Falls Efficacy Scale and Single Item Question: Screening Accuracy for Older Adults Residing in Nursing Homes.

Objectives: The Falls Efficacy Scale (FES) has been developed to evaluate self-efficacy in avoiding falling during Basic Activities of Daily Living (BADL) and Single Item Question (SIQ) evaluates fear of falling (FOF) by asking a single question. These tools have some pros and cons, therefore, the present study aimed to evaluate and compare screening accuracy of Falls Efficacy Scale (FES) and Single Item Question (SIQ) in measuring FOF for older adults.Methods: A total of 100 older adult residents of nursing homes (males: N = 63) were evaluated with Falls Efficacy Scale-International (FES-I), FES, and SIQ via interview. Cutoff points and validity parameters were calculated for the FES and SIQ by using FES-I as a criterion measure.Results: In a moderate FOF threshold, the sensitivity rate of 81.82% and 43.18% were obtained for FES and SIQ, respectively. High sensitivity and specificity rate were obtained for both FES (sensitivity and specificity: 100%) and SIQ (sensitivity: 94.44%; specificity: 90%) in severe FOF threshold.Conclusions: The results of this study indicated that, compared to the SIQ, the FES is a better tool to identify FOF in both moderate and severe thresholds in first screening.Clinical Implications: The FES is a valid and sensitive tool to identify FOF in older adults.

Genotype-phenotype correlation and the size of microdeletion or microduplication of 7q11.23 region in patients with Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is a chromosomal microdeletion syndrome with variable phenotypic features such as supravalvular aortic stenosis (SVAS), facial appearance characteristics, growth retardation, and infantile hypercalcemia. This study aimed to detect the 7q11.23 microdeletion in 10 patients with early clinical diagnosis of WBS using fluorescent in situ hybridization or array comparative genomic hybridization. As an alternative method, multiplex ligation-dependent probe amplification (MLPA) was used to confirm this microdeletion. Clinical features were also compared with detected genotypes. To reveal the parental origin of deletion, four polymorphic markers (D7S1870, D7S489, D7S613, and D7S2476) were used. The deletion had maternal origin in 80% and paternal origin in 20% of the cases. From 10 patients with early clinical diagnosis of the WBS, 3 patients presented with atypical phenotypes such as infantile hypocalcemia, normal IQ, and normal facial characterization, but the sizes of their deletions seemed to be almost similar to other cases. Regarding such observation, we suggest that the phenotypic variations of WBS are influenced not only by the deletion size and involving genes but also by the breakpoint regions and probably epigenetic effects. However, further research is required to explore the effect of such parameters on phenotypic features.

Validation of parametric mesh generation for subject-specific cerebroarterial trees using modified Hausdorff distance metrics.

Accurate subject-specific vascular network reconstruction is a critical task for the hemodynamic analysis of cerebroarterial circulation. Vascular skeletonization and computational mesh generation for large sections of cerebrovascular trees from magnetic resonance angiography (MRA) is an error-prone, operator-dependent, and very time-consuming task. Validation of reconstructed computational models is essential to ascertain their accuracy and precision, which directly relates to the confidence of CFD computations performed on these meshes. The aim of this study is to generate an imaging segmentation pipeline to validate and quantify the spatial accuracy of computational models of subject-specific cerebral arterial trees. We used a recently introduced parametric structured mesh (PSM) generation method to automatically reconstruct six subject-specific cerebral arterial trees containing 1364 vessels and 571 bifurcations. By automatically extracting sampling frames for all vascular segments and bifurcations, we quantify the spatial accuracy of PSM against the original MRA images. Our comprehensive study correlates lumen area, pixel-based statistical analysis, area overlap and centerline accuracy measurements. In addition, we propose a new metric, the pointwise offset surface distance metric (PSD), to quantify the spatial alignment between dimensions of reconstructed arteries and bifurcations with in-vivo data with the ability to quantify the over- and under-approximation of the reconstructed models. Accurate reconstruction of vascular trees can a practical process tool for morphological analysis of large patient data banks, such as medical record files in hospitals, or subject-specific hemodynamic simulations of the cerebral arterial circulation.

