Pretreatment of rhesus monkeys with transdermal patches containing physostigmine and procyclidine: implications of the delivery system for the potential application against VX nerve agent intoxication in humans.

Physostigmine (Phs) is a reversible inhibitor of acetylcholinesterase (AChE) that penetrates the blood-brain barrier (BBB) and could be used to protect the central nervous system (CNS) against the effects of nerve agents. For prophylactic effectiveness, long, steady, and adequate inhibition of AChE activity by Phs is needed to broadly protect against the CNS effects of nerve agents. Here, we evaluated the efficacy of transdermal patches containing Phs and procyclidine (PC) as prophylactic agents. Patches (25 cm2) containing 4.4 mg Phs and 17.8 mg PC had a protective ratio of approximately 78.6-fold in rhesus monkeys challenged with VX nerve agent and given an antidote. Physiologically based pharmacokinetic model in conjunction with an indirect pharmacodynamic (PBPK/PD) was developed for Phs and scaled to rhesus monkeys. The model was able to reproduce the concentration profile and inhibitory effect on AChE of Phs in monkeys, as evidenced by correlation coefficients of 0.994 and 0.992 for 25 cm2 and 49 cm2 patches, respectively (i.e., kinetic data), and 0.989 and 0.968 for 25 cm2 and 49 cm2 patches, respectively (i.e., dynamic data). By extending the monkey PBPK/ PD model to humans, the effective human dose was predicted to be five applications of a 25 cm2 patch (i.e., 22 mg Phs), and two applications of a 49 cm2 patch (i.e., 17.4 mg Phs). Therefore, given that patch application of Phs in rhesus monkeys has a prolonged effect (namely, AChE inhibition of 19.6% for the 25 cm2 patch and 23.0% for the 49 cm2 patch) for up to 216 h, patch formulation of Phs may provide similar protection against nerve agent intoxication in humans.

Differences in the 3-dimensional aging changes of the lips among female adults with skeletal Class I, II, and III malocclusion.

INTRODUCTION: The objective of this study was to evaluate and compare the 3-dimensional (3D) aging changes of the lips among adult skeletal Class I, II, and III malocclusion. METHODS: Female adult orthodontic patients aged 20-50 years with pretreatment cone-beam computed tomography scans were retrospectively classified according to age (20s [20-29 years], 30s [30-39 years], and 40s [40-49 years]) and then subclassified by malocclusion into skeletal Class I, II, and III relationship (9 groups; n = 30 per group). Positional differences in midsagittal and parasagittal soft-tissue landmarks and 3D morphologic aging changes of the lips were evaluated using cone-beam computed tomography scans. RESULTS: Labiale superius and cheilion for patients in their 40s indicated a significant downward and backward position compared with those in their 20s, regardless of skeletal classifications (P <0.05). Accordingly, the upper lip height decreased, and the mouth width increased significantly (P <0.05). For Class III malocclusion, the upper lip vermilion angle was greater for patients in their 40s than those in their 20s (P <0.05), whereas the lower lip vermilion angle was only lower for patients with Class II malocclusion (P <0.05). CONCLUSIONS: Middle-aged adult females (40-49 years) had a lower upper lip height and greater mouth width than those in their 20s, regardless of skeletal malocclusion. However, prominent morphologic aging changes of the lips were noted on the upper lip for skeletal Class III malocclusion and the lower lip for skeletal Class II malocclusion, implying that the underlying skeletal features (or malocclusion) may influence 3D aging changes of the lips.

Comparison of Lip Line Cant Change After 1-Jaw and 2-Jaw Surgery.

OBJECTIVES: The purpose of this study was to compare the lip line cant (LLC) changes after 1 and 2-jaw surgery, and to evaluate the correlations of the craniofacial factors affecting LLC. METHODS: The study subjects were selected (LLC amount within 1.5-6.0°) from among the patients diagnosed with Class III malocclusion who underwent one (n = 20) or 2-jaw surgery (n = 20). Cone beam computed tomography images were obtained immediately before the operation (T1) and 6 months after the operation (T2). Preoperative and postoperative craniofacial measurements were obtained. RESULTS: The study subjects showed 3.12° LLC on average before undergoing 1-jaw surgery, and their LLC changed to 1.27° after the surgery. As for 2-jaw surgery, the subjects showed 3.38° LLC on average before the surgery and 0.98° after the surgery. LLC at pre-treatment may be more affected by a cant of the occlusal plane in the mandible than maxilla. In the comparison of the value of changes of LLC, the value of 2-jaw surgery was bigger than the value of 1-jaw surgery but the difference was statistically insignificant. LIMITATIONS: This study had a limitation in that the muscles were not considered. And the metal bracket or metal crown and bridge, however, can cause noise and blurring artifacts in CT, which can lead to a low resolution. And the limited number of the patients should be considered. CONCLUSIONS: In correlation analysis, both pre-surgery LLC and change of LLC have correlation with almost all the craniofacial measurement. Lip-line cant of patients with facial asymmetry has higher correlation with mandibular cant than with other cants. To improve the LLC, a surgical plan should be established to minimize the mandibular cant using the computer simulation as well as the maxillary cant.

