfactory" terms exists, with some potential repercussions on patient treatments. We performed a publication database analysis to determine the frequency of misuse of names for seven anatomical "olfactory" spaces close to the CP and nasal cavity. We searched PubMed® publications having the keyword "olfactory" in their title or abstract, plus one of seven other keywords: "groove", "fossa", "recess", "cleft", "vestibule", "sulcus", and "cistern". We reviewed all abstracts for accuracy of these terms relative to accepted norms or customary definitions. By February 2020, we found all these keywords in 1255 articles. For the terms olfactory "groove" and "fossa", the number of relevant articles (and percentage of those inaccurately using these terms) were 374 (1.1%), and 49 (8.2%), respectively. All 52 abstracts containing "olfactory" and "vestibule" were irrelevant, relating to the "nasal vestibule" and olfactory function, instead of "olfactory vestibule". Overall, terms used to describe "olfactory" spaces near the CP are seldom ambiguous or inaccurate, but the terms olfactory "groove" and "fossa" are occasionally misused, We propose several new "olfactory" terms for inclusion in the Terminologia Anatomica, and stress the need for uniform nomenclature leading to greater consistency and accuracy in clinical use of anatomical terms containing the word "olfactory" as a descriptor.

Tortuosity of superior cerebral veins: Comparative magnetic resonance imaging morphometrics in normal subjects and arteriovenous malformation patients.

Blood vessel tortuosity results from increased diameter and length in response to higher hemodynamic loads. Tortuosity metrics have not been determined for abnormal superior cerebral veins (SCVs) draining cerebral arteriovenous malformations (AVMs). Draining vein (DV) tortuosity may influence safety and efficacy of retrograde microcatheter navigation during transvenous treatment of pial AVMs. Here, we quantify SCV tortuosity in normal subjects and AVM patients using two image segmentation methods. We used contrast-enhanced brain magnetic resonance (MR) images to define the axis of each SCV through a regularly spaced set of three-dimensional (3D) points defining its skeleton curve. We then calculated two metrics: the "sum of angles metric" (SOAM), which adds all angles of curvature along a vessel and normalizes by vessel length, and the "distance metric" (DM), a tortuosity measure providing a ratio of vessel length to linear distance between vessel endpoints. We analyzed 168 metrics in 43 veins of eight normal subjects and 41 veins of seven AVM patients. In normal subjects, the mean SOAM and DM for SCVs were 21.34 ± 7.49 °/mm and 1.42 ± 0.25, respectively. In AVM patients, DVs had a significantly higher mean SOAM of 30.43 ± 11.38 °/mm (p = .02) and DM of 2.79 ± 1.77 (p = .01) than normal subjects. In AVM patients, DVs were significantly more tortuous than matched contralateral uninvolved SCVs, which were similar in tortuosity to normal subject SCVs. We thus report normative tortuosity metrics of brain SCVs and show that AVM cortical DVs are significantly more tortuous than normal SCVs. Knowledge of these comparative tortuosities is valuable in planning endovenous AVM embolotherapies.

Imaging anatomy of the vertebral canal for trans-sacral hiatus puncture of the lumbar cistern.

A standard lumbar puncture may be impossible for many anatomic or technical reasons. Previous accounts of caudal epidural anesthesia and other procedures via the sacral hiatus prompted us to test if image-guided percutaneous trans-sacral hiatus access to the lumbosacral subarachnoid cistern would be anatomically feasible. To study vertebral canal morphometry and curvature, we analyzed midsagittal computed tomography-myelogram images of 40 normal subjects and digitally measured sacral curvatures between S1 to S5 and S2 to S4 using two methods whereby a lower angle signifies a straighter sacrum. We measured midsagittal vertebral canal area, hiatus width, dural sac termination levels, and distance from sacral hiatus to the dural sac tip (needle distance). Subjects were F:M = 25:15, with a mean age of 44.9 years. The two S1-S5 full sacral curvature mean angles were 57.3° and 60.4°. Almost all sacral hiatuses were at S4, and dural sac terminations were at S1-S2. The mean S2-S4 sacral curvature was 25.1°, and the mean needle distance was 57.7 mm. Using two-way analysis of variance, there were significant sex differences for needle distances (p = .001), and full and limited sacral curvatures (p = .02, and p = .046, respectively). There were no significant linear regression correlations between age and sacral curvature, needle distance, canal area, or hiatus width. Therefore, despite a frequently prominent full sacral curvature, the combination of S1-S2 dural sac termination plus a relatively straight trajectory of the lower vertebral canal between S2 and S4 support the theoretical feasibility of percutaneous trans-sacral hiatus and vertebral canal access to the lumbosacral cistern using a standard spinal needle.