Quantification of near-wall hemodynamic risk factors in large-scale cerebral arterial trees.

Detailed hemodynamic analysis of blood flow in pathological segments close to aneurysm and stenosis has provided physicians with invaluable information about the local flow patterns leading to vascular disease. However, these diseases have both local and global effects on the circulation of the blood within the cerebral tree. The aim of this paper is to demonstrate the importance of extending subject-specific hemodynamic simulations to the entire cerebral arterial tree with hundreds of bifurcations and vessels, as well as evaluate hemodynamic risk factors and waveform shape characteristics throughout the cerebral arterial trees. Angioarchitecture and in vivo blood flow measurement were acquired from healthy subjects and in cases with symptomatic intracranial aneurysm and stenosis. A global map of cerebral arterial blood flow distribution revealed regions of low to high hemodynamic risk that may significantly contribute to the development of intracranial aneurysms or atherosclerosis. Comparison of pre-intervention and post-intervention of pathological cases further shows large angular phase shift (~33.8°), and an augmentation of the peak-diastolic velocity. Hemodynamic indexes of waveform analysis revealed on average a 16.35% reduction in the pulsatility index after treatment from lesion site to downstream distal vessels. The lesion regions not only affect blood flow streamlines of the proximal sites but also generate pulse wave shift and disturbed flow in downstream vessels. This network effect necessitates the use of large-scale simulation to visualize both local and global effects of pathological lesions.

Large-scale subject-specific cerebral arterial tree modeling using automated parametric mesh generation for blood flow simulation.

In this paper, we present a novel technique for automatic parametric mesh generation of subject-specific cerebral arterial trees. This technique generates high-quality and anatomically accurate computational meshes for fast blood flow simulations extending the scope of 3D vascular modeling to a large portion of cerebral arterial trees. For this purpose, a parametric meshing procedure was developed to automatically decompose the vascular skeleton, extract geometric features and generate hexahedral meshes using a body-fitted coordinate system that optimally follows the vascular network topology. To validate the anatomical accuracy of the reconstructed vasculature, we performed statistical analysis to quantify the alignment between parametric meshes and raw vascular images using receiver operating characteristic curve. Geometric accuracy evaluation showed an agreement with area under the curves value of 0.87 between the constructed mesh and raw MRA data sets. Parametric meshing yielded on-average, 36.6% and 21.7% orthogonal and equiangular skew quality improvement over the unstructured tetrahedral meshes. The parametric meshing and processing pipeline constitutes an automated technique to reconstruct and simulate blood flow throughout a large portion of the cerebral arterial tree down to the level of pial vessels. This study is the first step towards fast large-scale subject-specific hemodynamic analysis for clinical applications.

Gap-free segmentation of vascular networks with automatic image processing pipeline.

Current image processing techniques capture large vessels reliably but often fail to preserve connectivity in bifurcations and small vessels. Imaging artifacts and noise can create gaps and discontinuity of intensity that hinders segmentation of vascular trees. However, topological analysis of vascular trees require proper connectivity without gaps, loops or dangling segments. Proper tree connectivity is also important for high quality rendering of surface meshes for scientific visualization or 3D printing. We present a fully automated vessel enhancement pipeline with automated parameter settings for vessel enhancement of tree-like structures from customary imaging sources, including 3D rotational angiography, magnetic resonance angiography, magnetic resonance venography, and computed tomography angiography. The output of the filter pipeline is a vessel-enhanced image which is ideal for generating anatomical consistent network representations of the cerebral angioarchitecture for further topological or statistical analysis. The filter pipeline combined with computational modeling can potentially improve computer-aided diagnosis of cerebrovascular diseases by delivering biometrics and anatomy of the vasculature. It may serve as the first step in fully automatic epidemiological analysis of large clinical datasets. The automatic analysis would enable rigorous statistical comparison of biometrics in subject-specific vascular trees. The robust and accurate image segmentation using a validated filter pipeline would also eliminate operator dependency that has been observed in manual segmentation. Moreover, manual segmentation is time prohibitive given that vascular trees have more than thousands of segments and bifurcations so that interactive segmentation consumes excessive human resources. Subject-specific trees are a first step toward patient-specific hemodynamic simulations for assessing treatment outcomes.