Heterogeneous Charge-Transfer Nanorods by Strained Melt-Molding Lithography.

Hetero-nanorods consisting of two charge-transfer (CT) complexes were fabricated by the strained melt-molding lithography. Utilizing the lowered melting temperature by the formation of eutectic mixture, various well-defined CT complex nanorods can be easily fabricated by soft-lithography-assisted melt crystallization below 100 degrees C. Hetero-nanorods were fabricated by selective doping of the secondary CT complex at defects induced by applying the uniaxial strain.

Direct-write patterning of bacterial cells by dip-pen nanolithography.

The ability of dip-pen nanolithography (DPN) to generate nano- or microarrays of soft or hard materials (e.g., small molecules, DNA, proteins, nanoparticles, sols, and polymers) in a direct-write manner has been widely demonstrated. The transporting of large-sized ink materials such as bacteria, however, remains a significant challenge with this technique. The size limitation of the water meniscus formed between the DPN tip and the solid surface becomes a bottleneck in such diffusion-based molecular transport experiments. Herein, we report a straightforward "stamp-on" DPN method that uses a nanostructured poly(2-methyl-2-oxazoline) hydrogel-coated tip and carrier agents to generate patterns of micrometer-sized Escherichia coli JM 109 bacterial cells. We demonstrate that this approach enables the deposition of a single bacterial cell array on a solid surface or arrays of layers of multiple cells by modulating the viscosity of the "ink" solution. Fluorescence microscopy images indicated that the deposited bacterial cells were kept alive on Luria-Bertani-agar layered solid surfaces after DPN patterning.

Translocation of the conus medullaris during dynamic lumbosacral magnetic resonance imaging in dogs.

OBJECTIVE: To investigate the change in the lumbosacral angle (ΔLSA) and conus medullaris (CM) displacement in healthy dogs undergoing dynamic MRI with changes in the posture of their pelvic limbs from neutral posture to flexion or extension posture and to evaluate for potential correlation between ΔLSA and CM displacement. ANIMALS: 9 healthy adult Beagles. PROCEDURES: Dogs underwent dynamic MRI with their pelvic limbs positioned in neutral, flexion, and extension postures. From T2-weighted sagittal midline plane MRI images, 2 observers measured the lumbosacral angle and CM location in duplicate for each posture for each dog. Intra- and interobserver agreement was assessed, and the Spearman rank correlation coefficient (ρ) was used to assess for potential correlation between ΔLSA and CM displacement for changes in pelvic limb posture from neutral to flexion or extension. RESULTS: Overall, the mean ΔLSA and CM displacement for changes in posture were 23° and 9.09 mm (caudal displacement) for the change from neutral to flexion posture, 8.4° and -2.5 mm (cranial displacement) for the change from neutral to extension posture, and 32.2° and 11.64 mm (caudal displacement) for the change from extension to flexion posture. The ΔLSA strongly correlated (ρ = 0.705; 95% CI, 0.434 to 0.859) with displacement of the CM. CONCLUSIONS AND CLINICAL RELEVANCE: The use of dynamic MRI, compared with conventional MRI, will better help to characterize clinically normal and abnormal features of the lumbosacral region of the vertebral column and associated spinal cord during postural changes. Further, when limited translocation of the CM is evident on dynamic MRI, veterinarians should suspect underlying lumbosacral pathophysiologic processes or anatomic abnormalities.

Proper fraction of inspired oxygen for reduction of oxygen-induced canine cerebrospinal fluid hyperintensity on fluid attenuation inversion recovery sequence using low-field magnetic resonance imaging.

Oxygen-induced cerebrospinal fluid (CSF) hyperintensity artifact is inevitable in fluid attenuation inversion recovery (FLAIR) magnetic resonance (MR) images of anesthetized animals. This experimental study aimed to confirm the occurrence of this artifact on low-field magnetic resonance imaging (MRI), and to determine the fraction of inspired oxygen (FiO2) that is safe and does not induce this artifact in canine brain MRI. Six healthy dogs underwent brain FLAIR MR scans under general anesthesia with 21%, 30%, 50%, 70%, and 100% FiO2. The signal intensity (SI) ratio was calculated as the SI of CSF spaces divided by that of normalizing regions. The SI ratios of 21% FiO2 images were significantly different from those of 100% FiO2 images, indicating the presence of artifacts on 100% FiO2 images. The SI ratios of 30% FiO2 images were not significantly different from those of 21% FiO2 images for any of CSF spaces. However, they were significantly different from those of 100% FiO2 images in the cerebral sulci, third ventricle, interpeduncular cistern, mesencephalic aqueduct, and subarachnoid space at the level of the first cervical vertebra (P<0.05). All dogs had normal partial pressure of arterial oxygen (PaO2) during inhalation of 30% FiO2, while two dogs had low PaO2 during inhalation of 21% FiO2. Our findings support the hypothesis that high FiO2 induces CSF hyperintensity artifact on low-field FLAIR MR images in dogs. FiO2 of 30% is appropriate for obtaining brain FLAIR MR images with fewer artifacts in dogs.