Highly sensitive eight-channel light sensing system for biomedical applications.

We demonstrate the potential of an eight-channel light sensing platform system, named Black Box I (BBI), for rapid and highly sensitive measurement of low-level light using a nonradioactive optical readout. We developed, normalized, and characterized the photon sensitivities of the eight channels of the BBI using placental alkaline phosphatase (PLAP) as a model imaging reporter. We found that the BBI system had a statistically strong linear correlation with the reference IVIS Lumina II system. When we applied normalization constants, we were able to optimize the photomultiplier tubes (PMT) of all eight channels of the BBI (up to r2 = 0.998). We investigated the biomedical utilities of BBI by: (i) determining alkaline phosphatase activities in mouse plasma samples as a diagnostic secretory biomarker of cancer, and (ii) diagnosing cancer metastases in the organs of mice bearing triple negative breast cancer. We provide an important new addition to low-cost biomedical instruments intended for pre-clinical diagnostic imaging with high sensitivity, high sample throughput, portability, and rapid on-site analysis of low-level light.

Magnetic resonance imaging anatomy and morphometry of lumbar intervertebral foramina to guide safe transforaminal subarachnoid punctures.

Percutaneous transforaminal lumbar punctures (TFLPs) offer alternative access routes to the lumbar subarachnoid cistern. Safe fluoroscopic insertion of a needle through a lumbar intervertebral foramen (IVF) should ideally avoid the exiting spinal nerve and surrounding vascular pedicles. A crescentic region in the posterior aspect of IVF is the conventional position for needle placement during TFLP, but the underlying anatomic basis for this has not been evaluated fully. To enhance TFLP safety, we defined the morphometry of normal lumbar IVFs and precise locations of neurovascular structures in the IVF posterior crescent. We retrospectively reviewed high-resolution T2-weighted lumbar spine magnetic resonance images of 40 normal adults to establish normative dimensions of each IVF from L1 to L5 bilaterally. We segmented the IVF posterior crescent into three parts, and within each, measured the areas occupied by neurovascular structures. We statistically correlated the presence or absence of neurovascular structures in each crescent segment using a chi-square test. The mean morphometrics for all 304 IVFs in 10 males and 30 females of similar ages were: area 115.3 ± 29.5 mm2 ; height 18.0 ± 2.4 mm; and width at mid-disc level 5.6 ± 2.1 mm. We found a significant association between crescent segment and presence or absence of neurovascular structures (χ2 = 95.9, p < .001). A post-hoc calculation of adjusted standardized residuals identified a significant association between the middle crescent segment and absence of neurovascular structures. Thus, the middle segment of the IVF posterior crescent is significantly most devoid of neurovascular structures, and more often would be the safest target for needle placement during TFLP.

Three-Dimensional Angles of Confluence of Cortical Bridging Veins and the Superior Sagittal Sinus on MR Venography: Does Drainage of Adjacent Brain Arteriovenous Malformations Alter this Spatial Configuration?

Few neuroimaging anatomic studies to date have investigated in detail the point of entry of cortical bridging veins (CBVs) into the superior sagittal sinus (SSS). Although we know that most CBVs join the SSS at an acute angle opposite to the direction of SSS blood flow, the three-dimensional (3-D) spatial configuration of these venous confluences has not been studied previously. This anatomical information would be pertinent to several clinically applicable scenarios, such as in planning intracranial surgical approaches that preserve bridging veins; studying anatomical factors in the pathophysiology of SSS thrombosis; and when planning endovascular microcatheterization of pial veins to retrogradely embolize brain arteriovenous malformations (AVMs). We used the concept of Euclidean planes in 3-D space to calculate the arccosine of these CBV-SSS angles of confluence. To test the hypothesis that pial AVM draining veins may not be any more acutely angled or difficult to microcatheterize at the SSS than for normal CBVs, we measured 70 angles of confluence on magnetic resonance venography images of 11 normal, and nine AVM patients. There was no statistical difference between normal and AVM patients in the CBV-SSS angles projected in 3-D space (56.2° [SD = 22.4°], and 46.2° [SD = 22.3°], respectively; P > 0.05). Hence, participation of CBVs in drainage of pial AVMs should not confer any added difficulty to their microcatheterization across the SSS, when compared to the acute angles found in normal individuals. This has useful implications for potential choices of strategies requiring endovascular transvenous retrograde approaches to treat AVMs. Clin. Anat. 33:293-299, 2020. © 2019 Wiley Periodicals, Inc.