Detection of Alkaline Phosphatase Enzyme Activity with a CatalyCEST MRI Biosensor.

Responsive CEST MRI biosensors offer good sensitivity and excellent specificity for detection of biomarkers with great potential for clinical translation. We report the application of fosfosal, a phosphorylated form of salicylic acid, for the detection of alkaline phosphatase (AP) enzyme. We detected conversion of fosfosal to salicylic acid in the presence of the enzyme by CEST MRI. Importantly the technique was able to detect AP enzyme expressed in cells in the presence of other cell components, which improves specificity. Various isoforms of the enzyme showed different Michaelis-Menten kinetics and yet these kinetics studies indicated very efficient catalytic rates. Our results with the fosfosal biosensor encourage further in vivo studies.

Supraspinal peroxynitrite modulates pain signaling by suppressing the endogenous opioid pathway.

Peroxynitrite (PN, ONOO(-)) is a potent oxidant and nitrating agent that contributes to pain through peripheral and spinal mechanisms, but its supraspinal role is unknown. We present evidence here that PN in the rostral ventromedial medulla (RVM) is essential for descending nociceptive modulation in rats during inflammatory and neuropathic pain through PN-mediated suppression of opioid signaling. Carrageenan-induced thermal hyperalgesia was associated with increased 3-nitrotyrosine (NT), a PN biomarker, in the RVM. Furthermore, intra-RVM microinjections of the PN decomposition catalyst Fe(III)-5,10,15,20-tetrakis(N-methyl-pyridinium-4-yl)porphyrin (FeTMPyP(5+)) dose-dependently reversed this thermal hyperalgesia. These effects of FeTMPyP(5+) were abrogated by intra-RVM naloxone, implicating potential interplay between PN and opioids. In support, we identified NT colocalization with the endogenous opioid enkephalin (ENK) in the RVM during thermal hyperalgesia, suggesting potential in situ interactions. To address the functional significance of such interactions, we exposed methionine-enkephalin (MENK) to PN and identified the major metabolite, 3-nitrotyrosine-methionine-sulfoxide (NSO)-MENK, using liquid chromatography-mass spectrometry. Next, we isolated, purified, and tested NSO-MENK for opioid receptor binding affinity and analgesic effects. Compared to MENK, this NSO-MENK metabolite lacked appreciable binding affinity for δ, µ, and κ opioid receptors. Intrathecal injection of NSO-MENK in rats did not evoke antinociception, suggesting that PN-mediated chemical modifications of ENK suppress opioid signaling. When extended to chronic pain, intra-RVM FeTMPyP(5+) produced naloxone-sensitive reversal of mechanical allodynia in rats following chronic constriction injury of the sciatic nerve. Collectively, our data reveal the central role of PN in RVM descending facilitation during inflammatory and neuropathic pain potentially through anti-opioid activity.

Retooling manganese(III) porphyrin-based peroxynitrite decomposition catalysts for selectivity and oral activity: a potential new strategy for treating chronic pain.

Redox-active metalloporphyrins represent the most well-characterized class of catalysts capable of attenuating oxidative stress in vivo through the direct interception and decomposition of superoxide and peroxynitrite. While many interesting pharmacological probes have emerged from these studies, few catalysts have been developed with pharmaceutical properties in mind. Herein, we describe our efforts to identify new Mn(III)-porphyrin systems with enhanced membrane solubilizing properties. To this end, seven new Mn(III)-tetracyclohexenylporphyin (TCHP) analogues, 7, 10, 12, 15, and 16a-c, have been prepared in which the beta-fused cyclohexenyl rings provide a means to shield the charged metal center from the membrane during passive transport. Compounds 7, 15, and 16a-c have been shown to be orally active and potent analgesics in a model of carrageenan-induced thermal hyperalgesia. In addition, oral administration of compound 7 (10-100 mg/kg, n=5) has been shown to dose dependently reverse mechano-allodynia in the CCI model of chronic neuropathic pain.