Therapeutic Efficacy of ABN401, a Highly Potent and Selective MET Inhibitor, Based on Diagnostic Biomarker Test in MET-Addicted Cancer.

The receptor tyrosine kinase c-MET regulates processes essential for tissue remodeling and mammalian development. The dysregulation of c-MET signaling plays a role in tumorigenesis. The aberrant activation of c-MET, such as that caused by gene amplification or mutations, is associated with many cancers. c-MET is therefore an attractive therapeutic target, and inhibitors are being tested in clinical trials. However, inappropriate patient selection criteria, such as low amplification or expression level cut-off values, have led to the failure of clinical trials. To include patients who respond to MET inhibitors, the selection criteria must include MET oncogenic addiction. Here, the efficacy of ABN401, a MET inhibitor, was investigated using histopathologic and genetic analyses in MET-addicted cancer cell lines and xenograft models. ABN401 was highly selective for 571 kinases, and it inhibited c-MET activity and its downstream signaling pathway. We performed pharmacokinetic profiling of ABN401 and defined the dose and treatment duration of ABN401 required to inhibit c-MET phosphorylation in xenograft models. The results show that the efficacy of ABN401 is associated with MET status and they highlight the importance of determining the cut-off values. The results suggest that clinical trials need to establish the characteristics of each sample and their correlations with the efficacy of MET inhibitors.

Effect of catheter diameter and injection rate of flush solution on renal contrast-enhanced ultrasonography with perfluorobutane in dogs.

OBJECTIVE: To assess effects of catheter diameter and injection rate of flush solution (saline [0.9% NaCl] solution) on renal contrast-enhanced ultrasonography (CEUS) with perfluorobutane in dogs. ANIMALS: 5 healthy Beagles. PROCEDURES: CEUS of the kidneys was performed by IV injection of contrast medium (0.0125 mL/kg) followed by injection of 5 mL of saline solution at rates of 1, 3, and 5 mL/s through a 20-gauge or 24-gauge catheter; thus, CEUS was repeated 3 times for each catheter diameter. Time-intensity curves were created for regions of interest drawn in the renal cortex and medulla. Repeatability was determined by calculating the coefficient of variation (CV). Statistical analysis was used to assess whether perfusion variables or CV of the perfusion variables was associated with catheter diameter or injection rate. RESULTS: Perfusion variables did not differ significantly between catheter diameters. Time to peak enhancement (TTP) in the renal cortex was affected by injection rate, and there were significantly lower values for TTP at higher injection rates. The CEUS variables with the lowest CVs among injection rates were TTP for the renal cortex; the CV for TTP of the renal cortex was the lowest at an injection rate of 5 mL/s. CONCLUSIONS AND CLINICAL RELEVANCE: Use of a 24-gauge catheter did not alter CEUS with perfluorobutane; therefore, such catheters could be used for CEUS of the kidneys of small dogs. Moreover, a rate of 5 mL/s is recommended for injection of flush solution to obtain greater accuracy for renal CEUS in Beagles.

Effects of airway pressure on contrast enhancement and diameter of the pulmonary artery in healthy dogs as determined by use of computed tomography angiography.

OBJECTIVE: To evaluate effects of airway pressure on contrast enhancement and diameter of the pulmonary artery and determine the optimal airway pressure for pulmonary CT angiography in dogs. ANIMALS: 8 healthy Beagles. PROCEDURES: Thoracic CT was performed at end-expiration (0 cm H2O) and 2 positive-pressure end-inspirations (10 and 20 cm H2O). Attenuation curves of enhancement for the sinus of the pulmonary trunk artery were obtained by use of a bolus technique. Contrast medium (300 mg of I/kg) was administered IV, and CT imaging began at the time of peak enhancement. At each pressure, time to peak enhancement, ratio of blood flow from the caudal vena cava to the right side of the heart (KCdVC), and enhancement characteristics and diameter changes of the pulmonary artery were evaluated. RESULTS: All dogs had a significant delay for time to peak enhancement in the sinus of the pulmonary trunk artery as airway pressure increased. The KCdVC progressively increased as airway pressure increased, and there was low contrast enhancement and increased pulmonary artery filling defects at 20 cm H2O. All pulmonary arteries had marked increases in diameter as pressure increased. Arterial distensibility in the gravity-dependent cranial lung region was greater than that in the gravity-independent caudal lung region at the 2 positive-pressure end-inspirations. CONCLUSIONS AND CLINICAL RELEVANCE: Airway pressure affected time to peak enhancement, KCdVC, contrast enhancement, and pulmonary artery diameter. Results suggested that 10 cm H2O could be an optimal pressure for evaluation of the pulmonary artery of dogs by use of CT angiography. (Am J Vet Res 2019;80;756-763).