The mammillothalamic tracts: Age-related conspicuity and normative morphometry on brain magnetic resonance imaging.

The mammillothalamic tract (MTT, bundle of Vicq d'Azyr) is a white-matter projection from each mammillary body to the anterior nucleus of the thalamus (ANT). Deep brain stimulation of the MTTs or ANTs is a treatment option for medically refractory focal epilepsy. Since the ANTs may be atrophied in epilepsy, targeting of the MTT terminations could be used as a proxy for ANT locations. However, MTT conspicuity and morphometry on MRI have not been evaluated to date. We investigated normative age- and sex-related MRI morphometrics of the MTTs in healthy individuals. We retrospectively analyzed magnified axial T2-weighted images of 80 subjects for bilateral MTT conspicuity, diameters, areas, shapes, precise locations, and symmetry. We statistically tested the effects of independent variables (sex and MTT side) on measured dependent variables using two-way ANOVA; and performed linear regressions with age as the independent variable for each of the dependent variables. Subjects were F:M = 44:36, with mean age 45.3 years. Only one (0.63%) MTT was inconspicuous. Mean MTT diameter was 1.8 mm, area was 2.0 mm2 , and distance from third ventricle was 3.1 mm. MTTs were mostly bilaterally symmetrical in shape, equally round, or ovoid. The right MTT diameter was larger than the left, and males had larger MTT areas than females. We found no statistical difference between MTT diameters and areas in young, middle-aged, and older adults. We report normative axial MRI morphometrics of the MTTs to guide neuromodulation treatments. Future detailed analyses will determine if the MTTs atrophy in proportion to the ANTs in refractory epilepsy.

A critical appraisal of Monro's erroneous description of the cerebral interventricular foramina: Age-related magnetic resonance imaging spatial morphometry and a proposed new terminology.

Anatomic connections between the cerebral lateral and third ventricles have been mischaracterized since Monro's original erroneous description of his eponymous foramina (FoMs) as being only one T-shaped passage. Accurate knowledge of the in vivo three-dimensional (3D) configuration of FoM has important clinical neuroendoscopic, neurosurgical, and neuroimaging implications. We retrospectively analyzed volumetric high-resolution brain magnetic resonance imaging of 100 normal individuals to characterize the normal spatial anatomy and morphometry for each FoM. We measured the true anatomical 3D angulations of FoMs relative to standard neuroimaging orthogonal planes, and their minimum width, depth, and distance between the medial borders of bilateral FoMs. The right and left FoMs were separate, distinct, and in a V-shaped configuration. Each FoM was a round, oval, or crescent-shaped canal-like passage with well-defined borders formed by the semicircular concavity of the ipsilateral forniceal column. The plane of FoM was angled on average 56.8° ± 9.1° superiorly from the axial plane, 22.5° ± 10.7° laterally, and 37.0° ± 6.9° anteriorly from the midsagittal plane; all these angles changing significantly with increasing age. The mean narrowest diameter of FoM was 2.8 ± 1.2 mm, and its depth was 2.5 ± 0.2 mm. Thus, the true size and orientation of FoM differs from that depicted on standard neuroimaging. Notably, in young subjects, FoM has a diameter smaller than its depth, a configuration akin to a short, small canal. We propose that the eponym "Monro" no longer be associated with this structure, and the term "foramen" be abandoned. Instead, FoM should be more appropriately renamed as the "interventricular canaliculus," or IVC, for short.

Eponymous "valves" of the nasolacrimal drainage apparatus. II. Frequency of visualization on dacryocystography.

Developmental remnants may follow segmental canalization of ectodermal epithelial cords forming the nasolacrimal drainage apparatus (NDA). This can result in false luminal "valves" along the path of the NDA, many of which have been named, but most have not been anatomically identified with consistency. By 1908, eight such "valves" were documented, those of: Foltz, Bochdalek, Rosenmüller, Huschke, Aubaret, Béraud or Krause, Taillefer, and Hasner or Cruveilhier or Bianchi. Digital subtraction dacryocystography (DS-DCG) is the highest spatial resolution imaging technique available to outline in vivo NDA anatomy, luminal profile, and pathology. We believe this is the first report of the conspicuousness and frequency of these "valves" on DS-DCG. We retrospectively analyzed routine DS-DCGs with normal findings for the presence and frequency of the eight NDA "valves." We examined 92 normal DS-DCGs on patients aged 14-82 years (71% female, 29% male). We observed "valves" most reliably in the inferior nasolacrimal duct: the inferior valve of Hasner (plica lacrimalis) was present in 98.9% of cases, and more superiorly, the valve of Taillefer (93.5%) and the valve of Krause (79.3%). Contrastingly, we infrequently identified the very superior "valves": Foltz or Bochdalek in 17.1%, Rosenmüller or Huschke in 46.4%, and Auberat in 40% of cases. Therefore, unlike the inferior NDA valves, these more superior "valves" were less consistently identified and are presumed to be simple mural mucosal irregularities rather than true structural valves. These findings will be useful in diagnostic interpretation of DS-DCGs and therapeutic planning for patients undergoing luminal procedures on the NDA. Clin. Anat., 2018. © 2018 Wiley Periodicals, Inc.

Eponymous "valves" of the nasolacrimal drainage apparatus. I. A historical review.

The nasolacrimal drainage apparatus (NDA) is of interest to anatomists, radiologists, and ophthalmologists alike, owing to its intricate luminal contour, complex surrounding structural morphology, and its clinical relevance. Here, we review the history of anatomical descriptions of so-called luminal "valves" of the NDA, including the numerous historical figures whose eponyms adorn the NDA. By 1908, multiple false "valves" that are likely no more than mounds of mucosa along the NDA had been recorded. In the modern era, these have all been largely considered speculative in nature and function aside from the consistently described true valve of Hasner (plica lacrimalis). Back then, eight so-called "valves" were believed to be identifiable. These were the "valves" of Foltz, Bochdalek, Rosenmüller, Huschke, Aubaret, Béraud or Krause, Taillefer, and Hasner or Cruveilhier or Bianchi. With the advent of detailed characterization through modern high-resolution imaging techniques, such as digital subtraction dacryocystography (DS-DCG), many of these valvular folds have come into question owing to their inconsistent identification. This historical review should be useful for greater understanding and accurate contextual interpretation of "valves" encountered on DS-DCG studies, and in clinical management and therapeutic planning of patients prior to undergoing luminal procedures on the NDA. Clin. Anat., 2018. © 2018 Wiley Periodicals, Inc.

Optic Chiasm Morphometric Changes in Multiple Sclerosis: Feasibility of a Simplified Brain Magnetic Resonance Imaging Measure of White Matter Atrophy.

Sophisticated volume measurements of brain structures on magnetic resonance imaging (MRI) may improve specificity in determining long-term progression of multiple sclerosis (MS), but these techniques are laborious. The optic chiasm (OC) is a white matter (WM) structure clearly visible on a routine MRI and is related to the optic nerves (ONs), which are known to atrophy in MS. We hypothesized that OC morphometric measurements would show OC atrophy in MS compared to normal patients. If so, this could help establish a novel simplified brain MRI measure of WM atrophy in MS patients. We retrospectively evaluated standard brain MRIs of 97 patients with known MS and 98 normal individuals. We electronically measured eight OC morphometrics on axial T2WIs and midsagittal T1WIs: OC width and anteroposterior (AP) diameter, diameters of each ON and optic tract (OT), and angles between the ONs or OTs. Mean OC width, AP diameter, and height in MS patients were 11.83 ± 1.25 mm (95% CI 11.58-12.09), 2.99 ± 0.65 mm (95% CI 2.85-3.12), and 2.09 ± 0.37 mm (95% CI 2-2.19), respectively. In normal individuals, they were 12.1 ± 1.4 mm (95% CI 11.78-12.34), 3.43 ± 0.63 mm (95% CI 3.3-3.58), and 2.15 ± 0.37 mm (95% CI 2.07-2.23), respectively. There were statistically significant differences between MS patients and controls for AP diameter (P = 0.000), but not for width (P = 0.204) or height (P = 0.183). The ONs were significantly smaller in MS (P < 0.0017), but not the OTs. Thus, the OC is significantly atrophied in an unstratified cohort of MS patients. Future studies may establish an MRI OC morphometric index to evaluate demyelinating disease in the brain. Clin. Anat. 32:1072-1081, 2019. © 2019 Wiley Periodicals, Inc.

Are high lumbar punctures safe? A magnetic resonance imaging morphometric study of the conus medullaris.