How assistive devices affect activities of daily living and cognitive functions of people with brain injury: a meta-analysis.

PURPOSE: This study aims to systematically evaluate and synthesize the literature on the effects of assistive technology devices on the activities of daily living and cognitive functions of people with brain injury. METHODS: Eight randomized controlled trials were selected from online databases pertaining to the scientific use of AT devices for people with brain injury. The Jadad scale was used to analyse the subjects qualitatively, and Comprehensive Meta-Analysis 2.0 was used to test the statistical heterogeneity, effect size, sensitivity and publication bias of each of the selected studies. RESULTS: All selected studies were assigned a score of three on the Jadad scale, which could classify them as high-quality studies. The total number of participants in the studies was 385. The effect size of activities of daily living was 0.72, which is a medium effect size and that of cognitive function was 0.30, which is a small effect size. CONCLUSION: Assistive devices are effective in improving the activities of daily living and relatively less effective in enhancing the cognitive function of people with brain injury. This meta-analysis is evidence that assistive devices could be an effective intervention method for people with brain injury. Implications for Rehabilitation The purpose of this study is to demonstrate the effectiveness of this approach and to generalize the use of assistive devices. We aim to provide a basis for popularizing assistive devices as a therapeutic intervention method.

Vivid colours in hyperuniform complex-index photonic structures by resonant interference of photonic band gaps and optical band gaps.

Hyperuniform photonic structures (HPSs) have been doped with complex index materials to increase their reflectivity and colour expression range. HPSs synthesized using dielectric SiO2 nanoparticles have been mixed with a small amount of dopant nanoparticles (c d ≤ 1%) having a complex refractive index. Various dyes including Sudan I, Sudan Blue II, Alizarin yellow GG, Bromocresol purple and polydopamine (PDA) are used as dopants. Large reflectivity enhancements of HPSs (∼100%) are observed by resonant interference of photonic band gaps (PBGs) and optical band gaps (OBGs). Reflectivity enhancements are observed only when PBGs of HPSs match with OBGs of dopants. The colour expression range of HPS increases by 600% by doping with melanine-like PDA nanoparticles, which have the imaginary part of the refractive index in whole visible range.

Perovskite Nanoparticle Composite Films by Size Exclusion Lithography.

Perovskite nanoparticle composite films with capability of high-resolution patterning (≥2 µm) and excellent resistance to various aqueous and organic solvents are prepared by in situ photosynthesis of acrylate polymers and formamidinium lead halide (FAPbX3 ) nanoparticles. Both positive- and negative-tone patterns of FAPbX3 nanoparticles are created by controlling the size exclusive flow of nanoparticles in polymer networks. The position of nanoparticles is spatially controlled in both lateral and vertical directions. The composite films show high photoluminescence quantum yield (up to 44%) and broad color tunability in visible region (λpeak = 465-630 nm).

Creating Patterned Conjugated Polymer Images Using Water-Compatible Reactive Inkjet Printing.

The fabrication of patterned conjugated polymer images on solid substrates has gained significant attention recently. Office inkjet printers can be used to generate flexible designs of functional materials on substrates on a large scale and in an inexpensive manner. Although creating patterns of conjugated polymers on paper using common office inkjet printers has been reported, only a few examples exist, such as polyaniline (PANI) and poly(3,4-ethylenedioxythiophene) (PEDOT), because only water-compatible inks can be utilized. Herein, we describe the production of poly(phenylenevinylene) (PPV) patterns on paper by employing a reactive inkjet printing (RIJ) method. In this process, printing of a hydrophilic terephthaldehyde, bis(triphenylphosphonium salt) and potassium t-butoxide using a common office inkjet printer leads to formation PPV patterns as a consequence of an in situ Wittig reaction. In addition, microarrayed PPV patterns are also readily generated on solid substrates, such as glass and PDMS, when a piezoelectric dispenser system is employed. The in situ prepared PPV was found to be insoluble in water and chloroform. As a result, unreacted excess reagents and byproducts can be efficiently removed by washing with these solvents.