A high lumbar puncture (LP) at L2-L3 or above is often necessary to consider on technical grounds, but complications of conus medullaris (CM) damage during high LP are potentially concerning. We hypothesized that a high LP might be safer than previously thought by accounting for movements of the CM upon patient positional changes. We retrospectively reviewed standard normal supine lumbar spine magnetic resonance imaging of 58 patients and used electronic calipers on axial images at the T12-L1, L1-L2, and L2-L3 disc levels to measure the transverse diameter of the CM relative to the size of the dorsal thecal sac space (DTSS) through which a spinal needle could be inserted. On 142 axial images, the means for CM diameters were 8.2, 6.0, and 2.9 mm at the three levels, respectively. We then used known literature mean CM displacement values in the legs flexed and unflexed lateral decubitus position (LDP) to factor in CM shifts to the dependent side. We found that at all three levels, the likely positional shift of the CM would be too small and insufficient to displace the entire CM out of the DTSS. However, if needle placement could be confined to the midsagittal plane, an LP in the unflexed LDP would theoretically be entirely safe at both L1-L2 and L2-L3, and almost so at L2-L3 in the legs flexed LDP. Thus, high LPs at L1-L2 and L2-L3 are in theory likely safer than considered previously, more so in the legs unflexed than in the flexed LDP. Clin. Anat. 32:618-629, 2019. © 2019 Wiley Periodicals, Inc.

Molecular Imaging Biosensor Monitors p53 Sumoylation in Cells and Living Mice.

Small molecule mediated stabilization of p53 tumor suppressor protein through sumoylation is a promising new strategy for improving cancer chemotherapy. A molecular tool that monitors p53 sumoylation status and expedites screening for drugs that enhance p53 sumoylation would be beneficial. We report a molecularly engineered reporter fragment complementation biosensor based on optical imaging of Firefly luciferase (FLuc), to quantitatively image p53 sumoylation and desumoylation in cells and living mice. We initially characterized this biosensor by successfully imaging sumoylation of several target proteins, achieving significant FLuc complementation for ERα (p < 0.01), p53 (p < 0.005), FKBP12 (p < 0.03), ID (p < 0.03), and HDAC1 (p < 0.002). We then rigorously tested the sensitivity and specificity of the biosensor using several variants of p53 and SUMO1, including deletion mutants, and those with modified sequences containing the SUMO-acceptor site of target proteins. Next we evaluated the performance of the biosensor in HepG2 cells by treatment with ginkgolic acid, a drug that reduces p53 sumoylation, as well as trichostatin A, a potential inducer of p53 sumoylation by enhancement of its nuclear export. Lastly, we demonstrated the in vivo utility of this biosensor in monitoring and quantifying the effects of these drugs on p53 sumoylation in living mice using bioluminescence imaging. Adoption of this biosensor in future high throughput drug screening has the important potential to help identify new and repurposed small molecules that alter p53 sumoylation, and to preclinically evaluate candidate anticancer drugs in living animals.

Tailored Nanoparticle Codelivery of antimiR-21 and antimiR-10b Augments Glioblastoma Cell Kill by Temozolomide: Toward a "Personalized" Anti-microRNA Therapy.

Glioblastoma remains an aggressive brain malignancy with poor prognosis despite advances in multimodal therapy that include standard use of Temozolomide. MicroRNA-21 (miR-21) and microRNA-10b (miR-10b) are oncomiRs overexpressed in glioblastoma, promoting many aspects of cancer biology. We hypothesized that PLGA nanoparticles carrying antisense miR-21 (antimiR-21) and antisense miR-10b (antimiR-10b) might beneficially knockdown endogenous miR-21 and miR-10b function and reprogram cells prior to Temozolomide treatment. PLGA nanoparticles were effective in intracellular delivery of encapsulated oligonucleotides. Concentrations of delivered antimiR-21 and antimiR-10b were optimized and specifically tailored to copy numbers of intracellular endogenous microRNAs. Coinhibition of miR-21 and miR-10b significantly reduced the number of viable cells (by 24%; p < 0.01) and increased (2.9-fold) cell cycle arrest at G2/M phase upon Temozolomide treatment in U87 MG cells. Cell-tailored nanoparticle-assisted concurrent silencing of miR-21 and miR-10b prior to Temozolomide treatment is an effective molecular therapeutic strategy in cell culture, warranting the need for further studies prior to future in vivo "personalized" medicine applications.